Carbamazepine (CBZ)
is an aromatic anticonvulsant known to cause
drug hypersensitivity reactions, which range in severity from relatively
mild maculopapular exanthema to potentially fatal Stevens–Johnson
syndrome and toxic epidermal necrolysis (SJS–TEN). These reactions
are known to be associated with human leukocyte antigen (HLA) class
I alleles, and CBZ interacts preferentially with the related HLA proteins
to activate CD8+T-cells. This study aimed to evaluate
the contribution of HLA class II in the effector mechanism(s) of CBZ
hypersensitivity. CBZ-specific T-cells clones were generated from
two healthy donors and two hypersensitive patients with high-risk
HLA class I markers. Phenotype, function, HLA allele restriction,
response pathways, and cross-reactivity of CBZ-specific T-cells were
assessed using flow cytometry, proliferation analysis, enzyme-linked
immunosorbent spot, and enzyme-linked immunosorbent assay. The association
between HLA class II allele restriction and CBZ hypersensitivity was
reviewed using Allele Frequency Net Database. Forty-four polyclonal
CD4+CBZ-specific T-cell clones were generated and found
to be restricted to HLA-DR, particularlyHLA-DRB1*07:01. This CD4+-mediated response proceeded through a direct
pharmacological interaction between CBZ and HLA-DR molecules. Similar
to the CD8+response, CBZ-stimulated CD4+clones
secreted granulysin, a key mediator of SJS–TEN. Our database
review revealed an association betweenHLA-DRB1*07:01and CBZ-induced SJS–TEN. These findings implicate HLA class
II antigen presentation as an additional pathogenic factor for CBZ
hypersensitivity reactions. Both HLA class II molecules and drug-responsive
CD4+T-cells should be evaluated further to gain better
insights into the pathogenesis of drug hypersensitivity reactions.