HYPERSENSITIVITY

Kathrina S. Perez, MD, DPSP

Exposure to antigen

SENSITIZATION
Repeat exposure to same antigen

HYPERSENSITIVITY REACTION

Hypersensitivity reactions
May be elicited by exogenous or endogenous antigens Endogenous Ag autoimmune diseases Minor trivial forms to fatal reactions reflects an imbalance between the effector mechanisms of immune responses and the control mechanisms that serve to normally limit such responses

Types of hypersensitivity reactions

Type I Immediate Type II Antibody-mediated Type III Immune complex-mediated Type IV - Cell-mediated

Immediate (type I) hypersensitivity

Rapid, occurs within minutes mediated by IgE antibody-dependent activation of mast cells and other leukocytes Ag + Ab bound to mast cells in persons with previous sensitization to Ag Reaction may be systemic (e.g. after injection of Ag) or local (depending on portal of entry of allergen) Examples: Skin allergy, conjunctivitis, rhinitis, bronchial asthma, gastroenteritis

IMMEDIATE OR INITIAL REACTION

Vasodilation, vascular leakage, smooth muscle spasm, glandular secretion Seen 5-30 minutes after exposure Subside in 60 minutes

LATE-PHASE REACTION
infiltration of tissues with eosinophils, neutrophils, basophils, monocytes, CD4+ T cells Tissue destruction (mucosal epithelial damage) Seen in 2-24 hours without additional exposure to allergen, may last for days

Mast cells
Widely distributed in tissues (blood vessels, nerves, subepithelium) have cytoplasmic membrane-bound granules that contain a variety of biologically active mediators activated by the cross-linking of highaffinity IgE Fc receptors, complement components C5a and C3a (anaphylatoxins)

Mast cells
chemokines (e.g., IL-8), drugs such as codeine and morphine, adenosine, mellitin (in bee venom), and physical stimuli (e.g., heat, cold, sunlight) Basophils- same as mast cells but are not normally present in tissues - circulate in the blood in very small numbers

Immediate (type I) hypersensitivity

TH2 has a central role in the initiation and propagation of immediate hypersensitivity reactions by stimulating IgE production and promoting inflammation; they produce IL-4 switching of Ab class to IgE IL-5 - development and activation of eosinophils IL-13 - enhances IgE production and acts on epithelial cells to stimulate mucus secretion

Preformed mediators
Vasoactive amines Histamine smooth muscle contraction, increased vascular permeability & mucus secretion Enzymes neutral proteases (chymase, tryptase) and several acid hydrolases Cause tissue damage Proteoglycans Heparin, chondroitin sulfate Pack the amines into granules

Lipid mediators
synthesized by sequential reactions in the mast cell membranes that lead to activation of phospholipase A2 yield arachidonic acid Leukotrienes Prostaglandin D2 Platelet-activating factor

Cytokines
Promote leukocyte recruitment, additional sources of cytokines and of histamine-releasing factors that cause further mast cell degranulation

Mast cell mediators. Upon activation, mast cells release various classes of mediators that are responsible for the immediate and late-phase reactions. ECF, eosinophil chemotactic factor; NCF, neutrophil chemotactic factor (neither of these is biochemically defined); PAF, platelet-activating factor

Immediate (type I) hypersensitivity

dependent on the coordinated actions of a variety of chemotactic, vasoactive, and spasmogenic compounds

Activated eosinophils and other WBCs also produce mediators which directly activate mast cells to degranulate -- recruited cells amplify and sustain the inflammatory response without additional exposure to the triggering antigen

Immediate (type I) hypersensitivity

Atopy predisposition to develop localized immediate hypersensitivity reactions to a variety of inhaled and ingested allergens higher serum IgE levels, and more IL-4producing TH2 cells positive family history of allergy found in 50% of atopic individuals

Immediate (type I) hypersensitivity

Non-atopic allergy triggered by temperature extremes and exercise, and do not involve TH2 cells or IgE mast cells are abnormally sensitive to activation by various non-immune stimuli

Systemic anaphylaxis
vascular shock, widespread edema, difficulty in breathing Triggers: foreign proteins (e.g., antisera), hormones, enzymes, polysaccharides, and drugs (e.g. penicillin) food allergens (e.g. peanuts, shellfish) insect toxins (e.g. bee venom)

Systemic anaphylaxis
itching, hives, and skin erythema appear within minutes, followed shortly thereafter by a striking contraction of respiratory bronchioles and respiratory distress Laryngeal edema hoarseness, dyspnea Vomiting, abdominal cramps, diarrhea patient may go into shock and even die within the hour!

