Increased BCR responsiveness in B cells from patients with chronic GVHD.
Published
Journal Article
Although B cells have emerged as important contributors to chronic graft-versus-host-disease (cGVHD) pathogenesis, the mechanisms responsible for their sustained activation remain unknown. We previously showed that patients with cGVHD have significantly increased B cell-activating factor (BAFF) levels and that their B cells are activated and resistant to apoptosis. Exogenous BAFF confers a state of immediate responsiveness to antigen stimulation in normal murine B cells. To address this in cGVHD, we studied B-cell receptor (BCR) responsiveness in 48 patients who were >1 year out from allogeneic hematopoietic stem cell transplantation (HSCT). We found that B cells from cGVHD patients had significantly increased proliferative responses to BCR stimulation along with elevated basal levels of the proximal BCR signaling components B cell linker protein (BLNK) and Syk. After initiation of BCR signaling, cGVHD B cells exhibited increased BLNK and Syk phosphorylation compared with B cells from patients without cGVHD. Blocking Syk kinase activity prevented relative post-HSCT BCR hyper-responsiveness of cGVHD B cells. These data suggest that a lowered BCR signaling threshold in cGVHD associates with increased B-cell proliferation and activation in response to antigen. We reveal a mechanism underpinning aberrant B-cell activation in cGVHD and suggest that therapeutic inhibition of the involved kinases may benefit these patients.
Full Text
Duke Authors
Cited Authors
- Allen, JL; Tata, PV; Fore, MS; Wooten, J; Rudra, S; Deal, AM; Sharf, A; Hoffert, T; Roehrs, PA; Shea, TC; Serody, JS; Richards, KL; Jagasia, M; Lee, SJ; Rizzieri, D; Horwitz, ME; Chao, NJ; Sarantopoulos, S
Published Date
- March 27, 2014
Published In
Volume / Issue
- 123 / 13
Start / End Page
- 2108 - 2115
PubMed ID
- 24532806
Pubmed Central ID
- 24532806
Electronic International Standard Serial Number (EISSN)
- 1528-0020
Digital Object Identifier (DOI)
- 10.1182/blood-2013-10-533562
Language
- eng
Conference Location
- United States