Immune Collateral: Hypersensitivity Reactions Quiz

Type II hypersensitivity involves IgG or IgM antibodies directed against antigens on the surface of host cells or the extracellular matrix. This triggers tissue damage through complement activation, antibody-dependent cellular cytotoxicity (ADCC), and opsonization-mediated phagocytosis. Classic examples include autoimmune hemolytic anemia, Goodpasture syndrome, and hemolytic disease of the newborn.

Hemolytic disease of the newborn occurs when an Rh-negative mother produces IgG antibodies against Rh-positive fetal red blood cells following sensitization during a previous pregnancy. In subsequent pregnancies, maternal IgG crosses the placenta and binds to fetal Rh-positive red blood cells, triggering complement activation and phagocytic destruction, leading to fetal anemia. This is a classic example of Type II antibody-mediated hypersensitivity.

Antibody-dependent cellular cytotoxicity (ADCC) is a Type II hypersensitivity mechanism in which IgG antibodies coat target cells. Natural killer cells and macrophages expressing Fc-gamma receptors recognize the Fc regions of bound antibodies and release cytotoxic granules, killing the antibody-coated cell. ADCC is involved in autoimmune conditions such as autoimmune hemolytic anemia and is also a mechanism exploited by certain therapeutic monoclonal antibodies.

The key distinction between Type II and Type III hypersensitivity lies in where the antibodies act. In Type II, antibodies bind directly to antigens on cell surfaces or extracellular matrix. In Type III, soluble antigen-antibody complexes form in the circulation and deposit in tissues such as blood vessel walls, kidneys, and joints, triggering complement activation and neutrophil recruitment that causes local inflammatory damage.

Type III hypersensitivity diseases are caused by immune complex deposition. In systemic lupus erythematosus, complexes of anti-DNA antibodies and DNA deposit in multiple organs including the kidneys, skin, and joints. Post-streptococcal glomerulonephritis involves streptococcal antigen-antibody complexes depositing in kidney glomeruli. Serum sickness results from immune complex deposition following exposure to foreign serum proteins. Myasthenia gravis is a Type II condition.

Complement activation is a shared damaging mechanism in both Type II and Type III hypersensitivity. In Type II, antibodies bound to cell surfaces activate complement, leading to membrane attack complex formation and cell lysis. In Type III, immune complexes deposited in tissues activate complement, generating anaphylatoxins C3a and C5a that recruit neutrophils and drive local inflammatory injury, particularly in blood vessels and kidneys.

The Arthus reaction is a localized Type III hypersensitivity response that occurs when antigen is injected into the skin of an individual with high levels of circulating IgG antibodies. Immune complexes form locally in vessel walls, activate complement, and recruit neutrophils, causing edema, erythema, and tissue necrosis at the injection site. It serves as an important experimental model for understanding immune complex-mediated inflammation.

Myasthenia gravis is a Type II hypersensitivity disease in which autoantibodies target nicotinic acetylcholine receptors at the neuromuscular junction. Antibody binding blocks acetylcholine from binding and triggers complement-mediated receptor destruction, reducing the number of functional receptors. This results in progressive muscle weakness and fatigability. Treatments include acetylcholinesterase inhibitors, immunosuppressants, and thymectomy in patients with thymic abnormalities.

Tissue damage in Type III hypersensitivity results from multiple interconnected mechanisms. Immune complex deposition activates complement, releasing C3a and C5a, which recruit and activate neutrophils. Neutrophils release proteases and reactive oxygen species, causing local tissue destruction. Platelet aggregation triggered by immune complex deposition contributes to microthrombus formation and ischemic damage within affected tissues such as glomeruli and synovial membranes.

Goodpasture syndrome is a Type II hypersensitivity disease caused by autoantibodies directed against the alpha-3 chain of type IV collagen, a component of glomerular and alveolar basement membranes. Antibody binding activates complement and recruits neutrophils, causing rapidly progressive glomerulonephritis and pulmonary hemorrhage. The linear pattern of IgG deposition along basement membranes seen on immunofluorescence is a hallmark diagnostic finding.

Immunofluorescence microscopy is the standard technique for detecting immune complex deposits in kidney biopsies. Fluorescently labeled antibodies against IgG, IgM, IgA, and complement components are applied to tissue sections. In Type III diseases such as lupus nephritis and post-streptococcal glomerulonephritis, a granular or lumpy-bumpy pattern of immune complex deposition is seen, contrasting with the linear pattern characteristic of Type II diseases like Goodpasture syndrome.

ABO incompatible blood transfusion reactions are a classic example of Type II hypersensitivity. Pre-existing IgM antibodies in the recipient recognize ABO antigens on transfused red blood cells. This triggers rapid complement activation, intravascular hemolysis, and potentially fatal systemic reactions including shock, renal failure, and disseminated intravascular coagulation. This is why careful blood type matching before transfusion is essential in clinical practice.

Graves disease is a unique form of Type II hypersensitivity in which autoantibodies called thyroid-stimulating immunoglobulins (TSI) bind and activate the thyroid-stimulating hormone receptor on thyroid cells. Unlike most Type II reactions that cause cell destruction, these stimulatory antibodies mimic TSH signaling, driving continuous thyroid hormone production. The condition results in hyperthyroidism with symptoms including weight loss, tachycardia, heat intolerance, and exophthalmos.

Serum sickness is a systemic Type III hypersensitivity reaction originally described after administration of horse-derived antitoxins. It occurs when large amounts of foreign protein antigens form immune complexes with IgG antibodies. These complexes deposit in blood vessels, joints, and kidneys, activating complement and causing fever, rash, arthralgias, and glomerulonephritis. Drug-induced serum sickness-like reactions can also occur following exposure to certain antibiotics and biologics.

In Type III hypersensitivity, immune complexes deposited in tissues are recognized by neutrophils and macrophages through their Fc-gamma receptors, which bind the Fc region of IgG within the complexes. This triggers cell activation and the release of proteolytic enzymes, reactive oxygen species, and inflammatory cytokines. This frustrated phagocytosis response, where cells cannot effectively engulf large deposited complexes, causes significant local tissue injury.