Unit 6: Hypersensitivity; Transplantation; Autoimmunity

Immune responses that normally protect the host can, when misdirected or exaggerated, cause tissue damage. This unit covers three such failures: hypersensitivity (excessive response to antigen), graft rejection (response to non-self tissue), and autoimmunity (loss of tolerance to self).

I. Orientation: Principles of Immune Injury

Immune-mediated damage arises when the same effector arms that clear pathogens act on the wrong target or with excessive force. The Gell and Coombs classification (1963) sorts hypersensitivity into four types by effector mechanism.

• Type I: IgE-mediated, immediate (minutes); mast-cell degranulation.
• Type II: IgG/IgM against cell-surface or matrix antigens; cytotoxic.
• Type III: Immune-complex (antigen–antibody) deposition; complement-driven.
• Type IV: T-cell mediated, delayed (24–72 h); no antibody.
• Central concept — tolerance: the capacity to distinguish self from non-self; its breakdown underlies autoimmunity, while intact allorecognition drives graft rejection.
• Shared effectors: complement (C3a, C5a), Fc receptors, cytokines, and cytotoxic lymphocytes recur across all mechanisms.

II. Hypersensitivity Reactions

Each type is defined by the immune component that mediates the tissue damage.

A. Type I hypersensitivity

An immediate IgE-dependent reaction to normally harmless environmental antigens (allergens).

• Sensitisation: first allergen exposure drives Th2 cells and IL-4/IL-13, causing B-cell class switch to IgE; IgE binds FcεRI on mast cells and basophils.
• Trigger: re-exposure cross-links surface IgE, degranulating the mast cell.
• Mediators:
  • Preformed: histamine (vasodilation, bronchoconstriction), tryptase, heparin.
  • Newly synthesised: leukotrienes (C4, D4, E4), prostaglandin D2, PAF.
• Phases: early response (minutes) from preformed mediators; late-phase (2–8 h) from recruited eosinophils and neutrophils.
• Clinical: allergic rhinitis, asthma, urticaria, and systemic anaphylaxis (hypotension, laryngeal oedema) treated with adrenaline.
• Test: skin-prick wheal-and-flare; elevated allergen-specific IgE.

B. Type II hypersensitivity

Antibody (IgG or IgM) binds antigen on a cell surface or extracellular matrix, marking it for destruction.

• Mechanisms:
  • Complement lysis: IgM/IgG fix C1q → membrane attack complex (C5b–9).
  • Opsonisation/phagocytosis: C3b and Fc receptors on macrophages.
  • ADCC: NK cells engage antibody-coated targets via FcγRIII.
  • Receptor modulation: antibody blocks or stimulates a receptor without lysis.
• Examples:
  • Haemolytic: ABO transfusion reaction, Rh haemolytic disease of the newborn, autoimmune haemolytic anaemia.
  • Receptor: Graves disease (stimulating anti-TSH-R antibody), myasthenia gravis (blocking anti-AChR antibody).
• Test: direct/indirect Coombs (antiglobulin) test detects cell-bound antibody.

C. Type III hypersensitivity

Soluble antigen–antibody complexes deposit in tissues and trigger complement-mediated inflammation.

• Pathogenesis: small complexes formed in antigen excess escape clearance, lodge in vessel walls, glomeruli, and joints; activate complement releasing C3a/C5a and recruit neutrophils.
• Damage: neutrophil lysosomal enzymes and vascular injury (fibrinoid necrosis).
• Prototype reactions:
  • Arthus reaction: localised, at site of intradermal antigen in a pre-sensitised host.
  • Serum sickness: systemic — fever, arthralgia, glomerulonephritis 7–10 days after foreign serum/protein.
• Examples: SLE (DNA–anti-DNA complexes), post-streptococcal glomerulonephritis, farmer's lung.

D. Type IV hypersensitivity

A delayed, T-cell-mediated reaction independent of antibody, peaking at 48–72 hours.

• Effectors:
  1. CD4⁺ Th1/delayed-type: secrete IFN-γ activating macrophages; drive granuloma formation.
  2. CD8⁺ cytotoxic: kill antigen-bearing cells directly (perforin/granzyme, Fas).
• Sequence: antigen presentation → memory T-cell activation → cytokine release → macrophage/monocyte infiltration.
• Examples: tuberculin (Mantoux) skin test, contact dermatitis (nickel, poison ivy haptens), granulomatous disease (TB, leprosy), and cell-mediated graft rejection.

III. Transplantation Immunology

Transplantation replaces diseased tissue with a graft; success depends on genetic similarity of donor and recipient histocompatibility antigens.

A. Immunologic basis of graft rejection

Rejection is an adaptive response against donor alloantigens, chiefly MHC molecules.

