Human leukocyte antigens Like other<unk> -induced SCARs disorders, the DRESS syndrome is a type IV hypersensitivity<unk>  in which a<unk>  or its metabolite stimulates cytotoxic T cells (i.e. CD8+ T cells) or T helper cells (i.e. CD4+ T cells) to initiate autoimmune<unk> s that attack self tissues. DRESS syndrome is a SCARs type IV, subtype IVb<unk> . This contrasts with SJS, SJS/TEN, and TEN which are type IV, subtype IVc<unk> s and AGEP which is a type IV subtype IVd<unk> . DRESS syndrome therefore differs from the other SCARs disorders in that it involves the tissue-injuring action of CD4+ cells and the cell- and tissue-injuring action of eosinophils as well as the release of the following cytokines: Interleukins 5 and 13 which simulate the growth, longevity, and activation of eosinophils; Interleukin 4 which promotes the differentiation of naive helper T cells into Th2 helper cells that then serve to activate eosinophils as well as other types of pro-inflammatory cells; IFNγ which activates macrophages and induces the expression of Class II MHC molecules; and TNFα which promotes inflammation but also has cell-killing actions. Like other SCARs-inducing<unk> s, DRESS syndrome-inducing<unk> s or their metabolites stimulate CD8+ T or CD4+ T cells to initiate autoimmune responses. Studies indicate that the mechanism by which a<unk>  or its metabolites accomplishes this stimulation involves subverting the antigen presentation pathways of the innate immune system. The<unk>  or metabolite covalently binds with a host protein to form a non-self,<unk> -related epitope. An antigen-presenting cell (APC) takes up these alter proteins; digests them into small peptides; places the peptides in a groove on the human leukocyte antigen (i.e. HLA) component of their major histocompatibility complex (i.e. MHC); and presents the MHC-associated peptides to the T-cell receptor on CD8+ T or CD4+ T cells. Those peptides expressing a<unk> -related, non-self epitope on their HLA-A, HLA-B, HLA-C, HLA-DM, HLA-DO, HLA-DP, HLA-DQ, or HLA-DR proteins may bind to a T-cell receptor to stimulate the receptor-bearing parent T cell to initiate attacks on self tissues. Alternatively, a<unk>  or metabolite may stimulate these T cells by inserting into the groove on a HLA protein to serve as a non-self epitope or bind outside of this groove to alter a HLA protein so that it forms a non-self epitope. Importantly, however, non-self epitopes must bind to specific HLA serotypes in order to stimulate T cells. Since the human population expresses some 13,000 different HLA serotypes while an individual expresses only a fraction of them and since a DRESSs-inducing<unk>  or metabolite interacts with only one or a few HLA serotypes, a<unk> 's ability to induce SCARs is limited to those individuals who express HLA serotypes targeted by the<unk>  or its metabolite. Thus, only rare individuals are predisposed to develop SCARs in response to a particular<unk>  on the bases of their expression of HLA serotypes. Studies have identified several HLA serotypes associated with development of the DRESS syndrome in response to certain<unk> s, have developed tests to identify individuals who express some of these serotypes, and thereby have identified individuals who should avoid certain DRESS syndrome-inducing<unk> s. T-cell receptors A<unk>  or its metabolite may also stimulate CD8+ T or CD4+ T cells to initiate autoimmune responses by directly binding to the T-cell receptors on these T cells. Again, this binding appears to develop only on certain T-cell receptors. Since the genes for these receptors are highly edited, i.e. altered to encode proteins with different amino acid sequences, and since the human population may express more than 100 trillion different (i.e. different amino acid sequences) T-cell receptors while an individual express only a fraction of these, a<unk> 's or its metabolite's ability to induce the DRESS syndrome by interacting with a T-cell receptor is limited to those individuals whose T cells express a T-cell receptor(s) that can interact with<unk>  or its metabolite. Thus, only rare individuals are predisposed to develop a SCARs disorder in response to a particular<unk>  on the bases of their expression of specific cell receptor types. While the evidence supporting these ideas is limited, one study identified the preferential presence of the TCR-V-b and complementarity-determining region 3 in T-cell receptors found on the T cells in the blisters of patients with allopurinol-induced DRESS syndrome. This finding is compatible with the notion that specific types of T-cell receptors are involved in the development of specific<unk> -induced SCARs. ADME Variations in ADME, i.e. an individual's efficiency in absorpting, distributing, metabolizing, and excreting a<unk>  has been found to occur in cases of the DRESS syndrome. These variations influence the levels and duration of a<unk>  or<unk>  metabolite in tissues and thereby impact the<unk> 's or<unk>  metabolite's ability to evoke the DRESS syndrome. For example, the CYP2C9 gene codes for CYP2C9, a cytochrome P450 enzyme which metabolizes various substances including phenytoin. The CYP2CP*3 variant of CYP29C has reduced catalytic activity; individuals expressing this variant show an increased incidence of developing the DRESS syndrome when taking phenytoin apparently due to increases in the<unk> 's blood and tissue levels. In a second example of a genetically based ADME defect causing SCARs, Japanese individuals bearing slow acetylating variants of the N-acetyltransferase 2 gene, (NAT2), viz., NAT2*6A and NAT2*7B, acetylate sulfasalazine more slowly than individuals homozygous for the wild type gene. Individuals expressing the NAT2*6A and NAT2*7 variants have an increased risk for developing DRESS syndrome-like<unk> s to this anti-inflammatory<unk> . None-genetic ADME factors are also associated with increased risks of developing the DRESS syndrome. Allopurinol is metabolized to oxipurinol, a product with a far slower renal excretion rate than its parent compound. Renal impairment is associated with abnormally high blood levels of oxipurinol and an increased risk of developing the DRESS syndrome, particularly the more severe forms of this disorder. Dysfunction of the kidney and liver are also suggested to promote this disorder in response to other<unk> s due to the accumulation of SCARs-inducing<unk> s or metabolites in blood and tissues. Currently, it is suspected that the expression of particular HLA proteins and T-cell receptors interact with ADME factors to promote SCARs particularly in their more serious forms. Viral reactivation During the progression of the DRESS syndrome certain viruses that previously infected an individual and then became latent are reactivated and proliferate. Viruses known to do so include certain members of the Herpesviridae family of Herpes viruses viz., Epstein–Barr virus, human herpesvirus 6, human herpesvirus 7, and cytomegalovirus. Individuals suffering the DRESS syndrome may exhibit sequential reactivation of these four viruses, typically in the order just given. Reactivation of these viruses is associated with a flare-up in<unk> , a prolonged course, and increased disease severity which includes significant organ involvement and the development of certain autoimmune diseases viz.,<unk>  lupus erythematosus, autoimmune thyroiditis, and type 1 diabetes mellitus. While these viral reactivations, particularly of human herpes virus 6, have been suggested to be an important factor in the pathogenesis of the DRESS syndrome, studies to date have not clearly determined if they are a cause or merely a consequence of T cell-mediated tissue injury.
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