No abstract

At the center of fibrosing diseases is the aberrant activation of tissue fibroblasts. The cellular and molecular mechanisms of how the immune system augments fibroblast activation have been described; however, little is known about how the immune system controls fibroblast function in tissues. Here, we identify regulatory T cells (Tregs) as important regulators of fibroblast activation in skin. Bulk cell and single-cell analysis of Tregs in murine skin and lungs revealed that Tregs in skin are transcriptionally distinct and skewed toward T helper 2 (TH2) differentiation. When compared with Tregs in lung, skin Tregs preferentially expressed high levels of GATA3, the master TH2 transcription factor. Genes regulated by GATA3 were highly enriched in skin “TH2 Treg” subsets. In functional experiments, Treg depletion resulted in a preferential increase in TH2 cytokine production in skin. Both acute depletion and chronic reduction of Tregs resulted in spontaneous skin fibroblast activation, profibrotic gene expression, and dermal fibrosis, all of which were exacerbated in a bleomycin-induced murine model of skin sclerosis. Lineage-specific deletion of Gata3 in Tregs resulted in an exacerbation of TH2 cytokine secretion that was preferential to skin, resulting in enhanced fibroblast activation and dermal fibrosis. Together, we demonstrate that Tregs play a critical role in regulating fibroblast activation in skin and do so by expressing a unique tissue-restricted transcriptional program that is mediated, at least in part, by GATA3.

No abstract

No abstract

No abstract

Regulatory T cells (Tregs) are closely related to TH17 cells and use aspects of the TH17-differentiation program for optimal immune regulation. In several chronic inflammatory human diseases, Tregs express IL-17A, suggesting that dysregulation of TH17-associated pathways in Tregs may result in either loss of suppressive function and/or conversion into pathogenic cells. The pathways that regulate the TH17 program in Tregs are poorly understood. We have identified two TNF receptor superfamily (TNFRSF) members, CD27 and OX40, that are preferentially expressed by skin-resident Tregs. Both CD27 and OX40 signaling suppressed the expression of TH17-associated genes from Tregs in a cell-intrinsic manner in vitro and in vivo. However, only OX40 played a nonredundant role in promoting Treg accumulation. Tregs that lacked both CD27 and OX40 were defective in controlling skin inflammation and expressed high levels of IL-17A, as well as the master TH17 transcription factor, RORγt. Last, we found that CD27 expression was inversely correlated with Treg IL-17 production in skin of patients with psoriasis and hidradenitis suppurativa. Together, our results suggest that TNFRSF members play both redundant and distinct roles in regulating Treg plasticity in tissues.

No abstract

We have reported autoimmune serological abnormalities in women with recurrent spontaneous abortions (RSAs).' Incidences of anti-phospholipid antibodies and antinuclear antibodies were significantly increased with each additional pregnancy loss in these women.* This was not seen in healthy, normal multiparous women. We also reported that 42% of women with three or more RSAs who were antiphospholipid antibody ( M A ) negative before the pregnancy became APA positive at the time of mi~carriage.~ Phospholipids are integral components of placental villous membrane, and there is evidence that trophoblastic antigenic stimuli during pregnancy may induce the production of various autoantibodies including antiphospholipid antibodies in failing pregnancies: In this study, we prospectively analyzed women with three or more RSAs and normal healthy women entering a pregnancy for autoantibodies at each trimester of pregnancy including cord blood samples.Thirty-one normal, healthy women with no history of RSAs who received antenatal care at Department of Obstetrics and Gynecology, Hospital Infantil in Bogota, Columbia and 32 women with three or more RSAs who registered at Reproductive Medicine, University of Health S c i e n c e f i e Chicago Medical School were investigated consecutively during the index pregnancy. All normal women were analyzed for IgG antibodies to six phospholipid epitopes, DNA, and histone at each trimester of pregnancy. Cord blood was also analyzed. Women with RSAs, IgM, and IgG APA were followed during pregnancy and at delivery or at the time of a repeated abortion. Titers of APAs were measured by ELISA as previously reported.'We report: (1) In women with a normal pregnancy, there is no APA positivity during pregnancy including cord blood (FIG. 1); (2) 6.5% of normal pregnant women demonstrated low positive ANA during pregnancy; (3) no one developed lupus anticoagulant during the index pregnancy; (4) 3.2% of normal pregnant women demonstrated IgG single-stranded DNA and 3.2% IgG double-stranded DNA. No one developed IgG antibodies to histone; ( 5 ) increased parity in women with a normal 242