Hypersensitivity reactions are abnormal immune responses to antigens, classified into four types: I to IV. They range from mild allergies to severe autoimmune conditions, impacting diagnostics, treatment, and patient safety in nursing and clinical care.
Introduction
Hypersensitivity reactions represent a spectrum of immune responses that are exaggerated or inappropriate and result in tissue damage or disease. While the immune system is fundamentally designed to protect the host from pathogens and foreign substances, it can sometimes react excessively or inappropriately to antigens, including self-antigens, leading to deleterious effects. Understanding hypersensitivity reactions is of paramount importance for clinicians, as these immune mechanisms underlie a wide array of clinical conditions, ranging from mild allergies to life-threatening anaphylaxis and chronic autoimmune diseases.
Definition and Significance of Hypersensitivity Reactions
Hypersensitivity can be defined as an abnormal or exaggerated immune response to an antigen, resulting in tissue injury or disease. Unlike normal immune responses, which are protective, hypersensitivity reactions are harmful and may be directed against exogenous (foreign) antigens or endogenous (self) antigens. The concept was first introduced by Clemens von Pirquet in the early 20th century, who observed that certain immune responses produced more harm than benefit.
The clinical significance of hypersensitivity reactions lies in their contribution to a wide range of disorders, including allergic diseases, autoimmune conditions, and some forms of drug reactions. A thorough understanding of these reactions is essential for accurate diagnosis, prevention, and therapeutic intervention.
Classification of Hypersensitivity Reactions
Hypersensitivity reactions are classically classified into four major types based on the underlying immunological mechanism, as described by Gell and Coombs in 1963. These are:
- Type I: Immediate (Anaphylactic) Hypersensitivity
- Type II: Antibody-Mediated (Cytotoxic) Hypersensitivity
- Type III: Immune Complex-Mediated Hypersensitivity
- Type IV: Cell-Mediated (Delayed-Type) Hypersensitivity
Each type is mediated by distinct immune mechanisms and is associated with characteristic clinical features and disease entities. The classification serves as a useful framework for understanding the pathogenesis, diagnosis, and management of various hypersensitivity-related conditions.
Types of Hypersensitivity Reactions
| Type | Mechanism | Immune Components | Onset | Examples |
| I | Immediate, IgE-mediated | IgE, mast cells, basophils | Seconds to minutes | Anaphylaxis, allergic rhinitis, asthma |
| II | Antibody-mediated cytotoxic | IgG/IgM, complement, phagocytes | Minutes to hours | Hemolytic anaemia, Goodpasture’s syndrome |
| III | Immune complex-mediated | IgG/IgM, complement, neutrophils | Hours | Serum sickness, SLE, Arthus reaction |
| IV | Cell-mediated (delayed type) | T cells (CD4+, CD8+), macrophages | 48–72 hours | Contact dermatitis, tuberculosis |
Type I Hypersensitivity Reaction: Immediate (Anaphylactic) Type
Mechanism
Type I hypersensitivity, also known as immediate or anaphylactic hypersensitivity, is mediated by immunoglobulin E (IgE) antibodies. The reaction occurs in two phases:
- Sensitisation Phase: Upon first exposure to an allergen, antigen-presenting cells (APCs) process the antigen and present it to T-helper 2 (Th2) cells. Th2 cells secrete interleukins (mainly IL-4, IL-5, IL-13), promoting B-cell class switching to produce IgE antibodies specific for the antigen. These IgE antibodies bind to FcεRI receptors on the surface of mast cells and basophils, “sensitising” them.
- Effector Phase: Upon re-exposure to the same allergen, the allergen cross-links the IgE molecules on mast cells and basophils, triggering their degranulation and release of preformed mediators (e.g., histamine, tryptase), newly synthesised mediators (e.g., prostaglandins, leukotrienes), and cytokines. These mediators cause vasodilation, increased vascular permeability, smooth muscle contraction, and mucus secretion, leading to the clinical manifestations of the reaction.
Clinical Features
Type I hypersensitivity reactions can present with a variety of clinical manifestations, depending on the route of exposure and the extent of mediator release. Common features include:
- Urticaria (hives) and angioedema
- Allergic rhinitis and conjunctivitis
- Bronchial asthma (extrinsic type)
- Anaphylaxis (systemic, life-threatening reaction)
- Food allergies (e.g., peanut, shellfish allergy)
- Atopic dermatitis
Examples
- Anaphylaxis: A severe, generalised hypersensitivity reaction triggered by allergens such as insect stings, certain foods, or drugs. It presents with hypotension, bronchospasm, laryngeal oedema, and can be fatal if untreated.
