Immunology Final

Louis Pasteur

- Developed cholera and rabies vaccines

Foods that cause inflammation

- Fried foods, soda, refined carbs, lard, processed meats

Why do we give a vaccine multiple times?

-Anamnestic or secondary response -Memory cells

Blood Transfusions:

-Most common form of Type 2 Reactions -These are reactions to the major antigens present on RBCs in humans (A,B,O) -Upon a transfusion, a recipient would recognize antigenic determinants on the RBCs of the donor as foreign, and type 2 hypersensitivity in the form of hemolytic anemia would result. -The initial sensitization required to get to a hypersensitivity reaction of this type is believed to involve the generation of natural (auto) antibodies called Isohemagglutinins. -Other Characteristics: Usually IgM isotype, Children less than 1 year will not develop auto-antibodies, Found uniformly in older children and adults.

Antibody Secretion at Special Anatomic Sites

-Most effector mechanisms of humoral immunity can and do take place in essentially all peripheral tissues with certain exceptions -Antibodies do have special defense functions as a result of their active transport into two specific anatomical sites: -The lumens of mucosal organs -The developing embryo, fetus, and neonate

Neutrophil Extracellular Traps

-Netosis -DNA trap -Used during severe infections -Neutrophils, macrophages, eosinophils

Adaptive IRs- Intracellular bacteria

-The most effective adaptive immune response to intracellular bacteria involve CMI 1. Activation and differentiation of Th1 cells: IFN gamma production by these cells activates macrophages to remove intracellular bacteria. Dendritic cells and IL-12 are commonly involved. 2. CD8 CTLs are also involved in attacking infected cells. Th1 cells are critically involved in these responses as well. Note: As discussed in previous lectures when discussing DTH reactions, macrophage activation that is necessary to remove some intracellular bacteria is often accompanied by tissue injury to the host (thus hypersensitivity).

Resolution phase of DTH

-The process of a monocyte leaving the blood to enter the site of antigen deposition induces a morphological and functional change in that cell to become a macrophage. This if the first step in the macrophage activation sequence -IFN gamma is the most potent activation signal (cytokine) for macrophages

Edward Jenner

-father of vaccination

NK cell-Lysis of Target cells

1. NK cells contain granules (similar to proteolytic granules in PMNs) that carry out anti-viral biologic activity 2. Binding of NK cells to glycoprotein markers on target cells induces de-granulation. Granule contents are released into the extracellular space between the NK cell and target. (not sprayed out everywhere, but in a small compartment between cells

Superantigens

Activate many more T cells than normal

Septic shock

Circulatory collapse, intravascular coagulation, cytokine storm

Thucydides

Greek historian who is responsible for Germ Theory

Robert Koch

Koch's postulates- understood disease caused by specific microbes

Endotoxin

LPS Produced by Gram - bacteria

Antigenic Drift

Minor changes to surface antigens

Crosslinking of MHC

Presentation of exogenous Ag on MHC I in specialized dendritic cells

Exotoxins

Secreted protein toxins that are cytotoxic to host cells by diverse biochemical methods.

The only human disease eradicated by vaccination

Smallpox was declared eradicated in 1979

Active immunization

Vaccination- Prophylactic- prevention of disease, Therapeutic- treatment of existing disease

Warburg effect

aerobic glycolysis providing ATP for cancer cells and proliferating T-cells

Toxoid vaccines

bacterial toxin inactivated chemically

Killed/inactivated vaccines

pathogens killed or inactivated

Mast cell Fc Receptors for IgE

-Mast cell Fc receptors are highly specific for IgE and bind IgE with the strongest affinity and avidity of any Fc receptor (Kd is far greater for this receptor-ligand pairing than for any other Fc receptor). -This allows for sufficient occupancy of Fc receptors on Mast Cells by IgE. Even though the concentration of IgE is low in the serum

Metabolic syndrome

-Obesity- chronic inflammation - Type I -Malnourished- anti-inflammatory- Type II

DTH reactions continued

-Removal of these bacteria requires activation of the phagocyte by T cell derived cytokines -Immunity to such bacteria is often not without consequence since activated macrophages in their efforts to eliminate intracellular bacteria often cause tissue injury. For these reasons, this type of immunity is also classified as a hypersensitivity reaction -Development of DTH reactions occurs over a 24 to 48 hour period... thus it is delayed type, and not "immediate" hypersensitivity.

Why do some live vaccines work better than killed vaccines?

