Genetic factors play a key role in the pathogenesis of autoimmune diseases, whereas the disease-causing variants remain largely unknown. Herein, we performed an exome-wide association study of systemic sclerosis in a Han Chinese population. In the discovery stage, 527 patients with systemic sclerosis and 5,024 controls were recruited and genotyped. In the validation study, an independent sample set of 479 patients and 1,096 controls were examined. In total, we found that four independent signals reached genome-wide significance. Among them, rs7574865 (Pcombined = 3.87 x 10(-12)) located within signal transducer and activator of transcription 4 gene was identified previously using samples of European ancestry. Additionally, another signal including three SNPs in linkage disequilibrium might be unreported susceptibility loci located in the epidermis differentiation complex region. Furthermore, two SNPs located within exon 3 of IGHM (rs45471499, Pcombined = 1.15 x 10(-9)) and upstream of LRP2BP (rs4317244, Pcombined = 4.17 x 10(-8)) were found. Moreover, rs4317244 was identified as an expression quantitative trait locus for LRP2BP that regulates tight junctions, cell cycle, and apoptosis in endothelial cell lines. Collectively, our results revealed three signals associated with systemic sclerosis in Han Chinese and suggested the importance of LRP2BP in systemic sclerosis pathogenesis. Given the limited sample size and discrepancies between previous results and our study, further studies in multiethnic populations are required for verification.

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of malignancies characterized by accumulation of malignant T-cells within the skin. Retinoids, metabolic derivatives, and synthetic analogs of vitamin A embody an effective CTCL therapy with over three decades of clinical use. The established mechanism of action is induction of growth arrest and apoptosis. However, the natural role of retinoids in T-cell biology is imprinting gut-homing properties by inducing integrin alpha 4 beta 7 expression. How the natural role of retinoids relates to therapeutic effectiveness in CTCL has not been addressed and merits investigation. Here we provide evidence that retinoids, including Bexarotene, selectively induce CTCL lineages to increase integrin beta 7 expression and function prior to growth arrest and apoptosis. Interestingly, augmented CTCL cell adhesion obtained with retinoid exposure was potently attenuated by 1,25-dihydroxyvitamin D-3, a metabolic vitamin derivative involved in prompting immune cell skin homing. The integrin-dependent adhesion changes in CTCL cells occurred through synergistic activation of RAR and RXR nuclear receptors. These data explore the early cellular changes induced by retinoids that may be pivotal to sensitizing CTCL cells to growth arrest and apoptosis.

Epigenetic modifications, including DNA methylation, play an important role in the pathogenesis of autoimmune diseases. In this study, we characterized the DNA methylome in primary T cells of patients with systemic sclerosis. Genome-wide DNA methylation assays of CD4(+) and CD8(+) T cells from 24 systemic sclerosis patients and 24 matched controls were conducted and differentially methylated regions were validated. In the discovery stage, we found that hypomethylation of genes involved in the type I IFN signaling pathway was significantly enriched in both CD4(+) (P = 7.59 x 10(-)6) and CD8(+) (P = 2.10 x 100(-8)) differentially methylated regions. In the validation stage, we confirmed these changes for five type I IFN-associated genes. In addition, protein levels of both type I IFN-alpha (P < 0.0001) and beta (P = 0.002) were significantly elevated in the sera of systemic sclerosis patients. Moreover, significant associations between type I IFN-alpha/beta protein levels with the DNA methylation status as well as the expression profiles of these IFN-associated genes were confirmed. In conclusion, the type I IFN pathway is dysfunctional at the epigenetic level in systemic sclerosis patients, indicating that hypomethylation and upregulation of type I IFN-associated genes might be critical in systemic sclerosis pathogenesis.

Excessive activation of CD4(+) T cells and T helper type (Th) 17/Th1 cell differentiation are critical events in psoriasis pathogenesis, but the associated molecular mechanism is still unclear. Here, using quantitative proteomics analysis, we found that cyclin-dependent kinase 7 (CDK7) expression was markedly increased in CD4(+) T cells from patients with psoriasis compared with healthy controls and was positively correlated with psoriasis severity. Meanwhile, genetic or pharmacological inhibition of CDK7 ameliorated the severity of psoriasis in the imiquimod-induced psoriasis-like mouse model and suppressed CD4(+) T-cell activation as well as Th17/Th1 cell differentiation in vivo and in vitro. Furthermore, the CDK7 inhibitor also reduced the enhanced glycolysis of CD4(+) T cells from patients with psoriasis. Proinflammatory cytokine IL-23 induced increased CDK7 expression in CD4(+) T cells and activated the protein kinase B/mTOR/HIF-1 alpha signaling pathway, enhancing glycolytic metabolism. Correspondingly, CDK7 inhibition significantly impaired IL-23-induced glycolysis via the protein kinase B/mTOR/HIF-1 alpha pathway. In summary, this study shows that CDK7 promotes CD4(+) T-cell activation and Th17/Th1 cell differentiation by regulating glycolysis, thus contributing to the pathogenesis of psoriasis. Targeting CDK7 might be a promising immunosuppressive strategy to control skin inflammation mediated by IL-23.

Cutaneous CD30(+) lymphoproliferative disorders (LPDs), including lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large-cell lymphoma, comprise the second most common group of cutaneous T-cell lymphomas. Previously, we reported that special SATB1, a thymocyte-specific chromatin organizer, was over-expressed and promoted malignant T-cell proliferation in a portion of CD30(+) LPDs. Here, we investigated the expression pattern of SATB1 in CD30(+) LPDs with a large cohort of patient samples, and examined the potential of SATB1 as a molecular marker to classify CD30(+) LPDs with differential clinicopathological behaviors. SATB1 expression was identified in the CD30(+) anaplastic T cells in 11 of 12 (91.7%) lymphomatoid papulosis and 16 of 42 (38.1%) primary cutaneous anaplastic large-cell lymphoma cases. SATB1 thorn cases showed T-helper 17 polarization, together with more prominent epidermal hyperplasia and granulocytic infiltration. SATB1 thorn lesions responded better to combined treatment of methotrexate and interferon. SATB1 activated the expression of T-helper 17 cytokines while repressing T-helper 1-related genes. The heterogeneity in SATB1 expression across CD30(+) LPDs was associated with the extent of promoter DNA methylation. Hence, SATB1 expression defines a subtype of CD30(+) LPDs with characteristic pathobiology and prognosis. These data provide valuable insights into the heterogeneity of cutaneous T-cell malignancies, which may lead to individualized therapy in the future.