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Rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD) is the most common pulmonary complication of RA, increasing morbidity and mortality. Anti-citrullinated protein antibodies have been associated with the development and progression of both RA and fibrotic lung disease; however, the role of protein citrullination in RA-ILD remains unclear. Here, we demonstrate that the expression of peptidylarginine deiminase 2 (PAD2), an enzyme that catalyzes protein citrullination, is increased in lung homogenates from subjects with RA-ILD and their lung fibroblasts. Chemical inhibition or genetic knockdown of PAD2 in RA-ILD fibroblasts attenuated their activation, marked by decreased myofibroblast differentiation, gel contraction, and extracellular matrix gene expression. Treatment of RA-ILD fibroblasts with the proteoglycan syndecan-2 (SDC2) yielded similar antifibrotic effects through regulation of PAD2 expression, phosphoinositide 3-kinase/Akt signaling, and Sp1 activation in a CD148-dependent manner. Furthermore, SDC2-transgenic mice exposed to bleomycin-induced lung injury in an inflammatory arthritis model expressed lower levels of PAD2 and were protected from the development of pulmonary fibrosis. Together, our results support a SDC2-sensitive profibrotic role for PAD2 in RA-ILD fibroblasts and identify PAD2 as a promising therapeutic target of RA-ILD.

Background Targeting TNFα is beneficial in many autoimmune and inflammatory diseases, including rheumatoid arthritis. However, the response to each of the existing TNFα inhibitors (TNFis) can be patient- and/or disease-dependent. In addition, TNFis can induce the production of type 1 interferons (IFNs), which contribute to their non-infection side effects, such as pustular psoriasis. Thus far, the molecular mechanisms mediating the drug-specific effects of TNFis and their induction of type 1 IFNs are not fully understood. Methods Peripheral blood mononuclear cells (PBMCs) were collected from healthy donors and stimulated in vitro with anti-CD3 and anti-CD28 in the absence or presence of adalimumab, etanercept, or certolizumab. Th cells were isolated from the stimulated PBMCs, and their RNA was subjected to RNA-seq and quantitative polymerase chain reaction. Results Adalimumab and etanercept, which contain Fc, but not certolizumab, which does not contain Fc, inhibited the expression of several effector cytokines by Th cells within anti-CD3/anti-CD28-stimulated PBMCs. Transcriptomic analyses further showed that adalimumab, but not certolizumab, reciprocally induced type 1 IFN signals and the expression of CD96 and SIRPG in Th cells. The unique effects of adalimumab were not due to preferential neutralization of soluble TNFα but instead were mediated by several distinct mechanisms independent or dependent of Fc-facilitated physical interaction between Th cells and CD14+ monocytes. Conclusions TNFis can have drug-specific effects on the transcriptional profile of Th cells.

Interleukin 4 (IL-4) and IL-13 are critical for responses to parasitic helminthes. We used genetically engineered reporter mice to assess the temporal and spatial production of these cytokines in vivo. In lymph nodes, IL-4, but not IL-13, was made by follicular helper T cells (T(FH) cells). In contrast, tissue type 2 helper T cells (T(H)2 cells) produced both cytokines. There was also divergent production of IL-4 and IL-13 among cells of the innate immune system, whereby basophils produced IL-4, whereas innate helper type 2 cells (Ih2 cells) produced IL-13. IL-13 production by T(H)2 and Ih2 cells was dependent on the transcription factor GATA-3, which was present in large amounts in these cells, and in contrast to the small amount of GATA-3 in T(FH) cells and basophils. The distinct localization and cellular expression of IL-4 and IL-13 explains their unique roles during allergic immunity.

Erratum: IL-4 inhibits TGF-β-induced Foxp3 + T cells and, together with TGF-β, generates IL-9 + Foxp3 − effector T cells

GATA-3 is a zinc finger protein that is preferentially expressed in T cells in adult animals. Previous studies have shown that GATA-3 is essential for the transition from common lymphoid precursors to the most immature thymocytes. In addition, GATA-3 is selectively expressed in Th2 cells. Overexpression of GATA-3 forced developing Th1 cells to produce Th2 cytokines, including IL-4, IL-5, and IL-13. However, it remains unclear whether GATA-3 is also important at the later stages of T-cell development. Nor do we understand whether GATA-3 is essential for the differentiation of Th2 cells or for the maintenance of the Th2 phenotype. The lack of GATA-3-deficient mice or T cells has precluded further studies to address these important questions. We have recently generated conditional GATA-3-deficient mice. Studies on the conditional GATA-3-deficient mice has uncovered several novel roles of GATA-3 in regulating the development and function of T cells.