Hypersensitivity

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 allergen exposure and clinical presentation

Types of type I hypersensitivity

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.

Mechanisms of type IV hypersensitivity