- Allergic rhinitis: Commonly known as hay fever, this condition is characterised by sneezing, nasal congestion, and watery eyes in response to airborne allergens such as pollen.
- Asthma: In atopic asthma, exposure to allergens leads to bronchoconstriction, airway inflammation, and increased mucus production.
Diagnosis
Diagnosis of Type I hypersensitivity is based on clinical history, physical examination, and specific investigations:
- Skin prick tests: Introduction of small amounts of suspected allergens into the skin to observe for immediate wheal-and-flare reactions.
- Serum IgE levels: Measurement of total and allergen-specific IgE antibodies.
- Challenge tests: Controlled exposure to allergens under medical supervision (rarely performed due to risk).
Management
- Avoidance of allergens: Identification and avoidance of trigger substances is the cornerstone of management.
- Pharmacotherapy:
- Antihistamines (e.g., cetirizine, loratadine)
- Corticosteroids (topical, inhaled, or systemic as appropriate)
- Leukotriene receptor antagonists
- Mast cell stabilisers (e.g., cromolyn sodium)
- Adrenaline (epinephrine) for anaphylaxis: Intramuscular injection is the first-line treatment in emergencies.
Immunotherapy: Allergen-specific immunotherapy (desensitisation) may be considered in selected cases, particularly for allergic rhinitis and venom allergies.
Patient education: Training on allergen avoidance, use of adrenaline auto-injectors, and recognition of early symptoms.
Type II Hypersensitivity Reaction: Antibody-Mediated (Cytotoxic) Type
Mechanism
Type II hypersensitivity reactions are mediated by antibodies, primarily IgG and IgM, directed against antigens present on the surface of cells or extracellular matrix components. The binding of these antibodies leads to cell or tissue damage through one or more of the following mechanisms:
- Complement-dependent cytotoxicity: Binding of antibodies activates the classical complement pathway, resulting in formation of the membrane attack complex (MAC) and lysis of target cells.
- Opsonisation and phagocytosis: Antibody-coated cells are recognised and ingested by phagocytes (e.g., macrophages, neutrophils) via Fc and complement receptors.
- Antibody-dependent cellular cytotoxicity (ADCC): Natural killer (NK) cells recognise antibody-coated target cells and induce apoptosis.
- Functional interference: Antibodies may bind to receptors and alter their function, either stimulating or inhibiting them.
Clinical Features
- Haemolysis (destruction of red blood cells)
- Thrombocytopenia (low platelet count)
- Neutropenia
- Tissue-specific symptoms depending on the affected organ (e.g., renal dysfunction in Goodpasture’s syndrome)
- Acute inflammation at the site of antigen-antibody interaction
Examples
- Autoimmune haemolytic anaemia: Autoantibodies target red blood cell antigens, resulting in haemolysis and anaemia.
- Goodpasture’s syndrome: Antibodies target basement membrane antigens in the glomeruli and alveoli, causing nephritis and pulmonary haemorrhage.
- Graves’ disease: Autoantibodies stimulate the TSH receptor, leading to hyperthyroidism (example of functional interference).
- Myasthenia gravis: Antibodies block acetylcholine receptors at the neuromuscular junction, causing muscle weakness.
- Haemolytic disease of the newborn: Maternal antibodies cross the placenta and destroy foetal red blood cells (e.g., Rh incompatibility).
Diagnosis
- Direct antiglobulin (Coombs’) test: Detects antibodies and/or complement on red blood cells (useful in haemolytic anaemia, haemolytic disease of the newborn).
- Indirect antiglobulin test: Detects free antibodies in the patient’s serum.
- Serological assays: Detection of specific autoantibodies (e.g., anti-TSH receptor, anti-acetylcholine receptor antibodies).
- Tissue biopsy and immunofluorescence: Demonstrates deposition of immunoglobulin and/or complement.
Management
- Removal of offending antigen: Discontinuation of causative drugs or avoidance of incompatible blood products.
- Immunosuppressive therapy: Corticosteroids, immunosuppressants (e.g., azathioprine, cyclophosphamide) to reduce antibody production.
