Hypersensitivity: It is an exaggerated immune response to an otherwise innocuous antigen. The immune response may lead to disease state especially if it becomes chronic or repetitive. Depending on the pathophysiology, hypersensitivity reactions can be classified as follows:
Type I: It is mediated by IgE. Allergens are antigens that evoke a type I hypersensitivity response in susceptible individuals, by driving a predominantly Th2 immune response. On initial exposure to an allergen, IgE is produced that is then bound to high affinity FcεRI receptors on mast cells, eosinophils and basophils. Subsequent exposure causes the allergen to bind to IgE causing cross-linking of FcεRI bound IgE on activated eosinophils, basophils and mast cells.
Mast cell granules contain preformed enzymes like tryptase, cathepsin, carboxypeptidase and inflammatory mediators like histamine and heparin. After activation, mast cells release cytokines, chemokines and lipid mediators like IL4, IL13, TNF alpha, MIP, leukotrienes C4,D4 and E4 and platelet activating factor. The result is a sustained inflammatory response with increased recruitment of eosinophils, basophils and TH2 T cells and increased IgE production.
Mast cell degranulation causes decreased airway diameter, mucosal swelling and increased mucus secretion (wheezing, cough); increased fluid secretion and peristalsis in the GIT (vomiting and diarrhea) and increased blood vessel permeability and increased blood flow (erythema, edema and shock). Clinical features depend on the site of the inflammatory response like nasal mucosa in allergic rhinitis or bronchioles in asthma.
Eosinophils , in addition, release several enzymes, cytokines, chemokines and lipid mediators like major basic protein, peroxidases, collagenases, eosinophil cationic protein, neurotoxin, IL3,5,8, PAF and leukotrienes C4,D4 and E4. It results in tissue damage. Basophils release histamine and IL4.
IgE mediated responses occur in two phases- an immediate response followed by a delayed response. Immediate response starts within seconds, is due to the actions of histamine, prostaglandins and release of preformed granules causing increased vascular permeability and smooth muscle contraction. The late phase response occurs 8-12 hours after activation and is due to newly synthesized mediators like leukotrienes, chemokines etc from mast cells, with sustained edema, smooth muscle contraction and airway hyperresponsiveness.
| Route of exposure to allergen | Manifestations |
| Inhalation | Allergic rhinitis, asthma |
| Intravenous | Anaphylaxis |
| Subcutaneous | Wheal and flare reactions |
| Ingestion | Vomiting, diarrhea, may cause urticaria and anaphylaxis after absorption |
| Type | Features |
| Atopy | Tendency of exaggerated response to common environmental allergens; genetic predisposition; high levels of IgE and eosinophils; increased risk of allergic diseases like asthma, hay fever etc. |
| Anaphylaxis | Life threatening syndrome caused by disseminated mast cell activation; presents with shock, bronchoconstriction, epiglottic swelling; seen in the presence of preformed IgE to drugs like penicillin, insect bites or venom, peanuts, brazil nuts,shellfish |
| Allergic rhinitis | Results from the activation of mast cells in the nasal mucosa by inhaled allergens like pollen; manifests as nasal itching, rhinorrhea, sneezing, nasal blockage; eosinophils are present in the nasal discharge; |
| Allergic asthma | Results from mast cell activation in the lower airways; presents with dyspnea, bronchoconstriction, increased mucus and fluid discharge, airway hyperresponsiveness to environmental pollutants like cigarette smoke, sulfur dioxide; chronic inflammation with airway damage may occur; attacks may be exacerbated by viral respiratory tract infections |
| Urticaria (hives) | Ingested allergens may be absorbed into the bloodstream, reach the skin and activate allergen-specific mast cells in the skin to cause urticaria or hives, lesions are itchy, red papules; chronic urticaria is an autoimmune disorder caused by antibodies to FcεRI receptor |
| Eczema or atopic dermatitis | Chronic, relapsing inflammatory disease of the skin, first appears in early childhood, 25% cases progress to adult atopic dermatitis; increased risk of asthma and hay fever; familial history of allergy, atopy; filaggrin gene mutations may be seen; parakeratosis and hyperkeratosis seen; presents as itchy, erythematous, vesicular, maculopapular rash, with oozing and crusting; characteristically seen in flexures of the elbows and knees in children and face, scalp and extensor surfaces of the arms and legs in infants; common locations in adults include face, neck, hands |
Type II or cytotoxic: It is also known as antibody mediated hypersensitivity. It is mediated by IgG or IgM produced in response to cell surface or matrix antigens. The antibody bound cells are then cleared by Fc receptor mediated phagocytosis by NK cells and macrophages in the spleen. It is seen in drug induced hemolytic anemia and thrombocytopenia with penicillin, quinidine and methyldopa, some transplant rejections, Goodpasture’s syndrome and in ADCC (antibody dependent cell mediated cytotoxicity). In complement dependent type II hypersensitivity, antigen-antibody complexes activate complement leading to cell lysis and tissue damage. In some cases, antibodies are directed against receptors e.g. Grave’s disease (stimulating anti TSH antibodies; anti acetylcholine receptor in myasthenia gravis and anti parietal cell in pernicious anemia).
Type III: It is seen with soluble antigens and is mediated by IgG. Antigen -antibody complexes deposit in blood vessels and locally in tissues causing type III hypersensitivity reactions. Arthus reaction is seen locally when an antigen is injected into the dermis, and it reacts with preformed IgG leading to complement activation, binds to Fc receptors on leukocytes (Fcgamma on eosinophils) and local inflammatory response.
Serum sickness is a systemic type III hypersensitivity. In the modern era, it is seen more commonly from drugs like penicillins, cephalosporins, bupropion, thiouracil, fluoxetine and sulfonamides. Other precipitating agents are antilymphocyte globulin, streptokinase, streptococcal infections and Hep B. In older days, it was seen after injection of foreign serum like horse serum, hence the name serum sickness. It typically presents 7-10 days after exposure to the antigen with fever, chills, arthralgia, urticaria, rash, arthritis and glomerulonephritis. Immune complexes are formed throughout the body, which fix complement and activate leukocytes, leading to tissue damage.
Some type III hypersensitivity reactions can occur due to a persistent infection like subacute bacterial endocarditis and chronic viral hepatitis, and in autoimmune disorders like SLE. It can be seen after exposure to high concentrations of inhaled allergens like mold and hay in farmer’s lung.
Type IV: It is also called delayed hypersensitivity and is mediated by T cells. Full-blown response takes 24-72 hours to manifest. Antigens injected into the skin like tuberculin, lepromin, insect venom can induce local edema, induration and dermatitis. Antigens or haptens that are absorbed into the skin due to itching or scratching, like poison ivy, nickel, chromate can cause local reaction with erythema, vesicular rash and intraepidermal abscesses. Exposure to gliadin in gluten sensitive individuals can cause villous atrophy of the small intestine and Celiac disease.
| Type | Cells involved | Mechanism |
| Tuberculin or lepromin tests | Th1 cells | Activated T cells release gamma interferon, TNF beta, TNF alpha, GM-CSF , IL3 and chemokines; followed by inflammation |
| Cutaneous or contact hypersensitivity | CD4 or CD8 cells | Protein -hapten complexes sensitize Langerhans cells in the dermis, which then activate T cells. In elicitation phase, repeat exposure causes memory T cells to release cytokines like gamma interferon and IL 17 which stimulate keratinocytes to release cytokines and chemokines, causing local inflammation |