Test 2

Pharmacokinetics H1 antagonists

Well-absorbed orally Metabolized by the liver Excreted by kidney

HIV-2 is less pathogenic than type 1, where is it more recurrent?

West Africa

Reverse transcriptase (2)

What HIV enzyme produces a dsDNA provirus? -Replication-

2010 ACR/EULAR Classification Criteria for RA

What if the score is <6? Patient might fulfill the criteria... Prospectively over time (cumulatively) Retrospectively if data on all four domains have been adequately recorded in the past

NNRTIs activity and indications and resistance

Work synergistically with NRTIs and are used in alternative regimens for patients who cannot tolerate or do not respond to the primary drugs. Are never used alone to treat HIV bc viral resistance develops rapidly unless combined with other drugs.

Nutrition also affects innate mechanisms of immunity by....

Wound healing is impaired, bacteria binds to epithelial cells, production of IL-2 and TNF-alpha is decreased; opsonization is decreased, largely bc of a reduction in levels of various complement components-C3, C5, and factor B.

SNUGGLY

Wuggly

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Antibody Deficiencies

X-lined Agammaglobulinemia (Bruton's) Selective Immunoglobulin Isotype Deficiencies The Hyper-IgM Syndrome

Wiskott-Aldrich Syndrome

X-linked characterized by eczema, thrombocytopenia and susceptibility to bacterial infections Inability to produce antibodies against polysaccharide antigens (encapsulated bacteria) With increased age, reduced numbers of lymphocytes and more severe immunodeficiency Mutations in the gene that encodes a cytoplasmic protein WASP expressed in BM derived cells, regulates actin cytoskeleton

Hyper-IgM Syndrome

X-linked with defective switching of B cells to the IgG and IgA Isotype Compensatory increase in IgM in the blood Mutations in the gene encoding CD40 ligand expressed on T cells T cells cant stimulate B cells to undergo Isotype switch Patients suffer from bacterial infections Cell mediated immunity is also compromised (T cell activation of macrophages) so patients suffer form intracellular microbes: pneumocystis jirovenci

RA yet again

X-rays show erosions and osteoporosis. First line of treatment: NSAIDs Second line: DMARDs (Disease modifying anti-reumatic drugs): Gold Salts, glucocorticoids, hydroxychloroquine, methotrexate, Immunologic Agents: Leflunomide, Etanercept and Infliximab Shortens life. Reduce mobility and quality of life. Little effect on bone and cartilage damage. First line of treatment: NSAIDs

In uterine transmission of HIV

ZDV significantly reduced it, administered from the 14th week of gestation the 34th

*Nucleoside* and Nucleotide Reverse Transcriptase Inhibitors

Zidovudine, Lamivudine, Emtricitabine, Didanosine, Abacavir, Stavudine, and Tenofovir disoproxil (nucleotide) _LAMe Zebras STAND EMBRACINg And DIDNt TrEmble

Relative Risk (RR)

[a/(a+b)]/[c/(c+d)] -cohort studies Ratio of the risk in the exposed group (risk factor;positive group) to the risk in the unexposed group (risk factor;negative group) If risk in the exposed group and the unexposed group are the same the RR=1

meta-analysis

a "study of studies" that combines the findings of multiple studies to arrive at a conclusion (systematic methods... best estimate of the effect) Benefits: aggregate findings have greater statistical power—-> more certainly Concerns: selection of studies to be synthesized, quality of study designs, and quality of execution

confidence interval

a range of values that the population mean likely falls into with a specific level of certainty. Scientific studies usually use 95% confidence intervals. 95% CI=95% certainty the population mean falls within the interval (within 1.96 SEs of the mean in either direction). As sample increases= SE decreases -a sample that includes the entire population has zero SE (the mean derived is that actual population mean, not an estimate)

t-tests

a statistic that compares two means to see whether they could come from the same population

PPD (purified protein derivative) skin test

a test performed on individuals who have recently been exposed to tuberculosis. Mycobacterium tuberculosis, elicits a DTH rxn, when it is injected into individuals who have been exposed to M. Tuberculosis. Challenged CD 4+ T cells, takes time for them to get to that place.

Interaction of IL-4 with T cells can be blocked either with:

an antibody to IL-4 or a soluble form of the IL-4 receptor.

Graves' disease (hyperthyroidism)

an autoimmune disorder characterized by the excessive production of thyroid hormones Specific organ antibodies bind to receptor and activate that cell. Excessive activation of those cells; hyperthyroidism at first; produce thyroid hormones, lose weight, talk fast, lose hair. Thyroid storm excessive amounts of thyroid hormones. Organ based autoimmune disease.

the wheal and flare rxn

an individual produces IgE to a specific antigen and then is challenged by intradermal injection of the same antigen, the injection site becomes: -red from dilated blood vessels. -swells as a result of leakage of plasma from venules, called the wheal, caused by histamine release. -blood vessels at the margins of the wheal dilate and produce a characteristic red rim called flare. The full wheal and flare rxn appears within 5-15 minutes after administration of antigen.

HIV diagnosis (2)

antibody or antigen testing (p24) ELISA/Western blot (HIV RNA detection)

IgE bound to mast cells in the skin has a half-life of...

approximately 10 days.

Nucleoside

base + sugar

Repeat exposure is necessary...

bc switching to IgE isotope and sensitization of mast cells must happen before a hypersensitivity rxn. Bee stings; 2nd sting by insect of the same species could induce fatal anaphylaxis.

Mast cell activation

binding of multivalent antigens to IgE molecules attached to Fc receptors Allergic individuals have large amount of specific IgE bound to FcERI on mast cells. Non-atopic individuals have IgE bound to mast cells for different antigens.

Viral life cycle step 3 Env envelope glycoprotein:

binds to both CD4 and a coreceptor that is a member of the chemokine receptor family-3.1) The Env complex is expressed as a trimeric structure of 3 gp120/gp41 pairs that mediates fusion of the virion envelope with the membrane of the target cell.

Eosinophils...

bone marrow life span days to weeks cytokine IL-5 low level expression of FcERI Major granule contents: MBP (destroy tissue; problem with eosinophils), eosinophils cationic protein, peroxidases, hydrolyses, lysophospholipase present in peripheral tissues, mucosal linings of the respiratory, GI, GU, their numbers can increase in the setting of inflammation or parasite infection. Granules of eosinophils contain basic proteins that bind acidic dyes such as eosin.

Hypersensitivity Disorders

caused by combination of humoral and cell-mediated immune responses and multiple effector mechanisms. Chronic inflammation: grouped under the rubric immune-mediated inflammatory diseases

The properties of IgE can be separated into 3 areas...

characteristics of the molecule including its half-life and binding to IgE receptors; control of IgE and IgG antibody production by T cells; and the consequences of allergen cross-linking IgE on the surface of mast cells or basophils.

3.Chronic Rejection (2)

characterized by fibrosis and vascular abnormalities with loss of graft fnx occurring during a prolonged period -Fibrosis may be the result of: stimulation of fibroblasts as part of the IR -wound healing after acute rejection -arterial occlusion as a result of proliferation of intimal smooth muscle cells--accelerated atherosclerosis.

what fundamental reason explains the low production of IgE?

class switch from IgM to IgE happens infrequently and is controlled by T cells.

What is HAART?

combination of retroviral drugs. *Decreases viral load, at times, to undetectable levels*

conjugated vaccines

combine the desired antigen with a protein that boosts the immune response. Polysaccharides are poorly immunogenic and often do not induce IgG responses or long lasting protection.... conjugating polysaccharides to carrier proteins, can recruit T cells and induce IgG responses and long lasting protection. Conjugate H. Influenza and meningococcal vaccines Attempts to boost immunity by repeat administration of these vaccines can actually compromise immunity by depleting the pool of antibody-producing B cells.

Mast cells...

connective tissue major site of maturation. Life span weeks to months cytokine: stem cell factor, IL-3 High level expression of FcERI Major granule contents: histamine,tryptase, chymase, heparin (avoid clotting), protease higher histamine production in connective tissue involved in immediate hypersensitivity disease of airways, intestinal submucosa, and skin

Toxoids are used in vaccines against

diphtheria and tetenus

Unlike microbes, allergens...

do not stimulate the Innate immune response

Immediate hypersensitivity consists of...

exposure to an antigen, activation of Th2 cells and B cells specific for the antigen, production of IgE antibody, binding of the antibody to Fc receptors of mast cells, resulting in the release of mediators from the mast cells and the subsequent pathologic rxn (sensitization) IgE-coated activated on antigen encounter. (illustration)

HIV symptoms

flu like. Acute retro viral syndrome

HIV Clinical Stage 1

flu-like symptoms that soon disappear; T-cell count falls then returns to normal Acute/primary Duration: 1 month

In what circumstances can large amount of allergen enter the circulation rapidly and induce an anaphylactic shock?

following direct injection of the antigen into the tissue, such as a bee sting, a therapeutic injection for hyposensitization, or injection of a drug (penicillin).

Results from mast cells activation

granule membrane fuse with plasma membrane, mediated by SNARE, to release granular contents. synthesis of lipid mediators by activation of cytosolic enzyme phospholipase A2 nuclear factor activated T cells (NFAT), nuclear factor kB (NF- kB), and activation protein 1 AP-1 translocated the nucleus, and stimulate transcription of cytokines (IL-4, 5, 6, 13, and TNF)

T-score

has a mean of 50 with every 10 points landing at a standard deviation above or below the mean Compares means Mean BP of a control group compared to expiermental group

H1 antagonist:

illustration

Histamine release from mast cells:

illustration

biologic effects of mediators

illustration

Neutrophils:

inflammatory mediators, liberate proteolitic enzymes and microbial substances

Propensity toward Th2 responses may be influenced by...

inherited genes, the nature of the antigens, and the history of antigen exposure.

enfuviritide MOA

inhibit fusion of viral and CD4+ cell membrane and prevent viral entry

Ritonavir does what to be a "booster"

inhibits cytochrome p-450, boosting concentration of other drugs. Inhibit metabolism of other drugs, increasing their plasma levels and duration, and this is known as boosted therapy.

case control studies

investigations designed to estimate the odds ratio. Case subjects (persons with a defined disease) are compared with control subjects (persons w/o the defined disease). Usual outcome measured: exposure to a defined risk factor.

Inhaled allergens cause hay fever, chronic rhinitis, and asthma. a small # of food proteins are causes of allergic responses...

linear epitopes

The primary cells that bear FcERI are...

mast cells and basophils, which are the only cells in people that contain significant amounts of histamines.

Site of action of enfuviritide and Maraviroc?

membrane; inhibit cell fusion and entry

Daclizumab and Basiliximab are...

monoclonal antibodies to the High-Affinity IL-2 receptor that is expressed on activated T cells. By this action IL-2- mediated activation of lymphocytes is prevented, and the response of the immune system to antigens is impaired. They are used mainly in combination with cyclosporine and prednisone to prevent rejection of renal transplants.

HIV Clinical Stage 2

more numerous mild, opportunistic infections, weight loss; T cell count between 200 and 500 Chronic/asymptomatic Duration: 7-11 years (varies) Asymptomatic. Many patients will be unaware they are infected.

GVHD more info...

most bone marrow transplants are performed between siblings with identical HLA loci To prevent GVHD: Removal of mature T cells with supplemental granulcyte macrophage-CSF Cyclosporin and methotrexate can be used for prophylaxis against GVHD Remember bone marrow transplants are not done unless we are sure there are mismatches of 0-1

Attenuation

mutation to a less virulent form. Resulting virus is viable and immunogenic, but avirulent, can be used as vaccine.

It is important to distinguish IRIS from...

new opportunistic infections, drug toxicities, or non-infectious complications of HIV-AIDS

Mast cells bind IgE via their Fc receptors...

on encountering allergen the IgE becomes cross-linked, inducing degranulation and release of mediators that produce allergic rxns.

Coccidioidomycosis Prophylaxis

positive IgM or IgG serologic test results who live in endemic areas Fluconazole 400 mg orally daily Coccidioidomycosis prophylaxis when CD4 counts exceed 250 cells/microliter for 6 months Caused by coccidioides immitis, soil fungus native to San Joaquin valley in California C. Posadasii, which is endemic to certain arid-to-semiarid areas of the southwestern United States Transmitted by inhalation of airborne spores of C. Immitis or C. Posadasii Incubation period of coccidioidomycosis average of 10-16 days Symptoms: non specific -fever -cough -chest pain -fatigue -dyspnea -cephalalgia -arthralgias -myalgia Testing -immunoglobulin testing, culture, polymerase chain reaction testing PCR, skin testing

primary immunodeficiencies: Be able to classify by mechanisms that is deficient in

present at birth (congenital), usually stemming from genetic errors Prevalence: 1 in 500 live births with a defect in some component of the immune system A smaller portion will suffer from a severe life-threatening condition

deductive reasoning

reasoning from the general to the specific (or from cause to effect) Drug x requires a 1mg dose per kg (patients weight) Obtain weight Provide specific guidelines 60kg so dose should be 60mg

Histamine Receptor agonist

release histamine w/o IgE interaction (drugs, amides, alkaloids, antibiotics) Ex: morphine releases, histamine; non allergic rxn broncoconstriction. antibiotics release it. Some venoms and toxins may cause damage by histamine release. No therapeutic uses, but is used in clinical fnx tests. gastric fnx test: low acid production= pernicious anemia, atrophic gastritis. High acid prodution= Zollinger-Ellison syndrome. So, can use histamine to observe gastric acid secretion. Sensory Nerve Test. Bronchial reactivity. Test spray histamine if they almost die, is asthmatic.

IgE antibody

responsible for sensitizing mast cells, IgE binds to Fc receptors on mast cells and after recognizing antigens they activate these cells and trigger degranulation.

Endocytosis of plasma...

serum constantly being taken up by endocytosis. Many macromolecules including IgE degrade in the endosome. One major exception is IgG, which is protected by binding to the neonatal Fc gamma receptor FcyRn with it's ß2-microglobulin.

Preventive medicine for medical student test questions.

test questions.

herd immunity

the presence of immunity in most of a population. Preventing spread of infection. Provides a measure of protection for individuals who have not developed immunity

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WUGGLY

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WUGGLY

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WUGGLY SNUGGLY

what may be a natural mechanism for controlling T cell differentiation?

the release of soluble IL-4R from T cells.

Some authors recommend a delay in the initiation of ART for 4-6 weeks, when...

there is an opportunistic infection with risk to disseminate.

the granule proteases of mast cells have been cloned and sequenced and are distinct for 2 types of mast cells. mucosal mast cells are characterized by the presence of... connective tissue mast cells contain both...

tryptase without chemise (MCT) chemise and tryptase (MCTC)

cell mediated immunity

type of immunity produced by T cells that attack infected or abnormal body cells

Mother to child transmission of the HIV virus is the result of

vertical transmission. Can occur during brith process or during breastfeeding.

