How does BAFF activate B cells in patients with autoimmune diseases?

In a study in a recent issue of Arthritis Research & Therapy, Yoshimoto and colleagues demonstrate that peripheral monocytes from patients with Sjögren's syndrome (SS) produce significantly higher amounts of B cell-activating factor (BAFF) and interleukin-6 (IL-6) in comparison with normal monocytes. This difference exists at baseline and is amplified after stimulation with interferon-gamma. Increased IL-6 secretion is partially suppressed by an anti-BAFF antibody, suggesting that signal transduction pathways mediated by BAFF are implicated in the regulation of IL-6 production by monocytes. The origin and pathways involved in this higher susceptibility to BAFF-driven IL-6 induction by monocytes of patients with SS are still unknown.

in diff erent autoimmune diseases, and fi ndings concerning SLE and pSS were more consistent (reviewed in [2]).
Recent fi ndings showed that BAFF could be expressed and secreted by resident cell targets of autoimmunity after stimulation with diff erent cytokines: synoviocytes in rheumatoid arthritis, astrocytes in multiple sclerosis, and epithelial cells in pSS [4]. Moreover, in the context of autoimmunity, BAFF could be secreted by T [5] and B [6] lymphocytes. However, the main sources of BAFF are myeloid cells and, especially, blood monocytes, myeloid dendritic cells, and macrophages [7].
It has been suggested that monocytes from patients with autoimmune diseases were more susceptible to BAFF expression and secretion after stimulation with type 1 interferon (IFN) than those from healthy controls [8]. Yoshimoto and colleagues [1] add an important point to this discussion by emphasizing the role of monocytes in the overproduction of BAFF in autoimmunity. Th e authors demonstrate that peripheral pSS monocytes produce signi fi cantly higher amounts of BAFF and IL-6 in comparison with normal monocytes. Th is diff erence exists at baseline and is amplifi ed after stimulation with type 2 IFN, IFN-γ. Increased IL-6 secretion is partially suppressed by an anti-BAFF antibody, suggesting that signal transduction pathways mediated by BAFF are impli cated in the regulation of IL-6 production by monocytes. Lastly, the authors fi nd elevated expression levels of BAFF-R and diff erent transcription factors regulat ing IL-6 in pSS monocytes.
We have three comments in regard to this interesting study.

The diff erential roles of type 1 and type 2 IFN in autoimmune diseases
Like lupus, pSS is considered to be a type 1 IFN-driven autoimmune disease (reviewed in [2]), whereas rheumatoid arthritis is supposed to be mediated mainly by TH1 and TH17 cells, and type 2 IFN is supposed to have a pathogenic role. Th e present study is another example emphasizing the fact that it is diffi cult to discriminate between type 1 and type 2 involvements in an autoimmune disease; this is quite surprising, given the Abstract In a study in a recent issue of Arthritis Research & Therapy, Yoshimoto and colleagues demonstrate that peripheral monocytes from patients with Sjögren's syndrome (SS) produce signifi cantly higher amounts of B cell-activating factor (BAFF) and interleukin-6 (IL-6) in comparison with normal monocytes. This diff erence exists at baseline and is amplifi ed after stimulation with interferon-gamma. Increased IL-6 secretion is partially suppressed by an anti-BAFF antibody, suggesting that signal transduction pathways mediated by BAFF are implicated in the regulation of IL-6 production by monocytes. The origin and pathways involved in this higher susceptibility to BAFF-driven IL-6 induction by monocytes of patients with SS are still unknown.

The mechanism of B-cell activation induced by BAFF
Almost 100% of B cells express BAFF-R (or BR3), the most important BAFF receptor. According to the classic understanding of BAFF-R, the action of BAFF for B-cell activation goes mainly through this receptor. However, as our group has shown in pSS [9] and others have shown in chronic hepatitis C virus infection [10], there was a negative correlation between the level of soluble BAFF in the serum and the level of expression of BAFF-R on B cells. Interestingly, in the study by Yoshimoto and colleagues, it seems that, as previously observed, BAFF-R expression is normal or decreased at the surface of B cells (Figure 4 of [1]). Th us, if there is a decrease in BAFF-R expression on B cells (even if the BAFF level is increased), this BAFF increase could not induce B-cell activation directly. Yoshimoto and colleagues propose an alternative mechanism: in the context of autoimmunity, the eff ect of BAFF on B-cell activation could be at least partly mediated by a BAFF-driven autocrine secretion of IL-6 by monocytes. Th e authors suggest that, in the context of SS, the monocytes may express a signifi cant level of BAFF-R, allowing an autocrine action on BAFF on monocytes for inducing IL-6. Th e possibility that monocytes of patients with autoimmune diseases express BAFF-R is a new fi nding and must be confi rmed. Moreover, the inhibition of IL-6 secretion by the adjunction of an anti-BAFF is only very partial ( Figure 2 of [1]) and thus secretion of IL-6 may also be independent of BAFF. Lastly, the respective contributions of BAFF and IL-6 on B-cell activation in the context of autoimmunity should be explored in greater depth in animal models and patients. Interestingly, in patients with lupus, it has been shown that B-cell activation was dependent on the combi nation of BAFF and IL-17 [11].

What are the pathways implicated in this BAFF-driven IL-6 secretion by monocytes, and why are patients with pSS more susceptible to this induction?
Yoshimoto and colleagues found an increased expression level of IL-6-specifi c transcription factors and of transcrip tion factors like nuclear factor-kappa-B in pSS monocytes compared with controls but this increased expression was constitutive and not induced by BAFF. Th us, it is necessary to do more work to study the eff ect of BAFF stimulation on upstream kinases and trans crip tion factors like JAK and STAT proteins in order to look for a specifi c deregulation of these pathways in patients versus controls.
In conclusion, BAFF could activate B cells through other cytokines like IL-6 and this cytokine could be an interesting target in BAFF-mediated autoimmune diseases. Th e mechanisms of the peculiar susceptibility of pSS monocytes to this BAFF-induced IL-6 secretion could also help in the search for new specifi c targets for therapy.