The division of immunology

The division of immunology

The IL-17 and BAFF partnership provide a new TWIST in the pathogenesis of SLE

The Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, UK.

The mechanisms which allow B cells to persist in the periphery are a source of great interest in the pathogenesis of autoimmune disease. Recent work provides new insights into the promotion of autoreactive B cells in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by inflammation and tissue damage throughout the body. This inflammatory response is triggered by the presence of autoantibodies which target components of the cell nucleus such as double stranded DNA, chromatin and ribonucleoprotein complexes. Nuclear components are usually sequestered from the immune system however during necrosis the nuclear membrane is lysed and nuclear organelles are released. Autoantibodies congregate and form small immune complexes which can block the blood supply to organs and activate complement and macrophages causing further inflammation and tissue damage.

The sustained production of autoantibodies, such as is seen in SLE, requires that auto-reactive B cells can persist and differentiate into antibody secreting plasma cells in the periphery. Whilst apoptotic signaling mutations may account for the survival of autoreactive B cells [1], additional cytokines, such as B-cell activating factor (BAFF), are likely to play an essential role in their persistence [2]. BAFF has indeed been implicated in SLE but as its levels in serum are unrelated to disease severity it is unlikely to be the sole mediator of autoreactive B cell promotion [3]. In this issue of Nature Immunology, Doreau and colleagues describe a novel mechanism by which the potential of naïve and memory B cells to survive, differentiate and proliferate is highly amplified in response to BAFF acting in synergy with the potent pro-inflammatory cytokine IL-17 [4]. Doreau and colleagues further provide evidence that high blood levels of IL-17, secreted by CD4+ T cells, could support autoreactive B cells both alone and in conjunction with BAFF to contribute to the pathology of SLE.

Using CD19+ peripheral B lymphocytes, Doreau et al first showed that a combination of BAFF and IL-17 in B cell cultures almost completely inhibited apoptosis. Whilst BAFF and for the first time IL-17, were both seen to increase cell viability individually, these were minimal and short-lived in comparison to their combined effect. This regulation of apoptosis was shown to occur through the expression of Twist-1, an NFκB signalling pathway molecule, Twist-1 subsequently activates transcription of Twist-2 and Bfl-1, two anti-apoptotic proteins.

Doreau and colleagues further explain two molecular mechanisms which may account for the collaborative, protective effect of IL-17 and BAFF exposure (Figure 1). BAFF receptor (BAFF-R) signalling requires a p100 substrate for successful NFκB signal transduction. This had previously been shown to be induced by BCR binding however Doreau demonstrated that IL-17 can stimulate production of p100 as well. In addition, BAFF signalling is negatively regulated by an adaptor protein, Act-1, which is indirectly recruited to the BAFF-R after BAFF binding. The IL-17 receptor also recruits Act-1, which conversely acts as positive promoter of IL-17 signalling. IL-17R recruitment is direct and therefore quicker than is seen at the BAFF-R. Doreau and colleagues showed that when B cells are exposed to both IL-17 and BAFF, the IL-17 receptor acts like a decoy and attracts Act-1 away from the BAFF receptor thus reducing Act-1 modulation of the BAFF-induced NFκB pathway. These combined effects optimise NFκB signal transduction and promote increased expression of the anti-apoptotic proteins Twist-1, Twist-2 and Bfl-1 consequently increasing cell survival.

Although IL-17 has previously been implicated in promoting proliferation and differentiation of autoantibodies [5], for the first time Doreau and colleagues showed these effects could be greatly enhanced by combining with BAFF in the presence of CD40 and

BCR stimulators. Cell cultured in this manner proliferated well and began to differentiate into CD38+ plasma cells producing IgA, IgM and most importantly IgG, the predominant antibody involved in SLE pathogenesis [6]. Twist-1 was shown to be essential for differentiation in the presence of IL-17 and BAFF. It exerted its effects through suppression of the differentiation inhibitors, Ets-1 and Ets-2 whilst enhancing expression of Blimp-1, a differentiation promoter. Notably, it was found that Twist-1 was redundant in the differentiation of BCR, CD40 and TLR9 stimulated cells. This suggests that Twist-1 mediated differentiation may be specific to B cells stimulated by IL-17 and BAFF.

These findings have a significant importance in our understanding of B cell biology and Doreau and colleagues further increased the impact of their research by defining a novel role for IL-17 as an efficient promoter of autoreactive B cells in SLE. Whilst it is already known SLE patient's serum contains heightened levels of IL-17 and BAFF, [7.8] the reasons for this had not been fully eluded. Doreau examined the effect of the serum on human B cells and found lymphocyte survival, proliferation and differentiation rates were all promoted, similar to their previous observations in vitro. Whilst these effects were generally dependant on the presence of both IL-17 and BAFF, the authors observed that in a small cohort of patients, removal of BAFF did not affect the serums supportive effects on B cells. Significantly, the presence of IL-17 was non-negotiable in all samples. The authors suggest that while IL-17 is essential, an as yet undescribed cytokine could take the place of BAFF in some patients. In addition, unlike BAFF levels, the levels of IL-17 and Twist-2 in patient's serum were found to correlate well with symptom severity. This new evidence further supports a significant role for IL-17 in the pathogenesis of SLE through the uncontrolled promotion of B cell activation.

The findings by Doreau et al provide key insights into the role of IL-17 in B cell survival, differentiation and proliferation which may be applied to autoreactive B cells. At a molecular level, the study was extensive however it would have been interesting to hear some of the group's theories on the source of IL-17 and whether they believe the increased levels to be a cause of SLE or a consequence. Nevertheless these findings are not only important in our understanding of B cell biology and SLE, they may have far reaching consequences in eluding the mechanisms behind other autoimmune conditions and in B cell targeted vaccine development.

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