scholarly journals CXCR4+ Treg cells control serum IgM levels and natural IgM autoantibody production by B1 cells in the bone marrow

2021 ◽  
Author(s):  
Shlomo Elias ◽  
Rahul Sharma ◽  
Michael Schizas ◽  
Izabella Valdez ◽  
Sun-Mi Park ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Plasma Cells ◽  
Treg Cells ◽  
Total Serum ◽  
Dependent Manner ◽  
Autoantibody Production ◽  
Hematopoietic Stem ◽  
Control Serum ◽  
B1 Cells

Regulatory T (Treg) cells represent a specialized lineage of suppressive CD4+ T cells, whose functionality is critically dependent on their ability to migrate to, and dwell in the proximity of cells they control. Here we show that continuous expression of the chemokine receptor CXCR4 in Treg cells is required for their ability to accumulate in the bone marrow (BM). Induced CXCR4 ablation in Treg cells led to their rapid depletion and consequent increase in mature B cells, foremost B-1 subset, observed exclusively in the BM without detectable changes in plasma cells or hematopoietic stem cells or any signs of systemic or local immune activation elsewhere. Dysregulation of BM B-1 B cells was associated with a highly specific increase in IgM autoantibodies and the total serum IgM levels. Thus, Treg cells control autoreactive B-1 B cells in a CXCR4-dependent manner. These findings have significant implications for understanding of regulation of B cell autoreactivity and malignancies.

scholarly journals An intrinsic B cell defect is required for the production of autoantibodies in the lpr model of murine systemic autoimmunity.

1991 ◽  
Vol 173 (6) ◽  
pp. 1441-1449 ◽  
Author(s):  
E S Sobel ◽  
T Katagiri ◽  
K Katagiri ◽  
S C Morris ◽  
P L Cohen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
B Cells ◽  
Lupus Erythematosus ◽  
Immunofluorescence Assay ◽  
Total Serum ◽  
Enzyme Linked Immunosorbent Assay ◽  
Cell Phenotype ◽  
Autoantibody Production ◽  
Systemic Autoimmunity

Mice homozygous for the gene lpr develop marked lymphadenopathy and a spectrum of autoantibodies closely resembling that of human systemic lupus erythematosus. The unusual T cell phenotype of the expanded lymphocyte population and the T-dependence of several antibodies in this strain have suggested that primary T cell abnormalities underlie the autoimmune syndrome. Using double chimeras, we now show that expression of the lpr gene in B cells is absolutely necessary for autoantibody production. Combinations of anti-Thy 1.2 + C' treated bone marrow from congenic strains of C57BL/6 mice, differing only at the immunoglobulin heavy chain (Igh) and lpr loci, were transferred into lethally irradiated B6/lpr mice. Double chimerism was documented by allotype-specific surface IgD and IgM immunofluorescence assay of peripheral blood and by allotype-specific enzyme-linked immunosorbent assay for total IgM in serum. Despite the presence of both +/+ and lpr B cells, IgM and IgG2a anti-chromatin as well as IgM anti-IgG were entirely the products of lpr B cells. Total serum IgG2a and IgG1 were also dominated by the lpr phenotype but not to the same extent. A similar experiment using B6/lpr-Igha recipients confirmed these findings. Additional experiments in which B6/lpr recipients were infused with ratios of donor bone marrow favoring B6.C20 +/+ over B6/lpr showed that even though +/+ B cells were overrepresented, autoantibodies were only of the lpr allotype. In addition, in the presence of lpr B cells, normal B cells showed little response to an exogenous, T cell-dependent antigen. The data thus indicate that lpr B cells manifest an intrinsic abnormality which is essential for autoantibody production in the lpr model.

scholarly journals The Normal Counterpart of IgD Myeloma Cells in Germinal Center Displays Extensively Mutated IgVH Gene, Cμ–Cδ Switch, and λ Light Chain Expression

1998 ◽  
Vol 187 (8) ◽  
pp. 1169-1178 ◽  
Author(s):  
Christophe Arpin ◽  
Odette de Bouteiller ◽  
Diane Razanajaona ◽  
Isabelle Fugier-Vivier ◽  
Francine Brière ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Light Chain ◽  
Germinal Center ◽  
Plasma Cells ◽  
Precursor Cells ◽  
Memory B Cells ◽  
Hematopoietic Stem ◽  
Myeloma Cells ◽  
Λ Light Chain

