In Vivo BLyS/BAFF Neutralization Ameliorates Islet-Directed Autoimmunity in Nonobese Diabetic Mice

Abstract

B lymphocytes are required for the pathogenesis of autoimmune diabetes in NOD mice. Previous studies established that a lymphopenic transitional (TR) B cell compartment reduces the competitive constraint on the entry of newly emerging TR B cells into the splenic follicle (FO), thereby disrupting a peripheral negative selection checkpoint in NOD mice. Thus, development of clinically feasible immunotherapeutic approaches for restoration of appropriate negative selection is essential for the prevention of anti-islet autoimmunity. In this study we hypothesized that in vivo neutralization of the B lymphocyte stimulator (BLyS/BAFF) may enhance the stringency of TR→FO selection by increasing TR B cell competition for follicular entry in NOD mice. This study demonstrated that in vivo BLyS neutralization therapy leads to the depletion of follicular and marginal zone B lymphocytes. Long-term in vivo BLyS neutralization caused an increased TR:FO B cell ratio in the periphery indicating a relative resistance to follicular entry. Moreover, in vivo BLyS neutralization: 1) restored negative selection at the TR→FO checkpoint, 2) abrogated serum insulin autoantibodies, 3) reduced the severity of islet inflammation, 4) significantly reduced the incidence of spontaneous diabetes, 5) arrested the terminal stages of islet cell destruction, and 6) disrupted CD4 T cell activation in NOD mice. Overall, this study demonstrates the efficacy of B lymphocyte-directed therapy via in vivo BLyS neutralization for the prevention of autoimmune diabetes.

Effects of CXCL13 inhibition on lymphoid follicles in models of autoimmune disease

“…Comparison of splenic structure following either CXCL13 or BAFF neutralization showed that while CXCL13 blockade resulted in loss of splenic primary follicles and reduction in FDC and GCs with unaffected MZ (Fig. 3b), loss of BAFF signalling resulted in disparate effects in that splenic MZ were obviously absent, as previously noted using anti-BLyS [31], but primary follicles, FDC and GCs were seemingly unaffected (Fig. 3c).…”

Humoral Autoimmunity in Type 1 Diabetes: Prediction, Significance, and Detection of Distinct Disease Subtypes

“…FO) checkpoint. This is a defect, which has been delineated as an aberrant characteristic of Blymphocyte homeostasis in NOD mice (Zekavat et al 2008). These data collectively suggest that long-term in vivo BLyS neutralization is capable of correcting a defect in NOD B-cell tolerance by increasing the stringency of negative selection at the TR !…”

“…The use of rituximab in human clinical trials has also stimulated the interest in B-cell antigen capture and presentation in T1D, particularly following the results of the rituximab trial in newly diagnosed T1D patients showing delay in disease progression, associated with transient B-cell depletion (Pescovitz et al 2009). These observations in humans are reinforced by studies in NOD mice using specific mAbs for CD20 (Xiu et al 2008) and by in vivo neutralization of the Blymphocyte stimulator (BLyS/BAFF), which in both cases prevented autoimmune diabetes progression l (Zekavat et al 2008). Interestingly, long-term in vivo BLyS neutralization also led to reduction of IAA titers.…”

The role of BAFF in the progression of rheumatoid arthritis

“…The available data [47] have [23,24] Take part in the formation of germinal center(GC) [25] Promote plasma cells survival in bone marrow [26] Play an important role in immune responses in T cell-dependent or T cell-independent antibody responses [12,27] T cells Promote T cells proliferation [28][29][30][31] Enhance cytokine production [32][33][34] demonstrated that subtle changes in nuclear factor j-gene binding (NF-jB) circuitry signaling can have measurable effects on the susceptibility to RA as well as on the progression of the disease. The activation of BAFF-R, mainly through the alternative NF-jB pathway (NF-jB2), weakly stimulates the classic NF-jB pathway (NF-jB1) and also transduces signals through PI3K/Akt/mTOR signaling-mediated antibody production by B lymphocytes [48][49][50][51].…”