Gel and Coombs classification of hypersensitivities. Hypersensitivity

Robert Beatty Type I Type II Type III Type IV

MCB150 IgE Mediated IgG/IgM IgG Mediated T cell Mediated

Classic Allergy Immune Delayed rbc lysis complex Type Disease Hypersensitivity

TYPE I Hypersensitivity Allergens Classic allergy

Mediated by IgE attached to Mast cells. Allergens are nonparasite antigens that can stimulate a type I hypersensitivity response. The symptoms resulting from allergic responses are known as anaphylaxis. • Includes: Hay fever, asthma, eczema, bee stings, food Allergens bind to IgE and trigger allergies. degranulation of chemical mediators.

Allergens Characteristics of allergens

In the US --- Small 15-40,000 MW proteins. 36 million people Specific protein components said to have hay fever! – Often enzymes. Low dose of allergen Mucosal exposure. Most allergens promote a Th2 immune.

1 Allergens Der P1 Allergen

Example: Der P1

Der P1 is an enzyme allergen from the fecal pellets of the dust mite.

Allergen is easily aerosolized and inhaled. Dermatophagoides pteronyssinus Der P1 breaks down components of tight junctions (common dust mite) which helps it to cross mucosa.

Atopy Genetic Predisposition Type I hypersensitivity

Candidate polymorphic genes include: Atopy is the term for the genetic trait to have a – IL-4 Receptor. predisposition for localized anaphylaxis. – IL-4 cytokine (promoter region). – FcεRI. High affinity IgE receptor. Atopic individuals have higher levels of IgE and – Class II MHC eosinophils. (present peptides promoting Th2 response). – Inflammation genes.

Mechanisms of allergic response Mechanisms of allergic response Sensitization Sensitization Th2/B cell interaction IL-4 Repeated exposure to allergens initiates IL-4R immune response that generates IgE isotype. CD40 Drive B cell Activation and IgE Th2 cells required to provide the IL-4 isotype switch. required to get isotype switching to IgE.

Busse and Lemanske NEJM Feb 2001. 344:350

2 Mechanisms of allergic response Mechanisms of allergic response Sensitization Fc ε receptors (FcεR)

FcεR1 The IgE can attach to Mast cells by Fc high affinity IgE receptor found on receptor, which increases the life span of the – mast cells/basophils/activated eosinophils. IgE. Half-life of IgE in serum is days whereas attached to FcεR it is increased to months. Allergen binding to IgE attached to FcεR1 triggers release of granules from cell.

Mechanisms of allergic response Mechanisms of allergic response FcεRI Effector Stage of Hypersensitivity

High affinity Secondary exposure to allergen IgE Fc Receptor Mast cells are primed with IgE on surface.

Allergen binds IgE and cross-links to activate Has ITAM signal with tyrosine phosphorylation, Ca++ motifs influx, degranulation and release of mediators.

Mediators of Type I Hypersensitivity FcεRI Triggers Release of Mediators Immediate effects

Histamine – Constriction of smooth muscles. Bronchiole constriction = wheezing. Constriction of intestine = cramps-diarrhea. – Vasodilation with increased fluid into tissues Early mediators causing increased swelling or fluid in mucosa. cause immediate symptoms e.g. histamine (preformed in granules) – Activates enzymes for tissue breakdown. leukotriene C4 and prostaglandin D2 are quickly made 2' mediators Leukotrienes Prostaglandins

3 Immediate vs Late Effects Mediators of Type I Hypersensitivity (early mediators) Primary Mediators Pre-formed mediators in granules Histamine Cytokines TNF-α, IL-1, IL-6. Chemoattractants for Neutrophils and Early/Late Eosinophils. Effect on lung Enzymes airflow – tryptase, chymase, cathepsin. OR – Changes in connective tissue matrix, tissue Wheezing breakdown.

Type I Hypersensitivity Secondary mediators Mediators formed after activation Continuation of sensitization cycle

Mast cells control the immediate response. Eosinophils and neutrophils drive late or Leukotrienes chronic response. Prostaglandins Th2 cytokines- IL-4, IL-5, IL-13, GM-CSF More IgE production further driven by activated Mast cells, basophils, eosinophils.

Continuation of sensitization cycle Eosinophils Localized anaphylaxis

Target organ responds to direct contact with allergen. Eosinophils play key role in late phase reaction. Digestive tract contact results in vomiting, Eosinophils make cramping, diarrhea. – enzymes, Skin sensitivity usually reddened inflamed – cytokines (IL-3, IL-5, GM-CSF), area resulting in itching. – Lipid mediators (LTC4, LTD4, PAF) Airway sensitivity results in sneezing and Eosinophils can provide CD40L and IL-4 rhinitis OR wheezing and asthma. for B cell activation.

