The term hypersensitivity reaction has been described as an exaggerated and inappropriate immune response, to self or foreign antigen, that is harmful to the host1. Gell and Coombs went further to define 4 distinct types of these reactions based on their pathophysiology (Types I, II, III, IV). These are classified with regard to the mechanisms of tissue injury involved: type I (immediate or anaphylactic [IgE] mediated), type II (cytotoxic or IgG/IgM mediated), type III (immune complex mediated), and type IV (delayed-type or T-cell mediated) 2. This classification is later described to reflect similar immunopathology of disease when referring to types I, II, and III which are antibody-mediated whereas type IV is cell mediated1,2.
With time the clinical utility of this classification has been called into question and in turn, has evolved in several ways. This report seeks to outline the original Gell and Coombs classification of hypersensitivity reactions, the immunopathological correlations as well as modern additions to its understanding.
Type I Hypersensitivity
Type I hypersensitivity is an immediate type of immune reaction that typically occurs on exposure to antigens commonly present in the environment1,2. It can be characterised by (1) its immediacy, usually taking place in minutes (2) the production of IgE antibodies, and (3) identifiable wheal and flare skin responses1-3. The antigens that give rise to immediate hypersensitivity are referred to as allergens and thus sometimes this type of reaction is called allergic hypersensitivity1.
Initial contact with the allergen sensitizes the host by inducing the production of IgE antibodies which then bind to Fc receptors on mast cells and basophils1. Large amounts of antibodies are formed owing to massive B cell class switching driven by T helper 2 cells’ release of cytokines, primarily IL-4. Subsequent exposure to the allergen results in cross-linking of the bound IgE antibodies causing degranulation of mast cells and basophils1,2. The reaction occurs in two phases; Immediate and late phase1-3. The immediate response is due to the release of preformed mediators (histamine, serotonin, proteases (tryptase and chymase) prostaglandin D2 and leukotriene C4 and lysosomal enzymes), from these effector cells within 15 minutes1,2. Late phase activity develops on average after 6 hours. Late reactions are accounted for by the mediators synthesized after degranulation, including cytokines such as IL 1, 4, 5, and 13, TNF, GM-CSF1,2. This also further recruits eosinophils and neutrophils which add to the effector actions in type I reactions.
Clinical manifestations are a result of the effects of mediators and include vasodilation, increased vascular permeability, and smooth muscle contraction such as bronchoconstriction4,5. By and large, the manifestations depend on the route of entry of the allergen and the location of reactive mast cells1. Localised exposure from inhalation or topical will result in symptoms like sneezing, rhinorrhoea, nasal congestion, or bronchospasm (as seen in allergic rhinitis, asthma, or hay fever) or urticaria, erythema, and induration (atopic dermatitis) respectively. Exposure from intravenous or oral route may result in systemic manifestations (like hypotension, angioedema, diarrhea, and shock seen in anaphylaxis4.
Only susceptible individuals will develop allergic disease when exposed to allergens. Certain individuals have a genetic predisposition to this type of hypersensitivity and are referred to as atopic5. They are characterised by high serum IgE levels. Disorders like asthma have a strong familial predisposition. The usual clinical presentation in asthma patients is chest tightness, wheezing, coughing, shortness of breath1–5. This results from reversible airflow obstruction, non-specific bronchial hyperreactivity, and chronic airway inflammation. The pathologist can obtain bronchioalveolar lavage and lung tissue specimen that demonstrates mucus plugging containing inflammatory infiltrates and MBP expression in lung tissue. Respiratory epithelium may show sloughing of epithelial cells and substantial eosinophil infiltrates. Indirect evidence of asthma is demonstrated from nasal smears and secretions showing eosinophils and certain cytokines such as IL-8. 5
Unlike asthma, Anaphylaxis however is a severe generalized immediate hypersensitivity that may cause death. It is not considered to be familial. Most of the pathophysiological changes are attributed to histamine6. These include respiratory symptoms (rhinorrhoea, angioedema, stridor, sneezing, wheezing, bronchoconstriction, cough, dyspnoea, hypoxia), cardiovascular (vasodilation, tachycardia, hypotension, increased vascular permeability), skin (flushing, urticaria, itch), digestive (nausea, vomiting, abdominal pain, diarrhoea). Almost all systems can be involved4. As it is most certainly life-threatening, diagnostic features are evaluated retrospectively and include; high circulating IgE levels, and serum tryptase, and plasma histamine, within an hour of symptom onset4,6.
