Hypersensitivity reactions (HR) are immune responses that are exaggerated or inappropriate against an antigen or allergen. Coombs and Gell classified hypersensitivity reactions into four forms. Type I, type II, and type III hypersensitivity reactions are known as immediate hypersensitivity reactions (IHR) because they occur within 24 hours. Antibodies including IgE, IgM, and IgG mediate them.
Type I or Anaphylactic Response
The anaphylactic response is mediated by IgE antibodies that are produced by the immune system in response to environmental proteins (allergens) such as pollens, animal danders, or dust mites. These antibodies (IgE) bind to mast cells and basophils, which contain histamine granules that are released in the reaction and cause inflammation. Type I hypersensitivity reactions can be seen in bronchial asthma, allergic rhinitis, allergic dermatitis, food allergy, allergic conjunctivitis, and anaphylactic shock.
Anaphylaxis is a medical emergency as it can lead to acute, life-threatening respiratory failure. It is an IgE-mediated process. It is the most severe form of an allergic reaction, where mast cells suddenly release a large amount of histamine and later on leukotrienes. In severe cases intense bronchospasm, laryngeal edema, cyanosis, hypotension, and shock are present.
Allergic Bronchial Asthma
Allergic bronchial asthma is an atopic disease, characterized by bronchospasm. It may also be a chronic inflammatory disease. In its etiology, environmental factors along with a genetic background play an important role. The diagnosis is dependent on history and examination. In allergic bronchial asthma, IgE is elevated, and sputum eosinophilia is common. Epidemiologically, a positive skin prick test or specific IgE are risk factors for asthma.
Allergic rhinitis is another atopic disease where histamine and leukotrienes are responsible for rhinorrhea, sneezing, and nasal obstruction. Allergens are similar to those found in bronchial asthma. Nasal polyps may be seen in chronic rhinitis.
Allergic conjunctivitis presents with rhinitis and is IgE-mediated. Itching and eye problems including watering, redness, and swelling always occur.
Clinicians must differentiate food allergy (IgE-mediated) from food intolerance that can be a cause for a variety of etiologies including malabsorption and celiac disease. It is more frequent in children as seen in cow's milk allergy. Food allergy symptoms mostly affect the respiratory tract, the skin, and the gut. Skin prick tests are helpful to test for food allergens that can trigger severe reactions, e.g., peanuts, eggs, fish, and milk.
Atopic eczema is an IgE-mediated disease that affects the skin and has an immunopathogenesis very similar to that of allergic asthma and allergic rhinitis, which are present in more than half of these patients. Radioallergosorbent (RAST) may reveal the specificity of the IgE antibody involved but has little help in management.
Drugs may cause allergic reactions by any mechanism of hypersensitivity. For example, penicillin may cause anaphylaxis, which is IgE-mediated but most responses are trivial. Penicillin cross-reacts with other semisynthetic penicillins including monobactams and carbapenems and may also cross-react with other antibiotics such as cephalosporins.
Type II or Cytotoxic-Mediated Response
IgG and IgM mediate cytotoxic-mediated responses against cell surface and extracellular matrix proteins. The immunoglobulins involved in this type of reaction damage cells by activating the complement system or by phagocytosis. Type II hypersensitivity reactions can be seen in immune thrombocytopenia, autoimmune hemolytic anemia, and autoimmune neutropenia.
Immune Thrombocytopenia (ITP)
ITP is an autoimmune disorder that occurs at any age. Phagocytes destroy sensitized platelets in the peripheral blood. Clinically, it manifests as thrombocytopenia with shortened platelet survival and increased marrow megakaryocytes. Sudden onset of petechiae and bleeding from the gums, nose, bowel, and urinary tract occurs. Bleeding can accompany infections, drug reactions, malignancy, and other autoimmune disorders such as thyroid disease and SLE.
Autoimmune Hemolytic anemia (AIHA)
There are two types of immune hemolytic anemia: IgG-mediated (warm AIHA) and IgM-mediated (cold AIHA). The warm type may be idiopathic autoimmune or secondary to other diseases such as malignancy affecting the lymphoid tissues. The cold type may be idiopathic or secondary to infections such as Epstein-Barr virus. The primary clinical sign of the two is jaundice. The laboratory diagnosis is made by a positive Coombs test, which identifies immunoglobulins and C3 on red blood cells.
Autoimmune neutropenia may be present with bacterial and fungal infections, or it may occur alone or with autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, autoimmune hepatitis), infections and lymphoma. Bone marrow examination is needed if neutropenia is severe. For associated autoimmune disorders, an autoimmune antibody panel is necessary (ANA, ENA, and dsDNA).
Hemolytic Disease of the Fetus and the Newborn (erythroblastosis fetalis)
The maternal immune system suffers an initial sensitization to the fetal Rh+ red blood cells during birth when the placenta tears away. The first child escapes the disease but the mother, now sensitized, will be capable of causing a hemolytic reaction against a second Rh+ fetus, which develops anemia and jaundice once the maternal IgG crosses the placenta.
Myasthenia gravis is an autoimmune disorder caused by antibodies to post-synaptic acetylcholine receptors that interfere with neuromuscular transmission. It is characterized by extreme muscular fatigue, double vision, bilateral ptosis, deconjugate eye movements, difficulty swallowing, and weakness in the upper arms. Babies born to mothers with myasthenia gravis can have transient muscle weakness due to pathogenic IgG antibodies that cross the placenta.
Goodpasture syndrome is a type II hypersensitivity reaction characterized by the presence of nephritis in association with lung hemorrhage. In most patients, it is caused by cross-reactive autoantigens that are present in the basement membranes of the lung and kidney. A number of patients with this problem exhibit antibodies to collagen type IV, which is an important component of basement membranes.
Pemphigus causes a severe blistering disease that affects the skin and mucous membranes. The sera of patients with pemphigus have antibodies against desmoglein-1 and desmoglein-3, which are components of desmosomes, which form junctions between epidermal cells. Pemphigus is strongly linked to HLA-DR4 (DRB1*0402), which is a molecule that presents one of the autoantigens involved in the immunopathogenesis of this disease (desmoglein-3).
Type III or Immunocomplex Reactions
These are also mediated by IgM and IgG antibodies that react with soluble antigens forming antigen-antibody complexes. The complement system becomes activated and releases chemotactic agents that attract neutrophils and cause inflammation and tissue damage as seen in vasculitis and glomerulonephritis. Type III hypersensitivity reactions can classically be seen in serum sickness and Arthus reaction.
Serum sickness can be induced with massive injections of a foreign antigen. Circulating immune complexes infiltrate the blood vessel walls and tissues, causing an increased vascular permeability and leading to inflammatory processes such as vasculitis and arthritis. It was a complication of anti-serum prepared in animals to which some individuals produced antibodies to the foreign protein. It was also experienced in the treatment with antibiotics such as penicillin.
Arthus reaction is a local reaction seen when a small quantity of antigens is injected into the skin repeatedly until detectable levels of antibodies (IgG) are present. If the same antigen is inoculated, immune complexes develop at the mentioned local site and in the endothelium of small vessels. This reaction is characterized by the presence of marked edema and hemorrhage, depending on the administered dose of the foreign antigen.
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