Apoptosis Susceptibility Prolongs the Lack of Memory B Cells in Acute Leukemic Patients After Allogeneic Hematopoietic Stem Cell Transplantation.
Long-term survival after allogeneic hematopoietic stem cell transplantation requires intact immunosurveillance, which is hampered by lymphoid organ damage associated with conditioning therapy, graft-versus-host disease, and immunosuppression. Our study aimed to identify the mechanisms contributing to sustained low memory B cell numbers after transplantation. Peripheral B and T cell subset recovery and functional marker expression were investigated in 35 acute leukemic patients up to 1 year after transplantation. Apoptosis of B cells after CD40/TLR-9, CD40/BCR, and CD40/BCR/TLR-9-dependent stimulation and drug efflux capacity were analyzed. One half of the patients suffered from infections after day 180. All patients had strongly diminished CD27(+) memory B cells despite already normalized total B cell numbers and fully recovered CD27(-)IgD(-) memory B cells, putatively of extra-follicular origin. Circulating memory follicular helper T cells were reduced in the majority of patients as well. Naïve B cells exhibited a decreased expression of CXCR5, which mediates follicular B cell entry. Additionally, a lower HLA-DR expression was found on naïve B cells, impairing antigen presentation. Upon CD40/TLR-9-dependent activation, B cells underwent significantly increased apoptosis paralleled by an aberrant up-regulation of Fas-L on activated T cells and Fas on resting B cells. Significantly increased B cell apoptosis was also observed after CD40/BCR and CD40/BCR/TLR-9-dependent activation. Drug efflux capacity of naïve B cells was diminished in cyclosporin A-treated patients, additionally contributing to an apoptosis-prone phenotype. We conclude that B cell survival and migration and T cell communication defects are contributing candidates for an impaired germinal center formation of memory B cells after allogeneic hematopoietic stem cell transplantation. Follow-up studies should evaluate effectiveness of revaccinations on the cellular level and should address the long-term sequelae of B cell defects after transplantation.
Institute for Medical Immunology, Charité University Medicine, CVK, Berlin, Germany.
Angela
A
Mensen
Institute for Medical Immunology, Charité University Medicine, CVK, Berlin, Germany.
Youngseong
Y
Oh
Institute for Medical Immunology, Charité University Medicine, CVK, Berlin, Germany.
Sonya C
SC
Becker
Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine CVK, Berlin, Germany.
Philipp G
PG
Hemmati
Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine CVK, Berlin, Germany.
Christian
C
Jehn
Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine CVK, Berlin, Germany.
Jörg
J
Westermann
Experimental and Clinical Research Center, Berlin, Germany.
Martin
M
Szyska
Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine CVK, Berlin, Germany.
Henning
H
Göldner
Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine CVK, Berlin, Germany; Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Bernd
B
Dörken
Institute for Medical Immunology, Charité University Medicine, CVK, Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Berlin, Germany.
Carmen
C
Scheibenbogen
Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine CVK, Berlin, Germany.
Renate
R
Arnold
Institute for Medical Immunology, Charité University Medicine, CVK, Berlin, Germany; Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine CVK, Berlin, Germany; Experimental and Clinical Research Center, Berlin, Germany. Electronic address: il-kang.na@charite.de.
Il-Kang
IK
Na
D000328:Adult; D017209:Apoptosis / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology; D016022:Case-Control Studies; D005260:Female; D015870:Gene Expression; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006650:Histocompatibility Testing; D006801:Humans; D007072:Immunoglobulin D / Q000235:genetics; D007156:Immunologic Memory; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D061251:Primary Cell Culture; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology; D054380:Receptors, CXCR5 / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000235:genetics / Q000276:immunology; D061349:Unrelated Donors
D015415:Biomarkers; D019013:CD40 Antigens; C095085:CXCR5 protein, human; D006684:HLA-DR Antigens; D007072:Immunoglobulin D; D011947:Receptors, Antigen, B-Cell; D054380:Receptors, CXCR5; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7
Allogeneic hematopoietic stem cell transplantation; B cell intrinsic and germinal center defects; Long-term memory B cell paucity