Danger signals- Lots of microbes in the gut but the immune system isn't firing off at these microbes. This sometimes happens with killed vaccines. The immune system does not always recognize any danger signals from killed vaccines

Type 4 Hypersensitivity

Delayed type- T-cell directed macrophage activation -DTH is a form of CMI in which the ultimate effector cell is the mononuclear phagocyte- macrophage -This is a very important defense mechanism against intracellular bacteria, including lysteria monocytogenes and Mycobacterium tuberculosis -Such bacteria can not be eradicated or removed from the body by inactivated phagocytes. -As such, such bacteria may preferentially reside (chronic or latent infections) within the phagosome of these non activated phagocytic cells

Vaccination

Involves the artificial induction of a protective memory immune response which prevents disease upon subsequent exposure. The ideal vaccine must meet several criteria-the most important of which are safety and efficacy

Adaptive immunity to viruses

Two principle mechanisms 1. Early phase of infection: humoral antibody blocks viral infection of individual cells. 2. Late phases of infection: Th1 CD4 cells and CD8 CTL mediated lysis of virally infected cells. Note: as with DTH reactions, CTL mediated lysis of virally infected cells can be associated with tissue injury to the host.

Innate immunity to viruses

Two principle mechanisms: 1. Inhibition of additional viral replication by Type 1 interferon secretion 2. NK cell activation and lysis of virally infected cells.

Passive immunization

administration of antibodies (natural or artificial)

Herd immunity

it is not necessary to vaccinate everyone to prevent infectious disease transmission

Antigenic Shift

major change creating something new ie. Bird flu to swine flu

Mechanisms of Parasitic Evasion

- It is very common for parasites to change their surface antigen composition in response to perception of the host response. Changes in antigenic structure make it difficult to mount an adaptive IR (e.g. African trypanosomes) - Some parasites develop surface structures or coverings that are impervious to attack by immune cells (eosinophils) - Some parasites are successful in sheltering themselves from the host response in cysts or other protected microenvironments. - Others shed their antigenic coat upon contact with antibody or other soluble form of the host response. This makes it difficult for the host to successfully remove the parasite. - Some parasite antigens include tolerance (tolerogens/clonal anergy) in lymphocytes

Live attenuated vaccines

- pathogen treated to reduce virulence

Fc binding of free vs. bound antibody

-A common observation in understanding this mechanism of humoral-mediated immunity would be to question hoe a phagocyte differentiates between free vs. cell/ microbe-bound antibody. -Binding of the Fab (antigen binding domain) region of the antibody (IgG) to the microbe for opsonization induces a structural change in the antibody protein that facilitates that binding of the Fc region by the Fc receptor on the phagocyte -In the absence of Fab binding of antigen, Fc binding of the antibody molecule is not promoted due to stearic hinderance. The conformational shift in protein structure that accompanies antigen binding reduces this stearic hinderance and promotes phagocytosis through opsonization. -As a result, antibody with bound antigen (microbe) attaches to the Fc receptor on phagocytrs with greater affinity and avidity

NK Cell Activating/Inhibitory Receptors

-A complex set of receptors grouped in three families: -KLRs: Killer lectin like receptors -KIRs: killer immunoglobulin like receptors -NCRs: Natural cytotoxicity receptors -The difficulty in understanding how these receptors interact to activate or inhibit a NK cell stems from all three families possessing BOTH and MULTIPLE inhibitory and activating receptors

NK cell Activation

-Activation ligands (for activating receptors) appear to be present at all times. -It is the ABSENCE of the inhibitory ligand on a target cell, as identified by the failure ot bind to the inhibitory receptor on the NK cell, that induces the NK cells to become active and lyse the virally infected target cell -This inhibitory ligand is MHC I

Phases of Immediate Hypersensitivity

-Acute- mediated by histamine (HIS) and serotonin (5-HT) which induce: Vasodilation, Increase in vascular permeability, Bronchiole constriction, Other immediate symptoms of allergy -Late phase- (2-4 hours post-degranulation): mediated by prostaglandins and leukotrienes (PGE and LTE) which induce: Increase in inflammatory influx to are of antigen encounter (neutrophils, basophils, eosinophils), and recruitment of lymphocytes (B cells, and Th2 CD4 cells for IgE and IL-4 production) -Inflammation is maximal by 24 hours and then begins to subside

Advantages and disadvantages of living vaccines

-Advantages-Single dose, long term protection, induce broad range of immune mechanisms, less expensive -Disadvantages- Less stable, Risk for immunocompromised, Reversion to virulence, difficult to standardize

What makes an antigen an allergen?

-Allergens are usually protein antigens or chemicals (drugs for example) linked to proteins to which an individual is CHRONICALLY exposed. -They are also generally small and highly soluble -Atopy in the individual is key -Chronic exposure is key -Individuals with respiratory (inhaled allergies to certain pollens, etc. can benfit from a change in geography to lessen symptoms. -This is also a valid explanation for why such allergies often develop much later in life in humans.

