Expansions of circulating plasmablasts producing commensal-reactive IgA antibodies are predictors for chronic GVHD
Abstract
Abstract Chronic graft-versus-host disease (cGVHD) is characterized by 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 days 90, 180, and 356 after allo-SCT in a prospective study design. After completion of follow-up, patients were assigned retrospectively to 3 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). Although CD21lowCD11c+ B cells were increased in all groups, the frequency of CD20–CD38hi plasmablasts was significantly elevated already 90 days after allo-SCT in patients who subsequently developed cGVHD, compared to patients without GVHD or with aGVHD only (median of CD19+ cells, 5.9% vs 2.2% vs 2.2%; P = .0016 and .0304, respectively). Detailed molecular analysis of expanded plasmablasts revealed a dominance of the immunoglobulin A 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 that bound to subgroups of commensals known to produce short-chain fatty acids. In summary, our data suggest that dysregulated intestinal antibody responses against commensals contribute to the pathophysiology of cGVHD.
Article Details
Authors (22)
Katharina M. Habenicht
1Division of Genetics, Department Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
Jana Wanzek
1Friedrich-Alexander-Universität Erlangen-Nürnberg, Division of Genetics, Department Biology, Erlangen, Germany
Anna Bootz
1Friedrich-Alexander-Universität Erlangen-Nürnberg, Division of Genetics, Department Biology, Erlangen, Germany
Simon Schäfer
1Friedrich-Alexander-Universität Erlangen-Nürnberg, Division of Genetics, Department Biology, Erlangen, Germany
Lara Vollmer
1Division of Genetics, Department Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
Andreas Hiergeist
Matthias Fante
2University Hospital Regensburg, Department of Internal Medicine III, Hematology & Internal Oncology, Regensburg, Germany
Jakob Hasenbank
1Division of Genetics, Department Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
Andrea Schneider
Ingrid Vasova
1Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Department of Internal Medicine 5 – Hematology and Oncology, Erlangen, Germany
Silvia Spoerl
1Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Department of Internal Medicine 5 – Hematology and Oncology, Erlangen, Germany
Anna Brandt
2Department of Internal Medicine 5–Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
Michael Rehli
Petra Hoffmann
Stefan Wirtz
7Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Department of Internal Medicine 1 - Gastroenterology, Pneumology and Endocrinology, Erlangen, Germany
Jesika Kotorri
8Institute of Clinical Microbiology, Immunology, and Hygiene, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
Roman G. Gerlach
8Institute of Clinical Microbiology, Immunology, and Hygiene, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
André Gessner
Andreas Mackensen
Friedrich-Alexander-Universität Erlangen–Nürnberg, Erlangen, Germany
Julia Winkler
2Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Department of Internal Medicine 5 - Hematology and Oncology, Erlangen, Germany
Daniel Wolff
Thomas H. Winkler
Division of Genetics, Department Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.