Local Immediate Hypersensitivity Reactions

urticaria, angioedema, allergic rhinitis (hay fever), and bronchial asthma Seen in 10-20% of the population

Immediate (type I) hypersensitivity

Summary: complex disorder resulting from an IgEmediated triggering of mast cells and subsequent accumulation of inflammatory cells at sites of antigen deposition

Immediate (type I) hypersensitivity

regulated mainly by the induction of TH2 helper T cells that stimulate production of IgE (which promotes mast cell activation), cause accumulation of inflammatory cells (particularly eosinophils), and trigger secretion of mucus clinical features result from release of mast cell mediators as well as the eosinophil-rich inflammation

Antibody-mediated (type II) hypersensitivity

caused by antibodies that react with antigens present on cell surfaces or in the extracellular matrix Intrinsic Ags Extrinsic Ags adsorbed on cell surface/matrix Resultant injury due to inflammation, complement- & Fc receptor-dependent reactions

Antibody-mediated (type II) hypersensitivity

Occur in the following settings: 1) Transfusion reactions cells from incompatible donor react with and are opsonized by preformed antibody in the host 2) Hemolytic disease of the newborn (erythroblastosis fetalis) Maternal IgG Abs cross placenta & destroy fetal red cells

Antibody-mediated (type II) hypersensitivity

3) Autoimmune hemolytic anemia, agranulocytosis & thrombocytopenia Person with Abs against his own blood cells

4) Certain drug reactions drug acts as a "hapten" by attaching to surface molecules of red cells Abs are produced against the drug-membrane protein complex

Antibody-mediated (type II) diseases

Autoimmune hemolytic anemia Autoimmune thrombocytopenic purpura Pemphigus vulgaris Vasculitis caused by ANCA Goodpasture syndrome Acute rheumatic fever Myasthenia gravis (Ab impairs receptor function) Graves disease (hyperthyroidism) (Ab stimulates
receptor function)

Insulin-resistant diabetes Pernicious anemia

Immune complex-mediated (type III) hypersensitivity

Results from antigen-antibody complexes producing tissue damage by eliciting inflammation at the sites of deposition ICs typically deposited in vessel walls Some ICs in extravascular sites where Ag may have been "planted" previously (in situ immune complexes) Ags may be exogenous or endogenous Diseases may be systemic or localized

Systemic immune complex disease

Prototype: Acute Serum Sickness sequela to the administration of large amounts of foreign serum (e.g., serum from immunized horses used for protection against diphtheria)

Introduction of protein Ag
Formation of Abs after 1 week

Abs secreted into blood

1st phase: Abs react with Ag still present in blood, forming Ag-Ab complexes

2nd phase: circulating antigen-antibody complexes deposited in various tissues

3rd phase: Immune complexes initiate acute inflammatory reaction (10 days after)

Systemic immune complex disease

Complexes of medium size are most pathogenic (slight Ag excess) Organs where blood is filtered at high pressure to form other fluids, like urine and synovial fluid, are favored (glomeruli, joints) 3rd phase: fever, urticaria, joint pains (arthralgias), lymph node enlargement, and proteinuria appear

Systemic immune complex disease

complement-fixing Abs (i.e., IgG and IgM) and Abs that bind to leukocyte Fc receptors (some subclasses of IgG) involved Consumption of complement in active phase of disease drop in serum C3 level can be used for monitoring Single exposure to Ag lesions resolve Prolonged exposure to Ag results in chronic form of serum sickness (e.g. SLE)

Local immune complex disease (Arthus Reaction)

localized area of tissue necrosis resulting from acute immune complex vasculitis, usually elicited in the skin
Injection of Ag in sensitized animal with circulating Abs vs the Ag

Ag diffuses thru vascular wall, binds with Ab & forms immune complexes Complexes precipitate in vessel walls

Fibrinoid necrosis, thrombosis, ischemic injury

Immune complex vasculitis. The necrotic vessel wall is replaced by smudgy, pink

Immune complex-mediated (type III) hypersensitivity

SLE nuclear antigens PSGN - streptococcal cell wall antigen(s); may be "planted" in glomerular
basement membrane

