Relationship between drug hypersensitivity and major histocompatibility (MHC) molecules

Hypersensitivity to drugs is a group of adverse drug reactions whose side effects can even be fatal worldwide, and in most cases, despite the huge investments and extensive research that has been done in the production of drugs, it causes the drug to be discarded. Adverse drug reactions (ADRs) are generally divided into two categories: A and B. Type A reactions are predictable and dose-dependent, but type B adverse drug reactions are unpredictable and dose-independent, sometimes accounting for up to 20% of all adverse drug reactions, including severe drug allergies. It is due to the immune system (drug allergy) or reactions without immune intervention. ADRs of type A, also known as adverse pharmacological drug reactions, occur for two reasons: the first, dose changes or pharmacokinetics that cause changes in reactions related to efficacy or detoxification. The second, a change in the structure of the target that leads to a change in the drugchr('39')s propensity for it or to a new flow of reactions due to the binding of the agonist to the target receptor. In contrast, adverse drug reactions of type B are caused by severe drug allergies due to allergenic or non-allergenic mechanisms of the immune system or its mediators such as histamine. The molecules of the major histocompatibility complex (MHC) are one of the most important factors in how and what is the variety of immune responses in different people. Numerous studies have reported the association of some variants of these molecules in the presence and absence of certain diseases, including malignancies and autoimmune diseases. Over the past decade, several studies have been performed on the association of MHC or HLA alleles with drug hypersensitivity syndromes (DHS), which promises to be able to diagnose and identify high-risk patients and thus may prevent the development of DHS, which seemed previously unpredictable. In 1989, a study was performed on patients in southern China taking allopurinol for skin rashes, with a strong positive association between HLA alleles, class AW33 and B17/BW58, and a negative association with the A2 allele. These findings indicate that the genetic background in dermal drug reactions is associated with and not associated with some MHC class I and II molecules. In 2007, the Food and Drug Administration (FDA) recommended a screening test to determine the HLA-B*15:02 allele in high-risk populations before carbamazepine. In 2011, a genome-wide association study (GWAS) of the Nordic and Japanese populations found that the Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic (DRESS) diseases observed in carbamazepine-associated patients were associated with the 31:01 HLA-A*allele. In 2013, a study of black African populations reported the association of the HLA-C*04:01 allele with SJS/TEN and the HLA-DRB1*01:02 and HLA-B*58:01 alleles with Nevirapine-induced hepatitis. In 2015, researchers applied chemical modifications using in silico methods to abacavir to create a molecule that retains its antiviral activity; meanwhile, being able to bind to HLA-B57: 01 and activate T cells. In 2018, a study was performed on the Taiwanese and Malaysian populations on the association of HLA-B*13:01 allele with severe cutaneous adverse drug reactions (SCAR) induced by dapsone antibiotic, which showed a positive association of this allele with DRESS phenotype. In 2019, a study of variants predisposing individuals to drug-induced liver injury (DILI) found that a missense polymorphism that causes tryptophan to be replaced by arginine in the PTPN22 gene was most associated with this phenotype and strongly associated with DILI due to the use of the antibiotic co-amoxiclav in patients with European ethnicities, and the probability of developing DILI in this population is twice as high in people who, in addition to the mentioned polymorphisms, are also carriers of HLA-A*02:01 and DRB1*15:01 predisposing alleles. Genetic differences in different races necessitate these studies in different populations and countries. Therefore, based on a review of the literature, we suggest that these studies should be performed in the Iranian population, especially in allergic diseases.