Type 1 Hypersensitivity

-Also known as Immediate Hypersensitivity in local reactions or anaphylaxis in large scale or systemic reactions -Type 1 hypersensitivity is initiated when mast cells bearing membrane bound IgE bind antigen (allergens) and degranulate -Mediators released from mast cells which mediate type 1 hypersensitivity reactions include: -Biogenic amines: 5-HT and HIS -Arachidonic acid (AA) metabolites: LTE and PGE

Antibody mediated Opsonization of Phagocytosis

-Antibody of the IgG isotype and C3b (from the complement system) participate in the process of coating microbes to facilitate phagocytosis... the process of opsoniation. -As such, they are referred to as specific opsonins -There are three types of Fc receptors for IgG foun don phagocytes and NK cells. They are named Fc(gamma)RI, Fc(gamma)RII, Fc(gamma)RIII -Both mononuclear phagocytes and PMNs possess Fc receptors for IgG and recognize IgG on the surface of opsonized microbes. The receptor most frequently associated with opsonin-enhanced phagocytosis is Fc(gamma)RI. Specific binding of IgG to Fc(gamma)RI initiates activation sequences in the phagocyte that facilitate the process of phagocytosis and killing of the microbe, and thus make the entire process much more efficient

Immunity to Intracellular bacteria

-As compared to extracellular bacteria, obligate and facultative intracellular bacteria must or can replicate within host cells. -By doing so, they successfully evade immunity that is mediated by antibodies and find a niche to replicate within host cells. -CMI becomes the principle mechanism of successful immunity to intracellular bacteria

CTL Granule Content

-Perforin- Aids in delivering contents of granules into the cytoplasm of the target cell (works similarly to compliment) -Granzymes- Serine proteases, which activate apoptosis once in the cytoplasm of the target cell -Granulysin- has antimicrobial actions and can induce apoptosis.

Mast Cell Mediators

-Biogenic amines- histamine and serotonin -These are acute phase mediators that act on endothelial cells to induce morphologic changes that promote vascular leakage (cells and fluid) -They also act on blood vessel smooth muscle to promote vasodilation and overall increases in vascular permeability -They also cause contraction of respiratory bronchiole or intestinal smooth muscle -Lipid Mediators (AA Metabolites): PGE/LTE/PAF -PGE-vasodilation and bronchiole constriction -LTE- bronchiole constriction -PAF- bronchiole constriction, endothelial cell contraction, RBC aggregation, and smooth muscle relaxation -Cytokines: TNF and IL-1 are for inflammation, IL2- Th2 Differentiation and IgE switch, IL-5- Eosinophil differentiation and activation, IL-3-Development of Eosinophils (bone marrow).

Neutralization of Microbes and Microbial Toxins

-By and large, either microbes or the toxins they secrete require binding to a specific cell surface receptor on the plasma membrane of a target cell to exert their pathogenicity or toxicity. -Antibody binding to microbes or toxins interferes with this ability to interact with these cell surface receptors -By this mechanism, microbes and toxins can be neutralized by antibody largely due to the stearic hinderance that is created by antibody binding -This neutralization requires only antigen binding using the antigen binding domain of the antibody protein. As such, Fc-mediated effector functions are not required to be involved and neutralization of microbes and toxins can be accomplished by essentially and Ab isotype.

Cytotoxic t-cells: CTLs

-CTLs are CD8 cells that recognize specific intracellular antigens associated with MHC I when derived from the cytosol of a target cell

Auto-Immune Diseases

-Celiac Disease- Gluten -Crohn's Disease -Diabetes Type I -Guillain-Barre Syndrome

Isohemagglutinins (auto-antibodies)

-Commensal gut bacteria bear antigens similar or identical to human ABO blood group antigens. -These bacterial antigens stimulate antibodies to be produces in humans who do NOT bear the corresponding blood group antigen on their own RBCs -Type O individuals will develop both anti-A and anti-B Isogemagglutinins. -Type A individuals will develop anti-B -Type B individuals will develop anti-A -Type AB will develop no auto-antibodies

Stearic hinderance

-Conformational change of a molecule preventing binding -Some Ig isotypes don't bind to Fc receptors unless already bound to Ag -IgE is one exception to the rule

Effector Mechanisms of Type 2 hypersensitivity

-Effector mechanisms elicited in these responses against these cell bound antigens include: -NK cells and ADCC -Opsonization//phagocytosis by mononuclear and polymorphonuclear phagocytes -Complement fixation (most common)

Eosinophils and ADCC

-Eosinophils mediate a special type of ADCC that is directed against certain parasites which are too large for simple phagocytosis or removal by other means -Eosinophils possess FceRI for IgE. Binding of IgE that is bound/coating a parasite in this manner releases pre- formed contents of eosinophilic granules (major basic protein) that causes damage to parasite membranes, causing them to degrade, thus killing the parasite.

Morphologic and Functional Changes in Macrophages

-Epithelioid cells are macrophages around the site of antigen deposition that have undergone morphologic changes and appear more like epithelial cells in nature. -Many epithelioid cells sometimes fuse to form multinucleate "giant cells". -Epithelioid cells and giant cells characterize the chronic condition of tuberculosis in man and many domestic animals when they aid in the formation of granulomas.

