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B cells from patients with chronic GVHD are activated and primed for survival via BAFF mediated pathways

Jessica L. Allen, Matthew S. Fore, Jenna Wooten, Philip A. Roehrs, Nazmim S. Bhuiya, Todd Hoffert, Andrew Sharf, Allison M. Deal, Paul Armistead, James Coghill, Don A. Gabriel, Robert Irons, Amber Essenmacher, Thomas C. Shea, Kristy Richards, Corey Cutler, Jerome Ritz, Jonathan Serody, Albert S. Baldwin and Stefanie Sarantopoulos

Abstract

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. Since BAFF increases murine B cell metabolism, survival, and maintains autoreactive B cell clones, we performed ex vivo analyses of peripheral B cells from fifty-one patients who either had or did not have active cGVHD and were greater than one year from the time of allogeneic hematopoietic stem cell (HSCT) 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 pro-apoptotic 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.

  • Submitted June 25, 2012.
  • Accepted July 29, 2012.