Patient factors for combination treatment

-Disease symptoms -concurrent illnesses

Immunodeficiency (side effects)

-Non-specific toxicity of drugs -Depletion of the patient's memory cells and long-lived plasma cells -susceptible to viral infection (CMV, EBV), bacterial and fungal infections -susceptible to cancer

Summary

-Primary prevention begins with health promotion. -Health behavior theories, motivational interviewing, and shared decision making can promote healthy behavior change. -Primary prevention strategies focus on the use of specific interventions to protect individuals against certain disease, deficiency states, injuries, or toxic exposures. -To decrease health care disparities, providers need to provide culturally and linguistically appropriate services.

Fundamental Influences on Health at the Broad Societal Level

-Socioeconomic conditions -Opportunities for safe employment -Environmental system -Regulation of the environment, commence, and public safety

Immunosuppressive Drugs

-Success in organ transplantation -Drugs that inhibit T cell activation -Anti-proliferative drugs -Anti-inflammatory agent

Types of Immunizations:

-active and passive

HAART Tx combination (synergy, decrease resistance)=2 NRTI+1 PI/NNRT/II

-avoid: 2 agents of the same nucleoside analog -overlapping toxicities + viral genotypes/phenotypic

Other things to consider before treatment combination

-drug interactions impact -regimen adherence

IgE is distinct from other dimeric immunoglobulins bc it has...

-extra constant region domain; a different structure to the hinge region; and binding sites for both high and low affinity IgE receptors, FcERI and FcERII respectively.

deductive vs inductive reasoning

...

HIV rash

1-2 days of acute illness, nonspecific diffuse macules and papules commonly, urticaria or vesicular oral or genital ulcers may occur, desquamation of palms and soles.

Vitamin C and E deficiency

Antioxidant fnx

Pharmacology 2:

Antiretroviral Drugs

Treatment consideratons

Antiretroviral therapy should be started before immunodeficiency becomes evident with goal of reducing plasma viral concentrations as much and as for long as possible.

Chapter 8: the statistical foundations of clinical decisions

Bayers' Theorem

Given a positive test result, how likely is it that the disease is present?

Bayers' theorem; describes the probability that a patient actually has the disease, if test result is positive (Positive predictive value)

PI darunavir

Better tolerated than most, and has lower propensity to cause diarrhea , lipodystrophy, and hyperlipidemia.

HIV transmission

Blood, Semen, Vaginal fluid, breast milk

ZDV adverse effects

Bone marrow suppression causing anemia and neutropenia, headache, and GI intolerance

2.Acute Rejection (2)

Both CD4+ and CD8+ contribute to acute rejection -CD4+ produce IFN-g, TNF, and IL-17: macrophage and endothelial cell activation. -Alloantibodies bind to endothelial cells leading to complement activation, and ADCC -Can lead to acute inflammation; infiltration of immune system cells. -Histologic pattern: transmural necrosis of graft vessel walls with acute inflammation.

Role of infection in autoimmunity

By standard activation =tolerance Inflammatory response promoting activation of DC and T cells that same peptide is also present in one of our cells. Tend to avoid fnx of B cells. Work as antigen presenting cells.

Maraviroc

CCR5 antagonist. Binds to it and prevents interaction with HIV-1 glycoprotein 120 which is necessary for CCR5-tropic HIV-1 to enter the cells. Does not bind to CXCR4. Synergistic effect with enfuvirtide.

Sensitization phase of contact Hypersensitivity

CD 4+ T cells become effector/memory cells Change the pattern of adhesion molecules by down regulating CCR7 and CD62L (loose propensity to traffic lymphoid tissues); up-regulating LFA-1, VLA-4, CXCR3, and CCR5 (move to peripheral circulation, and bind to inflamed endothelium.

Activation of T cells and Rejection of Allografts (2)

CD 4+ T cells can damage grafts by rxns that resemble delayed type hypersensitivity (DTH) CD8+ T cells activated by the direct pathway differentiate into CTL that kill nucleated cells in the graft, which express the allogenic class I MHC molecule (recognized as the antigen and therefore kill that cell)

Mycobacterium Adium Complex (MAC) Prophylaxis

CD4 count of fewer than 50 cells/microliter Azithromycin 1200 mg orally weekly (non disseminated) Should be continued with antiretroviral therapy (ART) until the CD4 count exceeds 100 cells/microliter for 3 months Primarily a pulmonary pathogen that affects individuals who are immunocompromised. Lung disease occurs rarely in immunocompetent hosts Symptoms -fever, diaphoresis, weight loss, fatigue, diarrhea, dyspnea Diagnostic testing includes acid fast bacillus (AFB) staining and culture of sputum specimens

HIV infects what cells? (3)

CD4 helper T cells, macrophages and DCs

AIDS

CD4+ <200 Presence of an opportunistic infection

NRTIs can cross the blood brain barrier and distributed where?

CSF

Paradoxical IRIS

Clinical deterioration after the administration of ART of a previously known opportunistic infection, in spite of receiving appropriate treatment and evidence of decrease in viral load.

Immune reconstitution inflammatory syndrome

Clinical worsening of a previous opportunistic infection or an unknown opportunistic infection after the initiation of ART, in spite of receiving appropriate treatment. They can do worse and die.

Role of Co-stimulation

Co-stimulation by B7 molecules on APC is required for proper T cell activation. Why are these co-stimulators expressed on graft APCs in the absence of infection?? -ischemic damage -danger signals

Less than 250 cells/microliter

Coccidioidomycosis Prophylaxis if seropositive in high risk area

Exocrine Glands:

Common mediator of gastric secretions. High production of acidic gastric juices is produced in response to histamine (H2): Stimulates secretion from pancreas, salivary glands and bronchial glands.

For outpatients

Compared with simultaneous approach, the sequential approach to testing is more conservative and is more economical (although duration of patient anxiety and opportunity costs associated with repeat visits should be considered).

NRTI MOA

Competitively inhibit nucleotide binding to reverse transcriptase and terminate DNA chain Inhibit host cell DNA polymerase (varying degrees)

Nuceotide

5 carbon sugar, phosphate group, and nitrogenous base

X-linked SCID caused by mutations in the cytokine receptor common gama chain

50% of cases Mutations in gene that encodes common gama chain (yc); present in receptors for IL-2,4,7,9, and 15 Autosomal recessive (women normal carriers) Impaired maturation of T cells and NK cells, usually B cells are normal or increased. Lack of antibody production bc of reduced T cells. Inability of the lymphopoietic cytokine IL-17, whose receptor used the gama c chain for signaling, to stimulate the growth of immature thymocytes (humoral immunodeficiency). IL-5 is required for NK cell development, also uses the gama c signaling chain, and the failure of IL-15 fnx accounts for the deficiency of NK cells.

Antibodies against viral proteins can be detected within ___ to ___ weeks after the infection.

6,9

A highly specific test is useful for ruling IN disease;

A positive result on a highly specific test is a reliable indicator of the presence of disease (SPin)

inductive reasoning

A type of logic in which generalizations are based on a large number of specific observations. Specific to general Ex. Obtain body mass and age of all people in particular city Analyze data: observe that the population of people between the ages of 5 nad 15 are obese on average Create general guidelines Suggest that he city implement health education in schools to help their age group lose weight

Methods to reduce Immunogenicity

ABO blood group antigens HLA matching: HLA-A, HLA-B, and HLA-DR (HLA-C is not polymorphic , HLA-DP and DQ are in strong linkage disequilibrium) -2 codominantly expressed alleles are inherited for each of these HLA genes, so it is possible to have 0 to 6 HLA antigens mismatches between the donor and the recipient. -0 antigen mismatches predict the best living donor graft survival.

HIV Clinical Stage 3

AIDS; neurological stages, rare infections or neoplasms, Burkitt's/Kaposi's; T-cell count below 200 Crisis/AIDS Duration varies. Patients are severely immunocompromised, allowing opportunistic infections to develop.

-congenital Immunodeficiencies- Immunology

Absence of a sufficient immune response

X-lined Agammaglobulinemia (Bruton's)

Absence of gamma globulins in blood One of the most common congenital Immunodeficiencies: Prototype of B cell maturation failure Mutation or deletions in the gene that encodes B cell tyrosine kinase (Btk) Treatment includes weekly or monthly injections of pooled gamma globulin preparations—-passive immunotherapy

2.Acute Rejection

Activation of T cells. CD4 + inflammation mediated damage and CD 8+ directly kill cells from grafted organ. -Vascular parenchymal injury mediated by T cells and antibodies, usually begins after the first week of transplantation. -T lymphocytes cause direct lysis of graft cells or produce cytokines that recruit and activate inflammatory cells, which can injure the graft. -Endothelial cells are the earliest targets of acute rejection---microvascular endothelitis.

H2 Receptor antagonists

Acts selectively on H2 receptors with virtually no effect on H1 receptors. Block gastric acid secretion. Cimetidine Ranitidine Famotidine

Drug nucleotides compete with endogenous nucleotides for incorporation into viral DNA. Once incorporated, NRTIs cause DNA chain termination in the same manner as described by what other drug?

Acyclovir

How does a positive test result modify the pretest probability of the disease?

Adjusts the pretest (prior) probability, yielding post test probability

Risk factors

Advanced immunosuppression Opportunistic infections before the initiation of ART (not providing correct treatment for that infection) Genetic predisposition: HLA-A, B44, and DR4 High viral load, or rapid viral load suppression after ART initiation Sub optimal treatment for the opportunistic infection before the initiation of ART

Population Attributable risk (PAR)

Among the general population, how much of the total risk for a defined disease is due to exposure to a specific risk factor? Calculated as the total risk for the general population minus the risk in the population not exposed to the specific risk factor

PAR percentage

Among the general population, what percentage of the total risk for a defined disease is due to exposure to a specified risk factor of interest? Can calculate using absolute differences and relative differences

Other factors

An atomic alterations in tissue (trauma), exposure of self antigens that are normally concealed from the IS Inflammation, structural alteration of self antigens with formation of new determinants Hormonal influences (t cells and a few B cells have receptors for estrogens) Higher incidence of AD in females than males SLE affects women 10:1, RA 3:1

Reverse transcriptase

An enzyme found in retroviruses that facilitates the production of DNA from RNA.

New therapies for systemic lupus erythrematosus.

Anti-IFNa antibodies Attempts to inhibit TLR signals are being considered

Omalizumab (mechanism, use, toxicity)

Anti-IgE antibody; used in refractory allergic asthma Pharmacology Respiratory It is administered subcutaneously every 2-4 weeks High cost limits its use to severe cases of asthma Injection site rxn rash and headache Extremely rare anaphylactic rxns

Cyclophosphamide

Cross-links DNA, preventing replication. Metabolite phosphoramide mustard. (toxic reactive metabolite) Suppress T and B cell function (30-40%). Indication for RA only in oral administration (no IV). SLE, Vasculitis, Wegener's granulomatosis, other sever rheumatic diseases. Adverse Effects. GI Ulcer formation Bone marrow suppression, alopecia Sepsis Hemorrhagic cystitis, bladder carcinoma (very rare). MESNA prevents cystitis

Clinical Use:

Cyclosporine and tacrolimus: prevention of rejection of organ transplants, psoriasis, RA, and severe autoimmune diseases that are resistant to other agents. Sirolimus and tacrolimus: localized in arteries, have been incorporated into vascular stents (MI: with coronary arteries narrowing) that slowly release the drugs to inhibit the proliferation of smooth muscle cells and other vascular cells that otherwise cause re-stenosis of arteries following stent placement.

Microbial Products

Cyclosporine, Tacrolimus, Sirolimus are immunosuppressants drugs that are derived from microbes. Bacterial products; theory that bacteria's use this to suppress the hosts defenses

Saquinavir, first PI. What is the preferred PI for the initial treatment of HIV?

DarUNAvir

Exclusion Criteria for IRIS

Failure of treatment for opportunistic infection. Poor adherence to treatment for the opportunistic infection Presence of another opportunistic infection or neoplasm

Methotrexate

First DMARD of choice in Rheumatoid Arthritis (RA). 60% patient used it. Lower doses than in cancer chemotherapy. Inhibits dihidrofolate reductase, blocks DNA synthesis Inhibits lymphocyte proliferation Inhibits cytokine and free radicals production 70% VO absorption. Half-life of 6-9hrs, increase with hydroxychloroquine. Excreted in urine (70%), Bile (30%) Decreases rate of appearance of new erosions. Mild and severe RA and refractory RA. Juvenile arthritis, Psoriasis, SLE, etc. Adverse Effects: Nausea and mucosal ulcer. Hepatoxicity (elevated liver enzymes) Mielosupression Thrombocytopenia "hypersensibility" reaction to the lungs Contraindicated in pregnancy Administration of folic acid supplements

HIV genes

Gag sequences encode core structural proteins. Env sequence encode the envelope glycoproteins: gp120 and gp41

Risk factors

Genes Strongest association with class II HLA molecules (CD4 + T cells)

Wait 1 week after infection symptoms and test with ELISA and then PCR to find what?

Genome of the virus and to diagnosis you need more than just one test.

Proteins ______ and ________ are necessary for HIV to attach to host cell CD4+ T lymphocytes along with their chemokine receptors?

Gp41 and gp120

Some NRTIs have demonstrated activity against what?

HBV and EBV

Mechanism of HIV entry to cell

HIV gp120 binds to T cells CD4 Conformational change in gp120 promotes binding to chemokine receptor Conformational change in gp41 exposes fusion peptide, which inserts into T cell membrane Fusion of viral and cell membranes

What alleles are associated with low viral set point and long-term asymptomatic control of infection?

HLA-B27 and HLA-B57 class I alleles

Thalidomide

Has immune modulating effects, and it is now being used to treat cancer, recurrent aphthous ulcers (canker sores), tuberculosis, leprosy, and erythema nodosum leprosum. Developed for pregnant women for nausea: controlled now. Thalidomide also has been use in AIDS-associated wasting syndrome. It acts by different mechanisms: it inhibits angiogenesis (formation of new BV, immunosuppressant effect and immunostimulant effects. It inhibits the produccion of IL-2 , TNFα and other cytokines. It stimulates CD8 cells in vitro.

Methotrexate (MTX) anti-folate:

Has some anti-inflammatory effects that make it especially useful in RA. It is used in the treatment of psoriasis and sever asthma.

Histoplasmosis Prophylaxis

High risk for exposure Itraconazole 200mg orally daily Until CD4 count has exceeded 150 cells/microliter for 6 months Dimorphic fungi Endemic in Ohio and Mississipi River Valley

Inpatients

Hospitalized patients

NRTIs are converted to triphosphate metabolites (nucleotides) by what?

Host cell kinases.

The waste disposal Theory

How nuclear components normally hidden are detected by the immune system as antigens? -of clearance of apoptotic cells -Macrophages from SLE patients are less efficient in the removal of apoptotic debris -Deficiencies in proteins from the complement: C1q, C2, and C4 can develop a lupus like disease Reduces clearance of immune complexes by the spleen

congenital Immunodeficiencies Classifications: Depending on part of immune system effected

I. Defects in Innate Immunity II. Severe combined immunodeficiencies (B and T cells) III. Antibody deficiencies IV. Defects in T Lymphocyte activation V. Multi-system Disorders with Immunodeficiency VI. Therapeutic approaches for congenital Immunodeficiencies

ISCOM delivery to antigen into cell

ISCOMs and lposomes deliver antigen into the cell, mimicking endogenous antigens thus inducing a cell-mediated response.

