Hypersensitivity Reactions

Classification of Hypersensitivity Diseases

immediate (15 min - 1hr); intermediate (1 - 24 hr); delayed (2 days)

humoral; cellular; combined humoral and cellular – depends on effectors

local vs. systemic – depends on extent of symptoms

xenoimmune vs. autoimmune – depends on antigen

xenoimmune – immunity against foreign antigens

Mechanistic Classification of Hypersensitivity Disease

Type I (anaphylaxis)

Recognition: IgE antibodies

basophils/mast cells have high affinity IgE Fc receptors (Fce ); receptors almost always filled with IgE

bivalent binding to receptor promotes cross-linking of receptors Þ receptor activation

i.e. multivalent Ag, bivalent antibodies to IgE, bivalent Ig for receptor
monovalent antigen (haptens) cannot stimulate response

Effect: release of potent small molecules from basophils/mast cells

histamine: comes from decarboxylation of histadine; stored in granules; released on receptor activation

causes smooth muscle constriction (airways, vasospasm)

causes dilation of afferent venules and leakiness of capillaries Þ edema, erythema

leukatriene C4, D4: PLA₂ (phospholipase) Þ arachadonic acid production Þ leukatrienes

PLA₂ released on receptor stimulation (leukatrienes are not stored)

also called slow reacting substance of anaphylaxis (SRS-A)

causes dilation of afferent venules and leakiness of capillaries Þ edema, erythema

physiological control of anaphylaxis: substances released in vesicles along with histamine

histaminase: cleaves histamine
arylsulfatase: cleaves leukatrienes
heparin: anticoagulent, causes basophilia of basophils

pharmacological control of anaphylaxis

corticosteriods: interfere with phospholipase formation
methyl xanthenes: kill cAMP
antihistamines: inhibit histamine; best pharmacological control of anaphylaxis

Duration: 15 min - 1 hr; self limited; complications or fatality possible

atopy: genetic tendency towards inc production of IgE; related to allergies (i.e. hayfever); found in 10% of pop

immunity with IgE is favored by immunization of mucosal sites

Type IIa (antibody dependant cytotoxicity) – requires cell death

Recognition: IgG or IgA; cross-linking of receptors Þ activation

Effect: release of potent small molecules and enzymes on NK cells, neutrophils, and macrophages

both have receptors for Fc region of IgG and IgA

histamine: present but much less than basophils

most of released substances are protein, carbohydrate, lipid digestion enzymes

myeloperoxidase: converts H₂O₂ to hypochloric acid (a strong halogenating agent)

superoxide and singlet oxygen are also produced

oxygenation/halogenation Þ membrane attack

i.e., rheumatic fever: reaction to certain type of streptococci produces IgG which recognizes myosin

Þ endocarditis, epicarditis as macrophages and NK cells attack the heart

because of low receptor affinity to IgG, killer cells only activated after IgG is bound to multivalent antigen

Þ reaction is slower than Type I because it takes longer for immune complex to form

Type IIb – requires cell death

Recognition: IgG, IgM

Effect: coating with Ig leads to complement activation Þ formation of MAC (membrane attack complex)

Type III (immune complex disease)

Recognition: any Ig class (mostly IgG, IgA, IgM)

Effects:

hygroscopic/steric: immune complexes are normally formed and cleared from the body, but they may accumulate

accumulation of immune complex effected by:

size (valiancy of antigen/antibody, affinity, etc)
charge
rate of clearance from ECF or circulation (influenced by complement and Fc binding affinity)
perfusion rate of the organ
resting permeability of the capilllary bed
time

steric effects: related to the size of the immune complex

can block vessels or change mechanical properties of the tissue

hygroscopic effects: refers to the ability of the immune complex to bind water

changes the physical properties of the tissue

complement activation: normal path by which immune complexes are removed (attract phagocytes)

in case of large immune complexes, a large inflammatory response is evoked

Þ aggregation of neutrophils and platelets (non-specific and dangerous to self tissue as well as pathogens)

Þ anaphylaxis, chemotaxis, enhancement of opsinization, cell lysis, increased hygroscopic effects

if antibody or complement binds to platelets can lead to thrombi (platelet aggragation also mediated by other leukocytes)

Duration: days to weeks; self-limited except when antigen stimulus is protracted

Type IV (delayed type hypersensitivity)

Recognition: cell membrane receptors (TCR/CD3 complex)

Effect: T cells bind antigen via MHC and cause damage in one of two ways

secrete cytokines that activate macrophages, NK cells, cause inflammation, etc
resonding cells could be cytotoxic
these are normal responses, but if healthy self-cells are attacked, it is a pathologic response

Type V (interference with receptor-ligand interaction) – no cell death

only applies to autoimmunity
antibodies bind to receptors or soluble biochemicals and stimulate, stabilize, or inhibit normal binding
physiologic effects derive from miscommunication and dysregulation between cells or organ systems