Levels of the B-cell activating factor (BAFF) (also known as B-lymphocyte stimulator) are associated with markers of B-cell hyperactivity in pSS, and a mouse model overexpressing BAFF has features of pSS and increased lymphoma risk. pSS, and a mouse model overexpressing BAFF has features of pSS and increased lymphoma risk. BAFF therefore offers a encouraging therapeutic target. The article by Seror et al. [1] , in makes an important observation relevant to treatment and pathogenesis of pSS, based on an analysis of samples from your BELISS (Efficacy and Security of Belimumab in Subjects With Main Fargesin Sj?gren’s Syndrome, “type”:”clinical-trial”,”attrs”:”text”:”NCT01160666″,”term_id”:”NCT01160666″NCT01160666) study. BELISS included 15 patients from France and 15 from Italy. Patients received belimumab, a monoclonal antibody against BAFF, at 0, 2 and 4?weeks and then every 4? weeks for up to a 12 months. Clinical data have already been published [2], but in the French cohort analyzed here, an improvement in the EULAR (European League Against Rheumatism) Sj?grens Syndrome Disease Activity Index (ESSDAI) was observed in 6 out of the 15 patients. We strongly welcome the biologic era in pSS. Although pSS is not associated with increased mortality (except for the small quantity of patients with aggressive forms of lymphoma), it is associated with significant and disabling symptoms and little evidence that standard immunosuppressant therapy is effective. In terms of the clinical data from BELISS, there is an obligatory notice of caution: a fully powered double-blind randomized controlled trial (RCT) of infliximab in pSS failed to demonstrate improvement [3], despite encouraging data from a pilot open-label study such as this one. Furthermore, despite encouraging data from two small RCTs, a Fargesin French phase IIb study of the anti-CD20 monoclonal antibody rituximab, targeting B cells, did not meet its main end result, despite significant beneficial effects on fatigue [4]. The reasons for this latter discrepancy are unclear but include methodological issues related to patient selection and end result measures as well as those relating to target selection such as co-depletion of regulatory B cells and potential protection of pathogenic B cells in tissue niches. Some of these issues may be clarified by a UK study due to statement later this year (http://public.ukcrn.org.uk/search/StudyDetail.aspx?StudyID=9809). However, alongside B cells, there is evidence of an important pathogenic role for T cells, epithelial cells, natural killer (NK) cells, and type I and II interferons (IFN/ and IFN, respectively). Analysis of minor salivary glands (MSGs) from an earlier open-label study of rituximab pointed to baseline differences in gene expression between responders and non-responders relating to B-cell and IFN pathways [5]. This suggests the tantalising possibility that patients may be stratified according to dominant pathogenic processes, and it is in regard to this that the study by Seror et al. is usually of greatest interest. The authors analyzed peripheral blood lymphocyte subsets and MSGs at weeks 0 and 28. The only findings associated with systemic response to belimumab were a lower percentage and quantity of peripheral NK cells and a smaller NK cell infiltrate around lymphocytic foci in the MSGs. Furthermore, the blood NK cell number rose in nonresponders but not in Fargesin responders at week 28. A role for NK cells in pSS is Rabbit Polyclonal to OR5P3 usually supported by a genetic susceptibility association with the locus, encoding the NK-specific activating receptor Fargesin NKp30 [6]. This polymorphism is usually associated with greater IFN expression by NK cells. NK cells also enhance production of dendritic cell interleukin-12 (IL-12), which is a key differentiation factor for T helper 1 (Th1) cells, themselves a major Fargesin source of IFN [7]. The data reported by Seror et al. might support the proposal of two dominant pathogenic axes, type I IFN/B cells and IFN/IL-12. However, it should be emphasised that there is crosstalk between these two axes and they are not discrete. IFN as well as type I IFN can drive BAFF expression [7], and B cells can produce IFN. Recent data have also suggested that a high MSG IFN, rather.