scholarly journals Bone Marrow Plasma Cells Are a Primary Source of Serum HIV-1–Specific Antibodies in Chronically Infected Individuals

2015 ◽  
Vol 194 (6) ◽  
pp. 2561-2568 ◽  
Author(s):  
Jairo M. Montezuma-Rusca ◽  
Susan Moir ◽  
Lela Kardava ◽  
Clarisa M. Buckner ◽  
Aaron Louie ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Plasma Cells ◽  
Primary Source ◽  
Specific Antibodies ◽  
Bone Marrow Plasma ◽  
Hiv 1

scholarly journals Pretransplant Desensitization with Costimulation Blockade and Proteasome Inhibitor Reduces DSA and Delays Antibody-Mediated Rejection in Highly Sensitized Nonhuman Primate Kidney Transplant Recipients

2019 ◽  
Vol 30 (12) ◽  
pp. 2399-2411 ◽  
Author(s):  
Brian Ezekian ◽  
Paul M. Schroder ◽  
Michael S. Mulvihill ◽  
Andrew Barbas ◽  
Bradley Collins ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Graft Survival ◽  
Germinal Center ◽  
Proteasome Inhibitor ◽  
Plasma Cells ◽  
Costimulation Blockade ◽  
Specific Antibodies ◽  
Antibody Mediated Rejection ◽  
Bone Marrow Plasma ◽  
Donor Specific Antibodies

BackgroundPatients with broad HLA sensitization have poor access to donor organs, high mortality while waiting for kidney transplant, and inferior graft survival. Although desensitization strategies permit transplantation via lowering of donor-specific antibodies, the B cell–response axis from germinal center activation to plasma cell differentiation remains intact.MethodsTo investigate targeting the germinal center response and plasma cells as a desensitization strategy, we sensitized maximally MHC-mismatched rhesus pairs with two sequential skin transplants. We administered a proteasome inhibitor (carfilzomib) and costimulation blockade agent (belatacept) to six animals weekly for 1 month; four controls received no treatment. We analyzed blood, lymph node, bone marrow cells, and serum before desensitization, after desensitization, and after kidney transplantation.ResultsThe group receiving carfilzomib and belatacept exhibited significantly reduced levels of donor-specific antibodies (P=0.05) and bone marrow plasma cells (P=0.02) compared with controls, with a trend toward reduced lymph node T follicular helper cells (P=0.06). Compared with controls, carfilzomib- and belatacept-treated animals had significantly prolonged graft survival (P=0.02), and renal biopsy at 1 month showed significantly reduced antibody-mediated rejection scores (P=0.02). However, four of five animals with long-term graft survival showed gradual rebound of donor-specific antibodies and antibody-mediated rejection.ConclusionsDesensitization using proteasome inhibition and costimulation blockade reduces bone marrow plasma cells, disorganizes germinal center responses, reduces donor-specific antibody levels, and prolongs allograft survival in highly sensitized nonhuman primates. Most animals experienced antibody-mediated rejection with humoral-response rebound, suggesting desensitization must be maintained after transplantation using ongoing suppression of the B cell response.

scholarly journals Generation of Long-Lived Bone Marrow Plasma Cells Secreting Antibodies Specific for the HIV-1 gp41 Membrane-Proximal External Region in the Absence of Polyreactivity

2016 ◽  
Vol 90 (19) ◽  
pp. 8875-8890 ◽  
Author(s):  
Luke R. Donius ◽  
Yuxing Cheng ◽  
Jaewon Choi ◽  
Zhen-Yu J. Sun ◽  
Melissa Hanson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Plasma Cells ◽  
Immunoglobulin Gene ◽  
Antigen Specificity ◽  
External Region ◽  
Membrane Proximal External Region ◽  
Specific Antibodies ◽  
Hiv 1

