Basic ImmunologyLecture21 - 22th

Hypersensitivity

Immunoglobulin and cytokin mediatedhypersensitive reactions.

Allergy. DTH.

• Pathologic overreactions of the effector phase of immune response with sever tissue damage (by necrosis).

• Different mechanisms can be detected in the background. Gell and Coombs (1963) proposed differentiating four types of hypersensitivity.

• The term of immunoglobulin or cytokinemediated hypersensitivity is used recently.

Hypersensitivity

Hypersensitive reactions

Immunoglobulin mediated hypersensitivitiesType I. immediate form (allergies)Type II. cytotoxic form (serum sickness)Type III. immunocomplex disease

Cell mediated hypersensitivitiesType IV. Delayed Type Hypersensitivity

Type I hypersensitivity

IgE binding receptors

Pharmacologic Mediators of Immediate HypersensitivityPreformed mediators in granules

histamine bronchoconstriction, mucus secretion, vasodilatation, vascular permeability

tryptase proteolysis

kininogenase kinins and vasodilatation, vascular permeability, edema

ECF-A(tetrapeptides)

attract eosinophil and neutrophils

Newly formed mediatorsleukotriene B4 basophil attractant

leukotriene C4, D4 same as histamine but 1000x more potent

prostaglandins D2 edema and pain

PAF platelet aggregation and heparin release: microthrombi

Food allergy skintest

Therapeutic relevances

• Allergen free environment• Antihistamins• Desensibilization• Membrane stabilizing drugs (?)• Non-specific immunosuppression• Recombinant CD23 (low affinity FceRII)

Type II hypersensitivity

Type II (tissue-specific or cytotoxic) hypersensitivity: the antibodies bind to the antigens (self or absorbed) on the cell surfaces and induce ADCC (antibody-dependent cell-mediated cytotoxicity) or/and complement activation.

Type II hypersensitivity performed by NK or macrophage cells

CD16 (FcγRIII)

IgG (or IgM)

Clinical manifestations of the Type II hypersensitivity

• Missed transfusion reactions• Rh incompatibility• Hyperacute graft rejection• Drug allergies• Autoimmune diseases

- autoimmune hemolytic anemia- Goodpasture syndrome- Myastenia gravis- immune thrombocytopenic purpura- bullous pemphigoid, pemphigus vulgaris- Guillen-Barre syndrome

Hypersensitivity Type II

Drug (penicillin) allergy caused by Type II hypersensitive immune reaction.

Hypersensitivity Type III(Immune complex diseases)

Clinical manifestations of Type III hypersensitivity

• Hennoch-Shönlein purpura (IgA vasculitis)• Hypersensitive vasculitis• Reactive arthritis• Farmer’s lung disease• Post-streptococcal glomerulonephritis• Arthus reaction• Autoimmuine diseases:

- SLE- Rheumatoid arthritis

Hypersensitivity Type III

Tpype III hypersensitivity in post-streptococcal glomerulonephritis

Type IV hypersensitivity

Macrophage activation phasesResting Activated Hyperactivated

------------------------------------->IFNgamma--------------------------->LPS, Immuncomplexdouble stranded RNA

Phagocytosis Antigen presentation Tumor cell and parasite killing

Chemotaxis Tumor cell bindingProliferation Decreased prolif. No proliferation.No cytotoxicity No APCMHC II -, MHC II+, O2 high MHCII -, O2highO2 low TNFalpha,cytotoxic cytokines

Protease secretion

Phases of DTH• Sensitization phase: 1-2 weeks following primary

contact with the antigen. APC (Langerhans cells, vascular endothelial cells or macrophages) derived IL-12 induce Th cells

• Activation phase: Th1 activation, proliferation, sometimes CD8+ CTL activation.

• Effector phase: the secondary antigen contact causes Th1 cell activation, cytokine secretion (24h), recruitment and activation of macrophages and nonspecific inflammatory cells (peaks 48-72 hours). Only 5% of the infiltrating cells are T cells, 95% is nonspecific.

Tuberculin skintest

Chronic phase of DTH

• Granulomatosus reaction: if the pathogen is not easily cleared, survives in the cells, release their antigens into the cytoplasm: CD8+ CTL activation and – prolonged DTH response –continuous macrophage activation, they adhere closely to one another: epitheloid shape, giant cell formation: tissue damage, necrosis, fibrosis.

Sarcoidosis (Type IV Hypersensitivity)

Clinical manifestations of the Type IV hypersensitivity

• Infectious diseases (E.g. tuberculosis, lepra)• Contact dermatitis• Autoimmune diseases:

- Type 1 diabetes mellitus- Hashimoto thyroiditis- inflammatory bowel diseases- multiple sclerosis- rheumatoid arthritis- autoimmune myocarditis

Hypersensitivity Type IV.

Contact dermatitis caused by„metal allergy”

DTH

Comparison of Different Types of hypersensitivity

type-I(anaphylactic)

type-II(cytotoxic)

type-III(immune complex)

type-IV(delayed type)

antibody IgE IgG, IgM IgG, IgM Noneantigen Exogenous cell surface soluble tissues & organs

response time 15-30 minutes minutes-hours 3-8 hours 48-72 hours

appearance weal & flare lysis and necrosis

erythema and edema, necrosis

erythema and induration

histology basophils and eosinophil

antibody and complement

complement and neutrophils

monocytes and lymphocytes

transferred with antibody antibody antibody T-cells

examples allergic asthma, hay fever

erythroblastosisfetalis, Goodpasture's nephritis

SLE, farmer's lung disease

tuberculin test, poison ivy, granuloma