Human myeloma are incurable hematologic cancers of immunoglobulin-secreting plasma cells in bone marrow. Although malignant plasma cells can be almost eradicated from the patient's bone marrow by chemotherapy, drug-resistant myeloma precursor cells persist in an apparently cryptic compartment. Controversy exists as to whether myeloma precursor cells are hematopoietic stem cells, pre–B cells, germinal center (GC) B cells, circulating memory cells, or plasma blasts. This situation reflects what has been a general problem in cancer research for years: how to compare a tumor with its normal counterpart. Although several studies have demonstrated somatically mutated immunoglobulin variable region genes in multiple myeloma, it is unclear if myeloma cells are derived from GCs or post-GC memory B cells. Immunoglobulin (Ig)D-secreting myeloma have two unique immunoglobulin features, including a biased λ light chain expression and a Cμ–Cδ isotype switch. Using surface markers, we have previously isolated a population of surface IgM−IgD+CD38+ GC B cells that carry the most impressive somatic mutation in their IgV genes. Here we show that this population of GC B cells displays the two molecular features of IgD-secreting myeloma cells: a biased λ light chain expression and a Cμ–Cδ isotype switch. The demonstration of these peculiar GC B cells to differentiate into IgD-secreting plasma cells but not memory B cells both in vivo and in vitro suggests that IgD-secreting plasma and myeloma cells are derived from GCs.

scholarly journals A monoclonal antibody that recognizes B cells and B cell precursors in mice.

1981 ◽  
Vol 153 (2) ◽  
pp. 269-279 ◽  
Author(s):  
R L Coffman ◽  
I L Weissman
Keyword(s):  
Monoclonal Antibody ◽  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Bone Marrow Cells ◽  
Cell Lineage ◽  
Hematopoietic Stem ◽  
B Cell Precursors

The monoclonal antibody, RA3-2C2, appears to be specific for cells within the B cell lineage. This antibody does not recognize thymocytes, peripheral T cells, or nonlymphoid hematopoietic cells in the spleen or bone marrow. Nor does it recognize the pluripotent hematopoietic stem cells, the spleen colony-forming unit, All sIg+ B cells and most plasma cells are RA3-2C2+. In addition, approximately 20% of nucleated bone marrow cells are RA3-2C2+ but sIg-. This population contains B cell precursors that can give rise to sIg+ cells within 2 d in vitro.

B-cell–autonomous somatic mutation deficit following bone marrow transplant

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 1064-1069 ◽  
Author(s):  
Annuska M. Glas ◽  
Erwin H. N. van Montfort ◽  
Jan Storek ◽  
Emily-Gene N. Green ◽  
Roy P. M. Drissen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Bone Marrow Transplant ◽  
Somatic Mutation ◽  
Healthy Subjects ◽  
Marrow Transplant ◽  
Dependent Manner ◽  
Hematopoietic Stem ◽  
Humoral Immunodeficiency

Hematopoietic stem cell transplantation is characterized by a prolonged period of humoral immunodeficiency. We have previously shown that the deficiencies are probably not due to the failure to utilize the appropriate V regions in the pre-immune repertoire. However, a striking observation, which correlated with the absence of immunoglobulin IgD− cells and was consistent with a defect in antigen-driven responses, was that rearrangements in bone marrow transplant (BMT) recipients exhibited much less somatic mutation than did rearrangements obtained from healthy subjects. In this paper, we present evidence suggesting that naive B cells obtained from BMT recipients lack the capacity to accumulate somatic mutations in a T-cell–dependent manner compared with healthy subjects. This appears to be a B-cell–autonomous deficit because T cells from some patients, which were not able to support the accumulation of mutations in autologous naive B cells, were able to support accumulation of mutations in heterologous healthy-subject naive B cells.