- Plasmapheresis: Removal of circulating antibodies in severe cases.
- Supportive care: Blood transfusions, management of complications (e.g., renal support in Goodpasture’s syndrome).
- Intravenous immunoglobulin (IVIG): Used in certain autoimmune cytopenias.
Type III Hypersensitivity Reaction: Immune Complex-Mediated Type
Mechanism
Type III hypersensitivity reactions are mediated by immune complexes formed by the combination of antigens and IgG or IgM antibodies. These complexes can be formed in circulation and subsequently deposited in various tissues, or formed in situ. The deposition of immune complexes triggers activation of the complement system and recruitment of inflammatory cells, particularly neutrophils, leading to tissue injury. The pathogenic sequence includes:
- Formation of antigen-antibody complexes in the circulation or at tissue sites.
- Deposition of immune complexes in blood vessel walls, renal glomeruli, joints, or other tissues.
- Activation of the complement cascade, generation of chemotactic factors (e.g., C5a), and recruitment of neutrophils.
- Release of lysosomal enzymes and reactive oxygen species by activated neutrophils, causing tissue inflammation and damage.
Clinical Features
- Systemic symptoms: fever, malaise, arthralgia
- Vasculitis: palpable purpura, urticaria
- Glomerulonephritis: haematuria, proteinuria
- Arthritis
- Serositis
- Organ-specific dysfunction depending on site of immune complex deposition
Examples
- Serum sickness: A systemic reaction following exposure to foreign proteins (e.g., antitoxins, antivenoms), characterised by fever, rash, arthralgia, and lymphadenopathy.
- Systemic lupus erythematosus (SLE): Autoantibodies form immune complexes with nuclear antigens, leading to multi-organ involvement, especially kidneys and joints.
- Arthus reaction: A localised form of immune complex-mediated vasculitis, typically seen after injection of antigen into previously sensitised individuals.
- Post-streptococcal glomerulonephritis: Immune complexes formed following streptococcal infection deposit in renal glomeruli, causing nephritic syndrome.
Diagnosis
- Clinical history: Recent exposure to foreign antigens, drugs, or infections.
- Laboratory findings:
- Low complement levels (C3, C4) due to consumption
- Elevated ESR, CRP
- Detection of circulating immune complexes
- Specific autoantibodies (e.g., ANA, anti-dsDNA in SLE)
Tissue biopsy: Demonstrates immune complex and complement deposition (immunofluorescence microscopy).
Management
- Removal of offending antigen: Discontinuation of causative drugs or treatment of underlying infection.
- Immunosuppression: Corticosteroids, cytotoxic agents for severe or organ-threatening disease.
- Plasmapheresis: May be considered in severe or refractory cases.
- Supportive care: Management of renal, cardiac, or other organ dysfunction as needed.
Type IV Hypersensitivity Reaction: Cell-Mediated (Delayed-Type) Type
Mechanism
Type IV hypersensitivity reactions are mediated by T lymphocytes rather than antibodies. These reactions are termed “delayed” because they typically manifest 48–72 hours after exposure to the antigen. Subtypes include:
- CD4+ T cell-mediated (delayed-type hypersensitivity, DTH): Upon antigen exposure, Th1 cells become activated and release cytokines (e.g., IFN-γ, TNF-α), which recruit and activate macrophages and other inflammatory cells, leading to tissue damage.
- CD8+ cytotoxic T lymphocyte (CTL)-mediated: CTLs directly recognise and kill target cells displaying antigenic peptides on MHC class I molecules, leading to cell lysis.
Clinical Features
- Localised erythema, induration, and swelling at the site of antigen exposure (e.g., tuberculin skin test)
- Chronic inflammation and granuloma formation in persistent infections (e.g., tuberculosis)
- Vesicular skin lesions (e.g., contact dermatitis)
- Tissue destruction in autoimmune diseases (e.g., type I diabetes mellitus, multiple sclerosis)
Examples
- Contact dermatitis: Eczematous skin reaction to allergens such as nickel, poison ivy, or certain chemicals. Characterised by pruritus, erythema, and vesiculation.
- Tuberculin (Mantoux) test: Intradermal injection of purified protein derivative (PPD) from Mycobacterium tuberculosis elicits a localised DTH response in sensitised individuals.
