Immun. Block 8_ALL

Individuals with antibody deficiency are more susceptible to infections by all of the following except _____. A. Streptococcus pneumoniae B. Haemophilus influenzae C. Streptococcus pyogenes D. Mycobacterium tuberculosis E. Staphylococcus aureus

D. Mycobacterium tuberculosis - the only intracellular pathogen Antibodies cannot don't control intracellular pathogen

List two laboratory tests for SLE diagnosis

(Skin) Biopsy - proven for presence of ANA: - Immunofluorescence (Hep-2 cells, minimum titer 1:80) - Lupus band test

Defects in Complement Cascade Pathway

Defect in pathway that results in deficiency of C3 can lead to problems with opsonization => Pyogenic infections, Neisseria infections; immune complex disease MAC is formed by C5, 6, 7, 8, 9 - Complement deficiency is highly associated with Neisseria infections (encapsulated) To deal with encapsulated bacteria need MAC and Opsonins

CVID (Common Variable Immunodeficiency) is characterized by ....

Defective B-cell maturation Loss of plasma cells and antibodies Many underlying genetic causes - Most cases = unknown cause - 10+ genes mutations associated with CVID - Often sporadic - no family history Normal B-cell count Absence of IgG and sometimes IgA and IgM (variable)

Leukocyte Adhesion Deficiency is caused by ...

Defective neutrophil/lymphocyte migration Most common type: Type 1 - Autosomal recessive defect in CD18 CD18 = lymphocyte function associated antigen-1 (LFA1) - needed to form beta subunit of several integrins (adhesion molecules) - WBCs (especially PMNs) cannot roll, migrate (integrins needed for this)

Absent thymus shadow on XR is seen in ....

DiGeorge: low Ca++, facial, heart abnormalities SCID: Ca++ normal, no facial/heart abnormalities

How are selective IgA Deficiencies diagnosed?

Diagnosis: - Serum IgA < 7 mg/dl - normal IgG, IgM Special features: False+ Beta-HCG test (30% pt) - Heterophile antibodies produced in deficiency and lead to false+ Beta HCG test

IS HIV diploid or haploid?

Diploid - carries 2 copies of +standard RNA

Immunodeficiency diseases are diseases that display defect in ... immunity and loss of ... cells

Disorders caused by defective immunity Immune system is not able to fight the infections Loss of T-cells, B-cells, granulocytes, complement - defects in innate or adaptive immunity

List high and low-risk drugs contributing to DILE

Drug Induced Lupus Erythematosus (DILE) Mechanism of DILE: - prolonged use of medications that require N'acetylation speeds acetylation rate (Nacetyltransferase is readily available) Leads to accumulation of drug metabolites reacting with immune cells and release of oxidants stimulating phagocytosis, antigen presentation and production of anti-nuclear antibodies As the drug therapy started, N-Acetyl Transferase is made to metabolize the drug. When pt takes drug for long periods (weeks, months etc), the body adjusts to enzyme metabolism and the drug is processed at faster rate. If dose isn't adjusted, metabolites accumulate and react with immune cells. Cells release oxidants, which stimulate phagocytes, antigen presented and can lead to immune system reacting to own antigens

Envelope of HIV virus contains ... protein Cap of this protein contains ....

Env protein Cap of env protein contains glycoproteins - gp120 -> binds CD4 T-cells -> binds chemokine receptor CCR5 or CXCR4 - gp41 -> fusion with host membrane to allow viral entry Both formed from a single protein gp160 and cleaved

Is HIV enveloped or non-enveloped?

Enveloped - phospholipid from membrane of human cell

What environmental, genetic and epigenetic factors predispose to Scleroderma?

Environmental factors: - silica - solvents - drugs - viruses Genetic predisposition: - HLA and non-HLA genes HLA phenotype association: - HLA-DRB1 - HLA-DQB1 - HLA-DPB1 - HLA-DOA1 non-HLA genes associated with genes for B and T cell activation and innate immunity Epigenetic dysregulation: - DNA methylation - Histone modification - non-coding RNAs - dysregulation of miRNA levels

Sjogrens Syndrome Diagnosis is made by ... test

***no single test is sufficiently sensitive or specific to diagnose Sjogren's syndrome Schirmer's Test: - filter paper strip placed at junction of eyelid margins - in 5 minutes, 15 mm of paper should be moistened if tear production is normal - people > 40 y.o. may moisten between 10 mm and 15 mm - Pts with Sjögren syndrome have less moistening Rose Bengal conjunctival stain test: - stains epithelial surfaces with diminished mucin protection or with exposed epithelial cell membranes Rheumatoid Factor (RF) test - positive in 52% patients with SS - antinuclear antibodies present = +ANA Anti-Sjogrens syndrome related antigen A and B (SSA/Ro - SSB/La) in 50-70% pts with SS - ABSENCE OF Antibodies DOES NOT eliminate diagnoses of pSS or sSS Sialometry - saliva from SS patients has elevated Na+, Cl-, LACTOFERRIN and IgA CBC - usually normal

Newborn screening for SCID

**T-cells not used since Maternal T-cells may falsely indicate normal counts TREGs (T-cell Receptor Excision Circles) - circular DNA formed in normal T-cells in thymus - low TREGs => SCID - Mandated in many states

What drugs have high and moderate risk for developing Drug-induced LE?

**not all of these drugs require N-acetylation Other processes can induce Lupus

What molecule of nucleosome is first tarted in production of autoantibodies?

*H1 is the first target to produce antibody to it ex. B and T cells specific to H1. In BCR, nucleosome is bound via histone attachment since histone antigen recognition site is specific to H1. Right: Complex is taken into endosome, processed into fragments and H1 is presented via MHC2 to T helper cell. Antibodies to H1 are produced. Left: Same nucleosome is endocytosed and processed in endosome. But for some reason H1 that's presented via MHC2 contains small DNA attachment. DNA isn't protein so normally can't be presented on MHC2. But in this case it acts as hapten when together with H1, and gets presented. As result antibodies to dsDNA are produced -> epitope is spread from H1 to dsDNA

Immunodominant and Subdominant epitope in epitope spreading

Epitope spreading in autoimmune disease is diversification of epitope specificity from initial epitope-specific immune response to self or foreign protein, to subdominant and/or cryptic epitopes on that protein (intramolecular spreading) or other proteins (intermolecular spreading) Picture: In autoimmune diseases initial trigger can be virus. There's molecular mimicry - antibody created to viral antigen can also recognize target on human cell, leading to attachment to human antigen and tissue damage. In order to produce antibodies, there has to be first interaction of antigen and BCR, and antigen and TCR, with subsequent formation of immunological synapse between B and T cell. Original activating pair of B and T cell that recognized molecularly similar epitope = initiating epitope on human cell Infection can be gone, but memory B and T cells are available for subsequent stimulation (these are the cells that were originally developed to virus but later also recognized human cell epitope) Memory B cell will start producing antibodies to human epitope + will spread recognition of its BCR to neighboring epitopes (subdominant epitopes) Immunodominance in B cell activation focuses on affinity of epitope binding to BCR (perfect fit) - if epitope strongly binds to BCR, it'll also bind strongly to resulting antibodies Immunodominant Epitope: antibodies produced after B cell activation will outcompete BCR for epitope; and B cell lineage won't be stimulated Subdomiannt epitope = if antibody binds weakly to BCR, subsequent antibodies will also bind weakly. That specific B cell lineage will be available to recognize subsequent epitopes in subdominant fashion. Different epitope that has better fit with BCR will become Dominant epitope ***may take years from recognition of Initiating epitope and latency stage (no symptoms, but more self-antigens are being recognizes) to the time symptoms appear

In Scleroderma (SSc) pathogenesis what leads to vasculopathy and tissue fibrosis?