B-cell–autonomous somatic mutation deficit following bone marrow transplant

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 1064-1069 ◽  
Author(s):  
Annuska M. Glas ◽  
Erwin H. N. van Montfort ◽  
Jan Storek ◽  
Emily-Gene N. Green ◽  
Roy P. M. Drissen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Bone Marrow Transplant ◽  
Somatic Mutation ◽  
Healthy Subjects ◽  
Marrow Transplant ◽  
Dependent Manner ◽  
Hematopoietic Stem ◽  
Humoral Immunodeficiency

Abstract Hematopoietic stem cell transplantation is characterized by a prolonged period of humoral immunodeficiency. We have previously shown that the deficiencies are probably not due to the failure to utilize the appropriate V regions in the pre-immune repertoire. However, a striking observation, which correlated with the absence of immunoglobulin IgD− cells and was consistent with a defect in antigen-driven responses, was that rearrangements in bone marrow transplant (BMT) recipients exhibited much less somatic mutation than did rearrangements obtained from healthy subjects. In this paper, we present evidence suggesting that naive B cells obtained from BMT recipients lack the capacity to accumulate somatic mutations in a T-cell–dependent manner compared with healthy subjects. This appears to be a B-cell–autonomous deficit because T cells from some patients, which were not able to support the accumulation of mutations in autologous naive B cells, were able to support accumulation of mutations in heterologous healthy-subject naive B cells.

scholarly journals Maintenance of Anti-Sm/RNP Autoantibody Production by Plasma Cells Residing in Ectopic Lymphoid Tissue and Bone Marrow Memory B Cells

2013 ◽  
Vol 190 (8) ◽  
pp. 3916-3927 ◽  
Author(s):  
Jason S. Weinstein ◽  
Matthew J. Delano ◽  
Yuan Xu ◽  
Kindra M. Kelly-Scumpia ◽  
Dina C. Nacionales ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Lymphoid Tissue ◽  
Plasma Cells ◽  
Memory B Cells ◽  
Autoantibody Production

Fhl2 Regulates The Function Of Hematopoietic Stem/Progenitor Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2414-2414
Author(s):  
Yu Hou ◽  
Zhijian Qian
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
B Cells ◽  
Progenitor Cells ◽  
Flow Cytometric Analysis ◽  
Myeloid Cells ◽  
Dependent Manner ◽  
Chimeric Mice ◽  
Hematopoietic Stem ◽  
Flow Cytometric

Abstract Fhl2 is a member of four and one half LIM domain protein family. It acts as a transcriptional modulator, regulating proliferation and apoptosis in a cell-context dependent manner. The role of endogenous Fhl2 in hematopoietic stem/progenitor cells (HSCs/HPCs) is still unknown. To determine the in vivo function of Fhl2 in hematopoiesis, we characterized the HSCs/HPCs in Fhl2-null mice. At age of 3 months, Fhl2-null mice revealed normal hematopoietic parameters. As shown by flow cytometric analysis, Fhl2-null mice had a normal distribution of Mac-1+Gr+ myeloid cells, B220+ B cells and CD3+ T cells in bone marrow and spleen, suggesting that Fhl2 loss does not affect mature cell differentiation in young mice. The frequency and total number of stem cell enriched population LSK (Lin-Sca+c-Kit+) and Long-term HSCs (LT-HSCs) (Lin-Sca+c-Kit+CD48-CD150+) were marginally increased in Fhl2-/- mice as compared to wildtype mice, whereas the frequency and the number of hematopoietic progenitor cells was reduced in Fhl2-/- mice as compared to Fhl2+/+ mice. Transplantation exposes HSCs to various stresses including replicative and oxidative stresses. To examine whether Fhl2 regulates the function of HSCs/HPCs under stress, we transplanted bone marrow cells from Fhl2-/- or control mice into lethally-irradiated wildtype mice to generate chimeric mice. 7 months after transplantation, the Fhl2-/- chimeric mice developed MDS-like disease with a significant decrease in platelet, red blood cell (RBC) counts and Hemoglobin (Hb) level as compared to control chimeric mice. The number of LT-HSC, LSK and HPCs in Fhl2-/- chimeric mice were significantly less than they were in control chimeric mice, as determined by flow cytometric analysis. However, the frequency of Mac-1+Gr-1+ myeloid cells, B220+ B cells and CD3+ T cells were comparable in Fhl2-/- and Fhl2+/+ chimeric mice, suggesting that Fhl2 loss reduces repopulation capacity of LT-HSCs but does not affect HPCs differentiation in recipient mice. As evidenced by the reduced G0 population of HSCs and LSKs in Fhl2-null chimeric mice as compared to control chimeric mice, Fhl2 may regulate HSCs self-renewal under stress by controlling HSC quiescence. To further determine the function of HSCs, we performed the competitive repopulation assay. In agreement with the observation that Fhl2-/- HSCs have a reduced repopulation capacity, the ratio of Fhl2-/- derived total Peripheral Blood (PB) cells vs. competitor-derived PB cells was significantly decreased as compared to Fhl2+/+-derived recipients at secondary transplantation, and the ratio gradually decreased up to 4-5-fold as compared to Fhl2+/+-derived recipients at tertiary transplantation. Previously, we showed that FHL2 is down-regulated in subsets of Therapy-related Myelodyplastic Syndrome or Acute Myeloid Leukemia (t-MDS/t-AML patients). Together, these data suggest that Fhl2 is required for maintenance of HSCs/HPCs, and its downregulation may contribute to the development of t-MDS/t-AML in patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Single-cell analyses of immune thrombocytopenic patients reveal multiorgan dissemination of high-affinity autoreactive plasma cells

