creation date: 2026-06-20 23:53
tags: Anatomy & Physiology
Hypersensitivity Reactions
Background
Hypersensitivity refers to an overreaction of the immune system towards some antigen, whether they are pathogenic or benign.
In general, hypersensitivity reactions requires prior exposure (“sensitization”) to the antigen.
The Gell and Coombs classification system categories reactions into 4 types as described below.
Types
Type I – IgE-Mediated
Type I hypersensitivity reactions are also known as immediate hypersensitivity as the reaction typically occurs within minutes of antigen exposure.
Briefly, these are antibody-mediated reactions which include anaphylaxis, angioedema, and atopic immune responses (ie. eczema, allergic rhinitis, and asthma)
Mechanism
On initial sensitization, antigen-presenting cells (APCs) such as dendritic cells, macrophages, or B cells, process the antigen and migrate to regional lymph nodes. The antigen is presented naive T-cells.
In individuals predisposed to allergic responses, T-cells differentiate into T-helper (Th) cells. The Th cells in turn stimulate B-cells to produce allergen-specific IgE antibodies. These IgE bind to FcεRI receptors on mast cells and basophils, priming them for subsequent exposures.
In a subsequent encounter, the antigen binds to two adjacent IgE antibodies on the primed mast cells and basophils, resulting in degranulation. This releases histamine and other mediators (eg. prostaglandin, platelet-activating factor, leukotrienes, heparin, tryptase) leading to:
- Increased smooth muscle contraction
- Peripheral vasodilation and vascular permeability
- Extravasation of capillary blood
- Fluid shift into the interstitial space
- Pruritus
Mast cells also secrete cytokines and other inflammatory mediators which leads to eosinophil and neutrophil invasion. This results in inflammation and tissue damage later in the reaction.
Examples
Causes are typically harmless antigens. Common examples include:
- Pollen from trees, grasses, and weeds
- Pet dander
- Dust mites
- Mold spores
- Foods such as tree nuts, shellfish, milk, eggs, wheat, and soy
- Medications
- Latex
- Insect stings
Additionally, certain allergens are subject to cross-reactivity, whereby an allergy to a main antigen causes reactions to other, seemingly unrelated allergens due to similarity in antigen reactivity to the sensitized IgE.
Manifestations & Evaluation
Clinical findings are as follows, listed in order of the effects of histamine above:
- Bronchospasm and abdominal cramping
- Hypovolemia and hypotension
- Erythema
- Edema and pulmonary edema
- Pruritus
Diagnostic testing options include:
- Allergy skin tests (skin prick, scratch, or intradermal test)
- Blood tests (tryptase levels, allergen-specific IgE, basophil activation)
Management
- Remove offending drug and avoidance
- Epinephrine (for anaphylaxis)
- Antihistamines
- Corticosteroids
- Allergen immunotherapy (gradual, subclinical dose of antigen to increase IgG instead of IgE)
Type II – Antibody-Mediated
Type II hypersensitivity reactions are known as cytotoxic reactions and is the mechanism responsible for a number of autoimmune disorders.
Briefly, this reaction is antibody-mediated and results in destruction of cells in the body.
Mechanism
This reaction is initiated through exposure to some exogenous agent such as drugs, transfused blood components, or pathogens. These either modify self-antigens or introduce neoantigens which results in the breakdown of immune tolerance.
Immune tolerance is crucial in preventing the immune system from targeting the body’s cell and its breakdown leads to production of autoantibodies (IgG and IgM).
Tissue injury then occurs due to:
- Direct cell destruction through self-antigens binding to cell surfaces – stimulates NK cells and macrophage phagocytosis and/or complement activation
- Autoantibodies activate classical complement pathway – leads to inflammatory mediator release and activation of neutrophils
- Impairment of cell function through autoantibody binding to receptors on target cells (eg. overactivation of thyroid hormone production by stimulating TSH receptor)
Examples
Hemolysis
- Acute hemolytic transfusion reaction
- Autoimmune hemolytic anemia
- Hemolytic disease of the newborn
Systemic disorders
- Goodpasture syndrome
- Rheumatic fever
- Myasthenia gravis
- Graves disease
Skin disorders
- Bullous pemphigoid
- Pemphigus vulgaris
Manifestations & Evaluation
Findings vary based on autoantibody targets. Similarly some autoantibody targets may be detected in laboratory studies.