Etiologic agent ↓ genetic predisposition ↓ endothelial cell and vascular alterations (endothelial activation, leukocyte attraction and adhesion, vascular occlusion, tissue hypoxia) ↓ chronic inflammation (macrophage, T lymphocyte, B cell activation + autoantibody, cytokine and chemokine production) ↓ Fibroblasts, Fibrocytes, Endothelial cells ↓ activated Myofibroblasts produce exaggerated amounts of ECM ↓ Vasculopathy and tissue fibrosis

What is the best test for Sjogrens Syndrome diagnosis?

BIOPSY of minor salivary gland shows LYMPHOCYTE INFILTRATION pic: Hematoxylin (a) and eosin (b) colored sections of minor salivary gland biopsy specimens showing lymphocytes infiltration

ANCA vasculitis - Granulomatosis with Polyangtis = Wegners granulomatosis

+ granulomas affects kidneys and lungs

AIDS-Indicator Illnesses

- Bacterial pneumonia, recurrent - Candidiasis of the esophagus, bronchi, trachea, or lungs - Cervical carcinoma, invasive, - Coccidioidomycosis, disseminated or extrapulmonary - Cryptococcosis, extrapulmonary - fungi - Cryptosporidiosis, chronic intestinal (>1 month) - protozoan - CMV disease (other than liver, spleen, or nodes) - Encephalopathy, HIV-related - HSV: chronic ulcers (>1 month), or bronchitis/pneumonitis/esophagitis - Histoplasmosis, disseminated or extrapulmonary - Isosporiasis, chronic intestinal (>1-month in duration) - Kaposi sarcoma - Lymphoma, Burkitt, immunoblastic, or primary central NS - Mycobacterium (TB, MAC, or others, disseminated or extrapulmonary - Pneumocystis jiroveci (formerly carinii) pneumonia (PCP)- fungi - Progressive multifocal leukoencephalopathy (PML) - Salmonella septicemia, recurrent (nontyphoid) - Toxoplasmosis of brain - Wasting syndrome caused by HIV

Which body fluids have highest HIV concentrations?

- Blood - semen - vaginal secretions - amniotic fluid - urine - breast milk - saliva => negligible Transmission is via exchange of body fluids: - typically via vaginal or anal intercourse, or oral-genital contact - 80% of transmission is via sex - MTCT (mother to child transmission)

Chediak-Higashi Syndrome is characterized by ....

Failure of lysosomes to fuse with phagosomes Mutation: lysosomal trafficking regulator (LYST) gene - causes microtubule dysfunction Recurrent bacterial infections - Especially Staph and strep Oculocutaneous albinism - Fair skin, blond hair, light blue eyes Children who survive -> sever neuro impairment - Peripheral neuropathy - Often wheelchair bound

ANCA-associated vasculitis includes 3 diseases characterized by presence of (+) ANCA:

- Granulomatosis with polyangiitis - Microscopic polyangiitis - Eosinophilic granulomatosis with polyangiitis, along with ANCA-associated glomerulonephritis 2 types of vasculitis-associated ANCA: - p-ANCA (perinuclear, directed against the neutrophil enzyme myeloperoxidase) - c-ANCA (cytoplasmic, directed against the neutrophil proteinase 3) Perinuclear and cytoplasmic refer to patterns of immunofluorescent staining - enzyme-linked immunosorbent assays are used to confirm antibody positivity

Patients with Chronic Granulomatous Disease get infected with ..

Five Catalase+ organisms 1. Staph aureus 2. Pseudomonas 3. Serratia 4. Nocardia 5. Aspergillus

Hep-2 cell test (iemmunoflourencese)

Fixed Hep-2 line cell is exposed to serum of pt with SLE and labeled using murine α-human IgG antibody. Hep-2 cells contain self-antigens; anti-IgG antibodies are added It shows IgG deposit in nucleus and nonspecific deposit in cytoplasm

90% of new HIV infections are ... (CXCR4/ CCR5)

CCR5

CCR5-tropic vs CXCR4-tropic viruses Which one depletes CD4 t cells?

CCR5- tropic viruses - replicate in monocytes/macrophages (M-tropic) - can also infect dendritic cells (trafficking to lymph nodes) - occur early: sexually transmitted to macrophages - mutations in CCR5 gene associated with ↓susceptibility to HIV infection (virus won't be able to enter cell) CCR5 virus involves into CXCR4 virus CXCR4-tropic viruses - replicate more efficiently in T-cell (T-tropic) - occur later, after infection developed

In the initial stages of HIV infection, the HIV load peaks at .... weeks CD4 set point is seen during .... and indicates .... What is viral set point?

CD4 = blue HIV load = red during Acute HIV Syndrome at about 6 weeks post infection, the viral load drops - pt shows s/s Viral set point = lower point -> longer takes to develop AIDS - viral load that's settled during acute phase Latent phase = 9 weeks - 9 years - CD8 fights infection predominantly - CD4 keeps declining - CD set point => the higher the CD4 count, the longer time it takes to develop AIDS Viral load rises again at 10-12 years => AIDS - CD8 can't cope with virus

What are the key differences between B cell Disorders (Bruton's, CVID, XLA)?

CVID at risk for autoimmune diseases, lymphomas

What are the molecular targets of autoantibody in Scleroderma (SSc) patients?

Centromere proteins A Centromere proteins B Topoisomerase-1 RNA polymerase III RNA Binding Region containing 3 Angiotensin type II receptor Endothelin-1 type A receptor

Hyper-IgM Syndrome is characterized by ... What are the lab finidngs?

Class switching disorder - Failure of B-cells (CD40) to bind with T-cell (CD40L) -> binding needed for class switching - 70% cases: defective CD40L gene (T-cell problem) B-cells make IgM only Labs: high IgM; other antibodies absent

Classic Case of Hyper IgE Syndrome (Job's Syndrome)

Classic Case: - Newborn baby - Deformed face/teeth - Diffuse rash - Skin abscesses that are "cold" - Recurrent infections without fever Labs: elevated IgE

HIV virus characteristics

Cone-shaped, conical capsid Capsid has multiple copies of p24 protein - p24 is non-variable proteins - even when virus replicates, p24 protein remains the same p24 antigen can be used for diagnosis as well as antibodies generated against p24 Although p24 are non-variable, they cannot be used to neutralize HIV since antibodies to p24 are not strong to neutralize virus but can be used to diagnose

Kawasaki Disease - Mucocutaneous lymph node syndrome - ADULT PRESENTATION

Coronary Aneurysm

Kawasaki Disease = mucocutaneous lymph node syndrome Pathogenesis

- acute-onset systemic vasculitis of medium-sized vessels - mostly in infants and children Environmental triggers: - infectious agent (unknown) Activation of Lymphocytes - 7-9 days after febrile stage -> neutrophils flood vascular internal elastic lamina - influx of CD8 T cells and IgA producing plasma cells - Secretion of cytokines TNF, IL-1, IL-4, IL-6 - inflammation & fragmentation of internal elastic lamina, vascular damage formation of vascular lesions = unique to KD - inflammation and necrosis of smooth muscle cells

How is SLE diagnosed?