Immunity to Extracellular bacteria

-Extracellular bacteria by definition are capable of replication outside host cells. -Disease is caused by two Principle mechanisms 1. Induction of inflammatory responses: Gram + cocci are pyogenic and cause suppurative infections in man and domestic animals by inducing string local inflammatory responses that can cause damage to tissues at the site of initial infection. 2. Toxin production: many gram + and gram - bacteria produce toxins as primary virulence factors.

Chronic DTH Outcomes

-Fibrosis is the outcome of chronic DTH when antigen removal has been unsuccessful. It involves the replacement of differentiated tissue with fibrous connective tissue (scar formation). -In chronic DTH reactions when antigen is not resolved (bacterium not killed and removed), macrophages also undergo morphologic and functional changes

Humoral Mechanisms Involving Complement

-Fixing the classical complement cascade (CCC): The classical compliment cascade is initated by bidning of C1 to the Ch2 domain of IgG or the Ch3 domain of IgM that is bound to antigen......i.e. on the surface of a microbe -Again, as with the above description for opsonization/phagocytosis, only antibody with bound antigen can fix complement. Free or unbound antibody can not. -This action results in the potentiation of both innate and specific mechanisms of immunity, as discussed in early lectures.

Jenner wasn't the first

-Greeks- understood that an individual surviving an infection was protected later on -Middle east and China- used variolation since at least the 1400's -Inhalation or transfer of infectious material into superficial skin wounds.

Atopy

-Humans and other domestic animals that are prone to immediate hypersensitivity (Type 1 hypersensitivity) suffer from a condition known as Atopy and are said to by Atopic individuals. -It is characterized by unusually high circulating concentrations of IgE -Atopic individuals are more prone to allergies than are other non-atopic individuals in a population -Such conditions are estimated to affect approximately 20-40% of the US human population

Adaptive mechanisms- Extracellular Bacteria

-Humoral mechanisms are the principle mechanisms of immunity to extracellular bacteria and act to eliminate the bacterium or neutralize it's secreted toxins. -Antibody mediated mechanisms: 1. Neutralization (bacteria and toxins) 2. Opsonization/Fc mediated phagocytosis 3. Complement actovation (CCC) a. bacterial lysis b. Inflammation c. Opsonization and phagocytosis by C3b

Cytokines Secreted by Antigen-activated T cells during DTH

-IL-2 Autocrine/paracrine growth factor. Responsible for expansion of T-cells specific for antigen. Also important in augmenting cytokine production by T-cells. -TNF and LT. Sustain the activated state of vascular endothelial cells to continue recruitment of leukocytes to the area of antigen deposition. -IFN-gamma Plays a primary role in boosting the capacities (I.E. activates) of APCs, including macrophages and VECs by increasing expression of MHC II and co-stimulatory molecules. This action enhances antigen presentation to T-cells. -IFN- gamma also stimulates macrophages to secrete cytokines, especially IL-12, which positively feeds back to Th1 cells to increase IFN gamma production (cyclic positive feedback) -IFN gamma has a central role in stimulating macrophage effector function

CMI vs. DTH

-If CMI goes on for too long, it becomes DTH (DTH is CMI that never stops or goes on so long that it causes tissue damage -If the inflammatory process and macrophage activation of DTH reactions fails to eliminate antigen (the bacterium), the products of activated macrophages (cytokines and growth factors) can cause tissue injury -Chronic DTH reactions ultimately lead to tissue replacement (sites of CMI responses) by connective tissue.

Mucosal Antibody Effector Function

-IgA is the best described antibody with function at mucosal sites or epithelia. It can be produced locally within the respiratory or gut mucosa immune systems or it can be produced systemically and transported to these sites. -At the mucosal border (basolateral membrane) of the intestinal or respiratory mucosa, secreted IgA is transported across epithelial cells by binding to a specialized Fc receptor known as the poly-Ig receptor -Using the gut is an example, IgA is usually produced and secreted in dimeric form by resident B-cells. From this point, IgA is picked up by the poly-Ig receptor for transport across the mucosal epithelium -Within the epithelial cell it picks up the "secretory component (piece)" and becomes sIgA for secretion into the intestinal lumen.

What are reasons for vaccine failures?

-Improper vaccination- poor protection, rolling reaction, Maternal immunity, Immature immune system, Killed vs. Live, Improper storage, Wrong strain, Genetics, Antibiotics, Mixing error, Contaminated equipment, immuno-supression, adjuvant failure, Not enough time

NK cells/ LAK cells

-In the presence of very high concentrations of IL-2, NK cells can differentiate into lymphocyte activated killer (LAK) cells. -LAK cells demonstrate enhanced cytolytic abilities and a very broad range of target specificity

Examples of Type 1 Hypersensitivity

-Inhaled allergens: Asthma-bronchiole constriction, "Hay Fever" like symptoms, typically directed against pollens and feces of dust mites -Food allergy: Degree of absorption determines location of hypersensitivity example. Non or partially absorbed, then effects will be seen in gut: diarrhea/cramping, etc. (increased motility, fluid secretion, and smooth muscle contraction. If absorbed intact, then effects can commonly be seen systemically: skin rxns, asthma, etc.

