Hypersensitivity describes an exaggerated or inappropriate response by the body’s immune system to an antigen that is typically harmless. This misdirected reaction can lead to significant tissue damage and physiological dysfunction, often manifesting as common diseases like allergies and various autoimmune conditions. While triggers can be harmless environmental substances, such as pollen, they can also include components of the body itself in the case of autoimmunity. Understanding these reactions is important because hypersensitivities affect millions of people worldwide.
The Four Categories of Immune Overreaction
In 1963, immunologists Philip George Houthem Gell and Robin Coombs introduced a systematic classification that divides hypersensitivity reactions into four distinct types based on their underlying immunological mechanism. This system organizes these reactions into Type I, Type II, Type III, and Type IV. The first three types are mediated by antibodies and are often termed “immediate” reactions, while Type IV is cell-mediated and develops more slowly.
Type I hypersensitivity is the immediate reaction mediated by Immunoglobulin E (IgE) antibodies. The immune system must first be sensitized, producing specific IgE that binds to high-affinity receptors on the surface of mast cells and basophils. Upon re-exposure to the specific antigen, or allergen, this binding causes cross-linking of the IgE molecules, which triggers the rapid degranulation of these cells. This process releases potent inflammatory mediators, such as histamine, leukotrienes, and prostaglandins, which produce symptoms within seconds to minutes.
Type II hypersensitivity is a cytotoxic reaction involving Immunoglobulin G (IgG) and Immunoglobulin M (IgM) antibodies that target antigens on the surface of cells or tissues. Antibody binding leads to cell destruction via two main pathways. The first involves activating the complement system, which causes cell lysis. The second recruits immune cells like macrophages and Natural Killer (NK) cells, which destroy the target cell through antibody-dependent cell-mediated cytotoxicity.
Type III hypersensitivity is mediated by immune complexes, which are circulating clusters formed when antigens bind to IgG antibodies. Unlike Type II, Type III involves complexes formed in the bloodstream that deposit in tissues. These complexes tend to lodge in small blood vessels, joints, or the kidneys, where they activate the complement system. The resulting inflammatory cascade recruits neutrophils, which release destructive enzymes that cause localized tissue damage.
Type IV hypersensitivity is fundamentally different because it is T-cell mediated and does not involve antibodies. This reaction is known as delayed-type hypersensitivity because it typically takes 48 to 72 hours to fully develop after antigen exposure. Specialized antigen-presenting cells activate sensitized T lymphocytes. These T cells then release signaling proteins called cytokines, which recruit and activate other immune cells, including macrophages and cytotoxic T cells, leading to inflammation and tissue destruction.
Clinical Manifestations in Disease States
The immunological mechanisms described by the Gell and Coombs classification translate into a wide spectrum of diseases. The rapid, IgE-mediated Type I reaction causes common allergic diseases. Examples include allergic rhinitis (hay fever) and allergic asthma, where inflammatory mediators cause airway constriction. The most severe manifestation is anaphylaxis, a systemic, life-threatening emergency involving widespread mediator release.
Type II cytotoxic reactions involve conditions where antibodies mistakenly target cells for destruction. Examples include hemolytic blood transfusion reactions, where antibodies rapidly destroy incompatible red blood cells, and autoimmune hemolytic anemia, where the body attacks its own red blood cells. Type II mechanisms are also implicated in conditions like Goodpasture syndrome, where antibodies target kidney and lung tissues.
The Type III immune complex mechanism causes diseases characterized by systemic inflammation resulting from deposited complexes. Systemic Lupus Erythematosus (SLE), an autoimmune disease affecting joints, skin, and kidneys, is a primary example. Other conditions include serum sickness, which historically occurred after receiving animal-derived antitoxins, and Poststreptococcal glomerulonephritis, a kidney disorder following a bacterial infection.
Type IV, the T-cell mediated delayed reaction, is often seen in various skin and inflammatory conditions. Contact dermatitis, such as the rash caused by poison ivy, is a classic example where T cells react to the antigen after a delay. The tuberculin skin test, used to screen for tuberculosis exposure, is a controlled demonstration of the Type IV mechanism. This type is also involved in autoimmune disorders like Type 1 diabetes and multiple sclerosis, as well as sarcoidosis.
Diagnostic Approaches and Therapeutic Principles
Diagnosing a hypersensitivity reaction begins with a detailed medical history and a careful classification of the symptoms based on their clinical appearance and the time course of the reaction. Clinicians use this information to determine which of the four reaction types is likely involved, which then guides the selection of specific diagnostic tests. For suspected Type I reactions, common tests include skin prick testing, where small amounts of allergens are introduced into the skin to check for an immediate wheal-and-flare response. Blood tests measuring specific IgE antibodies in the serum can also confirm sensitization.
For Type II and Type III hypersensitivities, diagnosis often involves blood tests to look for autoantibodies directed against the body’s own tissues or to detect circulating immune complexes. Type IV reactions, particularly contact dermatitis, are commonly diagnosed using patch testing. Suspected antigens are applied to the skin under patches for 48 hours to observe for a delayed inflammatory response. In complex cases, a controlled drug provocation test may be necessary under strict medical supervision.
Therapeutic management for all hypersensitivities relies on antigen avoidance to prevent future reactions. For symptomatic relief in Type I reactions, treatment involves medications like antihistamines to block mediators and, in severe cases, epinephrine to counter life-threatening anaphylaxis. Chronic or severe hypersensitivity conditions (Types II, III, and IV) require treatments that modify or suppress the immune system. This includes using corticosteroids to reduce inflammation or immunosuppressant drugs to dampen the immune response.