- based on clinical findings + labs SLE diagnosis - pt should have detectable antinuclear antibody (ANA) titer of at least 1:80 on Hep2 cells or equivalent test at least once!! SLE considered if: (new guidelines) - pt has at least 1 clinical criterion, occurrence of at least 1 immunologic criterion and 10 or more points

General Vasculitis Diagnosis

- elevated ESR (erythrocyte sedimentation rate) - elevated CRP (C-reactive protein) - elevated WBC - elevated ANCA (anti- neutrophil cytoplasmic antibody) - Anemia - Eosinophilia - Hematuria Depending on the case, vessel biopsy may indicate eosinophilic granulomatosis

SSc Epidemiology

- first onset of disease between ages of 20-50 - women > men by 4-9x Prevalence: in USA 240 cases per million people Annual incidence in US: 19 per million people

IgA Vasculitis (aka Henoch-Schonlein Purpura) Pathophysiology

- frequently self-limiting - 5% pts develop progressive renal failure or CNS disease Abnormalities in IgA1 glycosylation -> formation of antibodies to these molecules - HLA-A, HLA-B, HLA-C and DR phenotypes IgA aggregates or IgA complexes with complement deposited in target organs -> increase inflammatory mediators

HIV window period is ... years

- negative HIV test; no antibodies yet - high viral load, high transmission risk immune system responding to viral presence in system but virus hidden from lymphatic system

Scleroderma SSc Pathogenesis What are the main characteristics of Scleroderma?

- no known etiology Main characteristics of Scleroderma: - early vascular injury - immune activation - consequently fibrosis of skin and internal organs Tissue fibrosis often leads to organ dysfunction and is regarded as major cause of disease-associated morbidity and mortality

List immunologic criteria for diagnosis of SLE

- occurrence of criterion on at least 1 occasion is sufficient - criteria don't have to occur simultaneously - within each domain, only highest-weighted criterion is counted toward total score - do not count criterion if there is more likely explanation for it than SLE *these antibodies in addition to antinuclear antibodies

Buerger's Disease - ANCA Vasculitis

- pain in affected areas - increased sensitivity to cold - peripheral pulses are diminished or absent - color changes from cyanotic blue to reddish blue - no hair growth in affected areas - ulcerations and gangrene are most common outcomes of the disease * smokers

EGPA - Eosinophilic granulomatosis with polyangitis (= Churg-Strauss syndrome) 3 phases and clinical manifestations

- rare; in pt with airway allergic hypersensitivity Associated with hx of asthma, nasal polyps, rhinitis, sinusitis, and/or atopy. Prodromal phase (months to years): = Allergic manifestation = Asthma - arthralgia, myalgia, malaise, fever, weight loss Eosinophilic phase - increased peripheral and tissue eosinophilia => causes chronic eosinophilic pneumonia (eosinophilic pulmonary infiltrates) or gastroenteritidis Third Phase = Systemic vasculitis - includes mononeuritis multiplex or peripheral sensorimotor neuropathy, kidney, and skin involvement - vasculitis phase is often associated with improvement of asthma

Leukocyte Adhesion Deficiency is characterized by ...

- recurrent bacterial and fungal infections (can be fatal) - impaired wound healing Delayed separation of the umbilical cord - after cord cutting, inflammation occurs Cord stump normally falls off 2-3 days; delayed in LAD (sometimes 30+days) Classic presenting infection: - omphalitis = stump infection Labs: ↑WBCs (neutrophilia) = especially during infections

T-cell immunodeficiencies are diagnosed by

- ↓ peripheral blood T-cells - Low proliferative responses to T-cell activators

HIV tropism

-HIV infects and lyses CD4+ T lymphocytes during a productive infection -infects other cells but doesn't lyse them

T-cell immunodeficiencies include

1) DiGeorge Syndrome 2) Hyper IgE Syndrome 3) Severe Combined Immunodeficiency (SCID) 4) Ataxia-Telangiectasia Syndrome (AT) 5) Hyper IgM Syndrome 6) Wiskott-Aldrich Syndrome (WAS)

B-cell Deficiencies Include

1) X-linked Agammaglobulinemia (XLA) 2) Selective IgA Deficiency (SIgAd) 3) Common Variable Immunodeficiency (CVID)

Steps in HIV life cycle

1. Binding -> gp120 binds to CD4 and chemokine receptors CCR5 and CXCR4 2. Fusion -> gp41 - once inside the cell, viral envelope dissolves, RNA is released 3. Reverse transcription: converts RNA into DNA 4. Integration -> DNA integrates into host cell DNA 5. Transcription -> DNA is transcribed into mRNA 6. Assembly -> RNA is released into cytoplasm; capsid forms around them 7. Budding -> release of mature virion

DiGeorge Syndrome (Thymic Aplasia) classic Triad

1. Loss of thymus - Loss of T-cells, recurrent infections 2. Loss of parathyroid glands Hypocalcemia, tetany 3. Congenital heart defects (conotruncal)

Granulamatosis with polyangitis (GPA) = Wegner's

1. Most Common ANCA vasculitis 2. Nordic Countries 3. age 45-60s 1. affects upper and lower airways, kidneys, eyes, and ears. 2. > 95% of patients are ANCA+ >90% against proteinase 3 (anti-PR3 antibodies; c-ANCA) Histopathology: - tissues have pauci-immune necrotizing granulomatous vasculitis - pauci-immune necrotizing glomerulonephritis with granulomas on kidney biopsy

List 3 routes of HIV transmission. What is the leading mode of HIV transmission?

1. Sexual Contact => LEADING MODE - Male-to-male - Male-to-female or vice versa - Female-to-female 2. Blood Exposure: - Injecting drug use/needle sharing - Occupational exposure - Transfusion of blood products? 3. Perinatal: - Transmission from mom to baby - Breast feeding

What are the steps in SLE pathophysiology? What is the hallmark of SLE?

1. Trigger (poorly understood, may be viral infection) 2. Loss of T cell tolerance 3. Clonal proliferation of autoreactive cells reacting to nucleoprotein epitopes presented on MHC II (HLADR2/ HLADR3) 4. Epitope spreading = SLA hallmark 5. Aberrant TLR-9/BCR activity to produce anti nucleic acid antibodies

Microscopic Polyangitis characteristics ?

1. age 50-6- 2. Men > women 3. positive ANCA in 50-75% patients

Explain the role of TLR 9 in development of SLE

2 examples of how it can happen: T cell independent and T cell dependent mechanism TLR = endosomal receptors that recognize patterns like ex. dsDNA - normally TLR recognize viral or bacterial dsDNA In autoimmune disease, TLR-9 can recognize own dsDNA; INF-alpha and INF-beta are produced T-cell independent: INF-alpha will act on B cell to promote isotype switching; cell will start producing antibodies (this B cell was already previously primed) T cell dependent: INF-alpha induces B cell to interact with adaptor protein MYD88. MYD88 interacts with many TLRs and relays signals from outside to inside the cell. MYD88 signaling in DC is essential in priming cell-specific T cells in vivo. Naive CD4 T cells can be primed to interact with B cells, and send signals to B cells to start producing antibodies against self-antigens

32-year-old woman is evaluvated for concerns about STDs. She had multiple sexual partners and 2 are HIV+. She is otherwise healthy and is not taking any medication. Her vital signs are normal and physical examination is unremarkable. Laboratory evaluation demonstrates negative HIV RNA testing. Further evaluation shows that she carries mutation in CCR5 surface marker. This mutation most likely disrupts the function of which component of the HIV virus? 1. P17 2. P24 3. Gp120 4. Gp41 5. P9

3. Gp120

X-Linked Agammaglobulinemia (XLA) occurs in ... and is caused by .... Symptoms begin around ... (age)

= Bruton's agammaglobulinemia - Bruton noted absence of Ab in boy with recurrent PNA; first to use IgG IM injection for XLA disease Bruton's occurs in boys with B-cells totally knocked out with Btk mutation Caused by: - failure of B-cells precursors to become B cells (no mature B cells) - light chains not produced d/t defect in Bruton tyrosine kinase (BTK) gene Symptoms begin around 6 months of age (loss of maternal Ab)

Severe Combined Immunodeficiencies (SCID) is characterized by deficiencies of ...