ABSTRACTAn effective preventive vaccine is highly sought after in order to stem the current HIV-1 pandemic. Both conservation of contiguous gp41 membrane-proximal external region (MPER) amino acid sequences across HIV-1 clades and the ability of anti-MPER broadly neutralizing antibodies (BNAbs) to block viral hemifusion/fusion establish the MPER as a prime vaccination target. In earlier studies, we described the development of an MPER vaccine formulation that takes advantage of liposomes to array the MPER on a lipid bilayer surface, paralleling its native configuration on the virus membrane while also incorporating molecular adjuvant and CD4 T cell epitope cargo. Here we demonstrate that several immunizations with MPER/liposomes induce high levels of bone marrow long-lived plasma cell (LLPC) antibody production. Single-cell immunoglobulin gene retrieval analysis shows that these plasma cells are derived from a germ line repertoire of B cells with a diverse representation of immunoglobulin genes, exhibiting antigen-driven positive selection. Characterization of LLPC recombinant monoclonal antibodies (rMAbs) indicates that antigen recognition is achieved through convergence on a common epitopic focus by utilizing various complementarity-determining region H3 (CDRH3) lengths. Importantly, the vast majority of rMAbs produced from these cells lack polyreactivity yet manifest antigen specificity in the context of lipids, shaping MPER-specific paratopes through selective pressure. Taken together, these findings demonstrate that the MPER is a vaccine target with minimal risk of generating off-target autoimmunity.IMPORTANCEA useful vaccine must generate desired long-term, antigen-specific antibody responses devoid of polyreactivity or autoreactivity. The common polyreactive features of some HIV-1 BNAbs have raised concern about elicitation of anti-MPER antibodies. Utilizing single-LLPC repertoire analysis and biophysical characterization of anti-MPER rMAbs, we show that their fine specificities require a structural fitness of the antibody combining site involving heavy and light chain variable domains shaped by somatic hypermutation and affinity maturation of B cells in the germinal center. Perhaps more importantly, our results demonstrate that the majority of MPER-specific antibodies are not inherently polyspecific and/or autoreactive, suggesting that polyreactivity of MPER-specific antibodies is separable from their antigen specificity.

scholarly journals Bone Marrow Plasma Cells Modulate Local Myeloid-Lineage Differentiation via IL-10

2019 ◽  
Vol 10 ◽  
Author(s):  
Lingzhang Meng ◽  
Larissa Nogueira Almeida ◽  
Ann-Katrin Clauder ◽  
Timo Lindemann ◽  
Julia Luther ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Plasma Cells ◽  
Myeloid Lineage ◽  
Lineage Differentiation ◽  
Bone Marrow Plasma

scholarly journals Multiple myeloma: circulating lymphocytes that express plasma cell antigens

Blood ◽  
1984 ◽  
Vol 64 (2) ◽  
pp. 352-356
Author(s):  
GJ Ruiz-Arguelles ◽  
JA Katzmann ◽  
PR Greipp ◽  
NJ Gonchoroff ◽  
JP Garton ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Peripheral Blood Lymphocytes ◽  
Tumor Burden ◽  
B Cell Differentiation ◽  
Blood Lymphocytes ◽  
Bone Marrow Plasma

The bone marrow and peripheral blood of 14 patients with multiple myeloma were studied with murine monoclonal antibodies that identify antigens on plasma cells (R1–3 and OKT10). Peripheral blood lymphocytes expressing plasma cell antigens were found in six cases. Five of these cases expressed the same antigens that were present on the plasma cells in the bone marrow. Patients that showed such peripheral blood involvement were found to have a larger tumor burden and higher bone marrow plasma cell proliferative activity. In some patients, antigens normally found at earlier stages of B cell differentiation (B1, B2, and J5) were expressed by peripheral blood lymphocytes and/or bone marrow plasma cells.

scholarly journals LONG-LIVED BONE MARROW PLASMA CELLS DURING IMMUNE RESPONSE TO ALPHA (1→3) DEXTRAN

2015 ◽  
Vol 17 (2) ◽  
pp. 127
Author(s):  
I. N. Chernyshova ◽  
M. V. Gavrilova ◽  
L. V. Komarova ◽  
E. V. Sidorova
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Plasma Cells ◽  
Bone Marrow Plasma
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