Type III Hypersensitivity Reaction

Antigen–antibody immune complexes that form in circulation and subsequently deposit in tissues, trigger inflammation and tissue injury, and mediate type III hypersensitivity reactions. A hypersensitivity reaction is an exaggerated or dysregulated immune response to an antigen, leading to tissue injury in the host. These reactions typically occur in individuals previously sensitized to the antigen, implicating memory immune components in the response. According to the Gell and Coombs classification, the 4 classifications of hypersensitivity reactions are as follows: Type I or immediate hypersensitivity: IgE-mediated mast cell and basophil degranulation leading to histamine and cytokine release as seen in anaphylaxis and atopic dermatitis. Type II or antibody-mediated cytotoxicity: IgG or IgM directed against cell surface or extracellular matrix antigens, triggering complement activation or antibody-dependent cellular cytotoxicity. Underlying conditions include autoimmune hemolytic anemia, Graves' disease, and myasthenia gravis. Type III or immune complex-mediated hypersensitivity: Circulating antigen-antibody complexes deposit in tissues, activating complement and recruiting neutrophils, leading to inflammation and tissue injury, causing conditions such as serum sickness, systemic lupus erythematosus (SLE), post-streptococcal glomerulonephritis (PSGN), and hypersensitivity vasculitides such as IgA vasculitis or cryoglobulinemia. Type IV or delayed-type hypersensitivity: Mediated by T lymphocytes, particularly the CD4+ T helper cells, Th1 and Th17, and CD8+ cytotoxic T cells, this type of hypersensitivity drives inflammation and cytotoxicity, often accompanied by macrophage recruitment. Type IV causes conditions such as contact dermatitis and tuberculosis. Once deposited in tissues, the immune complexes associated with type III hypersensitivity reactions activate the classical complement pathway, generating C3a and C5a fragments that recruit neutrophils and macrophages to the site of deposition. The inflammatory cells then release proteolytic enzymes and reactive oxygen species that damage host tissues. The nature and site of antigen exposure determine the clinical manifestations. A wide range of systemic and organ-specific clinical manifestations occur as a result of type III hypersensitivity. Patients may present with constitutional symptoms such as fever, malaise, or arthralgias, or with findings related to renal, dermatologic, musculoskeletal, or vascular involvement. Management strategies attempt to eliminate or control the underlying antigenic stimulus while suppressing the immune response and limiting tissue injury. Treatment often involves the use of immunosuppressive therapies, including glucocorticoids or other agents, in conjunction with supportive care tailored to the specific organs affected. Quick recognition and intervention are critical to minimizing morbidity and preventing progression to chronic or irreversible organ damage, highlighting the need for clinicians to maintain awareness of the diverse presentations and management principles associated with type III hypersensitivity reactions.