= Congenital immunodeficiencies that affect both humoral and cell-mediated immunity Characterized by deficiencies of: - both B and T cells or - only T-cells => defect in humoral immunity is due to absence of T cells Children have infections during 1st year of life - Loss of thymic shadow - Loss of germinal centers in lymph nodes

What is scleroderma? What does the disease affect?

= Hard Skin = Systemic Sclerosis (SSc) = spectrum disorders Autoimmune disease affecting: - Skin - Internal organs - Blood vessels - Muscles

Congenital B-Cell Deficiencies are characterized by ...

= abnormalities in B-lymphocyte development & function Result in deficient antibody production Characterized by recurrent infections with pyogenic bacteria (Haemophilus and Streptococcus = encapsulated bacteria) Susceptibility to some viral infections, especially enteroviruses (Rotavirus) & Respiratory Syncytial virus (RSV), and certain parasites (Giardia) - antibodies esp. IgA are needed to deal with them Often appear in infants after 3-6 months of age when maternally derived IgG drop & host Ab level does not increase - 3m-1y.o = transit period = low level of maternal IgG

Selective IgA Deficiencies

= common in US (around 1 in 600) Defective IgA producing B-cells (exact mechanism not unknown) Most patients = asymptomatic Symptomatic patients : - recurrent sinus, pulmonary infections: - otitis media, sinusitis, PNA - recurrent diarrheal illness from Giardiasis Blood transfusions -> risk of anaphylaxis - IgA is in blood products; pt IgA deficient will start producing antibodies against IgA SLE and RA common (20-30%)

DiGeorge Syndrome is caused by .... The patients are at most risk for ....

= congenital developmental disorder (Thymic aplasia) Caused by: - deletion in chromosome 22q11.2 (TBX1 gene) Defective development of 3rd and 4th pharyngeal pouches (thymus and parathyroid glands not developing properly) - no thymic epithelium

Behcet's Disease

= multisystem inflammatory disease - recurrent canker sores, genital and uveitis ulcers or retinal vasculitis Most common symptoms: - mouth sores - genital sores - eye inflammation - rarely blood clots, aneurisms, blindness Differential diagnosis: - Reactive arthritis - Stevens-Johnson syndrome - Sweet syndrome - Viral infections Environmental triggers: - molecular mimicry after infections by H.pylori, S. sanguis, Mycoplasma, HSV & EBV - association with cytokines - presence of particular HLA-B51 phenotype Primarily Th1 response plays role in pathogenesis

5 y.o. boy suffer from condition characterized by recurrent fungal and viral infections, thymic hypoplasia, tetany and abnormal facies. Serum levels of Ig are mildly depressed and lymph node biopsy shows lymphocyte depletion of T - dependent areas. Which of the following is underlying pathogenic mechanism? A. Development defect of third/fourth pharyngeal pouches B. In utero infection by human immunodeficiency virus C. Mutation on an X linked gene coding for cytokine receptor subunit D. Mutation on an X lined gene coding for tyrosine kinase

A. Development defect of third/fourth pharyngeal pouches

Why extracellular pyogenic bacterial infections, particularly otitis, sinusitis, and pneumonia begin as early as age 3 to 6 months? A. Loss of maternal antibodies B. Loss of child's own antibodies C. Presence of maternal antibodies D. Presence of child's own antibodies

A. Loss of maternal antibodies

Which immune marker is present during window period of HIV infection? A. p24 antigen B. Antibodies to gp120 C. Antibodies to gp41 D. p17 antigens

A. p24 antigen - during window time period, antibody test like ELISA cannot be used because during this time antibodies are not produced by the body - p24 antigen is used to diagnose; it doesn't have any antigenic variation

Microscopic Polyangitis causes what Glomerular disease?

ANCA Glomerulonephritis nongranulomatous necrotizing pauci-immune vasculitis of small vessels or pauci-immune necrotizing crescentic glomerulonephritis in the kidney without granuloma. Absence of granulomas distinguishes MPA from GPA.

What type of diseases present with Autoimmune vasculitis?

ANCA Vasculitis => IgG - Cutaneous small vessel vasculitis - Microscopic polyangiitis - Granulomatosis with polyangiitis = GPA or Wegner Disease - Buerger's disease IgA Vasculitis => Henoch-Schonlein disease EGPA - eosinophilic granulomatosis with polyangiitis => Churg-Strauss syndrome - Allergy Behcet's Disease - CMI (Cell-mediated immunity) Kawasaki Disease - CMI (Cell-mediated immunity)

What labs are used to monitor HIV treatment? What is the standard test for babies?

Acute HIV: - HIV RNA testing (viral load) will be high Perinatal HIV: - Maternal HIV antibodies persist for months (about 6 months) so cannot test for antibodies - standard test for babies is HIV PCR testing (tests for genetic material of virus)

What are the HIV stages?

Acute Infection: - 1st month of infection - s/s: flu-like symptoms - level of HIV in blood is very high -> high risk of HIV transmission Chronic HIV Infection: - HIV multiplies in the body at very low levels - s/s: generally asymptomatic, can still spread - without Tx chronic HIV infection usually advances to AIDS in 10 years or longer AIDS - HIV+ and CD4<200 cells/uL or certain opportunistic infections, cancers - without Tx survive for about 3 years

Forms and presentation of cutaneous LE

Acute cutaneous lupus => butterfly rash Subacute cutaneous lupus: - red, raised, scaly rash on sun-exposed areas - tends to have circular skin lesions on sun-exposed skin Chronic cutaneous lupus = discoid lupus - tarts out red to purple scaly rash on scalp, face, ears and other sun-exposed areas; may heal with discolored scarring - Loss of hair on scalp - can have pain or rash Pt with suspected cutaneous LE need to be monitored for disease inside of the body, which can affect joints, kidneys, lungs, and other organs

Clinical Manifestations in Kawasaki Disease (Mucocutaneous lymph node syndrome) in acute and subacute phase

Acute: - fever - rash - myocarditis (cardio) - erythema and swelling of palms and soles - cervical lymphadenopathy - lips and conjuctiva infection - erythema of oral mucosa - aseptic meningitis - Myocarditis Subacute: *starts when fever, rash, lymphadenopathy resolve - arthritis - coronary aneurysms - red palms and soles, desquamation (skin peeling) - cervical lymphadenoapthy - thrombocytosis (excessive platelets) - lips and conductive Convalescent: *starts when all clinical s/s disappeared - nail changes - thrombocytosis Kawasaki disease presents with set of mouth symptoms. Most characteristic changes are: - red tongue - swollen lips + vertical cracking and bleeding ***In Adults => Coronary aneurysm

Anti-SSA/Ro & anti-SSB/La in Sjogrens target ....

