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Microarray study reveals a transforming growth factor‐β‐dependent mechanism of fibrosis in discoid lupus erythematosus
Author(s) -
Solé C.,
GimenezBarcons M.,
Ferrer B.,
OrdiRos J.,
CortésHernández J.
Publication year - 2016
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/bjd.14539
Subject(s) - fibrosis , microarray analysis techniques , microarray , pathology , biopsy , discoid lupus erythematosus , systemic lupus erythematosus , lupus erythematosus , cytokine , gene signature , biology , medicine , immunology , gene expression , antibody , gene , biochemistry , disease
Summary Background Discoid lupus erythematosus ( DLE ) is characterized by scarring lesions that develop and perpetuate fibrotic lesions. These are not observed in subacute cutaneous lupus erythematosus ( SCLE ). The pathophysiological basis of this is currently unknown. Objectives To identify contradistinctive signalling pathways and cellular signatures between the two type of lupus, with a focus on the molecular mechanisms leading to fibrosis. Methods We conducted a gene expression microarray analysis in lesional and nonlesional skin biopsy specimens of patients with DLE ( n = 10) and SCLE ( n = 10). Confirmatory reverse‐transcriptase quantitative polymerase chain reaction ( RT ‐ qPCR ) and immunohistochemistry were performed on selected transcripts in a new cohort of paraffin‐embedded skin biopsies ( n = 20). Changes over time of a group of selected inflammatory and fibrotic genes were also evaluated in a second biopsy taken 12 weeks later. In vitro functional studies were performed in primary isolated fibroblasts. Results Compared with nonlesional skin, DLE samples expressed a distinctive T‐cell gene signature. DLE samples displayed a significant CD 4 T‐cell enrichment with an imbalance towards T helper 1 cytokine predominance and a relative increased forkhead box ( FOX )P3 response. RT ‐ qPCR and immunochemical analysis over time showed a progressive increment of fibrotic markers and persistent FOXP 3 recruitment. Ex vivo upregulation of SERPINE 1 , MMP 9 , TGFBR 1 , phosphorylated SMAD 3 and TGFB 1 suggested a transforming growth factor ( TGF )‐β‐dependent mechanism of fibrosis in DLE , also confirmed by the results observed following in vitro stimulation with TGF ‐β. Conclusions These results highlight major pathogenic pathways in DLE and provide novel molecular targets for the development of new therapies. The data suggest the existence of a TGF ‐β‐dependent pathway inducing fibrosis in DLE .