title: Increased BCR responsiveness in B cells from patients with chronic GVHD.
abstract: 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.
authors.affiliation: Division of Hematological Malignancies and Cellular Therapy, Duke University Department of Medicine and Duke Cancer Institute, Durham, NC;
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Allen
authors.forename: Prasanthi V
authors.initials: PV
authors.lastname: Tata
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Fore
authors.forename: Jenna
authors.initials: J
authors.lastname: Wooten
authors.forename: Sharmistha
authors.initials: S
authors.lastname: Rudra
authors.forename: Allison M
authors.initials: AM
authors.lastname: Deal
authors.forename: Andrew
authors.initials: A
authors.lastname: Sharf
authors.forename: Todd
authors.initials: T
authors.lastname: Hoffert
authors.forename: Philip A
authors.initials: PA
authors.lastname: Roehrs
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Shea
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Serody
authors.forename: Kristy L
authors.initials: KL
authors.lastname: Richards
authors.forename: Madan
authors.initials: M
authors.lastname: Jagasia
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Lee
authors.forename: David
authors.initials: D
authors.lastname: Rizzieri
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Horwitz
authors.forename: Nelson J
authors.initials: NJ
authors.lastname: Chao
authors.forename: Stefanie
authors.initials: S
authors.lastname: Sarantopoulos
mesh_terms: D000328:Adult; D000368:Aged; D053264:B-Cell Activating Factor / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002908:Chronic Disease; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation / Q000502:physiology; D008297:Male; D008875:Middle Aged; D061251:Primary Cell Culture; D011947:Receptors, Antigen, B-Cell / Q000819:agonists / Q000502:physiology*; D055815:Young Adult
chemical_list: D053264:B-Cell Activating Factor; D011947:Receptors, Antigen, B-Cell