Drug allergy pathophysiology
Editor-In-Chief: C. Michael Gibson, M.S., M.D.  Associate Editor(s)-in-Chief: Charmaine Patel, M.D. 
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An allergic reaction will not occur on the first exposure to a substance. The first exposure allows the body to create antibodies and memory lymphocyte cells for the antigen. However, drugs often contain many different substances, including dyes, which could cause allergic reactions. This can cause an allergic reaction on the first administration of a drug. For example, a person who developed an allergy to a red dye will be allergic to any new drug which contains that red dye.Medications can cause allergic reactions through various mechanisms. The drug can either act as a direct antigenic particle, or it can cause activation of immune cells by the direct interaction with immune cell receptors.
Drugs Acting as Antigens
Most drugs do not act as antigenic particles in their mature form. This is because they are usually small, and therefore not recognized by immune receptors enough to actually activate T cells or B cells. However, drugs can act as antigens if they are presented to lymphocytes by antigen presenting cells such as dendrites. This response specific to the drug can be solely T-cell mediated, antibody mediated, or can have components of both.
- Stimulation of the antibody response- In general, antigens are processed by antigen presenting cells and presented to T-cells. This leads to t-cell activation and produces cytokines which then activate B cells. B cells then recognize the antigen through its IgG receptor, and becomes activated subsequently producing antigen-specific immunoglobulins. Modern pharmaceuticals that are proteins or resemble proteins, can stimulate antibody and T cell responses similar to other protein antigens. Examples of drugs that cause this type of reaction are:
- Recombinant proteins (monoclonal antibodies)
Some of these compounds can induce antibody formation without any T cell interaction.
- Drugs as haptens or pro-haptens- Small drugs can become immunogenic by binding covalently to larger macromolecules such as host proteins on cell surfaces or in plasma. The drug is then called a hapten, and the antigenic compound is then called a hapten-carrier complex. These complexes can also induce a a T cell and antibody response. Drugs that give rise to metabolites that can act as haptens are called pro-haptens. For example, penecillin often acts as a hapten when the beta-lactam ring breaks open and reacts with lysine to form a hapten-carrier complex called penecilloyl determinant, which is capable of stimulating T-cells and antibodies  . A few drugs which have this capability are
- Penicillin and other beta-lactam antibiotics
- Gold and other heavy metals
- Reactive metabolites- Some drugs may not be reactive with macromolecules in their original state, however may form reactive particles after undergoing metabolism by CYP450 enzymes. As part of drug metabolism by hepatocytes, some drugs may not undergo correct detoxification and bind to or haptenate intracellular proteins.  Alternatively, they may be excreted by the cell and processed by antigen presenting cells. These antigen presenting cells can then present the drug on the surface of the cells to T cells. T cells would then produce cytokines and to stimulate B cells, and both T cell and antibody mediated responses would then occur. Glutathione usually neutralizes drugs that give rise to intermediates during metabolism. Some drugs escape neutralization. Examples of these drugs are:
- Sulfonamide antimicrobials
- Phenytoin,carbamazepine, and lamotrigine
Specific Reaction Types
The Gell and Coombs system separates immunologic reactions into four categories, and can be used whether the reaction is caused by drugs, infectious processes, or autoimmune disease. Types I, II, and III reactions are mediated by antibodies as the main immunologic component, whereas type IV is mediated by T cell response. Type IV can also be subdivided into four categories.
- Type I (IgE mediated) - this type of reaction involves a drug specific IgE immunoglobulin. The drug or its metabolite can be a hapten, can act as part of a hapten-carrier complex, can be an antigen in its native form, or can be produced by an IgE mediated previous sensitization to a cross reacting substance. The sensitization stage involves the production of drug-specific IgE, and its binding to mast cells and basophils. It is clinically asymptomatic. The effector stage occurs when the already sensitized individual is re-exposed to the specific drug. The drug again couples to carrier proteins and then proceeds to cross-link IgE on mast cell surfaces. This results in an inflammatory cascade causing release of vasoactive mediators.
- Type II (antibody-mediated cell destruction)- This reaction usually occurs in the setting of high dose long-term drug exposure where the individual makes high titers of preformed drug specific IgG antibodies. These reactions are uncommon, and effect only certain individuals. They occur when the drugs bind to the surfaces of cells such as red blood cells, platelets, and neutrophils, and subsequently act as antigens. Binding causes the cells to be tagged for clearance. Drugs that cause a type II reaction are:
- Type III (immune complex deposition) - These reactions are caused by immune complex deposition reactions such as serum-sickness like reactions, vasculitis, and drug fever. Like type II reactions, type III reactions also occur in the setting of chronic, high dose drug exposure. The drug is solubilized and binds drug-specific IgG. These particles conglomerate and accumulate to form immune complexes which accumulate in areas such as the glomeruli, the joints, and the blood vessels. They then activate complement particles and cause a widespread inflammatory response. Exposing the individual again usually leads to more rapid and severe symptoms.
- Type IV - (cell mediated) - Type IV reactions involve T cells as well as the other cell types such as macrophages, eosinophils, and neutrophils. Unlike the other reactions, type IV mediated reactions do not involve antibodies. Reactions involving T cells present with prominent skin findings because the skin contains numerous T cells.
- ↑ Lafaye P, Lapresle C (1988). "Fixation of penicilloyl groups to albumin and appearance of anti-penicilloyl antibodies in penicillin-treated patients". J. Clin. Invest. 82 (1): 7–12. doi:10.1172/JCI113603. PMC 303468. PMID 3392217. Unknown parameter
- ↑ Padovan E (1998). "T-cell response in penicillin allergy". Clin. Exp. Allergy. 28 Suppl 4: 33–6. PMID 9761028. Unknown parameter
- ↑ Meekins CV, Sullivan TJ, Gruchalla RS (1994). "Immunochemical analysis of sulfonamide drug allergy: identification of sulfamethoxazole-substituted human serum proteins". J. Allergy Clin. Immunol. 94 (6 Pt 1): 1017–24. PMID 7798534. Unknown parameter