Patients with systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS) are typically characterized by the presence of autoantibodies and an IFN-signature. The strength of the IFN-signature positively correlates with disease severity, suggesting that type I IFNs are active players in these diseases. BAFF is a cytokine critical for development and proper selection of B cells, and the targeting of BAFF has emerged as a successful treatment strategy of SLE. Previous reports have suggested that BAFF expression is directly induced by type I IFNs, but the precise mechanism for this remains unknown. In this article, we demonstrate that BAFF is a bona fide ISG and that IFN regulatory factors (IRFs) control the expression of BAFF. We identify IRF1 and IRF2 as positive regulators of BAFF transcription and IRF4 and IRF8 as potent repressors; in addition, we have mapped the precise binding site for these factors in the BAFF promoter. IFN-β injections induced BAFF expression mainly in neutrophils and monocytes, and BAFF expression in neutrophils from pSS patients strongly correlated with the strength of the IFN-signature. In summary, we show that BAFF expression is directly induced by type I IFNs via IRF1 and IRF2, whereas IRF4 and IRF8 are negative regulators of BAFF expression. These data suggest that type I IFN blockade in SLE and pSS patients will lead to downregulation of BAFF and a consequential reduction of autoreactive B cell clones and autoantibodies.

Systemic autoimmune diseases are characterized by the overexpression of type I IFN stimulated genes, and accumulating evidence indicate a role for type I IFNs in these diseases. However, the underlying mechanisms for this are still poorly understood. To explore the role of type I IFN regulated miRNAs in systemic autoimmune disease, we characterized cellular expression of miRNAs during both acute and chronic type I IFN responses. We identified a T cell-specific reduction of miR-31-5p levels, both after intramuscular injection of IFNβ and in patients with Sjögren's syndrome (SjS). To interrogate the role of miR-31-51p in T cells we transfected human CD4 + T cells with a miR-31-5p inhibitor and performed metabolic measurements. This identified an increase in basal levels of glucose metabolism after inhibition of miR-31-5p. Furthermore, treatment with IFN-α also increased the basal levels of human CD4 + T-cell metabolism. In all, our results suggest that reduced levels of miR-31-5p in T cells of SjS patients support autoimmune T-cell responses during chronic type I IFN exposure.Keywords: Autoimmunity r Interferons r Immune regulation r Metabolism r Rheumatology Additional supporting information may be found online in the Supporting Information section at the end of the article.by the overexpression of a large set of IFN-stimulated genes (ISGs) collectively termed the IFN signature [1,2]. Type I IFNs signal through the heterodimeric IFNA receptor and induce the expression of ISGs, several of which have important antiviral * These authors contributed equally.

Background There are several problems with the current methods for detection of antiphospholipid antibodies (aPL) and there is an on-going discussion about the interpretation of different aPL-tests in everyday practice. (1) Objectives I. To evaluate agreement and performance of two tests for aPL, including a new automated assay. II. To study the importance of isotypes and titers with respect to thrombotic events in patients with Systemic Lupus Erythematosus (SLE). Methods We investigated 712 SLE-patients and 280 controls. Antibodies against cardiolipin and b2 glycoprotein-I were analysed by a routine ELISA method (Orgentec, Mainz, Germany) and a new, automated method (Elia Cardiolipin IgG/IgM, Elia –β2 –Glycoprotein I IgG/IgM performed on Phadia 250, Phadia AB, now Thermo Fisher Scientific, Germany). We used three cut-offs for positivity and calculated specificity, sensitivity and odds ratio (OR) for objectively verified previous thrombotic events. Results were compared with outcomes for Lupus anticoagulant (LAC) performed in 380 of the patients. Results Agreement between and performance of both aPL-methods were modest with no strong advantage in performance for either test. Using a cut-off corresponding to established criteria (2) sensitivity for the individual aPL-tests for any previous thrombosis ranged from 3.7 to 24.8% while specificity ranged from 84.7% to 97.7%. Regardless of assay, antibodies of IgG-isotype were associated with venous thrombosis and ischemic cerebrovascular disease while IgM-antibodies were associated with ischemic heart disease. Associations were highly affected by the positivity cut-off-level. ORs for LAC were generally higher than for the specific aPL-tests. For any previous thrombosis, OR (95% Confidence Interval) for LAC was 5.4 (3.1-9.4) while OR for the individual aPL-tests using a cut-off corresponding to established criteria ranged from non-significant to 1.9 (1.03-3.4) with the highest OR for routine ELISA cardiolipin IgG. Conclusions The most interesting finding in this study is that aPL of IgG and IgM isotypes were associated with different types of thrombotic events. Only moderate agreement between, but no clear advantage in relation to thrombotic manifestations, was observed when comparing a routine ELISA for aPL with a new automated method. The LAC test performed better than both aPL-assays. References Galli M. Clinical utility of laboratory tests used to identify antiphospholipid antibodies and to diagnose the antiphospholipid syndrome. Semin Thromb Hemost. 2008 Jun;34(4):329-34. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006 Feb;4(2):295-306. Disclosure of Interest None Declared