Altered Toll-like receptor 9 responses in circulating B cells at the onset of extensive chronic graft-versus-host disease.
B cells appear to play a role in chronic graft-versus-host disease (cGVHD) as shown in murine models and the success of anti-CD20 B cell antibody treatment in humans. Recent studies have shown that immunostimulatory microbial CpG-DNA splenic responses were enhanced in murine GVHD. We hypothesized that CpG-induced B cell responses are increased in human cGVHD. Newly diagnosed cGVHD patients enrolled on the COG protocol ASCT0031 were divided into early (3-8 months postblood and marrow transplant [BMT]) and late (> or =9 months post-BMT) onset groups and compared to time-matched control BMT patients. A significantly greater percentage of phosphorothioate (PS)-modified CpG stimulated B cells from cGVHD patients demonstrated an increased expression of CD86 compared to controls (P = .0004). This response had a significant correlation between B cell TLR9 expression (r(2) = 0.65; P = .002) and CD86 upregulation using the entirely TLR9-dependent native phosphodiester CpG (P = .003). The PS-modified CpG response at 2 months after initiation of cGVHD therapy demonstrated a trend toward predicting therapeutic response at 9 months post-BMT (P = .07). These findings suggest that an increased number of B cells, primed for a TLR9 response, may play a role in the pathophysiology of cGVHD.
She
Kevin
K
Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
Gilman
Andrew L
AL
Aslanian
Soudabeh
S
Shimizu
Hiromi
H
Krailo
Mark
M
Chen
Zhengjia
Z
Reid
Gregor S
GS
Wall
Donna
D
Goldman
Fred
F
Schultz
Kirk R
KR
D000293:Adolescent; D001402:B-Lymphocytes / Q000276:immunology*; D051940:B7-2 Antigen / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D018899:CpG Islands / Q000276:immunology*; D005260:Female; D006086:Graft vs Host Disease / Q000097:blood / Q000276:immunology* / Q000503:physiopathology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D008297:Male; D016555:Matched-Pair Analysis; D051217:Toll-Like Receptor 9 / Q000097:blood*; D015854:Up-Regulation
D051940:B7-2 Antigen; D015415:Biomarkers; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9