4 Treatment for Type I Systemic anaphylaxis

Pharmacotherapy Systemic vasodilation and smooth muscle Drugs. contraction leading to severe bronchiole – Non-steroidal anti-inflammatories constriction, edema, and shock. – Antihistamines block histamine receptors. – Steroids Similar to systemic inflammation. – Theophylline OR epinephrine -prolongs or increases cAMP levels in mast cells which inhibits degranulation.

Treatment for Type I Treatment for Type I Effect of allergy shots Allergen Specific Antibodies

Immunotherapy Change in amount of each isotype from more – Desensitization (hyposensitization) IgE to more IgG. also known as allergy shots. – Repeated injections of allergen to reduce the IgE on Mast cells and produce IgG.

TYPE II Hypersensitivity Antibody mediated cytotoxicity ABO Blood Groups Blood Transfusion reactions Innocuous antigens on red blood cells.

EXAMPLE: ABO blood group antigens Antibody against rbc antigen binds and mediates killing of rbcs via C’or ADCC causes systemic inflammation. A and B carbohydrate Quex: Why do we have antibodies to these antigens innocuous antigens even before we get blood transfusion?

5 TYPE II TYPE II Antibody mediated cytotoxicity Hemolytic disease of newborn

Rh factor incompatibility IgG abs to Rh an innocuous rbc antigen Drug reactions – Rh+ baby born to Rh- mother first time fine. Drug binds to rbc surface and antibody 2nd time can have abs to Rh from 1st against drug binds and causes lysis of rbcs. pregnancy. Immune system sees antibody bound to – Ab crosses placenta and baby kills its own rbcs. "foreign antigen" on cell. ADCC – Treat mother with ab to Rh antigen right after birth and mother never makes its own immune response.

TYPE III TYPE II Antigen antibody immune complexes. Rh factor incompatibility IgG mediated

Immune Complex Disease Large amount of antigen and antibodies form complexes in blood.

If not eliminated can deposit in capillaries or joints and trigger inflammation.

TYPE III TYPE III Immune Complexes Immune Complex Disease "Frustrated Phagocytes" PMNs and macrophages bind to immune complexes via FcR and phagocytize the complexes. If neutrophils and macrophages are unable to BUT phagocytize the immune complexes these cells If unable to phagocytize the immune complexes can will degranulate in the area of immune complex cause inflammation via C’ activation ---> C3a C4a, C5a and "frustrated phagocytes". deposition and trigger inflammation. Unable to eat ------try to digest outside cell.

6 TYPE III Immune Complex Disease TYPE III Immune Complex Disease

Localized disease

Deposited in joints causing local inflammation = Serum sickness from large amounts of antigen arthritis. such as injection of foreign serum.  Serum sickness is usually transient immune complex disease Deposited in kidneys = glomerulonephritis. with removal of antigen source.

Serum Sickness Delayed type hypersensitivity Systemic immune complex disease Th1 cells and macrophages

DTH response is from: – Th1 cells release cytokines to activate macrophages causing inflammation and tissue damage. Large amounts of antigen – Continued macrophage activation can cause chronic such as injection of inflammation resulting in tissue lesions, scarring, and foreign serum. granuloma formation. Delayed is relative because DTH response arise 24-72 hours after exposure rather than within minutes. Days after Antigen Injection

Stages of Type IV DTH Stages of Type IV DTH Effector stage

Secondary contact yields what we call DTH. Sensitization stage Th1 memory cells are activated and produce Memory Th1 cells against DTH antigens cytokines. are generated by dendritic cells during the – IFN-γ, TNF-α, and TNF-β which cause tissue sensitization stage. destruction, inflammation. These Th1 cells can activate macrophages – IL-2 that activates T cells and CTLs. and trigger inflammatory response. – Chemokines- for macrophage recruitment. – IL-3, GM-CSF for increased monocyte/macrophage

7 Stages of Type IV DTH Type IV DTH Effector stage Contact dermatitis

Secondary exposure to antigen The response to poison oak is a classic Type IV. Inflamed area becomes red and fluid filled can – Small molecules act as haptens and complex with skin form lesion. proteins to be taken up by APCs and presented to Th1 – From tissue damage there is activation of clotting cells to get sensitization. cascades and tissue repair. – During secondary exposure Th1 memory cells become Continued exposure to antigen can cause chronic activated to cause DTH. inflammation and result in granuloma formation.

Delayed type hypersensitivity Contact dermatitis (DTH)

DTH is a type of immune response classified by Th1 and macrophage activation that results in tissue damage.

DTH can be the result of Chronic infection or Exposure to some antigens.

Granuloma Formation from DTH Drug reactions can be any Type Mediated by Chronic Inflammation of Hypersensitivity

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