ILC's

-Innate lymphoid cells -Lymphoid progenitor -Lack antigen specific recepotors -Activated by cytokines produced by "sensor" cells. -Bridge between innate and adaptive -Type I response (ILC 1) -Intracellular bacteria/viruses -Th1, CTL, Macrophages, NK -Type II Response (ILC 2) -Multicellular organisms (parasites) -Th2, eosinophils, Mast cells, Basophils Type III Response (ILC 3) -Extracellular bacteria/fungi -Th17, Neutrophils

Biology of Mast Cells

-Mast cells are typically found in tissues adjacent blood vessels and nerves beneath epithelial tissue -The cytoplasm of Mast Cells contains many granules (containing HIS and 5-HT) and lipid bodies (for the biosynthesis of LTE and PGE). -The location of Mast Cells affects their primary granule contents: -Respiratory Mucosa: histamine and heparin -Intestinal Mucosa: serotonin and others

Opsonization and Phagocytosis Mediated by C3b

-Microbes on which complement has been activated, by either ACC or CCC means, becomes coated with C3b or C4b which can act as an opsonin to promote phagocytosis. -The best described of the compliment proteins with this activity is C3b. C3b binds complement receptors (CR1) on mononuclear phagocytes or PMNs and promotes phagocytosis in an analogous way to antibody-mediated opsonization and phagocytosis

Gut-Neuro-Immune Axis

-Microglia cells -Gut highly innervated -Gut major site of serotonin production -Gut bacteria produce and respond to neurochemicals

Natural Killer (NK) Cells

-NK cells function in the innate system to offer non-specific protection against viral infection -NK cells are essentially lymphocytes that do not acquire antigenic specificity of T and B cells. -They are derived from the lymphoid progenitor -They function similarly to T cytotoxic cells (CTLs)

ADCC: Antibody-dependent Cell-Mediated Cytotoxicity

-NK cells possess Fc(gamma)RIII receptors and respond to opsonized cells by lysing IgG coated cells. -This process is made more efficient in the same way that phagocytosis is made more efficient by opsonization. -Fc(gamma)RIII only binds cell associated IgG and ADCC only occurs when target cells are coated with antibody (IgG) -Fc(gamma)RIII binding of IgG during ADCC by NK cells induces the NK cells to become activated. This results in: -IFN-gamma synthesis and secretion to activate macrophages

Neonatal and Fetal Immunity

-Neonatal mammals are protected by antibody that is developed maternally and passed onto the developing fetus via placental transfer or to the developing neonate in milk (colostrum) that has been ingested and subsequently transported across the epithelium -IgG is the only antibody isotype capable of crossing the placental of mammals -The predominant isotypes present in colostrum are IgG and IgA -Chickens are also capable of passive transfer via transovarian transfer of IgG from the hen to the yolk material of the chick that becomes available for passive immunity after hatch

Type 2 Hypersensitivity: Antibody Dependent Cytotoxic Hypersensitivity

-Occurs when antigen (allergen) is cell bound. -Antibody generated against the antigen fixes complement and induces Fc mediated reactions (including opsonization and ADCC) against the target cell. -Type 2 reactions involve predominantly IgG and IgM and do not involve IgE or Mast Cells. -Hypersensitivity reactions of this type are largely uncommon under normal circumstances and are most frequently observed in situations of blood transfusion or tissue transplantation. -Allo-immune reactions between members of the same species can and do occur following transfusions and transplantations. -In these reactions, blood cell or tissue bound antigens trigger IgM and IgG production by the recipient and type 2 hypersensitivity responses occur.

Innate Immunity to Parasites

-Parasites in general are relatively resistant to innate defense mechanisms -In general they are too large for simple phagocytosis by PMNs and macrophages. -Some helminths activate complement by the ACC but are resistant to mechanisms of complement mediated lysis

Immunity to Parasites

-Parasitic infections account for greater morbidity and mortality world-wide than any other infectious organisms. -It is estimated that 30% of the world population suffers from some degree of parasitic infection -malaria alone infects 100 million people annually and kills 1 million of those infected -Most parasites undergo complex life cycles in primary and intermediate hosts. This alone makes the mounting of a successful immune response difficult.

Evasion of IRs by Intracellular Bacteria

-Resistance to phagocytosis and additional prevention of phagosome/lysosome fusion within phagocytes are principle mechanisms of resistance -Because of these virulence factors, it is not uncommon for some intracellular bacteria to remain within host cells (macrophages) for prolonged periods and to cause recurring infections in such individuals after their periods of latency.