- Granulomatous inflammation: Chronic infections (e.g., tuberculosis, leprosy) and certain autoimmune diseases result in granuloma formation mediated by T cells and macrophages.
- Type I diabetes mellitus: Autoimmune destruction of pancreatic beta cells by cytotoxic T lymphocytes.
Diagnosis
- Clinical assessment: History of exposure, characteristic delayed onset of symptoms.
- Patch testing: Application of suspected allergens to the skin and observation for delayed reaction (used in diagnosis of contact dermatitis).
- Tuberculin skin test (Mantoux test): Measurement of induration 48–72 hours after intradermal injection of PPD.
- Histopathology: Biopsy may reveal lymphocytic infiltrate, granulomas, or tissue destruction.
Management
- Avoidance of offending antigen/allergen: Identification and elimination of causative agents.
- Topical or systemic corticosteroids: Reduce inflammation in contact dermatitis and other DTH conditions.
- Immunosuppressive therapy: For autoimmune diseases with significant tissue damage.
- Management of underlying infection: In cases of granulomatous diseases, appropriate antimicrobial therapy is essential.
Comparison of Hypersensitivity Types
While all hypersensitivity reactions involve inappropriate immune responses resulting in tissue damage, they differ in terms of immune mechanisms, mediators, timing, and clinical manifestations. A summary of key differences is presented below:
| Feature | Type I | Type II | Type III | Type IV |
| Immune mediator | IgE, mast cells | IgG/IgM, complement | IgG/IgM, immune complexes | T lymphocytes |
| Time to onset | Seconds–minutes | Minutes–hours | Hours | 48–72 hours |
| Examples | Anaphylaxis, asthma | Haemolytic anaemia, Goodpasture’s | SLE, serum sickness | Contact dermatitis, TB |
| Type of antigen | Exogenous | Cell surface or matrix | Soluble antigen | Cell-associated or environmental |
| Tissue involvement | Local/systemic | Organ-specific | Systemic/local | Local/systemic |
Clinical Relevance: Diagnosis and Treatment Implications
Hypersensitivity reactions are implicated in a broad range of clinical disorders. Accurate identification of the underlying type is crucial for:
- Guiding diagnostic investigations (e.g., skin tests, serology, biopsy)
- Implementing targeted therapeutic strategies (e.g., immunosuppression, allergen avoidance, specific immunotherapy)
- Prognostication and patient education
For example, rapid recognition and management of Type I reactions (such as anaphylaxis) are life-saving, whereas chronic autoimmune diseases mediated by Type II or Type IV mechanisms may require long-term immunosuppression and multidisciplinary care. The risk of iatrogenic hypersensitivity (e.g., drug reactions) must also be considered in clinical practice, emphasising the importance of detailed history-taking and vigilance.
Conclusion
Hypersensitivity reactions exemplify the double-edged nature of the immune system, wherein mechanisms evolved for host defence can cause significant pathology when dysregulated. The Gell and Coombs classification remains a useful tool for conceptualising these reactions, though it is recognised that overlap and complexity exist in many clinical scenarios. Advancements in immunology continue to refine our understanding of these processes, paving the way for novel diagnostic markers and targeted therapies.
For clinicians and medical students, a solid grasp of hypersensitivity mechanisms is essential for the diagnosis, management, and prevention of a wide array of immune-mediated diseases. Ongoing research into the molecular underpinnings of hypersensitivity promises further improvements in patient care and outcomes.
REFERENCES
- Apurba S Sastry, Essential Applied Microbiology for Nurses including Infection Control and Safety, First Edition 2022, Jaypee Publishers, ISBN: 978-9354659386
- Joanne Willey, Prescott’s Microbiology, 11th Edition, 2019, Innox Publishers, ASIN- B0FM8CVYL4.
- Anju Dhir, Textbook of Applied Microbiology including Infection Control and Safety, 2nd Edition, December 2022, CBS Publishers and Distributors, ISBN: 978-9390619450
- Gerard J. Tortora, Microbiology: An Introduction 13th Edition, 2019, Published by Pearson, ISBN: 978-0134688640
- Durrant RJ, Doig AK, Buxton RL, Fenn JP. Microbiology Education in Nursing Practice. J Microbiol Biol Educ. 2017 Sep 1;18(2):18.2.43. https://pmc.ncbi.nlm.nih.gov/articles/PMC5577971/
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