In addition to atopic dermatitis dendritic cells in the skin can express a high affinity receptor for...

IgE, but this receptor lacks the beta chain of FcERI.

Severe cases and CNS involvement:

Immunosuppressants (corticosteroids), and immune modulators

Immunopathogenesis

Decrease in vital load allows T cells to proliferate and release cytokines. Patients with opportunistic infections usually have <200 CD4+ T cells Subtypes of CD4+ T cells: Th1, Th2, and Th17

1. Identify the problem

Determine alternative clinical decisions Determine sequence decisions must be made Determine patient outcomes of each decision Ex. Remove gallbladder in silent gallstones?

MHC molecules from the donor are presented for recognition by T cells in 2 forms:

Direct presentation: Recognition of an intact MHC molecule displayed by donor APCs. May be responsible for rejection of organ. Indirect Presentation: Processing of a donor MHC molecule by recipient APCs and presentation to T cells.

Vaccination: Use of attenuated live organism.

Dramatic effect on reducing infant mortality and increased life expectancy...

cimetidine causes what?

Drug drug interactions; restlessness and agitation.

What drug can cause neuropsychiatric rxns?

Efavirenz

NRTIs are combined with what 2 inhibitors?

Either integrase strand transfer inhibitor or protease inhibitor

Lower cost of medication, a number of 3 drug combination products for the treatment of HIV are?

Emtricitabine, tenofovir, and rilpivirine.

1.Hyper Acute Rejection (2)

Endothelial cells lose the cell surface heparin sulfate proteoglycans that normally interact with antithrombin III to inhibit coagulation. -If this isn't present then we don't have a way to inhibit coagulation. -Antibody and complement, in the graft endothelium, promote intravascular thrombosis, and endothelial cell injury with exposure of sub endothelial basement membrane proteins that activate platelets. -The grafted organ suffers irreversible ischemic damage.

Chapter 10: statistical Interference and Hypothesis testing

Epidemiology

Chapter 14: Intro to Preventive Medicine

Epidemiology

Chapter 15: Methods of Primary Prevention: Health Promotion

Epidemiology

Chapter 6 Assessment of Risk and Benefit in Epidemiological studies

Epidemiology

Definitions of Immunity

Intact Immunity: Implies that the immune system was normal at birth and has not suffered damage from a disease, such as infection with HIV. Passive Immunity: Protection against an infectious disease provided by circulating antibodies made in another organism: provides incomplete protection; usually short duration -Maternal antibodies, human immune globulin, antitoxin Active Immunity: conferred by vaccines: superior to passive immunity; lasts longer and is rapidly stimulated to high levels by a re-exposure to the same or closely related antigens. -Humoral (blood) antibody; cell-mediated immunity

Site of action of reltegravir

Integrase (integration of viral DNA to cell nucleus)

Preferred drug regimens consist of what?

Integrase strand transfer inhibitor or a PI, each combined with 2 NRTIs.

Cytokines relevant to a Th1 response include:

Interleukin-12 (IL-12) produced by macrophages; and IFN game produced by T cells

Adjuvants concentrate antigen at appropriate sites or induce cytokines

It appears that the effect of adjuvants is due mainly to two activities: • the concentration of antigen in a site where lymphocytes are exposed to it (the 'depot' effect); and • the induction of cytokines that regulate lymphocyte function. Aluminum salts probably have a predominantly depot function, inducing small granulomas in which antigen is retained

Adverse effects in all NRTIs

Lactic acidosis, hepatic steatosis, and lipodystrophy

Activation of B cells

Less is known about B cells activation. Alloantibodies against HLA molecules (class I and II) expressed on donor endothelial cells. Antibodies role in rejection: Same effector mechanism; complement activation, activation of neutrophils, macrophages, and NK through Fc receptor binding

Mechanically PEM may contribute to what else?

Limits in the availability of the amino acid glutamine, required for both nucleotide synthesis and cytokine production, as well as by the increase in oxidative stress.

What regulates viral integration into the host genome, viral gene expression, and viral replication?

Long terminal repeats (LTRs)

Chemical nature of antigens to become allergenic:

Low molecular weight, stability, glycosylation, high solubility in body fluids. anaphylactic response to foods: typically induced by highly glycosylated small proteins (not denatured in the GI tract)

Viral load Qualification

Major prognostic marker for disease prognosis and outcome of antiretroviral therapy in the tx of HIV-infected individuals

Malnutrition and infection exacerbate each other in the vicious cycle

Malnutrition leads to depletion of protein-energy reserves—> decrease immunity making room for infections by decreased intake via anorexia, nausea, and vomiting, decreased absorption, and increased catabolism, and increased nutrient loss from urine and feces

NNRTIs nevirapine increases what?

Metabolism and decreases the therapeutic effect of PIs.

Combinations

Methotrexate as base. And can add some of these drugs... Improve: cyclosporine, chloroquine, infliximab, leflunomide, adalimumab and etanercept. No effect: rest. Combinations does not increase risk of toxicities. Don't add drugs with different toxicity . When monotherapy fails, the rule is to start combination. Initially one drug.. more drugs if not responding well.

Clinical considerations of IRIS

Might develop from 2-12 weeks after the initiation of ART Incidence is not well defined: 10-50%

Abacavir (ABC) adverse effects

More likely to cause hypersensitivity rxn, whereas Tenofovir produces renal impairment in some patients

Serotonin

Multiple receptors identified. 5 HT2, 5HT4-7 are G-protein-coupled Organ system effects: CNS, acts as an inhibitory neurotransmitter. Localized in the raphe nucleus of the brain stem. Precursor of melanotonin in pineal gland. Carcinoid tumors: malignant tumor of the enterochromaffin cells, excess serotonin production. Diarrhea, abdominal cramps, malabsorption, flushing.

NRTI resistance

Mutation at viral RT codon 184 Single-drug tx Cross-resistance (drug with similar structure)

Adjuvant enhanced antibody production

Notably aluminum salts (alum), added to or emulsified with an antigen, greatly enhance antibody production - that is, they act as adjuvants. Aluminum hydroxide is still widely used with, for example, diphtheria and tetanus toxoids. Boost immune responses, when the antigen is insufficiently immunogenic. Elicit innate immune responses, with increased expression of co-stimulators and production of IL-12 that stimulates T cell growth and differentiation. Inflammation= side effects of immunization: pain, swelling at the injection site, malaise, fever New adjuvants; Monophosphoryl lipid A (MPL), derived from LPS (cell wall of gram negative bacteria) with low toxicity

Antiretroviral drugs

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors Nonnucleoside Reverse Transcriptase Inhibitors Protease Inhibitors Fusion and Entry Inhibitors (chemokine receptor antagonists) Integrate Strand Transfer Inhibitors

Tenofovir disoproxil fumarate

Nucleotide prodrug. Hydrolyzed in body to form tenofovir and then converted to tenofovir diphosphate by host CD4 cell kinases. Causes DNA chain termination by competing with deoxyadenosine 5'-triphosphate and is incorporated into vDNA by reverse transcriptase

Immunization Basics

Objective of immunization is to provide long-lasting immunologic protection against infectious agents.

Applications of decision trees

Objective: find decisions that are less satisfactory than others (cut off these branches) Use: clinical decisions, public health policy Exclusion: Decision trees cannot be used in problems that have a repetitive outcome (recurring embolic strokes with atrial fibrillation)

Acute retroviral syndrome

Occurs 1-6 weeks after HIV exposure in 50-70% of infected individuals; similar to mono.

Acute symptoms occur 2-4 weeks post infection

Occurs when HIV virion is transmitted from one individual to another and can infect immune cells (CD4+ T cells and APCs within mucosal tissues. DCs are the source of infection of a bunch of T cells located in lymph nodes.

IRIS treatments mild

NSAIDS to decrease inflammatory response

Th17 reposition induces production of IL-12 and IL-22:

Neutrophil recruitment

Iron: deficiency results in a reduced ability of________ to phagocytosis pathogens: iron-dependent enzymes.

Neutrophils

What NNRTI increases the metabolism and decreases the therapeutic effect of PIs?

Nevirapine

Vitamin A deficiency

Night blindness. Impaired epithelial and mucosal barriers, loss of mucous producing cells, decreased IgA

Cont'd corticosteroids

Oral and parental corticosteroids are reserved for patients who require urgent treatment, don' t respond to B-agonist or worsening symptoms despite maintenance therapy. Aerosol treatment is the most effective way to decrease the systemic adverse effects. Beclomethasone, triamcinolone, flunisolide, fluticasone, budesonide, and mometasone. Patient should wash mouth to remove secondary infections, spread in infections (oropharyngeal candidiasis) Hoarseness can also result from direct local effect of inhaled corticosteroids on the vocal cords. In children, shown to slow the rate of growth, but asthma itself delays puberty. Effectively reduces symptoms and improves pulmonary fnx in patients with mild asthma. reduces or eliminates the need for oral corticosteroids in patients with more severe disease reduces bronchial reactivity therapy is continued for 10-12 weeks and then withdrawn. Manifestations of asthma return within a few weeks after stopping therapy.

PIs pharmacokinetics

Oral, are extensively metabolized by cytochrome P 450 enzymes before undergoing fecal excretion

Classification of autoimmunity

Organ-specific disorders -Addison's disease (adrenal cortex) -Pernicious anemia (parietal cells) -Hashimoto's thyroiditis (thyroid) Systemic Examples -systemic lupus erythematous -rheumatoid arthritis -systemic sclerosis

Drugs for RA

Pharmacology

Drugs used in Asthma

Pharmacology

Immunosuppressant Drugs

Pharmacology: Also called IMMUNOMODULATING AGENTS because some of them act to enhace host immunity and are used in treating cancer. they supress immune mechanisms and are used to treat autoimmune diseases or to prevent allograft rejection following organ or bone marrow transplantation.

Histamine antagonist:

Physiologic= epinephrine. Opposite effects, different receptors. Asthma, Conjunctivitis allergic pollen--> Cromolyn and nedocromil reduce the degranulation of the mast cells.

Glucocorticoids

Prednisone is the drug of choice Important role in RA treatment Formation of lipocortin, inhibits phospholipase A2 Inhibition of cytokines, including interleukins and tumor necrosis factor. Acts rapidly Long-term use limited

Major criteria for IRIS

Presenting atypical opportunistic infection while having been treated with ART and having responded well; evidence of lowered plasma viral load

The partial loss of the recombination-activating enzyme components________ or _______ can lead to

RAG-1, RAG-2, reduced lymphocyte development (hence immunodeficiency) but also a defect in receptor editing, resulting in a failure of one mechanism of B cell tolerance (thus autoimmunity).

Etanercept

Recombinant fusion proteins of TNF p75 receptors linked to the Fc of a human IgG1 Antagonizes TNFa Slowly absorbed and half-life is 4.5 days. Decreases the rate of new erosions like methotrexate alone. Same indications as infliximab. Not first choice for RA Adverse effects. Lower incidence of TB reactivation. Similar incidence of opportunistic infections. Most be alert for lymphomas (as other TNF agents). Lupus-like syndrome higher incidence. 16% can produce antibodies.

Odds ration in Case-control studies

The odds that the cases were exposed divided by the odds that the controls were exposed [(a/c)/(b/d)]=ad/bc If the odds of being exposed are the same in both groups, OR=1 OR is really the OR (exposed). Mathematically equal to OR (disease) *what we care about*

Health Promotion

The process of enabling people to increase control over, and to improve, their health. General health promotion: Addresses general health -Dietary intake, physical activity and exercise, abs training from tobacco, medication adherence, weight loss. Specific Protection Activities: To prevent specific disease -Vaccines, antimicrobial drugs, nutritional interventions

Intro to transplantation

The process of taking cells, tissues or organs called a graft, from one individual (donor) and placing them into a different individual (recipient or host). Same person---orthotopic different person---heterotopic

3 methods for viral load quantitation:

The reverse trascriptase-polymerase chain rxn The numeric acid sequence-based amplification A signal amplification methodology: branchedchain DNA technique

the opportunistic infection is usually found in the macrophages of the HIV patients which are activated by IFN-gama

The secrete TNF and do phagocytosis. TNF has a systemic effect; inflammation, coagulation, vascular endothelium activation, neutrophils activation, and acute phase reactants production in liver

For inpatients

The sequential approach may increase the length of stay for a hospitalized patient; cost implications may be unclear

Syndrome is present due to....

The use of antiretroviral treatment, CD4 + T cells will be allowed to proliferate, making it worse.

Decision Analysis:

To perform, must understand: Data that go into a clinical decision Sequence in which decisions have to be made What personal values of the patients must be considered before making a decision

Less than 100

Toxoplasmosis Prophylaxis (if seropositive) Penicilliosis Prophylaxis if living in high risk area

Desensitization to control allergies...

Tx with modified allergens, clinical trials with contradictory results (less responders 9 vs 31), peptide recognition is restricted to the HLA-DR type of the patient. (chart)

SNUGGLY

WUGGLY

WUGGLY

WUGGLY

😘😛😩

WUGGLY

Metabolism:

acts rapidly when given parentally, oral histamine inactivated by bowel flora. Metabolized by methylation (N-methyltransferase), yielding N-methylhistamine. Most of the N-methylhistamine is converted by monoamine oxidase (MAO) to N-methyl imidazole acetic acid, then excreted by the kidney.

atopic individuals produce... and non-atopic individuals...

high levels of IgE, and synthesize IgM and IgG and small amounts of IgE.

Wuggly

snuggly

Immunodeficiency secondary to drug therapies

• Either intentional for therapeutic effects in autoimmune conditions, or iatrogenic (unwanted side effect) after organ transplantation or cancer treatments • Glucorticoids have the broadest applications with potent antiinflammatory effect • Naturally occurring steroids (cortisol) produced by the adrenal cortex in response to stress or inflammatory cytokines in the hypothalamus • Cortisol and its analogues cross the cell membrane and bind to cytoplasmic receptors that enter the nucleus and directly bind to DNA to affect gene transcription or disrupt other transcription factor complexes such as NFkB and AP-1 with profound suppression of inflammatory cytokine secretion: change from Th1 to Th2

Granulomatous hypersensitivity

• Failure to eliminate intracellular microbes, or particles that the cell is unable to destroy; induce the production of nodules of inflammatory tissue called granulomas • A cycle of chronic stimulation of T cells with tissue injury and chronic inflammation followed by replacement with connective tissue (fibrosis) • Activated macrophages develop increased cytoplasm and cytoplasmic organelles, called epithelioid cells. Others may fuse to form multinucleate giant cells

Tuberculin type hypersensitivity

• Following intradermal challenge, mycobacteria specific memory T cells get recruited and activated by dermal CD4 Th1 cells to secrete IFNg ---activated macrophages produce TNFa and IL-1 ---activated endothelial cells induce expression of adhesion molecules that bind to receptors on leukocytes and activated lymphocytes to recruit them • Neutrophils accumulate 4 hours after the injection • By12hours, the injection site becomes infiltrated by T cells and monocytes • Fibrinogen escapes from blood vessels into the surrounding tissues, where it is converted into fibrin. Deposition of fibrin and accumulation of cells around the injection site cause the tissue to swell and become firm (indurated) • Induration is detectable about 18 hours after the injection of antigen and is maximal by 24 to 48 hours

Sulfasalazine; avoid rapid absorption Not for RA usually inflammatory bowel disease

Salycilate derivative. Decreased production of IgA and IgM rheumatoid factor. No clear mechanism action related to the efficacy

All immunopathogenesis

Sever inflammatory rxn

Single gene mutations that cause AIDS AIRE

Slide

Toxicities of Beta 2 agonists

Small change in the bronchodilator response. B1 agonist effect; tachycardia Except Salmeterol Are safe and effective bronchodilators when given in doses that avoid systemic adverse effects (aerosol) Skeletal muscle tremor, nervousness, and occasional weakness. (P.O.)