Evasion of IRs by Extracellular Bacteria

-Resistance to phagocytosis- some bacteria with polysaccharide rich capsules resist phagocytosis and are much more resistant to removal by phagocytosis than homologous bacteria lacking a capsule. -Inhibition of complement activation- the capsule of some bacteria (Gram + and Gram -) contains a compound known as sialic acid that actually inhibits complement activation by the ACC -Genetic variation of surface antigens- some bacteria are capable of utilizing gene conversion events to change the AA sequence of outer membrane proteins to confuse the responding host response and interfere with the generation of successful immune responses

T-cell mediated immunity

-Similar to effector humoral responses, The effector phase of T-cell mediated responses begins with antigen recognition by memory or effector T-cells -Cell mediated immune (CMI) responses are directed against antigens on the surface of APCs. -CMI responses are most important in eradicating microbes that exist intracellularly

Rhesus (Rh) Blood Groups

-The RhD antigen is another major antigen present on human RBC in addition to the ABO system. Focus on Rh complications stems from antigen D. -Complications arise with RhD- mothers having RhD+ fetuses and babies -Sensitization occurs following placental bleeding following the birth of an RhD- mother having her first child. -Subsequent pregnancies will be at extreme risk as IgG passes through the placenta into the developing fetus would lyse RBCs in the RhD+ fetus -Immunotherapy noe is performed by administering therapeutic (immune-neutralizing) quantities of human anti-D antibodies directly following birth in an RhD- mother. This prevents the mother form becoming sensitized to the RhD antigen from RBC passes from her RhD+ baby by placental tearing.

Type 3 Hypersensitivity: Immune Complex Hypersensitivity

-This type of hypersensitivity results form incomplete phagocytosis of bacteria and other microbes that have previously been opsonized by IgG -In this scenario, antigens bound by IgG following incomplete phagocytosis can become deposited upon basement membranes, thereby inhibiting further phagocytosis of the antigen. -The presence of IgG bound to antigen on a basement membrane is sufficient to fix complement by the classical cascade. -C3a, C4a, and C5a (anaphylotoxins) can cause degranulation of mast cells and inflammation is induced.

Types of Hypersensitivity reactions

-Type 1- Immediate Hypersensitivity Anaphylaxis -Type 2- Antibody Dependent -Type 3- Immune complex -Type 4- Delayed Type (DTH)

Keys to Forming Type 3 Reactions

-Typically Type 3 reactions form in situations of moderate to gross antigen excess (when the ratio of antigen to antibody is slanting toward antigen). -In such conditions, antigen/antibody complexes can become soluble complexes and not precipitate out at sites of antigen introduction. -As such, these complexes are carried by the blood to certain isolated areas of the body where it is difficult for PMNs and mononuclear phagocytes to "remove" the antigenic stimulus. -As such, complement can continue to be fixed and such membranes and tissues continue to be injured by complement action. -Thus the debilitating conditions of rheumatoid arthritis and glomerulonephritis

Biology of IgE

-Under normal conditions, IgE is present in the circulation (humans) at very low concentrations. -When IgE concentrations increase by approximately 10X under normal conditions, that person is said to be atopic. The proportion of humans in our population with IgE levels equal to or greater than 1 microgram/mL is around 20-30%. -During parasitic infections, and specific antibody directed against allergens to which a person is specifically sensitized, IgE concentrations can rise to 1000 micrograms/mL. -A difference exists between normal and atopic individuals in that in normal individuals, in place of IgE production in response to antigen, the difference is compensated by normal concentrations of IgG and IgM and importantly, very low concentrations of IgE.

Immunity to Viruses

-Viruses are obligate intracellular pathogens -Both innate and adaptive IRs to viral infection focus upon stopping additional infection by removing virally infected cells.

Routes of administration of vaccines

-intranasal, oral, scarification, subcutaneous, intradermal, intramuscular

Overview of Humoral Immunity

1. Antibodies are typically produced by Bcells/plasma cells in lymphoid organs but antibodies usually perform their effector functions at distal sites 2. Antibodies that mediate protective immunity are secreted by longer-lived plasma cells or by secondary encounter of antigen by memory B-cells that resulted from clonal expansion of a primary antigen encounter (i.e. immunologic memory) 3. Many effector functions of antibody are mediated by the C regions of the Fc domain of the molecule, and different immunoglobulin isotypes may provide different effector functions. 4. Although many effector functions are mediated by the Fc region, the initiating event of all antibody effector functions involves binding to the hypervariable antigen binding site (Fab region).