Management
Management depends on the underlying immunopathological mechanism.
In cases of drug-induced or transfusion reactions, stopping the offending drug/infusion is sufficient to stop the disease.
Other management options may include:
- Anti-inflammatory drugs
- Glucocorticoids
- Systemic therapy such as methotrexate
Prevention may be possible in some cases:
- Avoidance of sensitization via RhIg prophylaxis
- Treatment of group A strep infection to prevent rheumatic fever
Type III – Immune Complex-Mediated
Type III hypersensitivity reactions are antibody-mediated reactions relating to the formation of immune complexes.
Mechanism
Following exposure to an antigen, the immune system produces IgG or IgM antibodies which bind to soluble free-floating antigens forming circulating immune complexes which are subsequently cleared by macrophages.
In cases of antigen excess, small soluble immune complexes form which are not efficiently cleared by macrophages (compared to larger complexes) persist in circulation.
These immune complexes deposit in vessel walls and tissues. Within the tissue, the complexes activate the complement pathway which increase vascular permeability and recruit neutrophils and monocytes. These leukocytes release lysosomal enzymes causing tissue damage and inflammation.
Examples
- Vasculitis
- Polyarteritis nodosa
- Drug-induced hypersensitivity vasculitis
- Nephropathy
- Poststreptococcal glomerulonephritis
- IgA nephropathy
- Membranous nephropathy
- Rheumatoid arthritis
- Hypersensitivity pneumonitis
- Systemic lupus erythematosus
- Serum sickness
- Arthus reaction (local subacute type III commonly caused by tetanus/diphtheria vaccination)
Manifestations & Evaluation
The reaction is typically self-limited, presenting as:
- Vasculitis
- Arthritis
- Glomerulonephritis
Management
Treatment consist of symptomatic relief:
- Cold compresses
- NSAIDs
- Limb elevation
Type IV – Cell-Mediated
Type IV hypersensitivity reactions also known as delayed sensitivity is a cell-mediated (contrasting to type I-III, which are antibody-mediated) reaction.
Mechanism
Type IV reactions involve direct activation of B- and T-cells. This reaction is important for defending against intracellular pathogens.
In most cases of drug reactions, the drugs are not large enough to stimulate these cells directly in their native form. However, once bound to intracellular proteins such as albumin or integrin, known as a hapten-carrier complex, become large enough to activate the cells as a self-antigen.
There are 4 subtype mechanisms that are classified based on the type of T cell involved and the specific cytokines or chemokines produced.
Type IVa
In these reactions, CD4+ Th1 cells recognize antigens on APCs and release IFN-γ, IL-2, and IL-1. INF-γ activates macrophages which damage tissue and forms granulomas if the antigen cannot be cleared.
Type IVb
In these reactions, CH4+ Th2 cells are activated and release IV-4, IL-5, and IL-13. IL-5 drives eosinophil recruitment and activation, resulting in an atopic/allergic-equivalent reaction (note, it is distinct as it is IgE- and antibody-independent).
Type IVc
In these reactions, CH8+ cytotoxic lymphocytes recognize antigens via MHC-I and directly destroys target cells through cytoplasmic lysis and apoptosis induction. This causes widespread keratinocyte apoptosis which manifests as blistering skin destruction.
Type IVd
In these reactions, CD4+ and CD8+ T cells release IL-8 and GM-CSF which attract neutrophils. These causes sterile neutrophilic pustules to form.
Examples
Type IVa
- Tuberculin skin test reaction
- Tuberculosis lung granulomas
- Leprosy
- Contact dermatitis
- Type 1 diabetes mellitus (partially)
Type IVb
- Chronic allergic asthma
- Chronic allergic rhinitis
- Maculopapular exanthema with eosinophilia
- DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms)
Type IVc
- Toxic epidermal necrolysis
- Contact dermatitis
- Tissue transplant rejection
- Drug-induced bullous reactions
Type IVd
- AGEP (Acute Generalized Exanthematous Pustulosis)
- Pustular psoriasis
- Behcet disease
Manifestations & Evaluation
Manifestations arise 48-72 hours after exposure. This is the major distinguishing factor for type IV compared to the other types.
Clinically, the subtypes are differentiated with a few key elements:
- IVa: infections that aren’t cleared
- IVb: chronic allergic-type reaction
- IVc: blistering/epidermal sloughing
- IVd: sterile pustules
Management
Management varies based on the underlying cause.