HIV treatment

Suppress replication, restore # CD 4 + cells and host immunocompetence, and highly active antiretroviral therapy=HAART

combination therapy

Synergy + decrease resistance

Efavirenz (Sustiva)

Teratogenic NNRTI

low dose antigen w/o adjuvant will induce...

Th2 cells, which produce both IL-4 and IL-5. IL-4 plays a role in enhancing the growth of Th2 cells, the expression of the gene for IgE. In turn IgE bind to the high-affinity receptor for IgE on mast cells (FcERI). IL-5 plays a critical role in production of eosinophils.

Defects in T cell activation

The Bare Lymphocyte Syndrome Wiskott-Aldrich Syndrome

The immunological spectrum in Leprosy

The exact same pathogen as leprosy can create different conditions. People who don't get it treated and with no symptoms can still infect others.

Measures of treatment-derived benefit

Absolute risk reduction: The risk difference is calculated in the same way as here where exposure is to a treatment rather than to a risk factor. ARR= (absolute risk of those exposed to intervention%)-(absolute risk of those unexposed to intervention%) ---> impact of an intervention How much risk for a fracture remains among those exposed to an intervention? Relative Risk: we divide AR of intervention group by AR of the control group. To calculate the relative risk reduction (RRR), subtracting RR % from 100% -intervention reduces RR for a fracture by __% among those exposed to intervention

Major Histocompatibility Complex (MHC)

Act as antigens causing graft rejection by the recipients' T cells activation MHC molecules from donor are presented for recognition by T cells in 2 forms.

Adverse effects and interactions of PIs

All PIs can cause lipid accumulation in tissues (lipodystrophy) and hyperlipidemia, insulin resistance and diabetes, elevated liver fnx test results, and drug interactions. (Ritonavir highest incidence of adverse effects). PIs interact with a # of other drugs via inhibition of cytochrome P450 enzymes. Have greatest effect on drugs metabolized by the CYP3A4 isozyme and can increase in the plasma concentration of these drugs and other PIs.

The # of deaths secondary to AIDS has been reduced lately, but still there is a considerable number of people that is getting infected every year

All will need ART eventually

Allogeneic Transplantation

Alloantigens elicit cell mediated and humoral immune responses. Rejection: due to immune response of the recipient to the donor tissue. Recognition of transplant cells determined by polymorphic genes inherited from both parents (HLA are responsible )

Indirect Recognition

Allogenic MHC molecules may be processed and presented by recipient's APCs, the processed MhC molecule is recognized by T cells like if they were conventional foreign protein antigens. Cross-presentation: Activation of CD8+ T cells. Processed by edosomal vesicular pathway; consequence of phagocytosis. Acute graft rejection mediated by CD8 + T cells, chronic rejection by CD4 + T cells (cytokine mediated inflammation)

Toxic shock syndrome

And IRIS hav here same type of mechanism, ends with a storm of cytokines that harms patients more than helps them.

Association of HLA Alleles with autoimmune disease

Ankylosing spondylitis: HLA B27 (mainly B2705 and 02)

Side effects of methylxanthine drugs

Anorexia, nausea, vomiting, abdominal discomfort, headache, and anxiety occur at concentrations of 15 mg/L Higher levels (>40 mg/L) may cause seizures or arrhythmias. Requires occasional measurement of plasma levels. Unpleasant minor side effects (especially insomnia) -accidental or intentional overdose can result in severe toxicity or death.

Gold Salts

Approved in 1960s Today are infrequently used (very toxic). Alters morphology and capabilities of macrophages. Inhibits: chemotactic factor-1, IL-8, IL-1B, vascular endothelial growth factor. Adverse effects Pruritic skin rashes, Stomatitis and metallic taste. Trombocytopenia, leukopenia and pancytopenia. Aplastic anemia (rare). Nephrotic syndrome Enterocolitis, cholestatic jaundice, peripheral neuropathy and pulmonary infiltrates.

Multi-system Disorder with Immunodeficiency

Ataxia-teleangiectasia (AR) Abnormal gait (ataxia) vascular malformations (teleangientases), neurological deficits, increased incidence of tumors, and immunodeficiency (both B and T cells) Lower respiratory tract bacterial infections, multiple autoimmune phenomena and cancers with advancing age. Due to mutations in the gene ATM that encodes a protein which participates in DNA repair.

RA cont'd (system disease)

Autoantibody production: Rheumatoid factor (RF): against autologous IgG Anti-cyclic citrullinated peptide antibodies (ACPA): against citrullinated proteins Most common systemic inflammatory disease Fluctuating course Morning stiffness with improvement Symmetrical small joints of hands and feet. Low-grade fever, malaise, fatigue. Joint swelling, redness an warmth Joint destruction, deformity, disability and premature death. Cardiopulmonary, neurologic and ocular inflammation often found Rheumatoid nodules in extensor surfaces Extra articular manifestations: vasculitis, lymphadenopathy and splenomegaly

Conclusion

Autoimmune diseases are among the most challenging scientific and clinical problems in immunology

RA

Autoimmune systemic disease, characterized by chronic inflammation that leads to joint destruction. Affects women (3:1) around 3rd and 6th decade Prevalence 1% worldwide, USA 2-3% Unknown etiology, pathogenesis partially understood

Prevention and Tx

Avoid or delay rejection: Immunosuppression, minimize the strength of the specific allogenic rxn, induce tolerance.

2. Diagram the options

Beginning point: patient's current clinical status Decision nodes: points where clinicians have to make decisions Chance nodes: points where clinicians have to wait

1.Hyper Acute Rejection

Begins within minutes to hours after host blood vessels are anastomosed to graft vessels and is mediated by preexisting antibodies: "natural antibodies"---against ABO antigen (surface of RBCs: Rxn from different blood group bc of naturally occurring antibodies can can also work in rejection of organ. At least compatibility of ABO group for blood transplants. Thrombotic occlusion of the graft vasculature.. binding of antibody to endothelium activates complement, and endothelial cells secrete von Willebrand factor that mediates platelet adhesion and aggregation---coagulation.

Basophil...

Bone marrow major site of maturation Life span days Cytokine IL-3 high level expression FcERI Major granule content: histamine, protease blood granulocytes similar to mast cells. also mature in bone marrow.. recruited in inflammatory sites express FcERI

Defects in complement system

C3 Deficiency: where the 3 pathways converge, not able to activate compliment system by any pathway Associated with frequent serious pyogenic infections, that may be fatal. Inability to opsonize, enhance phagocytosis, and destroy these organisms. Deficiencies in the terminal complement components (not going to be able to form membrane attack complex): Including C5, C6, C7, C8, and C9 Propensity for disseminated infections with Neisseria (meningitis, or gonorrhea) Deficiencies in complement regulatory proteins: Cannot regulate activation of the complement system by the classical pathway, Stress can induce activation of this pathway, C1 inhibitor deficiency—-hereditary angioneurotic edema

Binding of glycoprotein 120 to CD4 causes a conformational change in it, enabling it to interact with the chemokine co-receptors__________________ on the surface of lymphocytes.

CCR5 and CXCR4

What chemokine receptors are necessary for HIV to penetrate the host cell?

CCR5 and CXCR4 Causing a depletion of CD 4+ T cells resulting in development of opportunistic infections and neoplasticism processes.

Maraviroc MOA

CCR5 antagonist

Muromonab

CD3 is a monoclonal antibody to the CD3 glycoprotein that is part of the T-cell antigen recognition receptor. It is used to treat acute allograft rejection in renal transplant patients. Maybe used to reverse bone marrow, cardiac, hepatic, kidney and pancreatic transplant rejection episodes that are resistant to other drugs. Corticosteroids: decrease risk of rejection first tx,

Stage 4 is AIDS

CD4 + T cell count is below 200 cells/mm3 HIV viremia climbs dramatically Presence of opportunistic infections, neoplasms (oncogenic viruses), cachexia (wasting syndrome), kidney failure (HIV nephropathy) and CNS degeneration (AIDS encephalopathy)

After initial phase of HIV

CD4 + T cells start depleting gradually. During this latent phase, symptoms may be absent. Viral replication continues.

PEM leads to significant decrease in circulating what?

CD4 T cells disproportionately affected giving a low CD4+/CD8+ ration.

Malnutrition increases the risk of infant mortality from infection through reduction in cell-mediated immunity, including reduced numbers and function of what?

CD4+ helper cells and a reduction in levels of secretory IgA.

Morbidity and mortality are dependent on the type of pathogen and the affected organ...

CNS affection has the highest morbidity and mortality

Tuberculosis

Can cause infection anywhere -they can have tuberculosis in the spine, kidney. -Lymph nodes More patient in immunocompromised patients Extensive parenchymal streaking in the upper fields of the lungs. -the formation of granulomas is essential to control the infection -Frequently accompanied by extensive fibrosis visible in chest radiographs -Epithelioid cell, giant cells, mononuclear cell infiltration. There is also marked cassation don necrosis within granuloma Weight loss, night sweats, sputum orange or tinted with blood mycobacterium -PCR

Subcellular fragments Antigen: Capsular polysaccharides, surface antigen

Capsulated polysaccarides: Pneumococcus, meningococcus, Haemophilus influenzae Surface antigen: Hepatitis B

Beta 2 selective drugs cont'd

Cause bronchodilation equivalent to that produced by isoproterenol: Stimulation of B1 and B2 non selective, very potent. Maximal by 30 minutes and persists for 3-4 hours. Albuterol and metaproterenol can also be diluted in saline for a handheld nebulizer Terbutaline is available for SC injection. Long-acting: salmeterol and formoterol Long duration of action (12-hrs or more) due to high lipid solubility. Acting as "slow release depot" Inhalation results in the greatest local effect on airway smooth muscle with the least systemic toxicity.

Kaposi's sarcoma:

Caused by KS-associated herpes virus (KSHV), most common AIDS-associated malignancy. KSHV infections, similar to CMV herpesvirus infections, are often asymptomatic in individuals with competent T cell immunity. With HIV co-infection, however, KSHV titers increase and KS emerges with multi focal lesions of mixed cellularity often resulting in widespread involvement of the skin, mucous membranes, viscera, and lymph nodes.

DiGeorge Syndrome

Caused by deletion in chromosome 22 q 11.2 Defective development of the thymus, parathyroid glands and other structures that develop from the 3rd and 4th pharyngeal pouches. Thymus—- Deficient T cell maturation, absent parathyroid glands—-abnormal calcium homeostasis and muscle twitching (tetany) Abnormal development of the great vessels Facial deformities The immunodeficiency can be corrected by fetal thymus transplantation or by HLA-identical bone marrow transplantation Improvement with age occurs (by 5 years), undefined exrathymic sites for T cell maturation

Patients with ID are susceptible to cancer

Caused by oncogenic viruses; EBV and human papilloma viruses HPV. Increased incidence of cancer is most often seen in T cell immunodeficiencies bc T cells play important role in surveillance against malignant tumors.

Activation of mast cells: Immediate H Rxn can be mimicked by injection of mast cells activators (C5a, C4a, and C3a: anaphylatoxins or by local trauma:

Causes degranulation of mast cells. Neuropeptides: substance P, somatostatin, and vasoactive intestinal peptide, induce mast cell histamine release, neuroendocrine-linked mast cell activation. cold temperature and intense exercise may also trigger mast cell degranulation, mechanisms not known.

Breakdown of tolerance

Central tolerance: Presence of danger signals: defect in central tolerance: kill T cells that recognize your own cells. Helper T cells are key regulators of all immune responses to protein antigens Several autoimmune diseases are genetically linked to HLA molecules B cells are responsible for the production of autoantibodies but they need T cell help for Isotype switch.

Infliximab

Chimeric monoclonal antibody (25% mouse, 75% human) High affinity for the TNF receptors. IV route. Half-life 9-12 days. Produces antichimeric AB in 62% cases after use. Rarely used DNA recombinant technology very expensive Effective in RA, ulcerative colitis, Juvenile RA, Psoriasis, etc. Used alone or in combination with methotrexate. Adverse Effects Respiratory tract infections, nausea, headache, sinusitis, rash and cough. Associated with TB reactivation.

Antigens expressed from vectors

Cloning genes into a suitable expression vector Microbial genes expressed in the organism, induce humoral and cell mediated immunity HBsAg cloned into yeast (second generation) hepatitis B surface antigen Example: recombinant expression vectors produce L1 from HPV assemble into virus-like particles (VLP: highly immunogenic), without viral nucleic acids so it is very safe. -against serotypes 16 and 18 (70% of CC)

Creating a decision tree

1. Identify and set limits to the problem 2. Diagram the options 3. Obtain information concerning each option 4. Compare the utility values 5. Perform sensitivity analysis

Number needed to harm

1/attributable risk increase (ARI) ARI is the same as ARR in terms of math: ARI=risk(exposed)-risk(unexposed) Exposure: increasing risk for a defined disease.

Serum IgE is so low bc it has a half-life of...

2 days compared with 21-23 days for IgG. produced in response to a select group of antigens and IgE antibodies are sequestered on the high affinity receptor on mast cells and basophils.

HIV structure:

2 identical strands of RNA in a core of viral proteins surrounded by a phospholipid bilayer envelope with encoded membrane proteins.

What criteria is needed to diagnose IRIS

2 major or 1 major and 1 minor, and absence of exclusion criteria

Absolute vs. relative differences

2 risks are being compared, if there is no difference (the risks are equal) the absolute risk difference is expressed as 0. When the same 2 risks are compared by a ratio, the condition of no difference is represented by 1.