Anti-SSA/Ro antibodies - target Ro52 and Ro60 nuclear proteins - typically IgA and IgG isotypes - can be produced in cytoplasm of epidermal skin cells after exposure to UVB Anti-SSB/La antibodies - target SSB antigen (Lupus La protein) - typically IgG - SSB/La autoantibody target neutrophils; cause neutropenia and defects of PMN (polymorphonuclear leukocytes) in vivo in SLE pts PMN often refers specifically to neutrophil granulocytes since most abundant granulocyte; other types - eosinophils, basophils, and mast cells

General Vasculitis Treatment

Anti-inflammatory -> Prednisone Immunosuppressive -> Cyclophosphamide Antimicrobial -> if infection is detected Tocilizumab (Atlizumab) - monoclonal antibody to IL-6R Rituximab (Rituxan) - monoclonal Antiboy to CD20

Antibodies against what protein help to diagnose HIV?

Antibodies against P24 helps in diagnosis

Ataxia telangiectasia is caused by ...

Autosomal recessive genetic disorder Defective ATM gene on chromosome 11 (Ataxia Telangiectasia mutated gene = repairs double stranded DNA breaks) *Nonhomologus end joining (NHEJ) - Result: Failure to repair DNA mutations - mutations accumulate Hypersensitivity of DNA to ionizing radiation

B-cell vs T-cell vs Combined immunodeficiency What types of infection each immunodeficiency is greatly predisposed to?

B-cell Immunodeficiency: - range from absence of B-cells, plasma cells, immunoglobulins to absence of only certain classes of Antibodies - subject to bacterial infections but do well against viral since T-cell branch is ok (cellular immunity) T-cell Immunodeficiency: - Can affect cell-mediated immunity - prone to infections w/ Intracellular pathogens or viruses Combined Immunodeficiency: - Effects both B and T-cells - prove to all types of infections: intra- and extracellular

What 3 main genes encode major parts of virus?

Gag: nucleocapsid - long polypeptide that can be cleaved into different parts, including p24 (part of capsid; doesn't contribute to antigenic variation) Pol: polymerase - can be divided into Reverse transcriptase, Protease and Integrase Env: envelope proteins - corresponds to gp160, which can be cleaved into gp120 and gp41

Primary Sjogren's Syndrome (pSS) predisposing factors

Genetic: High expression of HLA-DR2/3 and DQ leads to: - influx of Th1 cells to exocrine glands and secretion of Th1 cytokines (IL1β, IL6, IFγ) - chronic inflammatory process Hormonal: - estrogen affects T cell signaling inducing cell activation and inflammatory response Estrogen deficiency stimulates presentation of autoantigens Environmental: - viral infections associated pSS - EBV/ HCV/ HTLV-1 activate TLRs 3, 7 and 9 - activation of innate immunity and interferon production

EGPA - Eosinophilic granulomatosis with polyangitis (= Churg-Strauss) presents as ....

Granuloma with central core of eosinophilic debris - rarest ANCA-associated vasculitis in addition to neutrophil activation, eosinophil infiltration, activation, and degranulation participate in pathogenesis

In order to enter the cell HIV has to bind ....

HIV has to bind with core receptors CCR5 and CXCR4 + CD4 to enter cells

What differentiates HIV from AIDS?

HIV is not AIDS - HIV = retrovirus that targets TH-cells (CD-4 cells) and macrophages (CCR5 tropic HIV-1) - body becomes vulnerable to infections and cancers AIDS - HIV positive + CD-4 count < 200/uL (normal 600-1200) OR AIDS-indicator illness - unexpected infection in normally immunologically competent individual - often weird fungal respiratory, brain, or systemic - it takes 8-12 years to develop AIDs AIDS is characterized by progressive loss of the CD4+ helper t cells (<200) leading to severe immunosuppression and constitutional disease, neurological complications, opportunistic infections and neoplasms that rarely occur in persons with intact immune function.

Who is at risk for HIV?

HIV+ mothers shouldn't breastfeed

IgA Vasculitis (aka Henoch-Schonlein Purpura) Symptoms

Henoch-Schonlein purpura (IgA associated vasculitis) = disease of skin, mucosa and organs!! 1st 3 Triad : - Palpable Purpura - Arthritis and swelling - GI symptoms and bleeding + - Glomerulonephritis s/s: - Rash in crops, with new crops appearing in waves younger children: buttocks & upper thighs older children + adults: feet, ankles & lower legs - Hemorrhagic macules, papules, & patches in pediatric patient - typical rash distribution in IgA vasculitis

What type of immunity deals with intracellular and extracellular pathogens?

Humoral immunity: - production of antibodies -> play role in neutralizing pathogen, activate complement proteins, opsonization - imp for Extracellular pathogens Cellular immunity: - CD4 and CD8 - Imp. for Intracellular pathogens

Ataxia telangiectasia pt characteristics and lab abnormalities

Hypersensitivity of DNA to ionizing radiation Many of systems involved with varying findings - Cerebral atrophy (CNS)-> ataxia in 1st year of life - Telangiectasia -> dilated capillary vessels on skin - Repeated sinus/respiratory infections -> ↓IgA and IgG - High risk of cancer (lymphomas) Commonly identified lab abnormalities: - Most consistent = high AFP - ↓IgA level

Role of Cytokines in Scleroderma SSc

IL-4 = promote fibrosis - enhance production of collagen - directly induce fibroblasts to promote fibrosis - induce TGF-β production of fibroblasts and macrophages TGF-β = potent inducer of fibrosis IL-6 = proinflammatory cytokine - mediates endothelial activation and apoptosis IL-17 and IL-13 are overexpressed and contribute to disease severity

DiGeorge Syndrome (Thymic Aplasia) symptoms (immune and physical)

Immune symptoms: - Recurrent infections - Viral, fungal, protozoal, intracellular bacteria s/s: Cleft lip: opening of the lip Shorten philtrum: area between nose and lip Hypertelorism: large distances between eyes

What is the inclusion criteria for diagnosis of Sjogrens syndrome (SS)?

Inclusion criteria: - Dry Eyes > 3 months - Dry Mouth > 3 months Possible basic Evaluation: - abnormal unstimulated salivary flow rate - abnormal Shirmer test - Autoantibody detection - histology/ Biopsy showing lymphocyte sialadenitis Sialadenitis = infection of salivary glands

SCID classic case

Infant with recurrent infections - multiple systems: otitis, GI, skin Absent of thymic shadow Normal Ca++/heart (contrast with DiGieorge)

HIV symptoms

Initial infection asymptomatic 10-60% Acute HIV syndrome: - 2-4 weeks after exposure - Fever, myalgia, sore throat, cervical adenopathy - Sometimes maculopapular rash - Similar to mononucleosis (EBV) Sever immunodefincies (AIDS): - average time of 8 years from exposure - CD4 <200 cells/mm^3 or AIDS defining infection - symptoms from opportunistic infections

What factors contribute to development of Lupus?

