Fixed drug eruptions: evidence for a cytokine‐mediated process

Abstract

Fixed drug eruptions (FDE) are immunologic reactions to drugs which produce erythematous plaques or blisters that characteristically recur at the same cutaneous sites with repeated antigenic challenges. While a detailed pathogenesis of these lesions remains obscure, T-lymphocyte infiltration has been documented repeatedly. In this study, we tried to determine if FDE were mediated, at least in part, by cytokines, such as gamma-interferon. We examined biopsies from 6 cases of clinically well-documented FDE with an HLA-DR antibody, LN3, and an antibody to gamma IP-10 (IP-10), a protein expressed by keratinocytes, monocytes, lymphocytes and endothelial cells following exposure to gamma-interferon. We found staining of the dermal lymphocytes with anti-HLA-DR antibody in all 6 cases examined. Keratinocytes and endothelial cells showed only focal staining at the antibody concentrations used. In addition, there was keratinocyte staining with the IP-10 antibody at all levels of the epidermis, with accentuation in areas of blister formation. There was more intense staining of keratinocytes with the IP-10 antibody in cases with accumulations of HLA-DR positive lymphocytes in the dermis. We believe that these findings are consistent with the hypothesis that FDE represent cell-mediated immunologic responses to a variety of antigens, and further, that the histologic alterations can be explained, at least in part, by a cytokine-mediated process.

The diagnostic role of the in vitro drug‐induced interferon‐γ release test in Stevens–Johnson syndrome

“…15 The use of the lymphocyte transformation test in TEN is controversial. [31][32][33][34] The role of IFN-γ in various types of CDRs has been inferred from immunohistochemical studies [35][36][37] and studies related to drug-specific T-cell clones, derived from the peripheral blood mononuclear cells (PBMCs). 5,38,39 The diagnostic potential of in vitro drug-induced IFN-γ release in CDRs has been reported recently by Koga et al 24 in a case of carbamazepine-induced erythroderma.…”

The IP-10 chemokine binds to a specific cell surface heparan sulfate site shared with platelet factor 4 and inhibits endothelial cell proliferation.

“…It is a member of the -C-X-C-(or or) chemokine family of secreted 8-10-kD proteins and is 31% identical to platelet factor 4 (PF4) 1 and 26% identical to Ib8, two other members of the -C-X-C-chemokine family. IP-10 expression is induced in a variety of tissues in inflammatory conditions, such as psoriasis (4), fixed drug eruptions (5), cutaneous delayed-type hypersensitivity reactions (6), experimental glomerulonephritis (7), and in experimental allergic encephalomyelitis (8). IP-10 also has a potent in vivo antitumor effect that is T cell dependent (9).…”

IP-10, a -C-X-C- chemokine, elicits a potent thymus-dependent antitumor response in vivo.

“…IP-10 was originally isolated as a predominant mRNA induced by IFN-3/(4) or LPS (5,6) in monocytes, and its expression has been detected in vivo during the development of a delayed-type hypersensitivity cellular immune response by keratinocytes, endothelial cells, and infiltrating mononuclear cells (7). In addition, IP-10 expression has been seen in the epidermis and dermis in cutaneous lesions of psoriasis (8), tuberculoid leprosy (7), and fixed DRUG eruptions (9). IP-10 is a member of the chemokine superfamily and is ,v30% homologous to IL-8 and platelet factor (PF4).…”