Hypersensitivity Reaction
Hypersensitivity reactions are exaggerated or inappropriate immune responses to antigens that can lead to tissue damage and disease. These reactions can occur after exposure to allergens, which are substances that trigger an immune response in susceptible individuals. Hypersensitivity is classified into four main types based on the underlying immunological mechanisms involved.
Definition of Allergen
An allergen is defined as a substance that can provoke an allergic reaction in susceptible individuals. Allergens are typically proteins or glycoproteins that elicit an immune response, leading to symptoms such as sneezing, itching, rashes, or more severe reactions like anaphylaxis. The immune system of sensitive individuals mistakenly identifies these harmless substances as threats and mounts an inappropriate response. Common allergens include pollen, dust mites, mold spores, pet dander, certain foods (such as peanuts and shellfish), insect stings, and medications.
The mechanism by which allergens induce allergic reactions involves the production of immunoglobulin E (IgE) antibodies. Upon first exposure to an allergen, the immune system produces IgE specific to that allergen. Upon subsequent exposures, these IgE antibodies bind to mast cells and basophils, leading to the release of histamines and other inflammatory mediators. This cascade results in the clinical manifestations associated with allergies.
Allergens can be categorized into various types based on their source: environmental allergens (like pollen), food allergens (like nuts), and drug allergens (like penicillin).
Classification of Hypersensitivity Reactions
Hypersensitivity reactions are classified into four main types based on the underlying immunological mechanisms involved. This classification system, established by Gell and Coombs in 1963, categorizes hypersensitivity into Type I, Type II, Type III, and Type IV reactions. Each type has distinct characteristics, pathophysiology, and clinical manifestations.
- Type I: Immediate Hypersensitivity (Anaphylactic Reaction)
- Type II: Antibody-Mediated Hypersensitivity (Cytotoxic Reaction)
- Type III: Immune Complex-Mediated Hypersensitivity
- Type IV: Delayed-Type Hypersensitivity (Cell-Mediated Reaction)
Diseases Associated with Hypersensitivity Reactions
- Type I Hypersensitivity (Immediate Hypersensitivity): Common diseases associated with Type I hypersensitivity include:
- Allergic Rhinitis: Often referred to as hay fever, it is characterized by sneezing, nasal congestion, and itchy eyes upon exposure to allergens like pollen or dust mites.
- Asthma: A chronic inflammatory disease of the airways that can be triggered by allergens, resulting in wheezing, shortness of breath, chest tightness, and coughing.
- Anaphylaxis: A severe, life-threatening allergic reaction that can occur rapidly after exposure to an allergen such as certain foods or insect stings.
- Type II Hypersensitivity (Antibody-Mediated Hypersensitivity): Diseases associated with Type II hypersensitivity include:
- Autoimmune Hemolytic Anemia: The body produces antibodies against its own red blood cells leading to their destruction.
- Graves’ Disease: An autoimmune disorder where antibodies stimulate the thyroid gland excessively, causing hyperthyroidism.
- Myasthenia Gravis: A condition where antibodies block acetylcholine receptors at the neuromuscular junction, leading to muscle weakness.
- Type III Hypersensitivity (Immune Complex-Mediated Hypersensitivity): Associated diseases include:
- Systemic Lupus Erythematosus (SLE): An autoimmune disease characterized by the formation of autoantibodies that form immune complexes affecting multiple organ systems.
- Rheumatoid Arthritis: A chronic inflammatory disorder where immune complexes contribute to joint inflammation and damage.
- Serum Sickness: A reaction that occurs after administration of certain medications or antiserums containing foreign proteins.
- Type IV Hypersensitivity (Delayed-Type Hypersensitivity): Diseases associated with Type IV hypersensitivity include:
- Contact Dermatitis: An inflammatory skin condition caused by direct contact with allergens such as poison ivy or nickel.
- Tuberculosis Skin Test Reaction: The induration observed in a tuberculin skin test is a result of delayed-type hypersensitive response to Mycobacterium tuberculosis antigens.
- Type 1 Diabetes Mellitus: An autoimmune condition where T cells attack insulin-producing beta cells in the pancreas.
Pathogenesis of Hypersensitivity
The pathogenesis of hypersensitivity can be categorized based on the four types defined in the Gell and Coombs classification system: Type I, Type II, Type III, and Type IV hypersensitivity.
(a) Type I Hypersensitivity (Immediate Hypersensitivity)
Type I hypersensitivity is primarily mediated by Immunoglobulin E (IgE) antibodies. The process begins with sensitization, where an individual is exposed to an allergen for the first time. During this initial exposure, antigen-presenting cells (APCs) capture the allergen and present it to naïve T-helper cells in lymph nodes. This interaction leads to the differentiation of these T-helper cells into a TH2 phenotype, which produces cytokines such as IL-4 and IL-13. These cytokines stimulate B cells to produce IgE antibodies specific to the allergen.
Once produced, IgE binds to high-affinity IgE receptors (FcεRI) on mast cells and basophils. Upon subsequent exposure to the same allergen, the allergen cross-links the bound IgE on these effector cells, leading to degranulation and release of mediators such as histamine, leukotrienes, and prostaglandins. These mediators cause immediate symptoms such as bronchoconstriction in asthma or vasodilation in anaphylaxis.
(b) Type II Hypersensitivity (Cytotoxic Hypersensitivity)
In Type II hypersensitivity, antibodies (IgG or IgM) bind directly to antigens on cell surfaces or extracellular matrix components. This binding can lead to cellular destruction through several mechanisms:
- Complement Activation: Antibody binding activates the complement cascade, resulting in lysis of target cells.
- Antibody-Dependent Cellular Cytotoxicity (ADCC): Natural killer (NK) cells recognize antibody-coated target cells and induce apoptosis.
- Alteration of Cell Function: Antibodies may interfere with normal cellular functions by binding to receptors or other critical proteins.
Examples include hemolytic anemia due to drug interactions or autoimmune diseases like Graves’ disease.
(c) Type III Hypersensitivity (Immune Complex-Mediated Hypersensitivity)
Type III hypersensitivity involves the formation of immune complexes consisting of antigens bound by antibodies (usually IgG). These immune complexes can deposit in various tissues such as skin, kidneys, and joints. The deposition triggers an inflammatory response through complement activation and recruitment of inflammatory cells like neutrophils.
The inflammation results from the release of enzymes and reactive oxygen species from these recruited cells, leading to tissue damage. Conditions associated with type III hypersensitivity include systemic lupus erythematosus and rheumatoid arthritis.
(d) Type IV Hypersensitivity (Delayed-Type Hypersensitivity)
Unlike Types I-III that are antibody-mediated, Type IV hypersensitivity is mediated by T-cells—specifically CD4+ T-helper 1 (TH1) and CD8+ cytotoxic T-cells. Upon first exposure to an antigen, dendritic cells present it to naïve T-cells in lymph nodes, leading them to differentiate into effector T-cells.
Upon re-exposure to the same antigen, these sensitized T-cells migrate back to the site of exposure where they release cytokines that recruit macrophages and other inflammatory cells. This delayed response typically occurs 24-72 hours after re-exposure and can result in conditions like contact dermatitis or graft-versus-host disease.
In summary, each type of hypersensitivity reaction has a distinct pathogenesis involving different immune components—ranging from antibodies in Types I-III to T-cells in Type IV—leading ultimately to tissue damage through various mechanisms including inflammation and cellular destruction.
