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Increased BCR responsiveness in B cells from patients with chronic GVHD

Allen, Jessica L. ; Tata, Prasanthi V. ; Fore, Matthew S. ; Wooten, Jenna ; Rudra, Sharmistha ; Deal, Allison M. ; Sharf, Andrew ; Hoffert, Todd ; Roehrs, Philip A. ; Shea, Thomas C. ; Serody, Jonathan S. ; Richards, Kristy L. ; Jagasia, Madan ; Lee, Stephanie J. ; Rizzieri, David ; Horwitz, Mitchell E. ; Chao, Nelson J. ; Sarantopoulos, Stefanie

Blood, 2014-03, Vol.123 (13), p.2108-2115 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Increased BCR responsiveness in B cells from patients with chronic GVHD
Autor: Allen, Jessica L. ; Tata, Prasanthi V. ; Fore, Matthew S. ; Wooten, Jenna ; Rudra, Sharmistha ; Deal, Allison M. ; Sharf, Andrew ; Hoffert, Todd ; Roehrs, Philip A. ; Shea, Thomas C. ; Serody, Jonathan S. ; Richards, Kristy L. ; Jagasia, Madan ; Lee, Stephanie J. ; Rizzieri, David ; Horwitz, Mitchell E. ; Chao, Nelson J. ; Sarantopoulos, Stefanie
Assuntos: Adult ; Aged ; B-Cell Activating Factor - metabolism ; B-Lymphocytes - metabolism ; B-Lymphocytes - pathology ; Cell Proliferation ; Cells, Cultured ; Chronic Disease ; Female ; Graft vs Host Disease - immunology ; Graft vs Host Disease - metabolism ; Humans ; Lymphocyte Activation - physiology ; Male ; Middle Aged ; Primary Cell Culture ; Receptors, Antigen, B-Cell - agonists ; Receptors, Antigen, B-Cell - physiology ; Transplantation ; Young Adult
É parte de: Blood, 2014-03, Vol.123 (13), p.2108-2115
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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Descrição: 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. •Human cGVHD B cells have increased proximal BCR signaling protein expression and are more BCR responsive than non-cGVHD B cells.•Inhibiting Syk kinase activity abrogates the BCR-driven ex vivo proliferative and survival advantage of human chronic GVHD B cells.
Editor: United States: Elsevier Inc
Idioma: Inglês

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Increased BCR responsiveness in B cells from patients with chronic GVHD

United States: Elsevier Inc

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