Phase of contact Hypersensitivity

2. Elicitation (recruitment of CD4 + and CD8+ T cells and monocytes) TNF and IL-1 produced by LCs are potent inducers of endothelial cell and adhesion molecules: E-selection, VCAM-1 (receptor for VLA-4), and ICAM-1 (receptor for LFA-1) for recruitment of activated T cells CD 8 + T cells have cytolytic effect on keratinocytes and release IFN g -A lot IFN gama and reflect damage to tissues -Remove antigen, for lesion to go away. -Tissue damage occurs with chronic presence of antigen. Suppression of the inflammatory rxn is due to the removal of: the antigenic stimulus, secretion of IL-10, PGE, TGFb (keratinocytes, dermal mast cells and macrophages), and regulatory T cells. Externally; UV light

Chronic Granulomatous Disease

2/3 cases are X-linked recessive pattern, the rest are AR Recurrent intracellular bacterial and fungal infections Mutation in genes encoding proteins of the phagocyte oxidase complex; phlox-91 (cytochrome b 558 alpha subunit) is mutated in the X-linked form —— defective production of reactive oxygen intermediates Bc infections are not controlled by phagocytes, they stimulate T cells—— granuloma formation INF gama therapy can be used to treat these patients

SCID caused by adenosine deaminase deficiency

25% of the AR cases, caused by a deficiency in the enzyme adenosine deaminase (ADA) Fnx in the salvage pathway of purine degradation and catalyze the irreversible deamination of adenosine and 2'-deoxyadenosine Deficiency of the enzyme leads to an accumulation of deoxyadenosine and its precursors (dATP), causing inhibition in DNA synthesis Developing lymphocytes are less efficient at degrading dATP, therefore they are sensitive to ADA deficiency Reduced # of T and B cells during the first year of life. A few patients may have normal T cell count but they do not proliferate in response to antigenic stimulation

Clycosporine

A complex fungal polypeptide, whereas tacrolimus and sirolimus are macrolide antibiotics produced by Streptomyces species. Cyclosporine(most prescribed) and tacrolimus have the same MOA: they inhibit the production and release of IL-2 that is required for activation of cytotoxic T Lymphocytes in response to alloantigenic challenge. They bind to intracellular proteins called immunophilins. The drug - immunophilin- complex then binds the phosphatase enzyme called calcineurin and inhibits calcineurin - mediated transcription of the IL-2 gene.

Osteoarthritis

A disease of the joints in which cartilage breaks down Degenerative joint disease. Increases with age, affects 80% people over 70 at least in one joint. Joint stiffness, decrease range of motion, effusions and bony swellings. X-rays shows narrowing of the joint space due to loss of cartilage. Vertebrae, hip, knees and distal interphalangeal joints.

HIV

A lentivirus, family retroviridae, that causes acquired immunodeficiency syndrome (AIDS) Two types of HIV-1 and HIV-2. HIV-1 is more widely distributed and more pathogenic. HIV is world wide in distribution and is transmitted by sexual activity and intravenous drug use.

A highly sensitive test is useful for ruling OUT disease;

A negative result on a highly sensitive test is a reliable indicator of the absence of disease (SNout)

rate difference

Absolute measures

Target one of the 4 viral processes

Fusion/entry Reverse transcriptase Integrate strand transfer HIV protease

Recombinant DNA-based Antigen: Gene cloned and expressed, genes expressed in vectors, and naked DNA

Gene cloned and expressed: hepatitis B (yeast-derived) Genes expressed in vectors: Experimental Naked DNA: Expiramental

Risk Factors for SLE

Genetic factors: HLA-DR2 or HLA-DR3 (or 2-3) and if both are present, the OR is about 5 Deficiencies of complement proteins: C1q, C2, or C4, are seen in about 10% of patients with SLE. Defective clearance of immune complexes and apoptotic cells. Environmental factors: Exposure to ultraviolet UV light. -leads to apoptotic death of cells and release of nuclear antigens.

This exposes virus fusion protein_____________ leading to fusion of the viral and host cell membranes and transfer of the viral genome into the cytoplasm.

Glycoprotein 41

Viral replication begins when what on the surface of HIV type 1 bind to the CD 4 antigen on the surface of HIV-specific helper lymphocytes (CD 4 cells)?

Glycoproteins 120

Primary infection where?

Gut-associated lymphoid tissue; GI tract has a large amount of lymphoid tissue, making this an ideal site for HIV replication.

Smooth Muscle

H1 agonist: contraction; bronchial muscle very sensitive. Fatal bronchoconstriction H2 agonist: relaxation.

multi drug tx

HAART

Mechanisms of immunodeficiency

HIV infection ultimately results in impaired fnx of both adaptive immune response and innate immune response Most prominent defects are in cell-mediated immunity

How does Nef mediated downregulation of only HLA-A and B, but not HLA-C and E promote viral evasion?

HLA-C and HLA-E are inhibitory signals for NK cells. Therefore Nef can decrease CTL recognition of infected cells without increasing susceptibility to NK cells.

Indications for use

HSC transplantation is used to treat leukemia's -the reconstituted donor immune system, recognizes residual tumor cells and destroy them And to treat genetic conditions with mutations in genes affecting cells derived from hematopoietic stem cells (SCID-lack B and T cells)

Pharmacology: Autacoids: Histamines

Histamine: Decarboxylation of amino acid histidine. Found in nearly all tissues. Highest concentrations skin, lung, GI mucosa. stored in circulating basophils and circulating mast cells (tissue basophils). Release: secretory process triggered by binding of specific IgE molecules to the Fc receptor expressed in the surface of the cell "degranulation". Involved in immediate hypersensitivity, allergy, and anaphylaxis.

Less than 150

Histoplasmosis Prophylaxis if high risk exposure

Accepting and rejecting a null hypothesis

How much false-positive error can be tolerated? -set alpha level P-value compared to alpha: -if p>alpha, null hypothesis is Not rejected (2 groups are not different) -if p<alpha, null hypothesis is rejected (2 groups are different) —-as p value decreases, difference between groups increases.

Adalimumab

Human IgG1 monoclonal antibody specific for human TNF-α Down regulation of macrophages and T cell function. Half-life of 9-14 days. Methotrexate decrease clearance. Produces antimonoclonal antibodies 12% cases (reduce to 4% with methotrexate) Decreases the rate of the formation of new erosions. Effective in alone or in combination with methotrexate. Tested for SLE, juvenile RA, Psoriasis. Adverse Effects Increase macrophage-dependent infection. Tuberculosis and opportunistic infections. Drug-induce lupus is extremely rare. Rare: leukopenia, vasculitis. Depress immune system

Tenofovir disoproxil

Hydrolyzed to tenofovir and by kinase action—-> tenofovir phosphate

Mechanisms of tissue injury are the same as those that normally fnx to eliminate infectious pathogens...

Innate Immune Response, T lymphocytes, various other effector cells, and mediators of inflammation. Hypersensitivity diseases tend to be chronic and progressive (intracellular infections)

Variolation

Inoculation of smallpox into skin (18th century). Effective but mortality could be as high as 10%

Type 1 hypersensitivity...

Involve Th2 cells, immunoglobulin E, mast cells, and eosinophils

H1 receptors

Involved in allergic rxns that cause dermatitis, rhinitis, conjunctivitis, and other forms of allergy. Internal and external environment involvement. Not used anymore for asthma bc they cause bronco constriction by drying of mucus.

Muscarinic antagonist used in asthma

Ipratropium bromide -involvement of parasympathetic pathways in bronchomotor responses and broncho-constriction is inhaled. -valuable for patients intolerant of inhaled B-agonist agents (less potent). Addition of ipratropium enhances the broncho-dilation produced by nebulaized albuterol in acute severe asthma. Effective in patients with COPD A longer-acting, selective antimuscarinic agent, tiotropium, is in clinical trials as a treatment for COPD

What trace elements are needed for immunity?

Iron, selenium, copper, and zinc

Other drugs... Azathioprine

Is converted in the body to 6- mercaptopurine as with methotrexate acts by inhibiting DNA synthesis Azathioprine (very toxic) is often given in combination with steroids and cyclosporine or tacrolimus to patients with tissue transplants and it is also useful in the treatment of patients with IBD, RA or LSE.

Elicitation Phase

LCs move from dermis to epidermis where they present the hapten-carrier to CD4+ and CD8+ T cells. Activated T cells produce IFNg that stimulates keratinocytes to produce IL-1, IL-6, and GM-CSF. T cells express ICAM-1. Activated specific CD8+ T cells return and induce apoptosis of keratinocytes that express the hapten-carrier. Non specific T cells get attracted as well as macrophages to mediate more tissue damage. Down-regulation of this response is driven by IL-10 and TGF b produced at the end by keratinocytes and macrophages

Enfuviritide (ENF, T-20)

Large peptide that binds HIV glycoprotein 41 and thereby blocks the fusion process. When used in combination with other drugs reduces viral load and increases CD4 cell counts. Used most often when resistance or intolerance to other drugs occurs. Must be injected subcutaneously twice daily

Asthma cont.

Long-term control is most often achieved with an anti-inflammatory agent Inhaled corticosteroid, a leukotriene antagonist, or with an inhibitor of mast cell degranulation -No longer valid because of theophylline -It is not specific, a phospholesterase inhibitor, crosses blood brain-barrier

Regimen for pregnant women HIV positive

Lopinavir/ritonavir + zidovudine + emtricitabine

Second phase of HIV course, Latency

Lymph nodes and spleen sites of continuous replication, immune system remains competent Few or no clinical manifestation Clinical latency period—-low viral loads Destruction of CD4+ T cells in lymphoid tissues Virus establishes stable viral reservoirs

Less than 50

MAC infection Prophylaxis

Epithelioid Cells

Macrophages activated by interferon-y from CD4 Th1 cells Large ER for producing large amounts of proteins: -collagen for scar formation The epithelioid cell is the characteristic cell of granulomatous hypersensitivity. Compare the extent of the endoplasmic reticulum (E) in the (1) epithelioid cell with that of (2) a tissue macrophage. (C, collagen; L, lysosome; M, mitochondria; N, nucleus; U, nucleolus)

Mechanisms of immunodeficiency cont'd

Macrophages, express CCR5, and are susceptible to HIV infection. Macrophages are relatively resistant to the cytopathic effects of HIV. Macrophages can be infected by phagocytosis of other infected cells. Bc they are not generally killed, they may become reservoirs.

Intro to GVHD

Could occur after Hematopoietic Stem cell (HSC) transplantation or bone marrow transplantation. -Transplantation of pluipotent hematopoietic stem cells. -inoculum of bone marrow cells collected by aspiration. -Hematopoietic stem cells from blood donors, after tx with CSF that mobilize stem cells from the marrow After transplant, stem cells repopulate recipient's bone marrow and differentiate into all of the hematopoietic lineages.

Other drugs

Cyclophosphamide acts by alkylating (covalent bonds) DNA used in cancer and organ transplant. Cyclophosphamide is used to treat LE and other autoimmune diseases. Because these agents prevent the proliferation of B and T lymphocytes, they are used to prevent organ graft rejection and treat autoimmune disorders and collagen diseases.

Langerhans' cells

DCs constitute 3% of all cells in the epidermis Favor inflammatory responses Express Langerin and CD1 1. Langerhans' cell; K: keratinocytes 2. Electron micrograph of a Langerhans' cell showing the Birbeck granule, an organelle derived from cell membranes

Disease-Modifying Antirrheumatic Drugs

DMARDs. Slow acting (6weeks - 6 months) 2nd line of treatment Controversy it's long term efficacy. Methotrexate, Cyclosphosphamide, Cysclosporine, Azathioprine, etc. Anti cancer drugs: Anitfolate, damage to DNA Osteoarthritis: ibuprofen treatment

Monoclonal Antibodies

Daclizumab, human Basiliximab, human mice Muromonab, human Palivizumab, human

Antinuclear antibodies for classifying and establishing a diagnosis

Disease: SLE 99% of patients Sjogren's syndrome80% Scleroderma 80%

Histamine Receptor: H1

Distribution: smooth muscle, endothelium, brain (used for sedatives in elderly people mainly in nursing homes) Partially selective agonists: 2-(m-fluorophenyl)-histamine. Partially selective antagonists: Mepyramine, triprolidine.

Corticosteroids

Do not relax airway smooth muscle directly but reduce bronchial reactivity Increase airway caliber. Reduce the frequency of asthma exacerbations if taken regularly Inhibition of the lymphocytic, eosinophilia airway mucosal inflammation of asthmatic airways.

Allogenic HSC transplantation

Donor and recipient must be carefully matched at all HLA loci. -mechanisms for rejection are not completely understood (immunosuppressed patients) -NK cells (against bone marrow precursors that lack class I HLA molecules) 2 main complications after HSC transplantation: -Graft-Versus-Host- disease Immunodeficiency (immune response from the donor not the recipient)

Rotavirus Vaccine

Double stranded RNA virus. Causes infantile diarrhea, and responsible for 600,000 deaths per year worldwide in developing countries. Highly effective vaccine developed from bovine live attenuated rotavirus (naturally attenuated in human hosts) with incorporation of antigens for 5 most prevalent viral strains.

Contact hypersensitivity

Eczematous skin rxn at the site of contact with the allergen Sensitizing agents include nickel, chromium, other industrial chemicals (rubber, leather, dyes, drugs, fragrances), and plants (pentode acute holiday in poison Ivy) Work as happens; bind to a carrier protein. Sensitizing agents have haptens: low molecular weight chemicals (< 1 kDa) not immunogenicity by themselves, lipophilic in nature penetrate the epidermis and dermis where they bind to cysteine or lysine residues or metal ions that chelate self-peptides and form new antigen determinants Destruction of tissues leaves scars

Nonnucleoside Reverse Transcriptase Inhibitors

Efavirenz, etravirine, nevirapine, and rilpivirine. (Nev E E R nonnucleosides) Do not require metabolic activation and directly inhibit reverse transcriptase and have good oral bioavailability and are highly lipophilic and reach a good concentration in CNS

Cont'd methylxanthine drugs

Effects on CNS, kidney, and cardiac and skeletal muscle as well as smooth muscle. CNS: cause mild cortical arousal with increased alertness and deferral of fatigue (caffeine) CV: decrease blood viscosity and may improve blood flow (pentoxifylline) Theophylline is the most effective bronchi-dilator. -Relieve airflow obstruction in acute asthma and to reduce the severity of symptoms and time lost from work or school in chronic asthma. Improvement in pulmonary fnx is correlated with plasma concentration in the range of 5-20 mg/L

CD4 + cell expression can occur in...?

Eosinophils, mast cells, basophils, NK lymphocytes.

Acute GVHD

Epithelial cell death in the skin, liver, and GI tract --clinically: rask, jaundice, diarrhea, and GI hemorrhage When the epithelial cell death is extensive, the skin or the lining of the gut may slough off--> fatal outcome! NK cells are often attached to the dying epithelial cells, suggesting their participation. CD8+ T cells and cytokines appear to be involved

Attributable Risk (AR)

Estimate of the amount of risk for a disease that is attributable to a specific risk factor AR= incidence of condition in those exposed-incidence of condition in those unexposed)...[a/(a+b total)]-[c/(c+d total)]

Cytokines relevant to Th2 response include:

IL-4, 13, 5, and 10

Community screening programs something to consider....

Even when a test is highly specific, if the prevalence of the disease is low, any positive test is much more likely to be a false positive. If TB skin test has a specificity of 94% and a prevalence of 1% then there is a low positive predictive value of 14%; 86% of the positive test results will be wrong

Active immunization

Exposure to antigen with the host generating protective immunity Start immune response active T cell memory and memory antibodies

Wheal and flare skin response...

Extremely sensitive method of detecting specific IgE antibodies by injecting histamine. Immediate skin response can be effectively blocked with antihistamines.

Anaphylaxis

Immediate hypersensitivity responses.

Classification of Hypersensitivity Type I

Immediate hypersensitivity: type 1 -IgE antibody -Mast cells and their mediators (vasoactive amines, lipid mediators, cytokines)

Bee sting patient...