Innate susceptibility (Genetic): - expression of HLA phenotype DR3 and/or DR2 => causes abnormal presentation of antigens through MHC2 - Hypocomplementemia ↓C3 and C4 & deficiency in immune complex clearance (complexes accumulate) - Fluctuations in hormonal levels (> in women) Sex hormones modulate functions of lymphocytes in all stages of life; regulate Th1/Th2 cytokine balance Th2 cytokines ↑ in SLE; Th1 cytokines ↑in RA Pt have ↑IL)-10, IL-17 and IFNα Environmental Stimuli - UV exposure (UVB promotes accumulation of reactive oxygen species -> DNA damage) - Frequency of infections, Exposure to pathogens - Drugs BOTH LEAD TO Autoimmune proliferation - Hyperactive, polyclonal B-cell activation with ↓population of non-switched memory B cells and ↑DN (double-negative) memory B cells phenotype (resistant to immunosuppression) DN B cells: memory B cells negative for CD19 and CD27 => cells can't be regulated via immunological pathways - ↓ CD4:CD8 ratio => measures balance of immune system; normally should be 2 (2CD8 for every CD8) - T cells escape regulatory mechanisms and have defects in signaling, adhesion, co-stimulation - Impaired tolerance Autoantibody Production • Apoptosis & self-antigen exposure • Self-recognition • Ab cross-reactivity *B cells have multiple chances to adjust its receptor. If first attempt to make BCR is unsuccessful, process can be repeated. B cells that recognize self antigen can be released from bone marrow but put into anergic state. But when self-antigen is presented to anergic B cell, it can get reactivated leading to clonal expansion of B cells that recognize self antigen

X-linked agammaglobulinemia (XLA)

Key Findings: - absence of mature B-cells (CD19, CD20, BCR) in peripheral blood - underdeveloped germinal centers of lymph nodes since no antibody production - absence of antibodies (all classes) Treatment: IVIG

Key findings and Treatment of DiGeorge Syndrome

Key Findings: Absent thymus shadow on Chest X-Ray - Normally thymus is large newborns and seen as faint white shadow on XR ***Abscent shadow is also seen in SCID (without low Ca, no facial/heart abnormalities) Low T-cell count - underdeveloped T-cell structures (Paracortex in lymph nodes; Peri-arteriolar sheaths in spleen) Low Calcium Face, Heart abnormalities Treatment: - Thymic transplantation - Hematopoietic cell transplantation

Scleroderma (Systemic Sclerosis SSc) systemic and localized symptoms

Localized: - Morphea = patches of discolored or hardened skin on the face, neck, hands, torso, or feet - Linear = progressive loss of subcutaneous fat with pigment changes in skin Systemic: Limited = CREST - Calcinosis = calcium deposits in any soft tissue - Raynaud's = blood vessels vasoconstrict in cold or stress (fingers, toes) - Esophageal dysfunction = smooth muscle atrophy and fibrosis; motility issues - Sclerodactyly = localized thickening and tightness of the skin of fingers/toes - Telangiectasia = spider veins Diffuse - skin tightening on arms, legs, torso - progresses rapidly (thickening of skin in many areas all over body in weeks to months - after one to two years of stability, skin thickening usually begins to recede and skin begins to thin or soften

Chronic Granulomatous Disease (CGD) is characterized by ...

Loss of function of NADPH oxidase Phagocytes use NADPH oxidase to generate H2O2 from O2 (respiratory burst) Catalase (-) bacteria generate their own H2O2, which can be used by phagocytes despite enzyme deficiency Catalase (+) bacteria break down H2O2 - host cell have no H2O2 to use -> recurrent infections

Wiskott-Aldrich Syndrome classic presentation and treatment

Male infant - 6 month old (maternal Ab fades); can worsen with age - Eczema - Bleeding, petechial, thrombocytopenia - Recurrent infections Lab: ↑IgE and ↑IgA common (eczema) ↓Platelets Tx: Bone marrow transplant

SCID cause

Most common forms are X-linked (boys) CAUSE: - Mutation of gamma subunit of cytokine receptors Gene: IL2RG (interleukin 2 receptor gamma gene) - Adenosine deaminase gene deficiencies

IgA Vasculitis (aka Henoch-Schonlein Purpura)

Most frequently self-limited disease. disease of SKIN, MUCOSA, and organs 5% of patients may develop progressive renal failure or CNS disease

How do ANCA antibodies develop?

NETosis => ANCA may be developed via ineffective apoptosis or ineffective removal of apoptotic fragments -> exposure of immune system to molecules normally sequestered inside cells Molecular Mimicry -> exposure to bacterial superantigens in asymptomatic carriers (Staph A) Antineutrophil cytoplasmic antibodies (ANCA) = autoantibodies directed against antigens found in cytoplasmic granules of neutrophils and monocytes

Does disseminated MAC cause disease in people with normal immune system?

NO Disseminated Mycobacterium avium complex (MAC) organisms cause disseminated disease in patients with AIDS (compromised immune system)

Can HIV spread through kissing, earring or through mosquito's bite?

NO HIV doesn't spread by 1) normal social contact: - living together in the same house / hostel - shaking hands - sharing clothes/towels - eating together - through mosquitoes bite 2) Sharing equipment (telephone, computers, machines) 3) Kissing => viral load in saliva is low - as long as there's no sores or bleeding gums

Natural host of HIV is ..... and it infects ... cells

Natural host = humans Infects CD4+ T-helper cells

Defects in the membrane attack components are associated with susceptibility to which strains of bacteria?

Neisseria infections

New therapeutic approaches of Sjogrens target ...

New therapeutic approaches -> monoclonal antibody therapies - Rituximab (targets CD20) - Belimumab (targets BAFF)

Chronic Granulomatous Disease diagnosis is made via ... test

Nitroblue tetrazolium test: - dye added to sample of neutrophils - absence of NADPH Oxidase -> cells do not turn blue Results: - negative test => indicates lack of enzymes More blue more NADPH oxidase present

Can antibodies against gp120 be used to neutralize HIV?

No Gene for gp120 mutates rapidly -> has antigenic variation; highly variable unlike p24 V3 loop portion is highly immunogenic - varies significantly Antibody neutralization difficult due to antigenic variation - antibody will not be effective against same pathogen every time since the protein will mutate each time

Is there a HIV vaccine?

No successful vaccine Successful vaccine would be one that boosts mucosal immunity since virus enters via mucosal surfaces

Explain the mechanism of epitope spreading

Normal role of epitope spreading (ES) = to attack as many targets as possible ES - immune response that leads to faster destruction of invading pathogens & malignancies Ex: HBV has 2 antigens HBcAg (core) & HBsAg (surface) - T cell specific to HBcAg will interact with B cell specific to HBcAg -> antibody to HBcAg will be produced - same T cell specific to HBcAg can drive another B cell to start producing antibody to HBsAg -> antibody to HBsAg will be produced Prerequisite to this reaction: both proteins (antigens) must be physically associated (same virus) ex. both epitopes should be associated with same virus as in HBV (c antigen can drive production of s antigen and antibodies to both are produced)

What are the current CDC recommended lab tests to diagnose HIV?

Older diagnosis scheme (antibody only) - Screen: ELISA for HIV antibodies - Confirmation: Western blot Current CDC recommendations: Screen: ELISA Combo HIV antigen/antibody test 4th generation test : tests for p24 antigen and HIV antibodies Confirmation: ELISA HIV1/HIV2 differentiation assay (differentiates between HIV1 and HIV2) - If positive for HIV1/HIV2 -> infection confirmed - If negative -> NAAT is needed NAAT: - If Positive -> infection is confirmed - If negative -> infection is ruled out

What are the newer guidelines for HIV treatment?