Type II Hypersensitivity
When IgG and/or IgM antibodies bind self-antigens on cell surface membranes, it results in complement-mediated lysis, the so-called cytotoxic hypersensitivity1–3. Activation of complement through antibody binding leads to the formation of membrane attack complex (MAC). Various mechanisms have been proposed for type 2 hypersensitivity reactions: (1) complement-dependent cytotoxicity; (2) antibody-directed cellular killing and (3) antibody-mediated phagocytosis (opsonization) 1–3.
In complement-dependent cytotoxicity, the resulting antigen-antibody complex activates complement cascade forming a MAC that causes host cell lysis1,2. This is an underlying mechanism in autoimmune haemolytic anaemia and autoimmune thrombocytopenic purpura. In antibody-dependent cell-mediated cytotoxicity, the bound IgG’s free Fc gamma receptor IIb (Fc_RIIb) interacts with NK cells and macrophages which degranulate (release perforin and granzyme) and potentiate cell lysis1,7. Finally, the antibodies in this reaction may act as opsonins coating the host cell and therefore facilitate cell death via phagocytosis. Conditions that have these mechanisms as their aetiology include ABO transfusion reactions, haemolytic disease of the newborn, rheumatic fever, ANCA-associated vasculitis, pemphigus, myasthenia gravis, and Goodpasture’s syndrome1,2,7,8.
In ABO transfusion reactions, pre-existing IgM or less commonly IgG antibodies interact with donor A or B antigens in mismatched individuals, activating complement and leading to red cell osmolysis7. The resultant release of haemoglobin and thus free heme may overwhelm the renal system and lead to acute renal tubular necrosis and even renal failure. A transfusion reaction involving other blood groups usually occurs when there is incomplete complement activation. C3b from complement cascade acts to opsonize the incompatible red cell causing extravascular destruction which takes place between 3 and 30 days. The usual signs of acute haemolytic reactions are flank pain, reddish urine, and fever7. A positive direct Coombs test (detecting IgG antibodies on the surface of red blood cells) is pathognomonic for this reaction. Testing for urine and plasma-free haemoglobin is also recommended. Alternatively, the transfusion sample should be tested for infectious agents by culture or gram stain to rule out possible differential causes. Additionally, spherocytes and micro spherocytes may be seen on peripheral blood smear7
Anti-glomerular basement membrane antibodies in a similar fashion are responsible for Goodpasture’s syndrome. The classical IgG antibodies against the non-collagenous domain 1 of the a3-chain of type IV collagen (a3(IV)NC1) bind the basement membranes of the glomerulus, alveoli (also testis, eye, inner ear, and choroid plexus in some cases) activating complement8,9. The affected individuals present with a reno-pulmonary syndrome characterised by rapidly progressive glomerulonephritis, possible nephrotic syndrome, and pulmonary involvement (alveolar haemorrhage, bilateral lung consolidation). On light microscopy of renal biopsy specimens, there is widespread crescent formation in more than 80% of glomeruli in most cases. Linear IgG staining on GBM accompanied by c3 deposition can be revealed by direct immunofluorescence microscopy8. Diffuse pulmonary haemorrhage and sometimes reticulonodular and interlobular septal thickening can be demonstrated in lung tissue. Most individual serology will have high titres of circulating anti-GBM which are pathognomonic when presented with renal and/or pulmonary insufficiency9.
A newly revised Gell and Coombs classification describes a type IIb reaction involving antibodies that stimulate cells directly. This is a characteristic of certain autoimmune disorders such as Graves’ disease1,2.