2021 ◽  
Author(s):  
Pablo Canales Herrerias ◽  
Etienne Crickx ◽  
Matteo Broketa ◽  
Aurelien Sokal ◽  
Guilhem Chenon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Plasma Cells ◽  
Individual Variability ◽  
Platelet Destruction ◽  
Autoantibody Production ◽  
High Affinity ◽  
Normal Platelet ◽  
Current Therapies ◽  
Anti Cd20

The major therapeutic goal for immune thrombocytopenia (ITP) is to restore normal platelet counts using drugs to promote platelet production or by interfering with mechanisms responsible for platelet destruction. 80% of patients possess anti-integrin αIIbβ3 (GPIIbIIIa) IgG autoantibodies causing platelet opsonization and phagocytosis. The spleen is considered the primary site of autoantibody production by autoreactive B cells and platelet destruction. The immediate failure in ~50% of patients to recover a normal platelet count after anti-CD20 Rituximab-mediated B cell depletion and splenectomy suggest that autoreactive, rituximab-resistant, IgG-secreting B cells (IgG-SC) reside in other anatomical compartments. We analyzed >3,300 single IgG-SC from spleen, bone marrow and/or blood of 27 patients with ITP revealing high inter-individual variability in affinity for GPIIbIIIa with variations over 3 logs. IgG-SC dissemination and range of affinities were however similar per patient. Longitudinal analysis of autoreactive IgG-SC upon treatment with anti-CD38 mAb daratumumab demonstrated variable outcomes, from complete remission to failure with persistence of high-affinity anti-GPIIbIIIa IgG-SC in the bone marrow. This study demonstrates the existence and dissemination of high-affinity autoreactive plasma cells in multiple anatomical compartments of patients with ITP that may cause the failure of current therapies.

scholarly journals Elevating body temperature enhances hematopoiesis and neutrophil recovery after total body irradiation in an IL-1–, IL-17–, and G-CSF–dependent manner

Blood ◽  
2012 ◽  
Vol 120 (13) ◽  
pp. 2600-2609 ◽  
Author(s):  
Maegan L. Capitano ◽  
Michael J. Nemeth ◽  
Thomas A. Mace ◽  
Christi Salisbury-Ruf ◽  
Brahm H. Segal ◽  
...  
Keyword(s):  
Heat Treatment ◽  
Bone Marrow ◽  
Body Temperature ◽  
Total Body Irradiation ◽  
Dependent Manner ◽  
Intestinal Tissue ◽  
Hematopoietic Stem ◽  
Neutrophil Recovery ◽  
Total Body ◽  
The Impact

Abstract Neutropenia is a common side effect of cytotoxic chemotherapy and radiation, increasing the risk of infection in these patients. Here we examined the impact of body temperature on neutrophil recovery in the blood and bone marrow after total body irradiation (TBI). Mice were exposed to either 3 or 6 Gy TBI followed by a mild heat treatment that temporarily raised core body temperature to approximately 39.5°C. Neutrophil recovery was then compared with control mice that received either TBI alone heat treatment alone. Mice that received both TBI and heat treatment exhibited a significant increase in the rate of neutrophil recovery in the blood and an increase in the number of marrow hematopoietic stem cells and neutrophil progenitors compared with that seen in mice that received either TBI or heat alone. The combination treatment also increased G-CSF concentrations in the serum, bone marrow, and intestinal tissue and IL-17, IL-1β, and IL-1α concentrations in the intestinal tissue after TBI. Neutralizing G-CSF or inhibiting IL-17 or IL-1 signaling significantly blocked the thermally mediated increase in neutrophil numbers. These findings suggest that a physiologically relevant increase in body temperature can accelerate recovery from neutropenia after TBI through a G-CSF–, IL-17–, and IL-1–dependent mechanism.

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