(10/3) Benken Lecture: Hypersensitivity Definitions:

- Hypersensitivity: A hyperactive immune response against ‘harmless’ antigens (pollen, food, drugs) - Auto-immunity: Caused by a breakdown in the mechanisms that normally ensure tolerance to self

Allergen: Small inhaled/ingested proteins that stimulate IgE production in atopic individuals. An effective allergen is: - Small and highly soluble, effective at low doses, and carried on dry particles. - Atopic? Say what? This is relative to a patient’s response to an allergen

o Non-atopic: Respond weakly to allergens, mainly produce IgG, nothing crazy o Atopic: Go nuts. Produce large amounts of IgE. Like 40% of the western pop is like this.

- Atopic Individuals have more Th2 allergen-specific cells. Recall, Th2 release IL-4, which increases B cell class switching to release IgE. Meanwhile, IL-5 is increasing the allergic response by releasing Eosinophils. EVEN MORE MEANWHILE, IL-10, also released by Th2, is inhibiting production of Th1. Lol seems hopeless.

- What’s the deal, how did this happen? - BIAS o FETUS: In the womb, the fetus and placenta have some foreign paternal Ag, and we don’t want to kill

them via maternal CTL and NK cells (stimulated by Th1 releasing TNFa). So placenta secretes IL-4 and IL-10, which results in a Th2 bias in mother and fetus. (IL-4 inhibits IFNg and Th1 type cells)

o CHILDHOOD INFECTION: Childhood infections are responsible for the establishment of Th1 responses. Memory cells will remember the allergen AND Th1 being there during the allergen’s exposure. (if concurrent allergen exposure)

§ However – “Hygiene hypothesis”- early microbial infections are important in biasing toward Th1 response to environmental allergans. But since we are so clean, it doesn’t happen. We aren’t rolling around in the dirt enough or eating enough food off the ground, so the body doesn’t know how to manage the usual dirts and grimes. We become hypersensitized to the smallest things.

o HEREDITY: Certain diseases, like Asthma and Atopic Dermatitis, have been linked to this improper bias towards Th2. Resultant mutant IgE receptors theoretically exhibit cross-linking à strong signal à IL-4 which makes B cells produce/release IgE

§ And hell, if we have a mutation in IL-4 promoter gene, we could get excess IL-4 that way as well o Treg CELLS: Atopic individuals have defective Treg responses. Normally, Tregs will help us suppress

our immune response, in this case to an Allergan, via IL-10 (stop the inflammation) and TGFb (prefer IgG over IgE). If defective, Th2 will exhibit dominant control and result in this nonsense.

Type 1 Hypersensitivity: The allergic reactions: Principle Mediator: IgE Ab. Effect: Immediate/Anaphylactic - Mechanism: In response to the allergen, IgE Ab will be produced by the atopic individual. Mast cell receptors

will recognize the Fc region of the IgE Ab and bind to them. However, if the allergen cross-links IgE, the Fc receptors are brought in close proximity, triggering the mast cells to degranulate. The mediators subsequently released are responsible for the allergy symptoms. Some of these mediators recruit basophils from the blood.

o Immediate Response: Mast Cells and Basophils o Late Phase Reaction (@hour6-48): Inflammatory Eosinophils and Neutrophils (recruited by mediators)

- The clinical manifestation of type 1 HSR depends on (1) Route of entry, (2) Location bearing the IgE o GI Tract: Increased fluid secretion, peristalsis à Diarrhea and vomiting o Airways: Bronchoconstriction, increased mucus secretion, wheezing coughing and phlegm o Blood Vessels: Vasodilation, Increased permeability à Hypotension/shock

- Mediators: o Histamine: Bind to H1Receptors on endothelial cells à vasodilation, bronchospasm, vascular permability o Prostaglandins: Part of the degranulated mast cell membranes. Attractants! And bronchoconstriction o Leukotrienes: Similar to Histamine, but slower in onset and more persistant (Drug: Singulair) o TNFa, IL-4 à Inflammation, Cytokine release, and stimulate Th2

- Tx: Generally, allergy treatments target the mediators o Bronchodilators (beta-agonists, albuterol, xanthine derivatives, theophylline): Treat bronchostriction o Antihistamines (DPH, Loratadine): Block histamine receptors and histamine effects o Corticosteroids (Medrol, Hydrocortisone): Block class switching and Ab production o Omalizumab: An Ab treatment that grabs Fc of IgE, preventing binding to mast cells. This helps

decrease the severity of asthma attacks o Mast Cell Membrane Stabilizers (Cromolyn); Decrease/prevent mast cell degranulation o Leukotriene Modifiers (Zafirlukast): Bind to leukotriene receptors and inhibit formation of Leukotrienes

§ Helps prevent airway edema, bronchoconstriction, inflammation o Specific Immunotherapy: Only successful approach for allergy cure, will attempt to shift the Th2 bias

to Th1 bias by gradually exposing pt to increasing doses of allergen. Several years can induce tolerance. § Theory on its MoA is that the repeated injections produce Treg to suppress IgE Ab production

Type 2 Hypersensitivity: Principle Mediator: IgG Effect: Cytotoxic - Mechanism: Antigens bound to the surface of a cell can be bound by IgG Ab. Activation of the complement

system will recognize IgG Fc receptor and result in opsonization, the formation of the Membrane attack complex MAC, and subsequent lysis. The mechanism proceeds by damaging the target membrane.

- The clinical manifestations of type 2 HSR include: Hemolytic Anemia, ABO transfusion reactions, Drugs, Infections, Goodpasture’s syndrome.

o Drug-induced? Yes. Quinine can attach to platelets and induce Ab formation à Thrombocytopenia. And we know in Rheumatic Fever we get Ab specific to… myosin is it?

Type 3 Hypersensitivity: Principle mediator: IgG Effect: Formation of Immune Complex - Mechanism: In this case, rather than Ag bound to a cell as in Type 2 HSR, there will be a IgG mediated response

to free floating Ag. This will result in the formation of immune complexes. Normally, the RES (reticuloendothelial system) would be responsible for removing them, but in this case the immune complexes deposit on blood vessel walls or some unreachable organ. The complement system will activate, C3a and C5a will be released and attract neutrophils, which release lysosomal enzymes that destroy the endothelium. à Tissue injury

- There can be autoimmune clinical manifestations of type 3 HSR, if the endothelium is a joint (arthritis) or perhaps the Kidney (nephritis). Arthus reaction, Serum sickness, Glomerulonephritis, Rheumatoid Arthritis.

Type 4 Hypersensitivity: Principle Mediator: T Cell Effect: Delayed - Mechanism: This delayed T-cell mediated process could be initiated hours or days after the initial infection. It

involves macrophage ingestion of the Ag, presentation via MHC II to Th1 cells, which release IFNg to further activate macrophages

- Some clinical examples include: Contact Hypersensitivity - Thus: A positive delayed-type hypersensitivity skin reaction involves the reaction of antigen, antigen-sensitive T

cells, and macrophages