Although HLA linkages have been used to define susceptibility to allergic medication responses, other genetic and nongenetic variables are also likely to be involved. Polymorphic genetic variations in cytokine genes, such as IL-10, and co-signaling pathways, such as CTLA4, have been linked to allergic drug responses, although the impact size is smaller than with HLA alleles, and the majority of correlations have not been reproduced. Although TCR specificity appears to be crucial for CBZ-induced SJS/TEN in South East Asian patients, it is possible that an unique repertoire may not play a role in responses to other medications. New mass spectrometric methods to identify natural eluted peptides from HLA alloys subjected to the medicines will allow definitions of the antigenic source of T-Cell activation. In fact, preliminary results reveal the tendency of medicated T cells to interact with viral antigen T cells. Furthermore, the environment can affect regulatory gene expression epigenetically, suggesting that the family history of exposure may change immunological thresholds and lead to a shift towards activation.
In most situations, susceptibility to allergic medication responses is likely to be complex. This will need the investigation of a large number of patients in order to discover genetic variables with a smaller effect size than HLA alleles. This should be complemented by a comprehensive clinical phenotyping of the patients as well as an assessment of the immunological phenotype in terms of the number and kind of drug antigen-responsive T cells.
