CD8+ T-cell activation by methazolamide causes methazolamide-induced Stevens–Johnson syndrome and toxic epidermal necrolysis

Abstract

Background

Methazolamide (MZ), a carbonic anhydrase inhibitor, occasionally causes Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Susceptibility to MZ-induced SJS/TEN is strongly associated with HLA-B*59:01.

Objective

To characterize the T-cell response against MZ in patients with MZ-induced SJS/TEN.

Methods

We enrolled four patients with MZ-induced SJS/TEN, performed lymphocyte transformation tests, generated MZ-specific T-cell clones, and evaluated the cytotoxic activities of these clones. Subsequently, we analyzed the human leukocyte antigen (HLA)-restricted T-cell response.

Results

Strong proliferative response to MZ was evident, whereas mild proliferative response to acetazolamide was also apparent. MZ-specific T-cell clones (CD8⁺ T-cells) were generated from the patient. These clones proliferated and secreted granzyme B upon MZ stimulation; MZ also increased the expression level of CD107a and granzyme B. Cell proliferation and granzyme B secretion stimulated by MZ were blocked by anti-HLA class I antibodies.

Conclusions

This is the first demonstration of the immunologic mechanism by which MZ -induces SJS/TEN.

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