• Graft categories: autograft (self, accepted), isograft (identical twin), allograft (same species, differing MHC), xenograft (different species).
• Alloantigens: MHC class I (HLA-A, -B, -C) and class II (HLA-DR, -DP, -DQ) are the dominant targets; minor histocompatibility antigens contribute to slow rejection.
• Allorecognition:
  • Direct: recipient T cells recognise intact donor MHC on donor APCs — drives acute rejection.
  • Indirect: recipient APCs present processed donor peptides — sustains chronic rejection.
• Law of transplantation: grafts succeed when donor MHC alleles are a subset of the recipient's, avoiding foreign epitopes.

B. Tissue typing

Matching donor and recipient antigens before transplant to minimise rejection.

• HLA typing: identifies class I and II alleles; done by PCR-SSP/SSO (DNA-based, now standard) or older serological microcytotoxicity.
• ABO matching: blood-group compatibility is mandatory to avoid hyperacute rejection.
• Crossmatch: recipient serum tested against donor lymphocytes to detect preformed anti-donor antibodies; a positive crossmatch contraindicates transplant.
• Panel-reactive antibody (PRA): estimates recipient sensitisation to a population's HLA.

C. Cell mediated graft rejection

Rejection is primarily a Type IV, T-cell-driven process supported by antibody.

• CD4⁺ T cells: recognise donor class II; secrete IL-2 and IFN-γ, orchestrating the response.
• CD8⁺ CTLs: recognise donor class I and lyse graft cells directly.
• Amplification: activated macrophages, DTH inflammation, and cytokines cause parenchymal and vascular damage.
• Antibody role: alloantibodies mediate complement fixation and endothelial injury, notably in hyperacute and antibody-mediated rejection.

D. Clinical manifestations of graft rejection

Rejection is classified by timing and mechanism, guiding diagnosis and treatment.

• Hyperacute (minutes–hours): preformed anti-donor/ABO antibodies; complement-mediated thrombosis; graft becomes cyanotic — untreatable, prevented by crossmatch.
• Acute (days–weeks): T-cell-mediated cellular infiltration ± antibody; presents as rising creatinine (kidney) or fever/tenderness; reversible with immunosuppression.
• Chronic (months–years): indirect allorecognition, fibrosis, and vascular narrowing (graft vasculopathy); progressive loss of function, poorly reversible.
• Graft-versus-host disease: in bone-marrow grafts, donor T cells attack host skin, gut, and liver.
• Management: immunosuppressants — calcineurin inhibitors (cyclosporine, tacrolimus), corticosteroids, mycophenolate, and anti-lymphocyte antibodies.

IV. Autoimmunity

Autoimmune disease results when self-tolerance fails and the immune system attacks host tissue.

A. Introduction to autoimmune disorders

Loss of tolerance to self-antigens produces sustained immune attack on the body's own cells.

• Tolerance mechanisms that fail:
  • Central: clonal deletion of self-reactive lymphocytes in thymus/marrow.
  • Peripheral: anergy, regulatory T cells, and Fas-mediated apoptosis.
• Contributing factors:
  • Genetic: strong HLA associations (e.g. HLA-B27 with ankylosing spondylitis).
  • Molecular mimicry: microbial epitopes resembling self (rheumatic fever after streptococcus).
  • Others: release of sequestered antigens, polyclonal activation, defective regulatory T cells, and female sex predominance.
• Effector overlap: damage uses Type II, III, and IV mechanisms.
• Spectrum: ranges from organ-specific to systemic disease.

B. Organ specific autoimmune disease

Immune attack is confined to a single organ or gland, with self-antigens localised there.

• Hashimoto thyroiditis: anti-thyroglobulin and anti-TPO antibodies plus T-cell infiltration destroy the thyroid → hypothyroidism.
• Graves disease: stimulating anti-TSH-receptor antibody (Type II) → hyperthyroidism.
• Type 1 diabetes mellitus: T-cell (Type IV) destruction of pancreatic β-cells; anti-GAD, anti-islet antibodies.
• Myasthenia gravis: anti-acetylcholine-receptor antibody blocks neuromuscular transmission → muscle weakness.
• Pernicious anaemia: anti-intrinsic-factor antibody impairs B12 absorption.
• Common feature: antigen and lesion are restricted, so clinical effects reflect that organ's function.

C. Systemic autoimmune disease

Self-antigens are widespread, so immune complexes and autoantibodies damage multiple organs.

• Systemic lupus erythematosus (SLE):
  • Autoantibodies: anti-nuclear antibody (ANA), anti-dsDNA (specific), anti-Sm.
  • Mechanism: Type III immune-complex deposition in kidney, skin, joints.
  • Features: malar rash, glomerulonephritis, arthritis, low complement.
• Rheumatoid arthritis: rheumatoid factor (anti-IgG) and anti-CCP antibodies; chronic synovial inflammation (pannus) eroding joints.
• Systemic sclerosis (scleroderma): anti-Scl-70/anticentromere antibodies; fibrosis of skin and viscera.
• Contrast with organ-specific disease:
  1. Organ-specific: single target, therapy replaces the lost function (e.g. thyroxine).
  2. Systemic: diffuse targets and complexes, therapy relies on broad immunosuppression.