Immediate rxn occurred within 20 minutes and is mediated by the release of histamine and other mediators from mast cells. Rxn became generalized, leading to a fail in blood pressure, generalized urticaria, and bronchospasm (anaphylaxis).

Immediate and late phase rxns

Immediate rxn: characterized by vasodilation, congestion, and edema. Late rxn: characterized by an inflammatory infiltrate rich of eosinophils, neutrophils, and T cells. kinetics, immediate vascular and smooth muscle rxn to allergen develops within minutes after challenge (allergen exposure in a previously sensitized individuals), and the late-phase rxn develops 2 to 24 hrs later.

autoimmune disease

Immune reaction against self-antigens, named autoimmunity and the diseases this condition causes are named autoimmune diseases. Loss of central and/or peripheral tolerance May be triggered by infections or aging More frequently in women

Role of infections in AI

Immune response: local inflammatory response Inflammatory: T cells almost activated; and APCs picking antigens that they localize; favored in this microbiology

Autoimmune Disorders

Immunology

Immune Reconstitution Inflammatory Syndrome

Immunology

Transplantation

Immunology

Type I Hypersensitivity Disorders

Immunology

Vaccines

Immunology

Graft vs Host Disease

Immunology Continuation

Type IV hypersensitivity disorders

Immunology: CD4 + T cells activation of cytokines and main one responsible here

HIV clinical features

Fever, persistent generalized lymphadenopathy, skin rash, pharyngitis, myalgia and arthralgia, gastrointestinal symptoms, neurological symptoms- GBS, peripheral neuropathy.

What 2 things inhibit zinc absorption that are found in plant-based diets?

Fiber and phytate

Chronic GVHD

Fibrosis and atrophy of one or more organs without evidence of acute cell death. Involve the lungs and produce obliteration of small airways: bronchiolitis obliterates (hard time breathing) Chronic GVHD may appear without evidence of acute GVHD Response to ischemia caused by vascular injury

Primary Immunodeficiencies Cont'd

First described X-linked agammaglobulinemia: not able to produce B cells Affects boys, caused by defect in B lymphocyte maturation Primary abnormalities at different stages of lymphocyte maturation or in lymphocyte responses to different antigens.

Living organisms Antigen: natural, attenuated

Natural: vaccine smallpox, vole bacillus (tuberculosis) Attenuated: Polio (Sabin; oral polio vaccine) measles, mumps, rubella, yellow fever 17D, varicella-zoster (human herpesvirus 3), BCG (tuberculosis)

4. Compare Utility Values

Often the decision analysis gives 2+ outcomes with similar utilities. When this occurs: Better data are needed OR Other factors should be used to make the clinical decision

Anti-Immunoglobulin E antibodies

Omalizumab Humanized mouse monoclonal antibody against the high affinity IgE-receptor-binding domain on human IgE. The effect is a decrease in the allergic response in asthma. Affects both the early and late phase asthmatic responses to challenge by an inhaled allergen.

ISTIs

Oral, produce few serious adverse effects; headaches, diarrhea, and nausea. Are not substrates for cytochrome P450 and do not inhibit these enzymes.

PIs interact with other drugs via inhibition of what cytochrome enzymes?

P450

Less than 200 cells/microliter

PCP prophylaxis Trimethoprim-sulfamethoxazole -80mg/400mg to 160mg/800mg daily or the latter every 3 days Should be continued until the CD4+ cell count exceeds 200 for 3 months

Causes

Malnutrition Impaired cellular and humoral immunity to microorganisms Global metabolic disturbances Cancer Tumors that arise in the BM may interfere with growth and development of normal lymphocytes and other leukocytes Infections HIV, measles, HTLV-1, chronic malaria Latrogenic immunosuppression (treatment for inflammatory diseases, cancer or to prevent rejection of tissue allografts) Most common: corticosteroids and cyclosporine Chronic diseases, debility, surgery, trauma or stress Spleen absence—-susceptible to streptococcus pneumoniae (encapsulated bacteria) Elderly: any cell # of replication has shorter telomeres. Proliferation capabilities are decreased with age. Most do not respond to vaccines only 20%.

Nutrient deficiencies

Malnutrition and infection act synergistically to depress immunity The WHO estimates that 50% of worldwide childhood deaths are due to malnutrition and in US only 50% of elderly are adequately nourished.

Fusion and Entry Inhibitors

Maraviroc and enfuvirtide are newer drugs Active against strains of HIV resistant to reverse transcriptase and PIs, and approved for treatment of HIV infections caused by drug-resistant strains.

Adverse Effects

Minor and are localized to the site of deposition Throat irritation, cough, mouth dryness, chest tightness, an wheezing. Reversible dermatitis, myositis, or gastroenteritis occurs in fewer than 2% of patients. Very few cases of pulmonary infiltration with eosinophilia and anaphylaxis.

Classification of Immunosuppressant drugs:

Monoclonal Antibodies Microbial Products Corticosteroids Other Drugs

Histological appearance of lesion in contact hypersensitivity

Mononuclear cells infiltrate both dermis and epidermis. The epidermis is pushed outwards and microvesicles form within it, due to edema.

Leukotriene Inhibitors

Montelukast. Effects on symptoms: airway caliber, bronchial reactivity, and airway inflammation, are less marked than the effects of inhaled corticosteroids but without the risk. -Equally effective in reducing the frequency of exacerbations. -average: PO administration -Astmatics are exquisitely sensitive to aspirin-> contraindicated in asthma patients. Block prostaglandins increase levels of leukotriene synthesis, pro inflammatory.

IRIS is an important complication that increases...

Morbidity and mortality in AIDS patients after the initiation of ART

Antigen preparations used in vaccines

More antigen the better protected patient is. Living organism tend to be effective than killed organisms. Used in disease where toxins are responsible for the pathology: toxin based vaccines Genes from microbial antigens inserted in vectors and expressed in host cell

Asthma

Most common chronic disabling disease of childhood Affects all age groups. Characterized by increased responsiveness of the trachea and bronchi to various stimuli Narrowing of airways Can be caused by a upper respiratory tract infection

Activation of T cells and Rejection of Allografts

Most organs contain APCs: Such as DCs. -DCs from the recipient may also go into the graft and then capture and present antigens from the donor (minor antigens or MHC molecules) leading to the Indirect pathway.

Inactivated toxins and toxoids

Most successful of all bacterial vaccines Based on inactivated exotoxins Tetanus and diphtheria

beta 2 selective drugs agonists

Most widely used sympathomimetrics for the treatment of asthma. Effective after inhaled or oral administration. Have a long duration of action and significant B2 selectivity Albuterol, terbutaline(P.O.), metaproterenol(P.O.), pirbuterol(P.O.) , and bitolterol

Selenium: Deficiency

Myalgia (muscle pain), cardiac myopathy. Promotes oxidative stress, since it is important for the antioxidant catalase: glutathione peroxidase. In vitro: decreased T cell responses, decreased NK fnx and altered cytokine production.

Tuberculin-type Hypersensitivity

Mycobacterium tuberculosis induce strong T cell and macrophage responses that result in granulomatous inflammation and fibrosis with extensive tissue destruction and fnx impairment Tuberculin-type hypersensitivity: patients injected with tuberculin, reacted with fevers and generalized sickness, an area of hardening and swelling developed at the site of injection. Cytokine-mediated inflammatory rxn resulting from the activation of CD 4+ T cells Called Hypersensitivity bc of excessive immune response, and delayed: develops in 24-48 hrs.

Side Effects:

Peripheral neuropathy, nephrotoxicity, hyperglycemia, hypertension, hyperlipidemia, hirsutism, gingival hyperplasia and muscle tremor. Cyclosporine is metabolized by CYP3A4 (metabolizes 50% of drugs) and interacts with many drugs that inhibit or induce this enzyme. Give list of foods that should be avoided

Cohort studies

Persons exposed to a risk factor are compared with persons not exposed to the same risk factor. Usual outcome measured: development of a defined disease Calculate Relative Risk

Opportunistic Infections PATHO

Pneumocystis Pneumonia (fungal) Mycobacterium Adium complex Toxoplasmosis (Protozoa) Cryptosporidium diarrhea Cryptococcal meningitis (fungal) CMV retinitis Kaposi sarcoma(start ART and treatment for kaposi) Thrush (candida) Histoplasmosis TB

Fatal opportunistic infections:

Pneumocystis jirovencii pneumonia, cytomegalovirus retinitis, cryptococcal meningitis, Kaposi's sarcoma, etc.

Why do polysaccharide antigens not induce an IgG response or lasting immunity?

Polysaccharide antigens are not processed for presentation to T h cell, so they do not induce class switching, affinity maturation, or generate memory T cells.

Treatment for TB-IRIS

Prednisone decreases IL-6, IL-10, IL-12, and IFN-gama TNF-alpha and CXCL10

Cont'd cromolyn and nedocromil MAO

Pretreatment with cromolyn or nedocromil blocks the bronchoconstriction. Cromolyn is useful for administration shortly before exercise or before unavoidable exposure to an allergen. Reduce symptomatic severity and the need for bronchodilator medications. Neither as potent nor as predictably effective as inhaled corticosteroids

Protein-energy malnutrition and lymphocyte dysfunction

Protein-energy malnutrition (PEM) deficiencies are correlated with defects in cell-mediated immunity——>lymphoid atrophy, specially the thymus in young children. T and B cells. Challenge-> proliferate needs glutamine

Subunit vaccines and carriers

Purified antigens or antigens produced by recombinant DNA technology

5. Perform a Sensitivity Analysis

Purpose: see if the results of the analysis are fairly stable over a range of assumptions. Analysis: Vary the estimated probabilities of occurrence of a particular outcome at various points in the decision tree: How are the overall outcomes and clinical decisions affected by these changes? Which assumptions and decisions have the largest effect on the outcomes?

Integrase Strand Transfer Inhibitor

Raltegravir, dolutegravir, and elvitegravir (-gravir ISTIs) Integrase incorporates the viral DNA formed by reverse transcriptase into the DNA of CD4 cells through a multistep process ending with DNA strand transfer. These agents prevent DNA strand transfer by binding divalent cations in the catalytic core of integrase that are required for interaction of the enzyme with host cell DNA. Used in combination they reduce viral load and increase CD4 cell count. Resistance: single-point mutations within the integrase gene.

HIV immune Evasion:

Rapid mutation Antibodies and CTL recognition fails Affection of cells from the immune system HIV Nef protein inhibits the expression of class I MHC molecules: HLA-A and HLA-B, no antigen presentation!!! HIV deviates the IR towards the Th2 pole, increasing host susceptibility to infection with in trace lunar microbes, including HIV itself

Zinc deprivation can cause severe progressive involution of the thymus...

Rapid reduction in thymine weight, primarily due to cortical region loss. Zinc is a structural element both in the peptide hormone, thymulin, as well as in many transcription factors. This leads to thymic and lymphoid atrophy, and decreased IL-2 and IFN gama production impairing cell mediated immune response. NK cell lytic activity is also decreased by zinc deficiency

Autoimmunity

Recognition of self components Tolerance is lost, autoantibodies are produced, and autoreactive T cells can be identified Targets for autoimmune diseases are wide Not every Autoimmune event leads to an AI condition: ANA, and RF in healthy population

Phases of contact Hypersensitivity

Recognition of the antigen 1. Sensitization (DCs, Langerhans' cells (LCs), and keratinocytes LCs are specialized cells with dendritic processes, that sample environmental antigens. They express MHC II, CD 1 and a C-type lectin (langerin) responsible for Birbeck granules. LCs can migrate fast to the closest draining lymph node and activate hapten-specific CD4+ and CD8+ T cells. K eratinocytes express MHC II and ICAM-1, when activated produce TNF, IL-1, GM-CSF, IL-3, IL-10, and TGFb

Anakinra

Recombinant form of the human interleukin-1 receptor antagonist (IL-1Ra) differing by the addition of a methionin at the amino terminus Blocks biological activity of IL-1 by competing for the IL-1R IL-1 induces cartilage degradation and stimulation of bone reabsorption AE: same as TNF blockers, serious infections and lymphoma Very aggressive target against IL

Clinical hallmarks of asthma

Recurrent, episodic bouts of coughing shortness of breath, tightness in the chest Wheezing Severe forms of asthma: frequent attacks of wheezing dyspnea, especially at night, or even chronic limitation of activity

Pol sequence encodes...

Reverse Transcriptase, integrase and viral protease (target for some therapies) enzymes required for viral replication.

Vitamin D deficiency

Rickets. Increased infections rate; signaling through the VDR enhances catelicidin and defensin expression

Risk difference

Risk exposed-risk unexposed (exposed and contracted disease)-(unexposed and contracted disease) Absolute difference in risk tells you how many cases of disease would be eliminated if those exposed would have not bee exposed

Direct Presentation

Rxn between recipient T cells and donor APCs. 2% of an individuals T cells are capable of directly recognizing and responding to a single donor MHC molecule. Direct recognition can be generated by both CD4+ and CD8+ T cells (cross presentation)

Systemic Lupus Erythematosus: Prototypic Immune Complex-Mediated

SLE is a chronic, relapsing/remitting, multisytem autoimmune disease that affects predominantly women. -UV light, stress, exercise Incidence of 1 in 700 women between 20 to 60 years (about 1 in 250 among block women) principal clinical manifestations: rashes, arthritis, and glomerulonephritis. Hemolytic anemia, thrombocytopenia, and CNS involvement are also common.

WUGGLE

SNUGGLE

WUGGLE

SNUGGLY

Mitsuda reaction in leprosy

Same as PPD test except use different protein • Reaction to dead M. leprae • (1) The resultant skin swelling (which may be ulcerated) is much harder and better defined than at 48 hours. • (2) Histology shows a typical epithelioid cell granuloma (H&E stain. × 60). Giant cells (G) are visible in the center of the lesion, which is surrounded by a cuff of lymphocytes. • The reaction is due to the continued presence of mycobacterial antigen.

Decision Tree Interpretation

Same conclusion for a wide range of data assumptions—-> use decision analysis to make decision. Small changes in the data, change the direction of the decision——> decision analysis unhelpful. Folding back: Process of choosing the best branch at each decision node by working backward (right to left)

Protease Inhibitors

Saquinavir, lopinavir, ritonavir, atazanavir, darunavir, and fosamprenavir( -navir <-->PI) Bind active site of enzyme and inhibit proteolytic activity —-> production of non infectious viral particles. HIV protease cleaves the gag-pol (group-specific antigen-polymerase) to provide fnxal viral proteins and is essential for the maturation of the virus.

Side Effects:

Sedation: very common, except the piperidines. CNS: dizziness, lack of coordination, tremors, diplopia. GI: anorexia, nausea, vomiting, constipation, diarrhea. Dryness of mucous membranes and urinary retention (antimuscarinic) Cardiovascular: Palpations, hypotension. Prolongation QT interval (serious), associated with astemizol and terfenadine, especially when used with azalea derivative (ketoconazol) or macrolide antibiotic.

