Lesional activation of T_c 17 cells in Behçet disease and psoriasis supports HLA class I-mediated autoimmune responses.

Abstract

Behçet disease (BD) presents with lymphocytic and neutrophilic vasculitis of unknown aetiology. HLA-B*51, the endoplasmic reticulum aminopeptidase 1 (ERAP1), and interleukin 23 receptor (IL23R)/IL12R are genetic risk factors. IL-23 regulates IL-17A, which controls the recruitment and activation of neutrophils. To determine pathological changes in BD skin lesions related to the complex genetic predisposition. We characterized the expression of IL-17A and IL-23A in various cell types by immunohistological double staining of sections from papulopustular skin lesions of acute attacks of BD and psoriasis vulgaris lesions, another HLA-class I-associated T-cell-mediated autoimmune disease in which excessive T-cell-derived IL-17A production promotes neutrophil activation. We found that in BD lesions, as in psoriasis, actively expanding CD8⁺ T cells were the predominant source of IL-17A. IL-17A⁺ CD8⁺ T (T_c 17) cells outnumbered infiltrating IL-17A⁺ CD4⁺ T cells. Unlike the epidermal localization of CD8⁺ T cells in psoriasis, T_c 17 cells in BD lesions mainly infiltrated the perivascular tissue and the blood vessel walls of dermis and subcutaneous tissue. They co-localised with a marked IL-23A expression by CD11c⁺ dendritic cells and CD68⁺ macrophages. IL-17A expression was associated with extensive recruitment of neutrophils around blood vessels that formed neutrophil extracellular traps (NETs). In BD, the genetic predisposition may mediate antigen-specific activation and differentiation of a T_c 17 response, possibly targeting endothelial (auto)antigens. Neutrophils recruited by IL-17A in this process may enhance tissue damage by extensive NET formation (NETosis). Thus, the IL-23/IL-17 axis presumably controls neutrophilic inflammation in BD vasculitis in the context of a predominant antigen-specific CD8⁺ T-cell response.