Older guidelines based on CD4 count: - Treat patients < 500 cells/mm3 Newer guidelines = treat all patients - multi-drug therapy (often different classes) - highly active antiretroviral therapy (HAART) **gene mutations occur over time due to drugs ** Require altering medical regimen

Which diseases are red flag for AIDs?

PCP, Cryptococcosis, Toxoplasmosis (CD4<200) Disseminated MAC, CMV pneumonitis, lymphoma (CD4 <50)

3 Types of ANCA Vasculitis

PR3 (proteinase 3) and MPO (Myeloperoxidase) => found in granules of neutrophils 1. Wegner's Granulamatosis = GPA - Granulomatosis with polyangiitis typically affects upper and lower airways, kidneys, eyes, and ears - Tx: high-dose glucocorticoids + cyclophosphamide or rituximab 2. Microscopic Polyangitis - affects lungs and kidneys - Tx: high-dose glucocorticoids + either cyclophosphamide or rituximab 3. Churg-Strauss syndrome = EGPA - associated with asthma, nasal polyps, rhinitis, sinusitis, atopy, peripheral and tissue eosinophilia, migratory pulmonary infiltrates, and mononeuritis multiplex - Tx: glucocorticoids for mild disease + cyclophosphamide for more severe disease

Sjogren Syndrome is the second most common Autoimmune Disease causing exocrinopathy. Two main presentations are ?

Primary Sjogren's Syndrome (pSS) - occurs in absence of other underlying rheumatic disorder Secondary Sjogren's Syndrome (sSS) - associated with SLE, RA, Scleroderma

What is the difference between primary and secondary immunodeficiency?

Primary or Congenital: - present at birth - result from genetic abnormalities (ex. mutations) in one or more components of immune system Secondary or Acquired: - later in life - result from infections, malnutrition, or treatments that cause loss or inadequate function of various components of immune system - most common = Acquired immunodeficiency syndrome (AIDS)

Hyper IgE Syndrome (Job's Syndrome)

Rare syndrome, poorly understood Immune symptoms with skin/ bone findings Defective Th17-cells - Failure to produce IL-17 - Loss of attraction of neutrophils *CD4 can be differentiated into Th17 * Th17 produce IL-17, IL6 Defects of STATE3 signaling pathway STAT = Signal transducer and activator of transcription - Activated by cytokines Characteristics labs: ↑IgE, ↓IFN-Y

What are the first signs of primary immunodeficiency?

Recognized because of ↑susceptibility to infections 1. Chronic/recurrent infections w/o other explanations 2. Infections in multiple different organs 3. Infections with organisms of low virulence 3. Infections of unusual severity 4. Failure of thrive

Patients with Hyper-IgM Syndromes are at risk for ....

Recurrent bacterial infections in infancy - Sinus and pulmonary infections - PNA, sinusitis, otitis media *mostly caused by encapsulated bacteria (S. punemo, H. Influenzae) Loss of IgG (opsonizing Ab) ***encapsulated bacteria needs to be opsonized!!! Opportunistic infections - Pneumocystis, cryptosporidium, histoplasmosis

Types of HIV virus

Retrovirus (RNA virus) - uses reverse transcriptase: RNA ->DNA There are 2 types: - HIV-1 (common globally with high infectivity and high virulence) - HIV-2 (Africa) *each type has diff. reverse transcriptase *treatments on HIV-1 may not work on HIV-2

RNA of HIV virus is bound to .... enzymes

Reverse transcriptase: make DNA from RNA Aspartate protease: cleavage of proteins Integrase: integrate viral DNA into host cell DNA *inhibitors to these enzymes are used as treatments

What proteins are the targets in production of anti-nuclear antibodies in SLE? Which ones are SLE specific?

Ribonuclear proteins (SLE, Sjogren's) SLE specific: - Centromere - dsDNA - anti-histone

Patients with CVID are at risk for ....

Risk for: - Recurrent respiratory bacterial infections - Enteroviruses, Giardiasis - RA, pernicious anemia, lymphoma

What are the function of Ro52 (TRIM21), Ro60 ribonucelomprotein and SS-B Lupus La protein? Blockage of Ro52 or Ro60 leads to ...

Ro52 (TRIM 21) = regulatory protein - blocks proinflammatory response - loss of function or blockage leads to uncontrolled inflammation at onset of injury or disease. Ro60 (Ribonucleoprotein) = regulatory protein - stabilizes non-coding rRNAs & protects them from degradation - loss of function or blockage of Ro60 causes elevated immune response. Epitope has similarity to epitopes on EBV. SS-B (Lupus La protein) regulates RNA metabolism

What are the general considerations for SLE

SLE can affect almost any organ system and its presentation and course are highly variable, patient to patient. General considerations: Triad s/s: fever, joint pain, and rash in woman of childbearing age Family hx of autoimmune disease increases risk Pts can present with other s/s: - Constitutional (weight loss, fever, fatigue, malaise) - Musculoskeletal - Dermatologic - Renal - Neuropsychiatric - Pulmonary - Gastrointestinal - Cardiac - Hematologic

Lupus Band test

Sample is mixed with anti-IgG antibody Skin is from pt with SLE shows IgG deposit at 2 different places: - band-like deposit along epidermal basement membrane (lupus band test +) - within nuclei of epidermal cells (anti-nuclear antibodies)

Acquired immunodeficiency can be .... and results from ..

Secondary or acquired - Later in life Result from: - infections, burns, malnutrition, or chemotherapy that cause loss or inadequate function of various components of immune system Most common is Acquired Immunodeficiency Syndrome (AIDS)

What are the similarities and differences between CVID and X-linked agammaglobulinemia?

Similarity: - Recurrent respiratory bacterial infections - Enteroviruses, Giardiasis Differences: - CVID not X-linked; affects males and females equally (XLA affects boys) - CVID onset later in life = majority 20-45y.o. (XLA - in infancy)

Hyper IgE Syndrome (Job's Syndrome) patient presentation

Skin Findings: In First few weeks of life: - Diffuse eczema + crusted lesions, boils etc - Histamine release -> itching Staph abscesses on face, scalp -> cold: lack warmth/redness of inflammation - Loss of cytokine production Recurrent sinusitis, otitis (often without fever since no cytokines) Facial deformities (broad nasal bridge) Retained primary teeth (two rows of teeth)

Sjogrens Treatment New therapeutic approaches of Sjogrens target ...

Skin and vaginal dryness -> skin lotions, vaginal lubricants - Postmenopausal women -> estrogen creams Arthralgias & arthritis -> prescribe NSAIDs For patients with stage III SS -> steroids and immunosuppressive (cyclophosphamide) treatments New therapeutic approaches -> monoclonal antibody therapies - Rituximab (targets CD20) - Belimumab (targets BAFF)

Symptoms of pSS (primary Sjogren's) can be divided into the following 3 groups ...

Stage I - Sicca Syndrome Stage II - General Symptoms Stage III - Systemic Manifestations

Symptoms of Stage I pSS (primary Sjogren's) = Sicca Syndrome

Stage I pSS Sicca Syndrome occurs in more than 95% patients Xerophthalmia = eyes dry, red, sensitive to light Can lead to: - photosensitivity - chronic irritation & destruction of corneal epithelium - ocular infections Xerostomia - dryness of oral cavity, pharynx and/or larynx Can cause secondary problems: - oral candidiasis - tooth decay - periodontal disease - hoarseness - non-productive cough Erythema Annulare = Sjogren's Rash Diffuse Submandibular Salivary Gland Enlargement Parotitis - Parotid Gland Enlargement Vaginal Dryness : - Disparenuria = pain with intercourse - Vaginal Candidiasis - Bacterial Vaginosis (BV)

Patients with SCID are susceptible to ... What is the treatment?