Selective Immunoglobulin Isotype Deficiencies

Selective IgA deficiency (most common), affects 1 in 700 white individuals Usually occurs sporadically, some familiar cases with AD and AR inheritance patterns Respiratory and GI tract infections, in rare occasions autoimmune diseases related Low IgA < 50 microg/mL (2-4 mg/mL), with normal or elevated levels of IgG and IgM B cells are unable to differentiate into IgA antibody-secreting plasma cells

Abatacept

Selective costimulation modulator, inhibits T-cell activation by binding to cell surface markers on leukocytes Recombinant protein: CTLA-4 with a modified Fc portion of human IgG1 Also a new drug. Rarely used. Tofacitinib: is the newest drug used in the tax of RA. Janus kinase 3 inhibitor

Nerve Endings:

Sensations of pain (dermis) and itch (epidermis). Part of the triple response. Stimulates the adrenal medulla to release catechols.

Aids diagnosis test

Serological tests such as RDTs or enzyme immunoassay (EIAs), detect the presence or absence of antibodies to HIV and/or HIV p24 antigen. No single HIV test can provide an HIV-positive diagnosis.

😛😘😩

Snuggly

Genetic susceptibility for AD

Some HLA alleles occur at higher frequencies in patients than in general population -Linkage disequilibrium inheritance "extended HLA haplotypes" -disease associated HLA differ to non disease-associated HLA in their peptide binding clefts -key determinants for antigen presentation and T cell recognition

Considering testing sequences

Start with most sesitive test —(if positive results)———> continue with increasingly specific test——-> stop when a test yields negative results

ZDV and what other drug are not used together? And what two drugs are used in cases in which first line drug is not tolerated or when viral resistance occurs?

Stavudine. Stavudine and Didanosine

Glucocorticoids released during what is increased with PEM while lepton levels are decreased?

Stress

Azathioprine

Suppresses B and T cell function, immunoglobulin productions and IL-2 secretions Used in psoriasis, reactive arthritis and SLE Bone marrow suppression. GI disturbances, risk for infections. Increase risk for lymphomas. Rarely: rash, fever and hepatotoxicity.

PI activity, indications, and viral resistance

Synergistic with NRTIs and are often combined in treatment regimens. Administration with 1 PI and 2 NRTIs significantly reduces viral load, increases CD4 cells, and slows the clinical progression of disease and the emergence of drug resistance. Resistance associated with accumulation of mutations resulting in amino acid substitutions in the viral protease structure.

AIDS (acquired immune deficiency syndrome) criteria for diagnosis

T CD 4+ count of <200 microliters Establishment of an AIDS opportunistic infection Reference range for CD 4+ count is 500-2000 cells/microliter

T cells control the response to inhalant allergens...IgE production is dependent on Th2 cells...

T cells can also suppress the Th2 responses including IgE production: -act predominantly by producing IFN gama... it became clear that IgE production is dependent on Th2 cells and that any priming that generates a Th1 response will inhibit IgE production.

TNFα Blocking agents.

TNFα is one of the proinflamatory cytokines produced by macrophages and activated T cells Elevated levels of TNF found in synovial fluid and play important role in pathologic inflammation and joint destruction Mechanism of action include antagonims of TNF, inactivating it. For refractory cases. Adalimumab, Infliximab, Etanercept.

Sulfasalazine

PO: 10-20% absorbed. Fraction undergoes enterohepatic recirculation and is reduce by colonic bacteria into sulfapyridine and 5-aminosalicylic. Sulfapyridine: well absorbed, excreted after hepatic metabolism (RA). 5-aminosalicylic: unabsorbed. Half-life 6-17hrs. Reduces the rate of appearance of new joint damage. Juvenile RA, ankylosing spondylitis. Adverse effects Nausea, vomiting, headache and rash. Hemolytic anemia (rare), Neutropenia, thrombocytopenia (very rare).

Indications:

Palliation(making less severe) of symptoms of allergy, hay fever, allergic rhinitis. Also for cutaneous allergies associated with urticaria, atopic and contact dermatitis. Motion sickness and vestibular disturbances (Meniere's disease) Antipsychotic side effects. Not useful in the treatment of asthma.

Didanosine and stavudine adverse effects

Pancreatitis and Didanosine can cause peripheral neuropathy and GI intolerance

2 types of IRIS:

Paradoxical IRIS and Unmasked IRIS

Histamine Receptor: H2

Peptic ulcers Distribution: Gastric mucosa, cardiac muscle, mast cells, brain Postreceptor mechanism: increase cAMP (Gs) Partially selective agonists: dimaprit, impromidine, amthamine partial selective antagonists: ranitidine, tiotidine

Attributable risk percent in the exposed (AR% exposed)

Percent of total risk for a disease that can be attributed to a specific risk factor; percent of total risk for lung cancer that can be attributed to smoking: can calculate using absolute difference and relative difference.

Number needed to treat (NNT)

The number of patients who need to be treated for every one patient who benefits from a treatment. NNT=1/ARR

Viral load. How often should it be tested on the patient?

The number of virus particles circulating in the body. HIV RNA copies per milliliter. Determined at the outset of therapy and 2 to 8 weeks after therapy is begun, and then every 3 to 4 months thereafter.

Protease inhibitors

Target assembly: inhibit the processing of large viral proteins into individual components

IL-4 is important in the differentiation of...

Th2 cells and is also a growth factor for these cells. Bc it is produced by Th2 cells, it is at least in part acting on the cell that produced it.

what tissue do Th2 type immune response predominate, and which tissue are Th1 responses promoted?

Th2 responses predominate in mucosal tissues, whereas Th1 responses predominate in the skin and CNS.

combined immunodeficiency (CID) means...

That they are susceptible to infections by all classes of microorganisms

Deficient humoral immunity means...

That they have an increased susceptibility to pyogenic infections (Bacteria)

Deficient cell mediated immunity means...

That they have an increased susceptibility to viruses and other intracellular microbes

Many bacterial carbohydrates and glycolipids are good adjuvants, even though they are not good immunogens. Why should this be so?

The discovery of Toll-like receptors and other pattern recognition receptors, such as lectin-like receptors for carbohydrates, has provided an explanation for the long-known efficacy of many bacterial products as adjuvants. It is clear that they act mainly by binding to PRRs and stimulating the formation of appropriate cytokines by APCs.

Antinuclear antibodies: defect in apoptosis; in proper removal of apoptotic bleps

The most frequent antibodies in SLE, particularly anti-DNA, against ribonucleoproteins, histones, and nucleolar antigens. Immune complexes are responsible for glomerulonephritis, arthritis, and vascularitis. Hemolytic anemia and thrombocytopenia are due to autoantibodies against erythrocytes and platelets, respectively.

Methylxanthine drugs

Theophylline, theobromine, and caffeine. Black tea, chocolate, caffeine Theophylline: the greatest in effectiveness of inhaled adrenoceptor agents for acute asthma of inhaled anti-inflammatory agents for chronic asthma Very low cost Important advantage for enconomically disadvantaged patients in societies where health care resources are limited. Theophylline preparation most commonly used for therapeutic purposes is aminophylline. -action of the methylaxanthines, has not been very well established as responsible for the bronchodialating effect. At high concentrations, the drug can be shown in vitro to inhibit the enzyme phosphodiesterase. Very slow injection 30-40 minutes block cAMP and gAMP. All organs effected, CNS, insomnia, seizures, tight control of dose.

3. Chronic Rejection

Therapy of acute rejection has improved, major cause of failure is chronic rejection -can develop within 6 months to a year after transplant, with or without acute rejection. -pathogenesis not well understood-

Effector mechanism of allograft rejection

Time course of rejection after transplantation.. Hyper Acute, Acute, and Chronic.

Treatment: Antiretroviral therapy

To limit viral replication and it should be started on patients with detectable viremia independently of CD4+ T cell count < 350

HIV opportunistic infections?

Toxoplasmosis Cryptococcus neoformans PML CMV Cryptosporidium (diarrhea).

Passive Immunization

Transfer of specific antibodies Rapid treatment of potentially fatal disease caused by toxins, such as tetanus or against snake venom. Short-lived, do not induce immune response, there is no memory thus the subject is not protected against subsequent exposure

What is the main reason for changing drug therapy after treatment is begun? What indicates this reason?

Treatment failure and drug toxicity. Increased viral loads and decreased CD4 cells. If the patient fails to respond to a drug regimen, the new regimen should include at least 2 new drugs.

SLE pathophysiology

Triggering agents induce response over producing auto-antibodies, targeting cells in multiple organs. Produce abnormal amounts of IFNa. antigen is intracellular.

MMR vaccination and autism and chronic bowel disease was suggested in 1988 leading to...

UK and Ireland decline in MMR vaccination decline over several years and epidemics of measles occurred because of declining herd immunity

Hydroxychloroquine

Used in malaria. Reduces chemotaxis and phagocytosis of PMNs, and decreases superoxide radicals production Slow onset of action (6 months) Rapidly absorbed, only 50% bound to proteins. Extensively tissue bound. Deaminated by the liver, half-life up to 45 days. Take advantage of side effects for malaria , reduce chemotaxis... for use in RA Adverse effects Ocular toxicity (check-ups each 12 months) Dyspepsia, nausea, vomiting, abdominal pain, rashes and nightmares. Safe in pregnancy.

Cont'd Cromolyn and nedocromil

Useful in reducing symptoms of allergic rhino-conjunctivitis Effective in about 75% of patients, even during the peak pollen season.

Leukotriene pathway inhibitors

Useless in acute asthma attack. 2 approaches to interrupting the leukotriene pathway: Inhibition of 5-lipoxygenase (synthesis) Inhibition of the binding of leukotriene D4 to its receptor on target tissues (action). -Zileuton, a 5-lipoxygenase inhibitor Zafirlukast and montelukast, LTD4-receptor antagonists

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VUGGLY

Hazardous effects of vaccines may be lowered due to or arise from...

Vaccine: -contamination (proteins, toxins, or live viruses) -killed vaccines non properly killed -attenuated vaccines may revert to wild-type Host: -Hypersensitivity -Immunocompromised

Summary

Vaccines have had tremendous impact on human life quality and longevity by eliminating devastating pathogens. New approaches hold a tremendous promise for treating allergic, autoimmune, and chronic inflammatory conditions.

SNPs in non HLA genes, association studies

Variants associated with different condition, no single NP

Chronic Rejection: Graft arteriosclerosis:

Vascular lumen replaced by an accumulation of smooth muscle and connective tissue.

Antigen activated mast cell...release histamine/lipid mediators-----> Antigen activated mast cell...release cytokines------>

Vascular/smooth muscle responses: immediate rxn Inflammation: late phase rxn

Cont'd Leukotriene Inhibitors

Very expensive drug Zileuton is the least prescribed, requirement of 4 items daily dosing. Occasional liver toxicity The receptor antagonists appear to be safe to use. Churg-Strauss Syndrome (vasculatitis), angioedema. -hepatic eosinophilic infiltration, hepatoxicity (rare)

Intact but non-living organisms Antigen: viruses, bacteria

Viruses: polio (Salk), rabies, influenza, hepatitis A, typhus Bacteria: pertussis, typhoid, cholera, plague

Killed (whole organisms) vaccines

Viruses: polio, rabies, influenza, hepatitis A -preferred in Scandinavia; safe in immunocompromised -can be given post-exposure, with passive antiserum -strain-specific -also attenuated vaccine Bacteria: pertussis, typhoid, cholera, plague, Q fever

Intradermal Injection

"Triple Response" Localized erythema (vasodilation) Bright red flare surrounding the local spot (axon reflexes, more vasodilation) Wheal of edema (increase permeability of post capillary venules)

Cardiovascular:

Dilatory effect on the vasculature, causes flushing, hypotension, low peripheral resistance, increase capillary permeability. Inotropic and chronotropic effect (H2)

Leprosy

1. A borderline leprosy rxn. this small nerve is almost completely replaced by the granulomatous infiltrate. 2. Lepromatous leprosy. Large numbers of bacilli are present. Bacilli 3. Borderline lepromatous leprosy. There are gross infiltrated erythematous plaques with well-defined borders.

HIV pathophysiology

Single-stranded positive-sense RNA virus that contains 3 structural genes (gag, pol, env) and 6 regulatory genes. HIV infects CD 4+ T cells and uses its reverse transcriptase to transcribe its RNA genome into double-stranded DNA, which is integrated into the host cell genome

attenuated live vaccine

Aim of diminishing its virulence while retaining the desired antigens Passage of a virus in non-human species: decrease virulence Viral sequencing: selection of virulent genes 3 types of live (Sabin) polio vaccine: -type 1 polio has 57 mutations -type 2 and 3 have only 2 mutations, reversion to wild type has occurred, outbreaks of paralytic poliomyelitis

Activation of H1 receptors:

Skin and mucous membranes causes vasodilation, erythema, congestion and edema. -Mucocutaneous nerve endings causes pruritus and in lung cough reflex -smooth bronchial muscle causes bronchoconstriction (increased amounts)

Direct allogenic recognition

After presentation will go back and start killing every cell that presents that antigen (MHC)

Pneumocystis pneumonia

The most common opportunistic infection in HIV infected patients Fungal pneumonia Symptoms are non-specific -dyspnea, fever, non productive cough, weight loss, chills Lactic dehydrogenase (LDH) is elevated in 90% of patients with HIV infections

Bayers' Theorem Epidemiologically

(Sensitivity*prevalence)/(sensitivity*prevalence)+(1-specificity)*(1-prevalence) Numerator: true positives tests Denominator: all positives tests (true and false positives) Whole equation: positive predictive value (PPV)

T cell differentiation during human immune response:

(illustration)

what is the T cell differentiation?

(illustration)

Sirolimus

(less prescribed), also called rapamycin forms a complex with FK12 - binding protein, which then inhibits a key regulatory kinase (mTOR) involved in cytokine-driven T-cell proliferation.

Risk Difference Formula

(rate of disease Y among those exposed to X) - (rate of disease Y among those NOT exposed to X) Absolute difference in rate. The rate in the exposed group minus the rate in the unexposed group.

z-score formula

(x-mean)/standard deviation Compares proportions Proportion of patients BP improving on drug vs. not on drug

causes of Hypersensitivity disorders

-Autoimmunity -Rxns against microbes. May cause disease if they are excessive or the microbes are usually persistent. -Rxns against environmental antigens. Almost 20% of the population is abnormally responsive to one or more of harmless environmental substances.

The Bare Lymphocyte Syndrome

AR disease in which patients express little or no HLA-DP, HLA-DQ, or HLA-DR on B lymphocytes, macrophages, and dendritic cells. Three different types, with normal or decreased HLA class I molecules expression Due to mutations in genes encoding proteins that regulate MHC molecules, for example TF RFX5, or CIITA, TAP-1, or TAP-2

Chediak-Higashi Syndrome

AR disorder characterized by recurrent bacterial infections, partial oculocutaneous albinism and lymphocytes infiltration in various organs. Neutrophils, monocytes and lymphocytes of these patients contain giant cytoplasmic granules. The gene responsible codifies for intracellular proteins LYST, which regulates intracellular trafficking of lysosomes: Defective phago-lysosomes fusion in neutrophils, macrophages, DC, NK cells, and cytotoxic T cells defective melanosme formation, and lysosomal abnormalities in cells of the nervous system and platelets.