Polyarteritis nodosa HBV Ag in some cases Reactive arthritis bacterial Ag (e.g. yersinia) Serum sickness various proteins (e.g. foreign serum protein) Arthus reaction - various proteins

T-Cell mediated (type IV) hypersensitivity

initiated by antigen-activated (sensitized) T lymphocytes, including CD4+ and CD8+ T cells Adaptive immune system plays a vital role (immune inflammation) Reactions by CD4+ T cells initially called delayed-type hypersensitivity (DTH) Responsible for chronic reactions vs self-tissues

T-Cell mediated (type IV) hypersensitivity

phases: Proliferation & differentiation of CD4+ T cells Responses of Differentiated Effector T Cells

Proliferation & differentiation of CD4+ T cells

Peptides displayed by dendritic cells, APCs Nave CD4+ T cells Secrete IL-2, proliferation of Ag-responsive forms

APCs produce cytokines

TH1 subset macrophage-mediated reactions

TH2 subsetPMN-mediated reactions

Responses of Differentiated Effector T Cells

Repeat exposure to antigen

Previously activated T cells respond to Ag presented by APCs

TH1 cells secrete IFN-

TH17 secrete cytokines

Macrophages activated, augmented power, secrete more cytokines to amplify TH1 response

Neutrophils & monocytes recruited to the reaction

Ag eliminated

Promoted inflammation

A, In delayed-type hypersensitivity reactions, CD4+ TH1 cells (and sometimes CD8+ T cells, not shown) respond to tissue antigens by secreting cytokines that stimulate inflammation and activate phagocytes, leading to tissue injury. CD4+ TH17 cells contribute to inflammation by recruiting neutrophils (and, to a lesser extent, monocytes). B, In some diseases, CD8+ cytotoxic T lymphocytes (CTLs) directly kill tissue cells

T-Cell mediated (type IV) hypersensitivity

CD8+ CTLs kill antigen-bearing target cells CTLs vs cell surface MHC Ags graft rejection Kill virus-infected cells responsible for tissue damage seen in infections (e.g. viral hepatitis) Involved in tumor rejection Killing mechanism involves perforins & granzymes Cytokines also involved, notably IFN-

T-Cell mediated (type IV) hypersensitivity

Associated medical conditions Type I diabetes mellitus -Antigens of pancreatic islet cells
(insulin, glutamic acid decarboxylase, others)

Crohn disease - Unknown antigen; role for commensal bacteria Rheumatoid arthritis - Unknown antigen in joint synovium Multiple sclerosis - Protein antigens in CNS myelin Peripheral neuropathy, Guillain-Barr syndrome - Protein antigens of peripheral nerve myelin Contact dermatitis - Various environmental antigens (e.g., poison ivy)

T-Cell mediated (type IV) hypersensitivity

Tuberculin reaction Injection of PPD/tuberculin reddening and induration of the site appear in 812 hours, peak in 24-72 hours, and thereafter slowly subside accumulation of mononuclear cells, mainly CD4+ T cells and macrophages, around venules, producing perivascular "cuffing"

intradermal injection of exactly one tenth of a milliliter (mL) of PPD tuberculin

size of induration is measured 4872 hours later; erythema (redness) should not be measured

A, Perivascular infiltration by T cells and mononuclear phagocytes. B, Immunoperoxidase staining reveals a predominantly perivascular cellular infiltrate that marks positively with antibodies specific to CD4.

T-Cell mediated (type IV) hypersensitivity

Granulomatous inflammation With persistent nondegradable Ag (e.g. TB) Activated macrophages epithelioid cells associated with strong T-cell activation with cytokine production an also be caused by foreign bodies that activate macrophages without eliciting an adaptive immune response

A section of a lymph node shows several granulomas, each made up of an aggregate of epithelioid cells and surrounded by lymphocytes. The granuloma in the center shows several multinucleate giant cells.

T-Cell mediated (type IV) hypersensitivity

Contact dermatitis may be evoked by contact with urushiol (Ag component of poison ivy or poison oak) vesicular dermatitis

Contact dermatitis. The lesion shows an epidermal blister (vesicle) with dermal and epidermal mononuclear infiltrates.