Type III Hypersensitivity
Occurs when antigen-antibody (IgG and IgM) complexes persist and are deposited in tissues causing many disorders; by activating complement, attracting PMN cells, and resulting in inflammation and tissue damage at the site of complex deposition. The resulting immune complex disease can be due to complexes formed from (1) persistent infection (viral hepatitis, malaria, leprosy), (2) autoimmunity (systemic lupus erythematosus, SLE, rheumatoid arthritis, RA), or (3) inhaled antigen (farmers’ lung, pigeon fancier’s lung) 1–3.
One of the commonest inflammatory diseases, RA, results from complex deposition in the joint space. It is characterised by persistent synovial inflammation coupled with damage to the articular cartilage and bone erosion10,11. Autoantibodies against citrullinated peptides and IgG (rheumatoid factor) are diagnostic; whether in circulation or from a synovial biopsy. Other diagnostic tests may include elevated markers of systemic inflammation such as CRP or ESR10,11. Patients with RA may also suffer extraarticular manifestations including vasculitis and interstitial lung disease and systemic comorbidities such as rheumatoid nodules, secondary amyloidosis, lymphoma, and cardiovascular disease. Ocular, cutaneous neurological, and renal disease are sometimes seen as well10,11.
Systemic lupus erythematosus is also another chronic inflammatory autoimmune disease. Its pathogenesis is somewhat complex but more commonly associated with immune complex deposition, complement activation, and progressive inflammation12,13. Other known mechanisms include direct cell lysis and cellular opsonization. Autoantibodies forming the complexes (IgA, IgM, or IgG) are formed against a number of self-antigens: DNA (single-stranded and double-stranded), chromatic, histone, Sm, SSA/Ro SSB/La, and RNP as well as anti-C1q phospholipid associated proteins, cytoplasmatic molecules, endothelial-membrane antigens, complement fragments, and IFNs12,13. Of these, antinuclear antibodies are the most well associated. High titres of these antibodies in serology and immunofluorescence and presence of clinical sign/symptoms is usually diagnostic. A positive direct Coombs test in the absence of haemolytic anaemia is also useful. 13
SLE symptoms can be either constitutional or organ-specific. Fever, fatigue, and weight changes are the constitutional manifestations. The organ-specific/ systemic manifestations include musculoskeletal, renal, gastrointestinal, pulmonary, cardiovascular, neuropsychiatric, hematologic, ocular, cutaneous, and oropharyngeal. Lupus nephritis, a most common presentation, on immunofluorescence and transmission electron microscopy, demonstrates glomerular damage and anti IgG antibodies, bowman’s capsule, and mesangial and capillary endoluminal immune complex deposition12,13.
Type IV Hypersensitivity
This delayed-type hypersensitivity is T-cell mediated. As described by Gell and Coombs, the classic type IV reactions are mediated by Th1 cells which activate macrophages1. This reaction can be elucidated in contact dermatitis, tuberculin skin tests, type 1 diabetes, and even multiple sclerosis1,2. In contact dermatitis, exposure to an antigen such as poison ivy results in the release of cytokines (IFN and TNF) from Th1 mediated activation of macrophages and causing tissue injury to keratinocytes. Tissue injury is due to reactive oxygen species and lysosomal enzymes primarily. Its clinical features include pruritis, erythema, dryness, and scaling of skin1,14. Diagnosis of contact dermatitis is made primarily from clinical history and sometimes patch testing14.
Following the definition of various subsets of T-cells, the initial description of type IV reactions has been subdivided into types IV a, b, c, d. Th1 type mediated macrophage activation is type IV a. type IV b is described further as Th2 cell-mediated eosinophilic inflammation, as seen in persistent asthma, allergic rhinitis, and DRESS syndrome. Type IV c reactions are CD8 mediated cytotoxic reactions and include disorders such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Type IV d reactions involve T-cell mediated neutrophilic inflammation and can be elucidated in Behçets disease1–3.
In SJS, a severe cutaneous adverse reaction, there is erythematous skin and extensive detachment of the epidermis, and haemorrhagic erosion of mucous membranes. Differentiated from TEN based on less than 30% body surface area coverage. Biopsy of the skin lesions demonstrates scattered keratinocytes, necrosis and apoptosis, and full-thickness epidermal damage. The cytotoxic granulysin produced by T cells is the most important cause of epidermal destruction15.
