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Blood, 16 April 2009, Vol. 113, No. 16, pp. 3865-3874.
Prepublished online as a Blood First Edition Paper on January 23, 2009; DOI 10.1182/blood-2008-09-177840.
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Submitted September 30, 2008
Accepted January 11, 2009
Altered B cell homeostasis and excess BAFF in human chronic graft versus host disease
Stefanie Sarantopoulos*, Kristen E. Stevenson, Haesook T. Kim, Corey S. Cutler, Nazmim S. Bhuiya, Michael Schowalter, Vincent T. Ho, Edwin P. Alyea, John Koreth, Bruce R. Blazar, Robert J. Soiffer, Joseph H. Antin, and Jerome Ritz
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, United States
Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, United States
Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, United States
* Corresponding author; email: stefanie_sarantopoulos{at}dfci.harvard.edu.
Chronic graft versus host disease (cGVHD) causes significant morbidity and mortality in patients otherwise cured of malignancy after hematopoietic stem cell transplantation (HSCT). The presence of allo-antibodies and high plasma BAFF levels in patients with cGVHD suggest that B cells play a role in disease pathogenesis. We performed detailed phenotypic and functional analyses of peripheral B cells in 82 patients after HSCT. Patients with cGVHD had significantly higher BAFF:B cell ratios compared to patients without cGVHD or healthy donors. In cGVHD, increasing BAFF concentrations correlated with increased numbers of circulating pre-germinal center (GC) B cells and post-GC 'plasmablast-like' cells, suggesting in vivo BAFF-dependence of these two CD27+ B cell subsets. Circulating CD27+ B cells in cGVHD comprised in vivo activated B cells capable of IgG production without requiring additional antigen stimulation. Serial studies revealed that patients who subsequently developed cGVHD had delayed reconstitution of naive B cells despite persistent BAFF elevation as well as proportional increase in CD27+ B cells in the first year post-HSCT. These studies delineate specific abnormalities of B cell homeostasis in patients with cGVHD and suggest that BAFF targeting agents may be useful in this disease.
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