Leukocyte adhesion deficiency type

AR disorder characterized impaired wound healing Defective leukocyte adhesion to endothelial cells (APCs too) and migration into tissues linked to decreased or absent expression of beta 2 integrins; recurrent bacterial and fungal infections. Mutations in gene encoding the beta chain (LFA-1, CD18) of Beta 2 integrins Failure of leukocytes, particularly neutrophil recruitment. Severe periodontitis and other recurrent infections starting early in life, and inability to make pus

When diagnosis of an opportunistic infection is established what should be done?

ART should be started immediately

Passive Immunization

Administration of humoral and/or cellular factors that provide immunity for the host. No isotope switch, no memory T cells or antibodies Objective: provide temporary immediate protection against an imminent or ongoing exposure/ threat (venom, rabies)

Severe combined immunodeficiencies:

Affect both humoral and cell-mediated immunity. In some types the defect in humoral immunity is due to absence of helper T cells. Children usually are affected by severe infections during first year of life and succumb to these infections. X-linked SCID caused by mutations in the cytokine receptor common gama chain SCID caused by Adenosine deaminase Deficiency DiGeorge Syndrome

Case series of HIV patients with Mycobacterium Adium infection.

After ZDV treatment presented fever and lymphadenitis without mycobacteremia Adium to PPD tests, after ZDV PPD+

Asthma and atopic dermatitis

Continuous local recruitment of mast cells and basophils: Increased response to the same allergens. -Release of leukotrienes, chemokine, and cytokines (IL-5, TNF-a) -Recruitment and activation of eosinophils -Recruitment of T cells with inflammatory effects.

Immune response to HIV

Continuous presence of the virus (reservoirs) overwhelms the immune system in most individuals Initial response is characterized by massive expansion of CD8+ CTL specific for peptides derived from HIV

Immunodeficiency may result from...

Defects in lymphocyte maturation or activation and defects in the effector mechanisms of innate and adaptive immunity

Immunology Immunodeficiencies

Deficiencies in Immune system that develop bc of abnormalities that are acquired during life (not genetic) Treatment usually involves treating the extrinsic disease, combined with increase vigilance for infection and prophylaxis.

How would a decrease in complement components affect innate immunity?

Decreased opsonization and killing of extracellular microorganisms increases susceptibility to bacterial infections.

Penicillamine

Decreases bone destruction in RA. Unknown mechanism of action. Reduce blood levels of inflammatory cytokines Severe side effects. Rarely used. Not related to penicillin at all

defects in innate immunity (usually involve the skin)

Defects in complement system Chronic granulomatous disease Leukocyte adhesion deficiencies Chediak-Higashi syndrome

Intro to Type IV Hypersensitivity

Delayed type hypersensitivity T cell mediated inflammatory response. Stimulation of antigen specific effector T cells leads to macrophage activation and localized inflammation with edema and damage to host tissue Antigens are microbial, sensitizing chemicals, or self-antigens (in the system for a chronic period of time) T cells are sensitized by DCs in T cell area of secondary lymphoid tissues Antigens that drive this type of response are persistent in tissues: chronic activation of T cells and macrophages, leading to granuloma formation and tissue damage. If the antigen is organ-specific (self-antigen), auto-reactive T cells may produce localized cellular inflammation, and autoimmune disease: type I diabetes mellitus. Secondary exposure to the antigen (intradermal) results in recruitment of antigen-specific T cells and a local inflammatory response, evident in 24-72 hours. Type IV hypersensitivity can be transferred from one animal to another by transfection of T cells (CD 4+ TH1 cells) and is lost in the absence of these cells.

Casual Research

Depends on the measurement of differences between defined groups

absolute difference

If an exposure is harmful (as in the case of cigarette smoking) the risk difference is expected to be greater than 0 If an exposure is protective (as in the case of a vaccine), the risk difference is expected to be less than 0 Risk difference is also known as attributable risk

B cell fnx is less pronounced in PEM, although serum antibody levels are usually normal, clinical studies found reduction in the secretory ________ antibody response to common vaccine antigens, leading to higher incidence of what??

IgA, mucosal infections

Mast cells and basophils contain histamines

IgE antibodies bind to a specific receptor, FcERI, on mast cells and basophils. This Fc receptor has a very high affinity, and when bound IgE is cross-linked by specific allergens, mediators including histamine, leukotrienes, and cytokines are released

Treatment for Type I

Immunotherapy with regular injections of allergen 1-10 ng to 10µg Increase in serum IgG (block IgE bindings) The use of adjuvants attached to the allergen shift the immune response towards Th1 Humanized monoclonal antibodies against the binding site of FcERI on IgE (soluble not cell attached) Block activity of IL-4 and IL-5

Vitamin B deficiency

Impaired thymic and lymphoid cellularity, decreased proliferative response, decrease antibody production

Eradication of smallpox

In 1980 Factors made this possible: -Effective, life-long immunity -No carrier state -No non-human reservoir

After repopulation of CD4+ T cells:

In IRIS-TB increase of serum IFN- gama others increase IL-2, IL-12, IL-6, TNF-alpha, and CXCL10

H2 receptors:

Increase gastric acid secretion Also involved in allergic rxns Increase in heart rate and contractility -rare cause of arrhythmia

Minor criteria for IRIS

Increase in # of CD4+ T cells after treatment with ART. Increase in IR to a specific pathogen. Resolves spontaneously without a specific antimicrobial treatment

CD4+ T cells are lost by direct cytopathic effects:

Increase plasma membrane permeability and influx of calcium, which induces apoptosis, or osmotic lysis. Interference with protein synthesis and expression. Unintegrated viral DNA in the cytoplasm or excess in nonfnxal viral RNA in the cytoplasm. HIV-specific CTL can kill infected CD4+ T cells Antibodies against HIV envelope proteins can induce ADCC

Nutritional thymectomy

Increased apoptosis of immature CD4+ CD8+ thymocytes and a decrease in proliferation contribute to thymine involution. Atrophy in thymus-dependent periarteriolar are of spleen and paracortical section of the lymph nodes.

Deficiencies in glutamine leads to what?

Increased apoptosis of immature T lymphocytes and decreased proliferation.

Chronic progressive phase

Increased susceptibility to other infections Increased transcription of HIV genes Depletion of CD4 + T cells

mediators released from mast cells and basophils cause...

Increased vascular permeability, vasodilation, and bronchial and visceral smooth muscle contraction: immediate hypersensitivity.

Vaccine Efficacy

Induce the right sort of immunity: -antibody for toxins and entracellular organisms -cell-mediated immunity for intracellular organisms -be stable on storage (living vaccines) -have sufficient immunogenicity Living vaccines: great advantage of providing antigenic challenges

Zidovudine (ZDV)

Inhibit host cell DNA polymerase to varying degrees (account for some toxic effects: anemia)

Leflunomide

Inhibits dihydroorotate dehydrogenase, needed for pyrimidine synthesis. Leads to inhibition in leukocytes and T-cell proliferation Inhibits B cell antibody production. Completely absorbed. Half-life of 19 days. Cholestyramine enhances clearance by 50%. Not used commonly. As effective as Methotrexate (is preference) for RA. Inhibition of bony damage. Can be combined. Diarrhea. Elevation of liver enzymes. Mild alopecia, weight gain, increase BP. Contraindicated in pregnancy.

Serotonin 5-HT

Neurotransmitter for the CNS Platelets: regulates platelet fnx.

Control of HIV

No cure. Effective antiretroviral (ARV) drugs can control the virus and help prevent transmission.

Adjuvant types

Particulate antigens such as virus-like particles (polymers of viral capsid proteins containing no viral DNA or RNA) are highly immunogenic and have the useful property that they may also induce cross-priming (i.e. enter the MHC class 1 processing pathway though not synthesized within the APC

Therapeutic approaches for congenital immunodeficiencies

Passive immunization with pooled gamma globulin Bone marrow transplantation Gene replacement

Asthma

Pathological features: Contraction of airway smooth muscle. Mucosal thickening from edema and cellular infiltration Viscid plugs of mucus Asthma therapies are divided into two categories: "short-term relievers" and "long-term controllers" Agents that increase airway caliber by relaxing airway smooth muscle B-agonists, theophylline, antimuscarinic agents.

Toxoplasmosis Prophylaxis

Patients are not previously known to be seronegative for toxoplasma IgG Trimethoprim-sulfamethoxazole 160mg/800mg orally daily (sulfamethoxazole causes depletion of neutrophils) or Dapsone 50mg orally daily + pyrimethamine 50mg orally weekly + leucovorin 25mg orally weekly (also accepted for PCP) Continue until CD4 count exceeds 200 cells/microliter for 3 months Acquired in an immunocompromised patient. Reactivation in an immunocompromised patient Leading cause of focal CNS disease in AIDS

Resistance to NRTIs is more likely to happen to who?

Patients doing therapy for 6 months or longer receiving single-drug therapy.

Unmasked IRIS

Patients that start ART without identification of an opportunistic infection with clinical deterioration associated to an opportunistic infection

Outpatients

Patients/clients who do not require hospitalization but are under a physician's care

Bradykinin

Produced by a group of enzymes called kininogenases. half-life of 10-20 seconds. Most inactivated in the pulmonary beds by kinase II. Regulate urine volume smooth muscle constriction of the tracheobronchial muscle. Powerful pain stimulators. Powerful stimuli for cathecol discharge. 2 receptors: B1: increase during inflammation B2: mediates actions in the absence of inflammation. No clinical uses. ACE inhibitors Cough common complain Adds vasodilator effect to the ACE Inhibitors.

Summary

Preventive medicine

Pharmacologic effects H1 antagonists

Preventive use. occupies the H1 receptor w/o initiating a response (competitive inhibition) No effect on gastric secretions antagonize bronchoconstrictor activity as well as the triple response. cough suppression via presumed CNS effect. Also acts on the vomiting center. relief motion sickness via CNS effect Nighttime sleep aids bc their sedative effects.

After initial transmission HIV will infect what?

Primary CD 4+ cells (T lymphocytes, monocytes, macrophages)

3. Obtain Information for Each Option

Probability of each possible outcome must be obtained: published studies OR Estimate based on clinical experience Utility (value) of each outcome must be obtained: Desirable outcome (years of disease-free survival) OR Undesirable outcome (death, illness, or high const)

Cyclosporine

Regulates gene transcription. Inhibits IL-1 and IL-2 receptor. Inhibits macrophage -T cell interaction and T cell responsiveness. Erratic absorption, new preparations give up to 20-30% bioavailability. Grapefruit decreases bioavailability up to 62%. Metabolized by CYP3A (many drug-drug interactions). Grapefriuts to be avoided: Potent inhibitor of Cytocrome p450 system which metabolizes 80% of the drugs that we ingest. Retards the appearance of new bony erosions. Indicated in SLE, Wegener's granulomatosis, polymyositis, juvenile chronic arthritis. Side effects: hypotension, hyperkalemia, hepatotoxicity, hirsutism, nephrotoxicity. Interactions: diltiazem, K-sparing diuretics, other CYP3A inhibitors.

NRTIs are eliminated by what?

Renal excretion, and renal impairment will prolong their plasma elimination half-life and may necessitate a reduction in dosage.

Cellular rxn in DTH

Requirements for granuloma formation: -T cells with alpha beta TCRs -lots of IFN g -Lymphotoxin a (inflammation) -TNF Induce production of all the fibrotic tissue

Organ system effects

Respiratory: transient increase in respiratory rate. Bronchoconstriction. Coronary chemoreflex: hypotension and bradycardia (vagal and sympatholytic effect) Produces venous constriction and enhances platelet aggregation. smooth muscle: inhibit and enhances gastric and large intestine motility, stimulates small bowel motility. Nerves: generally stimulatory, produces pain at site of injection, stimulates autonomic effect.

Rash in NNRTIs

Should be monitored bc it can progress to Stevens-Johnson syndrome

Mycophenolate Mofetil

The immunosuppressive effects of this drug are mediated by inhibiting T and B lymphocyte proliferation through inhibition of purine synthesis. Less toxic: It is an antimetabolite like azathioprine and is reported to have greater selectivity for T and B lymphocytes than for neutrophilis and platelets It also affects expression of adhesion molecules on lymphocytes, thereby inhibiting their binding to vascular endothelial cells, which is necessary for migration from the circulation to tissues.

Name one genetic factor that determines whether an individual can make an immune response to a specific allergen

The individual's MHC haplotypes determine which antigens and antigen fragments are presented to T cells.

HIV (human immunodeficiency virus) PATHO

The infectious agent that causes AIDS. HIV is a retrovirus. Targets immune system and weakens people's defense system against infections and some types of cancer. Gradually becoming immunodeficient. Immune fnx is measured by CD4+ T cell count in blood.

Intro

The principle consequence is that they are susceptible to infections

GVHD

The principle limitation in bone marrow transplantation --2 types of responses acute and chronic-- Caused by rxn of grafted mature T cells in the marrow inoculum with antigens in the recipient -the recipient is immunocompromised and therefore unable to reject the allogenic cells in the graft. -Rxn directed against minor histocompatibility antigen bc bone marrow transplantation is not performed when the donor and the recipient have differences in HLA molecules.

Corticosteroids

They inhibit T-cell proliferation and the expression of genes encoding various cytokines. They are used to prevent organ transplant rejection and to prevent graft - versus- host disease in patients who have undergone bone marrow transplantation. Steroids are frequently used to treat various autoimmune disorders by both, the immunosuppressant effects and the anti-inflammatory actions that they exhibit.

cromolyn and nedocromil MOA

stabilize mast cells-> no hist or leukotriene release only preventative. Can be used in allergic conjunctivitis and asthma attack Beta 2 agonist. These are prophylactic; prevention. As aerosols, they effectively inhibit both antigen and exercise induced asthma. Chronic use (four times daily) slightly reduces the overall level of bronchial reactivity. No effect on airway smooth muscle tone. Ineffective in reversing asthmatic bronchospasm. Inhibition of cough (alteration in the fnx of delayed chloride channels in the cell membrane). Mast cells (for inhibition of the early response to antigen challenge) Eosinophils (inhibition of the inflammatory response to inhalation of allergens) Cromolyn inhibits mast cell degranulation in lung but not in skin

Histamine release

stimuli that increase cyclic guanosine monophosphate cGAMP increase histamine release, whereas those that increase cyclin adenosine monophosphate cAMP oppose this action. Formation of IP3 and DAG will cause the release of intracellular calcium and the release of histamine.

Granulomatous Hypersensitivity (2)

• Granuloma formation is an attempt to contain the infection, causes significant tissue injury and functional impairment • Occur with chronic infections associated with a Th1 type of response such as tuberculosis, leprosy, leishmaniasis; with Th2 type such as schistosomiasis • In the absence of infection, sensitivity reactions to zirconium and beryllium, or in sarcoidosis and Crohn's disease where the antigens are unknown • Granuloma structure: core of epithelioid cells and macrophages, sometimes with giant cells. In some diseases, such as tuberculosis, this central area may have a zone of necrosis, with complete destruction of all cellular architecture.