A20 inhibition of STAT1 expression in myeloid cells: a novel endogenous regulatory mechanism preventing development of enthesitis.

OBJECTIVES: A20 is an important endogenous regulator of inflammation. Single nucleotide polymorphisms in A20 have been associated with various immune-mediated inflammatory diseases, and cell-specific deletion of A20 results in diverse inflammatory phenotypes. Our goal was to delineate the underlying mechanisms of joint inflammation in myeloid-specific A20-deficient mice (A20myelKO mice). METHODS: Inflammation in A20myelKO mice was assessed in a time-dependent manner. Western blot analysis and quantitative PCR analysis were performed on bone marrow-derived macrophages from A20myelKO and littermate control mice to study the effect of A20 on STAT1/STAT3 expression and STAT1/STAT3-dependent gene transcription in myeloid cells. The in vivo role of Janus kinase-Signal Transducer and Activator of Transcription (JAK-STAT) signalling in the development of enthesitis in A20myelKO mice was assessed following administration of a JAK inhibitor versus placebo control. RESULTS: Enthesitis was found to be an early inflammatory lesion in A20myelKO mice. A20 negatively modulated STAT1-dependent, but generally not STAT3-dependent gene transcription in myeloid cells by suppressing STAT1 but not STAT3 expression, both in unstimulated conditions and after interferon-γ or interleukin-6 stimulation. The increase in STAT1 gene transcription in the absence of A20 was shown to be JAK-STAT-dependent. Moreover, JAK inhibition in vivo resulted in significant reduction of enthesitis, both clinically and histopathologically. CONCLUSIONS: Our data reveal an important and novel interplay between myeloid cells and tissue resident cells at entheseal sites that is regulated by A20. In the absence of A20, STAT1 but not STAT3 expression is enhanced leading to STAT1-dependent inflammation. Therefore, A20 acts as a novel endogenous regulator of STAT1 that prevents onset of enthesitis.

Assessment of sensitivity to change of the European Scleroderma Study Group activity index.

OBJECTIVES: The European Scleroderma Study Group (EScSG) activity index meets nearly all the OMERACT-standards of truth, discrimination and feasibility. The sensitivity to change remains to be attested. This study assesses sensitivity to change of the EScSG activity index in patients with early and severe diffuse cutaneous Systemic Sclerosis (dcSSc) treated with rituximab. METHODS: 12-month follow-up (open-label study) of 14 consecutive patients with early dcSSc. Patients received an infusion of two times 1000 mg rituximab at month 0 and 6, together with 100 mg methylprednisolone. Clinical read outs (modified Rodnan skin score [mRSS], lung function and echocardiography) and EScSG activity index were performed at month 0, 3, 6 and 12. Mixed models analyses (MMA) were used to evaluate changes in parameters over time. RESULTS: There was a clinically significant change in skin score with a mean (SD) mRSS of 24.8 (4.44) at baseline and 10.4 (3.12) at month 12 (MMA p<0.001). Also the EScSG activity index decreased significantly, with a mean (SD) of 4.3 (1.79) at baseline and 0.7 (0.83) at month 12 (MMA p<0.001). The estimated mean change of the EScSG activity index was -3.6 (95%CI -4.9; -2.4) over 12 months. Indices of internal organ involvement remained stable throughout the study. CONCLUSIONS: A significant improvement of the EScSG activity index was observed, in line with the significant improvement of the mRSS and the stabilisation of internal organ involvement. To our knowledge, this is the first study to attest sensitivity to change of the EScSG activity index in the subset of 'early' dcSSc. TRIAL REGISTRATION: ClinicalTrials.gov Registration, http://clinicaltrials.gov, number NCT00379431.

The thymic microenvironment differentially regulates development and trafficking of invariant NKT cell sublineages.

