Expansions of circulating plasmablasts producing commensal-reactive IgA antibodies are predictors for chronic GVHD.

Abstract

Chronic graft-versus-host disease (cGVHD) is characterized by a dysregulation of the adaptive immune system including an aberrant B cell homeostasis after allogeneic hematopoietic stem cell transplantation (allo-SCT). It is uncertain, however, whether this B cell dysregulation is a result of manifest cGVHD or develops as a sign of aberrant B lymphopoiesis after allo-SCT before cGVHD becomes apparent. To gain insight into the development of B cell dysregulation before the onset of cGVHD, we analyzed B cell subpopulations by multiparameter flow cytometry on day 90, day 180 and day 356 post allo-SCT in a prospective study design. After completion of follow-up, patients were assigned retrospectively to three groups according to onset of GVHD: 1) no GVHD (n=17), 2) acute GVHD (aGVHD) without subsequent cGVHD (n=32) and 3) cGVHD (n=59). Whereas CD21low CD11c+ B cells were increased in all groups, the frequency of CD20neg CD38hi plasmablasts was significantly elevated already 90 days after allo-SCT in those patients subsequently developing cGVHD, as compared to patients without GVHD or aGVHD only (median 5.9% vs 2.2% vs 2.2% of CD19+ cells; p=0.0016 and p=0.0304, respectively). Detailed molecular analysis of expanded plasmablasts revealed a dominance of the IgA isotype with molecular evidence for recent generation in mucosal sites and markers for intestinal homing. A large fraction of the clonally expanded plasmablasts produced antibodies binding to subgroups of commensals which are known to produce short-chain fatty acids. In summary, our data suggests that dysregulated intestinal antibody responses against commensals contribute to the pathophysiology of cGVHD.