Characteristics of CTL Mediated Lysis of Targets

1. CTL killing/lysis of target cells is antigen specific 2. CTL killing requires cell:cell contact 3. CTLs themselves are not injured during cytolysis of targets

CTL Differentiation

1. CTLs differentiate from pre-CTLs. Pre-CTLs possess functional CD3 and CD8 surface molecule, but do not possess cytolytic properties. Further differentiation is required for the attainment of these properties 2. Pre-CTLs do not require a special microenvironment for this differentiation.... It can occur in infected tissue 3. Differentiation from a Pre-CTL to a functional (activated CTL) requires two signals: a. The specific recognition of antigen of a target cell b. Co-stimulator expression on APCs and/or cytokine production by CD4 (Th1) Tcells. 4. Differentiation from Pre-CTLs to CTLs involves the acquisition of cytolytic machinery. -Granules develop which contain the following: perforin or cytolysins (granzymes)

Innate mechanisms- Extracellular Bacteria

1. Complement activation- Peptidoglycan (cell wall component in Gram + bacteria) and LPS (from Gram - becteria) are capable of activating ACC by promoting the formation of C3 convertase 2. Phagocytosis- Gram + and Gram - bacteria activate phagocytosis to induce phagocytosis 3. Inflammatory responses- Inflammation is induced by bacterial products (peptidoglycan and LPS) acting on macrophages. Macrophages respond by producing pro-inflammatory cytokines (TNF and IL-1).

Types of T-cell mediated CMI Responses:

1. Delayed-type hypersensitivity (DTH) 2. Cytotoxic T lymphocyte responses 3. NK Cells/ LAK cells

-After entering inflamed tissue in DTH, leukocytes may either:

1. Die within a few days (characteristic of neutrophils) 2. Become activated (characteristic of lymphocytes and macrophages) 3. Migrate to lymphatics and re-enter circulation

Two major types of membranes affected by Type 3 hypersensitivity

1. Glomerular capsule membranes in a kidney nephron: antigen/antibody complexes deposited here can interfere with the filtration process of the nephron by ausing an inflammatory influx to invade the glomerulus. This condition is known as glomerular nephritis. 2. Capsular regions of joints: antigen antibody complexes deposited here cause chronic inflammation in the joint regions which degrade joint cartilage. This is a common contributer to rheumatoid arthritis—autoantibodies can contribute in elderly people.

Regulation of IgE synthesis

1. Heredity: Atopy is inherited and common within families 2. Natural history of antigen exposure: Repeated exposure to a particular antigen can induce atopy. 3. Nature of the antigen: Antigens that elicit strong immediate hypersensitivity reactions are referred to as allergens. What makes an antigen and allergen is not entirely known. Food allergens are usually glycosylated proteins which allow them to be absorbed intact. 4. Stimulation of Th2 cells for IL-4 production: IgE will not be produced in large quantities if these cells are not differentiated and stimulated.

Characteristics of Activated Macrophages

1. Killing mechanisms upregulated 2. Fc receptors upregulated 3. Cytokine (pro-inflammatory +IL-12) secretion upregulated 4. MHC II expression upregulated

Effector mechanisms of Humoral Immunity

1. Neutralization of microbes and microbial toxins 2. Antibody-mediated opsonization and phagocytosis 3. Antibody-dependent cell-mediated cytotoxicity (ADCC) 4. Activation of compliment 5. Functions at special/ localized sites

NK cell Granule Content

1. Perforin- a high degree of structural homology with C9 of the complement system—also a transmembrane aqueous channel- this allows granule contents to enter target cells. 2. Tumor necrosis factor- beta (TNF-beta) 3. Granzymes 4. Fragmentins (Granzymes and fragmentins Induce PCD or apoptosis in target cells -How do NK cells kill virally infected targets? -By using granzymes and fragmentins

Innate mechanisms of Immunity to Intracellular Bacteria

1. Phagocytosis by mononuclear and polumorphonuclear phagocytes 2. Lysis of targets by NK cells- The classically described scenario where NK cells are activated by targets and then produce IFN gamma is very applicable here. IFN gamma in turn activates macrophages which then in response begin to secrete IL-12 to further activate NK cells. The cycle continues until hopefully the pathogen is destroyed.

Sequence of events in Immediate Hypersensitivity Reactions

1. Production of IgE by B-cells 2. Binding of IgE to specific Fc receptors on Mast Cells 3. Binding of antigen in a way that cross links IgE on the mast cell surface. 4. Release of mast cell mediators

Five steps of CTL mediated lysis of targets

1. Recognition of antigen and conjugate formation- This involves antigen recognition by the TCR and MHC I on the target. CD8, CD3, and LFA-1 promote the cell:cell adhesion (conjugate formation) 2. Activation of the CTL.- Both antigen and co-stimulatory molecules must be present. CTL activation is completely analogous to CD4 activation 3. Delivery of a "lethal hit" by the CTL to the target- Granule exocytosis of perforin or cytolysin indices osmotic lysis of the target cell. 4. Release of CTL from the target 5. PCD of the target as a result of the lethal hit by the CTL

Three sequential processes of DTH reactions

1. Recognition/Activation Phase: T-cells (CD4/Th1 cells) recognize peptide antigens on the surface of APCs and begin producing cytokines. 2. Inflammation: vascular endothelial cells, activated by cytokines from activated T cells, recruit circulating leukocytes into tissues at the local site of antigen challenge or location. 3. Resolution: Activated macrophages eliminate foreign antigen. This process may be accompanied by tissue injury.

