Elevated BAFF Is Correlated with Inflammatory Processes in Chronic Graft Versus Host Disease and Supports Increases in Transitional B Cells

Abstract

B Cell Activating Factor of the TNF Family (BAFF) plays a critical role in the survival, activation and function of B cells. Elevated levels of BAFF in plasma, however, have been reported in systemic autoimmune disorders and in chronic graft versus host disease (CGVHD). We similarly observed elevated plasma BAFF levels in 98 patients in an ongoing NCI CGVHD natural history protocol, with a median of 2653 pg/ml (range 92 to 14907), as compared to 556 pg/ml (range 75 to 1834) in 18 normal donors. Furthermore, in a subset of 40 patients in which severity of cutaneous CGVHD could be assessed by the presence of marked erythema or sclerosis, BAFF levels correlated with total percentage body surface area involvement (p<0.02). We then explored the factors that might contribute to elevated BAFF levels. In recipients recovering from either autologous or allogeneic transplant (without GVHD) we observed the highest BAFF levels at day 0 (median of 10534 and 12240 pg/ml respectively), when B cells were severely depleted. As B cell populations recovered to normal levels post transplant, plasma BAFF concentrations declined (Spearman r = −.80 and r = −.60, respectively), consistent with homeostatic cytokine-consumption dynamics. Despite comparably high levels of BAFF (median of 11342 pg/ml) at transplant day 0 in 16 patients who later developed CGHVD, BAFF levels in the cross-sectional, natural history patient population were only moderately correlated with the degree of post transplant B cell recovery (r = −.46). Since inflammatory triggers can induce elevated BAFF production, we assessed plasma levels of cytokines indicative of an inflammatory process. In 98 patients, the plasma levels of IP-10 and sTNFRII correlated positively with BAFF levels (r = +.579 and r = +.396, respectively), consistent with active inflammatory processes in those CGVHD patients with elevated BAFF levels. In a multi-step regression model, the levels of circulating B cells, plasma IP-10 and sTNFRII combined to strongly predict BAFF levels (R =.704). These findings suggest that both homeostatic recovery of B cell populations consuming BAFF and inflammatory cytokine cascades initiated by donor-anti-host reactivity combine to regulate BAFF levels post transplant. Although a broad range of autoimmune symptoms have been described in CGVHD, the mechanisms by which donor-anti-host reactivity can result in autoimmunity remains poorly understood. In murine models, elevated BAFF levels have been associated with increased survival of the transitional B cell population, altering the normal processes of B cell negative selection, and resulting in failure to eliminate auto-reactive B cells. We therefore assessed whether elevated BAFF levels were associated with increased frequencies of transitional CD21− T1 B cells in CGVHD patients. In 79 CGVHD patients, the median percentage of CD19+CD21− transitional B cells was 6.13% (range 1% to 39.4%) as compared to 2.24% (range 0.66% to 7.44%) in 40 healthy adult donors. Furthermore, the frequency of CD21− transitional B cells was significantly higher in those patients with higher BAFF levels (p<.002). Finally, the expression (mean fluorescent intensity (MFI)) of the BAFF receptor (BAFF-R) was reduced in patients with CGVHD compared with normal donors, consistent with down-regulation upon BAFF consumption; among CGVHD patients, receptor MFI was inversely correlated with BAFF levels (Spearman r = −.44). Elevated BAFF levels in CGVHD therefore may both reflect the inflammatory processes initiated by donor-anti-host reactivity and contribute to the later generation of pathologic autoantibodies by dysregulation of B cell negative selection.