BAFF promotes heightened BCR responsiveness and manifestations of chronic GVHD after allogeneic stem cell transplantation
Autor: | Daniel R. Saban, Jonathan C. Poe, Vedran Radojcic, Diana M. Cardona, Ivan Maillard, Stefanie Sarantopoulos, Amy N. Suthers, Itaevia M. Curry-Chisolm, Hsuan Su, Glenn K. Matsushima, Zhiguo Li, Sarah Anand, Wei Jia, Jeffrey C. Rathmell, Nelson J. Chao, Kazuhiro Imai, Nancy J. Reyes, Benny J. Chen, Rachel A. DiCioccio |
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Rok vydání: | 2021 |
Předmět: |
Isoantigens
T-Lymphocytes Immunology Graft vs Host Disease Syk Lymphocyte Activation Biochemistry Mice stomatognathic system Antigen Isoantibodies immune system diseases Reticular cell hemic and lymphatic diseases B-Cell Activating Factor Animals Syk Kinase Transplantation Homologous Medicine Receptor Notch2 skin and connective tissue diseases B-cell activating factor Receptor Bone Marrow Transplantation Mice Inbred BALB C business.industry breakpoint cluster region Cell Biology Hematology Mice Inbred C57BL Transplantation stomatognathic diseases Proto-Oncogene Proteins c-bcr Female Stem cell business |
Zdroj: | Blood. 137:2544-2557 |
ISSN: | 1528-0020 0006-4971 |
Popis: | Patients with chronic graft-versus-host disease (cGVHD) have increased B cell–activating factor (BAFF) levels, but whether BAFF promotes disease after allogeneic bone marrow transplantation (allo-BMT) remains unknown. In a major histocompatibility complex–mismatched model with cGVHD-like manifestations, we first examined B-lymphopenic μMT allo-BMT recipients and found that increased BAFF levels in cGVHD mice were not merely a reflection of B-cell number. Mice that later developed cGVHD had significantly increased numbers of recipient fibroblastic reticular cells with higher BAFF transcript levels. Increased BAFF production by donor cells also likely contributed to cGVHD, because BAFF transcript in CD4+ T cells from diseased mice and patients was increased. cGVHD manifestations in mice were associated with high BAFF/B-cell ratios and persistence of B-cell receptor (BCR)–activated B cells in peripheral blood and lesional tissue. By employing BAFF transgenic (Tg) mice donor cells, we addressed whether high BAFF contributed to BCR activation in cGVHD. BAFF increased NOTCH2 expression on B cells, augmenting BCR responsiveness to surrogate antigen and NOTCH ligand. BAFF Tg B cells had significantly increased protein levels of the proximal BCR signaling molecule SYK, and high SYK protein was maintained by BAFF after in vitro BCR activation or when alloantigen was present in vivo. Using T cell–depleted (BM only) BAFF Tg donors, we found that BAFF promoted cGVHD manifestations, circulating GL7+ B cells, and alloantibody production. We demonstrate that pathologic production of BAFF promotes an altered B-cell compartment and augments BCR responsiveness. Our findings compel studies of therapeutic targeting of BAFF and BCR pathways in patients with cGVHD. |
Databáze: | OpenAIRE |
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