- Hypersensitivity refers to exaggerated or inappropriate immune responses that cause tissue damage and disease, rather than protection. Unlike normal immune reactions, which eliminate pathogens without harming host tissues, hypersensitivity reactions occur when the immune system overreacts to harmless substances (such as pollen or food proteins), overreacts to persistent pathogens, or mistakenly targets self-components. These responses are often classified into four major types, based on the underlying immune mechanisms described by Gell and Coombs: Type I (immediate), Type II (antibody-mediated cytotoxic), Type III (immune complex–mediated), and Type IV (delayed-type, T-cell–mediated). Together, these mechanisms explain a wide range of clinical disorders, from seasonal allergies to autoimmune diseases and transplant rejection.
- Type I hypersensitivity, or immediate hypersensitivity, is mediated by IgE antibodies. Upon first exposure to an allergen, B cells produce IgE, which binds to Fc receptors on mast cells and basophils. Subsequent exposure triggers rapid degranulation of these cells, releasing histamine, leukotrienes, and other mediators that cause vasodilation, smooth muscle contraction, and increased vascular permeability. Clinical manifestations include allergic rhinitis, asthma, eczema, urticaria, and anaphylaxis—a life-threatening systemic reaction. This type of hypersensitivity explains why harmless antigens, such as pollen or peanuts, can provoke intense immune responses in sensitized individuals.
- Type II hypersensitivity is antibody-mediated and involves IgG or IgM antibodies directed against antigens on cell surfaces or extracellular matrix components. These antibodies trigger complement activation, opsonization, and cytotoxicity, leading to cell or tissue destruction. Examples include autoimmune hemolytic anemia, Goodpasture’s syndrome, and transfusion reactions. In some cases, antibodies do not destroy cells but instead alter their function, as in Graves’ disease (antibodies stimulate the TSH receptor) or myasthenia gravis (antibodies block acetylcholine receptors at the neuromuscular junction).
- Type III hypersensitivity is caused by immune complexes formed between circulating antigens and antibodies. When these complexes are deposited in tissues, they activate complement and recruit neutrophils, leading to inflammation and tissue injury. This mechanism underlies diseases such as systemic lupus erythematosus (SLE), post-streptococcal glomerulonephritis, and serum sickness. Clinically, type III reactions often affect blood vessels, kidneys, and joints, producing symptoms such as vasculitis, nephritis, and arthritis. The severity depends on the size and persistence of immune complexes and the efficiency of their clearance from circulation.
- Type IV hypersensitivity, also known as delayed-type hypersensitivity (DTH), is mediated by sensitized T cells rather than antibodies. Upon re-exposure to an antigen, CD4+ T helper cells release cytokines that recruit macrophages and other immune cells, leading to inflammation and tissue damage. CD8+ cytotoxic T cells may also directly kill target cells. These responses typically occur 24–72 hours after antigen exposure. Classic examples include contact dermatitis (e.g., from poison ivy or nickel), the tuberculin skin test (Mantoux test), and certain forms of chronic transplant rejection. Granulomatous inflammation, as seen in tuberculosis or sarcoidosis, is another manifestation of type IV hypersensitivity.
- Diagnosis of hypersensitivity disorders involves a careful combination of patient history, clinical symptoms, and laboratory testing. Skin prick tests, specific IgE assays, and challenge tests are commonly used for type I allergies. Detection of autoantibodies, complement activity, and biopsy findings help identify type II and III reactions. Type IV hypersensitivity can be assessed with patch testing or delayed skin tests. Because many hypersensitivity conditions overlap with autoimmunity or chronic inflammation, differential diagnosis is essential.
- Management strategies aim to reduce symptoms, suppress inappropriate immune responses, and prevent exposure to triggers. For type I hypersensitivity, antihistamines, corticosteroids, and leukotriene receptor antagonists are commonly used, along with allergen avoidance. Epinephrine remains the life-saving treatment for anaphylaxis. Allergen-specific immunotherapy (desensitization) can provide long-term relief by promoting tolerance. Type II and III hypersensitivity diseases often require immunosuppressive drugs, plasmapheresis to remove antibodies or immune complexes, or targeted biologic therapies such as anti-CD20 antibodies. Type IV hypersensitivity is managed by identifying and removing the offending antigen, along with corticosteroids or immunosuppressants for severe or chronic cases.
- Hypersensitivity reactions highlight the double-edged nature of the immune system—the same mechanisms that protect against infection can, when dysregulated, drive pathology. Understanding hypersensitivity not only improves management of allergies, autoimmunity, and transplant rejection but also informs therapeutic advances in immunomodulation, vaccine development, and biologic drug design. As immune-mediated disorders become more prevalent worldwide, hypersensitivity remains a critical focus of clinical immunology and modern medicine.
