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.
University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27599, USA.
Jessica L
JL
Allen
Matthew S
MS
Fore
Jenna
J
Wooten
Philip A
PA
Roehrs
Nazmim S
NS
Bhuiya
Todd
T
Hoffert
Andrew
A
Sharf
Allison M
AM
Deal
Paul
P
Armistead
James
J
Coghill
Don A
DA
Gabriel
Robert
R
Irons
Amber
A
Essenmacher
Thomas C
TC
Shea
Kristy
K
Richards
Corey
C
Cutler
Jerome
J
Ritz
Jonathan
J
Serody
Albert S
AS
Baldwin
Stefanie
S
Sarantopoulos
D000328:Adult; D000368:Aged; D017209:Apoptosis; D053264:B-Cell Activating Factor / Q000276:immunology / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D048429:Cell Size; D002478:Cells, Cultured; D002908:Chronic Disease; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000209:etiology* / Q000473:pathology / Q000628:therapy; D019337:Hematologic Neoplasms / Q000150:complications* / Q000473:pathology / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D015151:Immunoblotting; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction; D014184:Transplantation, Homologous; D055815:Young Adult
D053264:B-Cell Activating Factor; C505719:TNFSF13B protein, human