SJS is a
type IV hypersensitivity reaction in which a drug or its metabolite stimulates
cytotoxic T cells (i.e. CD8+ T cells) and
T helper cells (i.e. CD4+ T cells) to initiate
autoimmune reactions that attack self tissues. In particular, it is a type IV, subtype IVc, delayed hypersensitivity reaction dependent in part on the tissue-injuring actions of
natural killer cells. and
acute generalized exanthematous pustulosis which is a Type IV, subtype IVd, hypersensitivity reaction dependent in part on the tissue-injuring actions of
neutrophils. Like other SCARs-inducing drugs, SJS-inducing drugs or their metabolites stimulate CD8+ T cells or CD4+ T cells to initiate autoimmune responses. Studies indicate that the mechanism by which a drug or its metabolites accomplishes this involves subverting the
antigen presentation pathways of the
innate immune system. The drug or metabolite covalently binds with a host protein to form a non-self, drug-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
T-cell receptors on CD8+ T cells or CD4+ T cells. Those peptides expressing a drug-related, non-self epitope on one of their various HLA protein forms (
HLA-A,
HLA-B,
HLA-C,
HLA-DM,
HLA-DO,
HLA-DP,
HLA-DQ, or
HLA-DR) can bind to a T-cell receptor and thereby stimulate the receptor-bearing parent T cell to initiate attacks on self tissues. Alternatively, a drug or its 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. In all these cases, however, a non-self epitope must bind to a specific HLA
serotype (i.e. variation) 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 SJS-inducing drug or metabolite interacts with only one or a few HLA serotypes, a drug's ability to induce SCARs is limited to those individuals who express HLA serotypes targeted by the drug or its metabolite. Accordingly, only rare individuals are predisposed to develop a SCARs in response to a particular drug on the bases of their expression of HLA serotypes: Studies have identified several
HLA serotypes associated with development of SJS, SJS/TEN, or TEN in response to certain drugs. In general, these associations are restricted to the cited populations. In some
East Asian populations studied (
Han Chinese and
Thai),
carbamazepine- and
phenytoin-induced SJS is strongly associated with HLA-B*1502 (
HLA-B75), an
HLA-B serotype of the broader serotype
HLA-B15. A study in Europe suggested the
gene marker is only relevant for East Asians. This has clinical relevance as it is agreed upon that prior to starting a medication such as allopurinol in a patient of Chinese descent, HLA-B*58:01 testing should be considered. Other HLA associations with the development of SJS, SJS/TEN, or TEN and the intake of specific drugs as determined in certain populations are given in
HLA associations with SCARs.
T-cell receptors In addition to acting through HLA proteins to bind with a T-cell receptor, a drug or its metabolite may bypass HLA proteins to bind directly to a T-cell receptor and thereby stimulate CD8+ T or CD4+ T cells to initiate autoimmune responses. In either case, 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 drug'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 the drug or its metabolite. Thus, only rare individuals are predisposed to develop SJS in response to a particular drug on the bases of their expression of specific T-cell receptor types. These variations influence the levels and duration of a drug or its metabolite in tissues and thereby impact the drug's or metabolite's ability to evoke these reactions. variant of CYP2C9, which has reduced metabolic activity compared to the
wild type (i.e. CYP2c9*1) cytochrome, have increased blood levels of phenytoin and a high incidence of SJS (as well as SJS/TEN and TEN) when taking the drug. In addition to abnormalities in drug-metabolizing enzymes, dysfunctions of the kidney, liver, or GI tract which increase a SCARs-inducing drug or metabolite levels are suggested to promote SCARs responses. ==Diagnosis==