The regulatory role of the thymic microenvironment during trafficking and differentiation of the invariant NKT (iNKT) cell lineage remains poorly understood. In this study, we show that fractalkine receptor expression marks emigrating subpopulations of the NKT1, NKT2, and NKT17 sublineages in the thymus and peripheral organs of naive mice. Moreover, NKT1 sublineage cells can be subdivided into two subsets, namely NKT1(a) and NKT1(b), which exhibit distinct developmental and tissue-specific distribution profiles. More specifically, development and trafficking of the NKT1(a) subset are selectively dependent upon lymphotoxin (LT)α1ß2-LTß receptor-dependent differentiation of thymic stroma, whereas the NKT1(b), NKT2, and NKT17 sublineages are not. Furthermore, we identify a potential cellular source for LTα1ß2 during thymic organogenesis, marked by expression of IL-7Rα, which promotes differentiation of the NKT1(a) subset in a noncell-autonomous manner. Collectively, we propose a mechanism by which thymic differentiation and retention of the NKT1 sublineage are developmentally coupled to LTα1ß2-LTß receptor-dependent thymic organogenesis.

Integrating the pathogenesis of spondyloarthritis: gut and joint united?

PURPOSE OF REVIEW: The association between spondyloarthritis (SpA) and inflammatory bowel disease (IBD) is well known. Additionally, about half of SpA patients show microscopic gut inflammation. Substantial progress has been made in understanding the pathogenesis of SpA and IBD, with new therapeutic targets for either of them in clinical development. RECENT FINDINGS: Microscopic gut inflammation was found in early forms of SpA in about 50% of cases and is associated with age, sex, disease activity and degree of MRI inflammation on sacroiliac joints. Although prospective follow-up data in men and murine animal studies show a parallelism between gut and joint evolution in SpA, therapeutic outcomes are not always the same in SpA and IBD. These differences can be ascribed to differences in not only the cytokine pathways and cells involved in disease, tissue localization and environmental factors but also in pharmacokinetics and biodistribution. SUMMARY: A significant amount of data all point in the direction of arthritis and gut inflammation being pathogenetically closely linked in the SpA concept. However, when it comes to therapeutic effectiveness, the gut and the joints do not always react in the same way. These differences in therapeutic effect could be attributed to the different ways in which cytokine pathways are involved in SpA and IBD.

Growth differentiation factor 15, a marker of lung involvement in systemic sclerosis, is involved in fibrosis development but is not indispensable for fibrosis development.

OBJECTIVE: Transforming growth factor ß superfamily members are involved in the pathogenesis of systemic sclerosis (SSc). Growth differentiation factor 15 (GDF-15) is a distant member of this family. We undertook this study to evaluate the role of GDF-15 in SSc pathogenesis. METHODS: A longitudinal prospective cohort of SSc patients was screened for serum GDF-15 levels using enzyme-linked immunosorbent assay, and associations with clinical data were analyzed. In vitro stimulation experiments were performed on lung fibroblasts. The role of GDF-15 in fibrosis development in vivo was evaluated in the bleomycin lung fibrosis model in GDF-15-deficient mice. RESULTS: GDF-15 was measured at baseline in serum samples from 119 SSc patients. An increase in GDF-15 levels was observed in patients classified as having no skin involvement, those with limited cutaneous SSc, and those with diffuse cutaneous SSc. Moreover, baseline serum GDF-15 levels correlated strongly with disease activity and extent of organ involvement, particularly clinical symptoms of lung fibrosis, including impact on lung function at prospective followup. This was mimicked in the bleomycin model of SSc, in which animals exposed to bleomycin had elevated expression levels of GDF-15 in lung tissue. Lung fibroblasts isolated from GDF-15-deficient mice showed reduced induction of interleukin-6 and CCL2 upon bleomycin stimulation. Surprisingly, no differences in fibrosis development were observed between wild-type and GDF-15-deficient animals. CONCLUSION: An intriguing profile of serum GDF-15 levels was found in SSc patients. GDF-15 expression is induced during fibrosis development and markedly correlates with lung function impairment in this disease. The protein may participate in fibrosis initiation, but is not indispensable in the course of fibrosis development in vivo.