Increased BCR responsiveness in B cells from patients with chronic GVHD.

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
Blood. 2014 123 (13): 2108-15

PMID: 24532806 · PMCID: PMC3968393 · DOI:10.1182/blood-2013-10-533562

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.

MeSH Terms (16)

Adult Aged B-Cell Activating Factor B-Lymphocytes Cell Proliferation Cells, Cultured Chronic Disease Female Graft vs Host Disease Humans Lymphocyte Activation Male Middle Aged Primary Cell Culture Receptors, Antigen, B-Cell Young Adult

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