Drug Hypersensitivity Reactions: Pathomechanism and Clinical Symptoms
Section snippets
Hapten and Prohapten Concepts
Small chemical compounds, usually less than 1000 Da, are not immunogenic per se. These compounds are normally degraded, metabolized, and eliminated without stimulating an immune response. However, if the chemical is reactive and able to bind covalently to proteins, DNA, and so forth, a new antigenic determinant arises that can produce a new immune response. This modification can, theoretically, affect any kind of autologous protein, such as soluble extracellular proteins (eg, albumin), membrane
Classification of drug hypersensitivity reactions
Coombs and Gell28 classified drug hypersensitivity, as well as other immune reactions, into 4 categories termed type I-IV reactions: This classification relies on the formation of IgE antibodies that bind to high-affinity IgE receptors on mast cells and basophilic leukocytes, on complement-fixing antibodies, and in T-cell reactions. Because recent immunologic data reveal that T cells orchestrate different forms of inflammation, which may result in different symptoms, the classification of
Pseudoallergy (non–immune-mediated hypersensitivity)
So-called pseudoallergic reactions (non–immune-mediated hypersensitivities) to drugs, which are as frequent as true IgE-mediated reactions, are a pathogenetically poorly defined problem.
Most of these reactions resemble the clinical features of milder forms of immediate, IgE-mediated reactions (erythema, urticaria), but some reactions cause anaphylaxis and can be lethal. Detection of specific immune mechanism is negative. NSAID-induced pseudoallergic reactions seem to arise less rapidly (often
IgG-mediated reactions (cytotoxic mechanism and immune complex deposition, types II and III)
Type II and type III reactions rely on the formation of complement-fixing IgG antibodies (IgG1, IgG3). IgM is occasionally involved. They are similar, in that both depend on the formation of immune complexes and interaction with complement and Fc-IgG receptor (Fc-IgGI, IIa, and IIIa)–bearing cells (on macrophages, natural killer [NK] cells, granulocytes, and platelets), but the target structures and physiologic consequences are different.
In type II reactions, the drug-specific antibodies formed
Subclassification of Type IV Reactions
The detailed analysis of T-cell subsets and functions in the last 30 years has revealed that T cells play a major role in most immune reactions: as helper T cells, which regulate B-cell maturation to antibody-producing cells; as drug-specific T cells, which orchestrate different forms of inflammation; or as effector T cells mediating cytotoxicity. Based on these findings, as well as studies of immune reactions to drugs in vitro and in vivo, a refined subclassification of T-cell–meditated type
Summary
Small chemical compounds can interact with the immune system in 2 ways: by forming hapten-carrier complexes, which can stimulate innate and adaptive immunity (T and B cells) and cause localized or systemic reactions due to an immune response against the hapten-carrier complex; alternatively, chemicals that are unable to form covalent bonds can directly interact with proteins by van der Waals and other forces. Some of these labile interactions occur with immune receptors (pharmacologic
References (52)
- et al.
Detection of specific IgE to quinolones
J Allergy Clin Immunol
(2004) - et al.
Allergic and autoimmune reactions to xenobiotics: how do they arise?
Immunol Today
(1998) Direct T-cell stimulations by drugs–bypassing the innate immune system
Toxicology
(2005)- et al.
Delayed-type hypersensitivity reaction to paraphenylenediamine is mediated by 2 different pathways of antigen recognition by specific alphabeta human T-cell clones
J Allergy Clin Immunol
(2002) - et al.
Generation and characterization of antigen-specific CD4+, CD8+, and CD4+CD8+ T-cell clones from patients with carbamazepine hypersensitivity
J Allergy Clin Immunol
(2007) - et al.
Genetic variations in HLA-B region and hypersensitivity reactions to abacavir
Lancet
(2002) - et al.
Association between presence of HLA-B∗5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir
Lancet
(2002) - et al.
Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity
Immunity
(2008) - et al.
HLA-B∗1502-bound peptides: implications for the pathogenesis of carbamazepine-induced Stevens-Johnson syndrome
J Allergy Clin Immunol
(2007) - et al.
Fulminant liver failure after vancomycin in a sulfasalazine-induced DRESS syndrome: fatal recurrence after liver transplantation
Am J Transplant
(2009)
Several distinct properties of the IgE repertoire determine effector cell degranulation in response to allergen challenge
J Allergy Clin Immunol
Perioperative anaphylaxis
Immunol Allergy Clin North Am
The pholcodine story
Immunol Allergy Clin North Am
Rapid desensitization for hypersensitivity reactions to medications
Immunol Allergy Clin North Am
Second symposium on the definition and management of anaphylaxis: summary report–Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium
J Allergy Clin Immunol
Drug specific cytotoxic T-cells in the skin lesions of a patient with toxic epidermal necrolysis
J Invest Dermatol
Long-lasting reactivity and high frequency of drug-specific T cells after severe systemic drug hypersensitivity reactions
J Allergy Clin Immunol
Immunological principles of adverse drug reactions: the initiation and propagation of immune responses elicited by drug treatment
Drug Saf
Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies
JAMA
Severe adverse cutaneous reactions to drugs
N Engl J Med
Drug-induced cutaneous reactions. A report from the Boston Collaborative Drug Surveillance Program on 15,438 consecutive inpatients, 1975 to 1982
JAMA
Comprehensive hospital drug monitoring (CHDM): adverse skin reactions, a 20-year survey
Allergy
Drug hypersensitivity: classification and relationship to T cell activation
Sulfamethoxazole and its metabolite nitroso sulfamethoxazole stimulate dendritic cell costimulatory signaling
J Immunol
Direct, MHC-dependent presentation of the drug sulfamethoxazole to human alphabeta T cell clones
J Clin Invest
HLA-restricted, processing- and metabolism-independent pathway of drug recognition by human alpha beta T lymphocytes
J Clin Invest
Cited by (110)
Drug-induced hypersensitivity reactions in a Lebanese outpatient population: A decade-long retrospective analysis (2012-2021)
2024, Journal of Allergy and Clinical Immunology: GlobalDrug Hypersensitivity Reactions
2023, Immunology and Allergy Clinics of North AmericaDrug Hypersensitivity Reactions
2022, Emergency Medicine Clinics of North AmericaAsthma and Allergy
2022, Clinical ImmunologyBiological toxicity of nanoparticles
2022, Nanoparticle Therapeutics: Production Technologies, Types of Nanoparticles, and Regulatory Aspects