The development or pathogenesis of infectious disease depends on two primary characteristics:

1. The virulence of the invading microbe 2. The response of the host

Features of Type 1 or immediate hypersensitivity

1. Type 1 hypersensitivity can be transferred and demonstrated passively by serum transfer by a process known as passive cutaneous anaphylaxis. 2. Immediate hypersensitivity can be mimicked or reproduced experimentally by the administration of anti-IgE antibodies that cross link IgE on mast cells 3. Mast cells can be induced to degranulate by complement proteins C3a, C4a, and C5a (anaphylotoxins)

Adjuvant- Two general mechanisms of action

1. Vehicle for delivery: water in oil emulsion, nanoparticles, aluminum crystals 2. Immunostimulation- cytokines, PAMPs, agonistic antibodies

NK cell- Target Cell Recognition

1. With cell surface receptors specific for ligands on host cells, NK cells recognize glycoprotein markers expressed on the surface of virally infected cells. 2. NK cells recognize/respond to activating signals and inhibitory signals with activation receptors and inhibitory receptors, respectively. 3. These receptors are specific for common carbohydrate ligands found on all host cells in the body.

Cross presentation or Cross priming

Ability of a DC to present exogenous antigen on MHC I

Advantages and disadvantages of non-living vaccines

Advantages- Very stable, safe, Easy to manufacture and standardize Disadvantages- Require and adjuvant, Require multiple doses and boosters, more expensive to make and deliver

Chickens contribution to science

B cells, Gamma interferon, Vaccine development, Mass production of antibodies in eggs

Inflammation Phase of DTH:

CD4 Th1 cells produce TNF and other cytokines that alter the function of vascular endothelial cells in the following ways: 1. They induce vascular endothelial cells to secrete prostacyclin (PGI2) and NO to increase local blood flow and thus optimize the delivery of leukocytes to the site of inflammation 2. Pre-capillary endothelial cells become more adhesive for leukocytes by expressing protein receptors for leukocyte migration: a. E-selectin appears in the acute phase (<6 hours) of inflammation to allow neutrophils to home to the area. You want neutrophils because they are fast acting, and they can hold off the infection until other immune cells get there b. VCAM-1 and ICAM-1 appear at approximately 12 hours post antigen challenge and allow memory T-cells to home to the site of antigen deposition 3. Antigen activated T-cells (their cytokines) cause endothelial cells to secrete chemokines (including IL-8) and monocyte chemotactic protein-1. These molecules promote extravasation (diapedesis) of leukocytes. 4. Cytokines and contact dependent signals from activated CD4 Th1 cells cause endothelial cells to undergo shape (morphological) changes and basement membrane remodeling that favor leukocyte leakage to the extra-vascular tissue.

DIVA

Differentiating infected from vaccinated animals

Recognition/Activation phase of DTH:

First step: sensitization phase: resident APCs, such as Langerhans cells in the epidermis, transport antigen to draining lymphatics where antigen is next presented to naïve T cells in LN or spleen -Naïve t cells then expand into effector cells during the primary phase of this IR. -Note: this phase usually takes place over about 2 weeks or longer time Second step- Elicitation Phase: Reaction of Memory T-cells (CD4/ Th1 Cells) with antigen. -APCs are usually resident cells such as macrophages or Langerhans cells -These exposures (secondary) usually occur in peripheral tissues (extra-lymphoid).

Immune privileged

Limitation of IR in tissues/organs where inflammation would cause severe damage. sites where viruses can linger- Brain, Eyes, Spinal cord, Pregnant uterus, Testicles

Foods that fight inflammation

Tomatoes, fruits, nuts, olive oil, leafy greens, fatty fish

Adaptive Immunity to Parasites

a. In parasites capable of internalization by simple phagocytosis, Th1 mediated activation of macrophages with IFN gamma appears to be important. b. Th2 activation of B-cells with Il-4 for IgE production and eosinophil activation is a classical form of anti-parasitic immunity. -ADCC involving eosinophils -Type 1 hypersensitivity reactions at mucosal surfaces (gut) involving mast cells and changes in the gut microenvironment are also important--- especially enteric parasites.

Biogenic Amines and Arachidonic acid metabolites

pre-formed and are found in granules within the Mast Cell cytoplasm. 5-HT and HIS are the mediators of the acute phase Type 1 hypersensitivity and are released IMMEDIATELY upon cross linking of IgE on the Mast Cell surface -Arachidonic Acid metabolites- have to be synthesized. PGE and LTE mediate the later phase of Type 1 hypersensitivity. Synthesis does not begin until after the IgE cross-linking event.

Latency

present, but not active. Dormant

subunit vaccines

protein or polysaccharide purified from pathogen or synthesized using recombinant DNA technology

Peptide Vaccines

purified from pathogen or recombinant DNA