B cells from patients with chronic GVHD are activated and primed for survival via BAFF-mediated pathways.
Recent data reveal an important role for B cells in the pathogenesis of chronic GVHD (cGVHD). Patients with cGVHD have delayed B-cell reconstitution and elevated BAFF to B-cell ratios compared to patients without cGVHD. The mechanisms promoting and sustaining B-cell activation in this disease, however, remain unknown. As BAFF increases murine B-cell metabolism and survival and maintains autoreactive B-cell clones, we performed ex vivo analyses of peripheral B cells from 51 patients who either had or did not have active cGVHD and were greater than 1 year from the time of allogeneic hematopoietic stem cell transplantation. We found that B cells from patients with active cGVHD were in a heightened metabolic state and were resistant to apoptosis. Exogenous BAFF treatment amplified cell size and survival in B cells from these patients. We found significantly increased signaling through ERK and AKT that associated with decreased levels of proapoptotic Bim, suggesting a mechanistic link between elevated BAFF levels and aberrant B-cell survival. Thus, we identify a role for BAFF in the pathogenesis of cGVHD and define B-cell activation and survival pathways suitable for novel therapeutic development in cGVHD.
Allen, JL; Fore, MS; Wooten, J; Roehrs, PA; Bhuiya, NS; Hoffert, T; Sharf, A; Deal, AM; Armistead, P; Coghill, J; Gabriel, DA; Irons, R; Essenmacher, A; Shea, TC; Richards, K; Cutler, C; Ritz, J; Serody, J; Baldwin, AS; Sarantopoulos, S
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