Interleukin 6 Accelerates Mortality by Promoting the Progression of the Systemic Lupus Erythematosus-Like Disease of BXSB.Yaa Mice

Abstract

IL6 is a multifunctional cytokine that drives terminal B cell differentiation and secretion of immunoglobulins. IL6 also cooperates with IL21 to promote differentiation of CD4+ T follicular helper cells (TFH). Elevated serum levels of IL6 correlate with disease flares in patients with systemic lupus erythematosus (SLE). We previously reported that IL21 produced by TFH plays a critical role in the development of the SLE-like disease of BXSB.Yaa mice. To examine the possible contributions of IL6 to disease, we compared disease parameters in IL6-deficient and IL6-competent BXSB.Yaa mice. We report that survival of IL6-deficient BXSB.Yaa mice was significantly prolonged in association with significant reductions in a variety of autoimmune manifestations. Moreover, B cells stimulated by co-engagement of TLR7 and B cell receptor (BCR) produced high levels of IL6 that was further augmented by stimulation with Type I interferon (IFN1). Importantly, the frequencies of TFH and serum levels of IL21 were significantly reduced in IL6-deficient mice. These findings suggest that high-level production of IL6 by B cells induced by integrated signaling from the IFN1 receptor, TLR7 and BCR promotes the differentiation of IL21-secreting TFH in a signaling sequence that drives the lethal autoimmune disease of BXSB.Yaa mice.

The phenolic fraction of extra virgin olive oil modulates the activation and the inflammatory response of T cells from patients with systemic lupus erythematosus and healthy donors

“…Several elements of the immune system are potential targets for therapeutic intervention in patients with SLE. In this sense, IL‐6 is implicated in the development and progression of SLE in mice and it is identified as one of the major genetic risk factors for SLE in humans ; thus, its modulation seems to be a potential therapeutic approach in SLE management . In the present study, we found a remarkable increase of IL‐6 production in patients with SLE compared with healthy subjects.…”

TLR9 activation induces aberrant IgA glycosylation via APRIL- and IL-6–mediated pathways in IgA nephropathy

“…43,44 In a lupus mouse model, IL-6 deficiency prevented T follicular helper cell differentiation and germinal-center B-cell expansion, resulting in reduced autoantibody production. 45 The present study clarified that TLR9 activation by CpG-ODN enhanced IL-6 production in splenocytes of murine IgAN. IL-6 induced overproduction of aberrantly glycosylated IgA and IgG-IgA IC in a murine model of IgAN.…”

Altered B cell signalling in autoimmunity

“…Although an absolute requirement for IL-6 in T FH cell generation is controversial 131,139–141 , IL-6 is known to promote early T FH cell differentiation by transiently inducing B cell lymphoma 6 (BCL-6) expression in CD4 + T cells binding cognate antigen 142 . In addition, Il6 deletion reduces disease severity in the BXSB- Yaa mouse lupus model, and increased serum IL-6 levels have been observed in human SLE, which suggests potential roles for this cytokine in disease pathogenesis 143,144 . Consistent with this idea, IL-6 receptor blockade with tocilizumab decreased the levels of dsDNA-specific antibodies and circulating plasmablasts in early-stage clinical trials in patients with SLE 145 .…”