Susceptible to many infections - Thrush, bacterial, diaper rash, failure to thrive Children have infections during 1st year of life Tx: Death unless bone marrow transplant

Summary of epitope spreading in nucleosomal unit

Transcription factors like TATA biding protein can be also found in nucleosome. So antibody to TATA can also be produced or anti CREB antibodies

Which cytokines are upregulated and downregulated in Behcet's?

Upregulated: - IFNgamma, TNF, IL12, IL2 => inflammatory lesions - IL-17, IL-21, IL-22 => inflammatory autoimmune lesions - IL-13, IL-22 => mucocutaneous lesions Downregulated: - IL-10, IL-35 => lack of immunosuppressive effect

Wiskott-Aldrich Syndrome is caused by ....

X-linked disorder = in boys WAS protein absence/dysfunction - needed for T-cell cytoskeleton maintenance - Immunological synapse between T cell and APC can't form

Patients with X-Linked Agammaglobulinemia (XLA) are characterized by

absence of antibodies in blood and recurrent infections: Recurrent respiratory bacterial infections: - loss of opsonization by antibodies - Streptococcus pneumoniae, H. influenzae (these are encapsulated bacteria; capsule is made of polysaccharide. And the only way to phagocytose it is via help of antibodies via opsonization/macrophages) Classic presentation: - recurrent otitis media, sinusitis and throat, conjunctiva, skin, middle ear, bronchi and lungs pneumoniae GI pathogens infections (loss of IgA): - Enteroviruses (echo, polio, coxsackie) - Giardia (GI parasite)

Kawasaki Disease - Mucocutaneous lymph node syndrome

acute-onset systemic vasculitis of medium-sized vessels. Mostly in infants & children.

Lupus nephritis

another hallmark of SLE

MRI of pt with SLE

area of ischemia in right periventricular white matter of 41-y.o. woman with long-standing SLE

Microscopic polyangiitis is associated with ...

associated with p-ANCA (alpha-MPO) - necrotizing vasculitis involves multiple organs, especially lung and kidney. NO granulomas NO asthma

Scleroderma patients with RNA polymerase III (RNApol3) antibodies are at increased risk for ...

cancer within 3 years of diagnosis: - breast and lung cancers Autoantibodies against angiotensin II type I receptor (AT1R) and endothelin-1 type A receptor (ETAR) may have functional consequences in scleroderma

Patients with HIV have high incidence of ... cancers

cancers such as Kaposi sarcoma

Does M-tropic HIV infect T cells?

critical type of HIV during an initial infection. Infects monocytes/macrophages, but NOT T cell lines

gp120 and gp41 bind ... Which one allows fusion with host cell membrane for viral entry?

enveloppe proteins gp120 -> binds CD4 T-cells and chemokine receptor CCR5 or CXCR4 gp41 -> fusion with host membrane to allow viral entry

The hallmark of SLE is

epitope spreading + presence of autoantibodies to nucleic acids (NA) and dsDNA Nocleosome = basic structural unit of chromatin - composed of pairs of histones H2A, H2B, H3, H4 - DNA wrapped tightly around histones - unit is stabilized by H1 *H1 is the first target to produce antibody to it

What gives HIV virus high antigenic variation?

gp120 variable loops gp120 has to bind with CD4 and CCR5 or CXCR4 to enter the cell After that, gp41 helps to fuse virus into the cell

gp120 and gp41 are formed from

gp160 protein and cleaved

Sjogrens pathogenesis

immune system-mediated loss of exocrine glands (acinar and ductal) => lack of saliva and lacrimal fluid Environmental and hormonal factors trigger infiltration of lymphocytes (CD4+, B cells, and plasma cells) -> glandular dysfunction in salivary and lacrimal glands Increased IL-1RA in CSF (interleukin 1 antagonist) means disease begins with increased activity in interleukin 1 system, followed by an autoregulatory upregulation of IL-1RA to reduce successful binding of interleukin 1 to its receptors. Secondary SS pts have s/s of their primary rheumatic disorders, such as systemic lupus erythematosus, rheumatoid arthritis, or systemic sclerosis (text not from lecture)

Systemic Lupus Erythematosus is characterized by formation of ...

immune-complex disease characterized by formation of auto-antibodies against DNA and other nuclear antigens

What is Vasculitis?

inflammation of arteries and veins

In Lupus nephritis, kidney failure is seen in class... and sub endothelial deposits are seen in class ...

kidney failure = class 6 sub endothelial deposits = class 5 Pic shows glomerular capillary affected by lupus nephritis Immune deposits - black arrow Mesanglial cell hypercellularity -blue arrow Mesanglial & capillary influx of leukocytes - green Subepithelial immune deposits - red arrow

X-Linked Agammaglobulinemia (XLA) is caused by ...

mutations in Btk gene, located on chromosome Xq 21.3-22 Defect in B-cell maturation Genetic disorder - gene on X-chromosome Codes for Bruton's tyrosine kinase - BTK essential for B cell development

ANCA Pathology

not from lecture

Symptoms of Stage III pSS (primary Sjogren's) = Systemic Manifestations

occur in up to 71% of patients - Lymphomas - most frequent is MALT (mucosa associated lymphoid tissue lymphoma) - Arthritis - Interstitial Lung Disease - Renal disease- most frequent is interstitial nephritis - Neuropathies pic: 48 y.o. with pSS -> large Lt parotid mass. On biopsy, B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type was identified. Microscopic section of parotid biopsy, stained with immunoperoxidase for kappa light chains (brown-stained cells), showed monoclonal population of B cells, confirming the diagnosis

Neonatal Lupus Erythematosus is associated with .... What is the clinical presentation?

occurs in infants born to mother with SLE - associated with presence of α-SSA/Ro antibodies in mother Clinical presentation at birth/within first 2 weeks: - Rash - like subacute cutaneous LE - Systemic abnormalities • Hepatosplenomegaly • Congenital heart block Anti-SSA/Ro - anti Sjogren's syndrome related antigen A - anti nuclear antibodies

Symptoms of Stage II pSS (primary Sjogren's) = General Sumptoms

occurs in up to 70-80% of patients s/s: - Fatigue - Chronic pain d/t Fibromayalgia and Polyathralgia - Depression - Anxiety

TBX1 gene is needed for development of ....

pharyngeal pouches (3rd and 4th) DiGeorge's syndrome

HIV patients are susceptible to ....

unique opportunistic infections: - Pnuemocystis carinii - Candida albicans - Mycobacterium avium *people with normal immune system would not be susceptible

Pt with DiGeorge's syndrome are at highest risk for ...

viral, fungal, protozoal, intracellular bacterial infections

Patients with defective T-cell Dependent Cell Mediated Immunity (CMI) are at highest risk for ....

↑susceptibility viral, fungal, intracellular bacteria protozoa (lack of effective Th1 response) infections ↑susceptibility to virally induced malignancies

Mutations in CCR5 gene are associated with ....

↓susceptibility to HIV infection (virus won't be able to enter cell)