scholarly journals Receptor Editing as a Mechanism of B Cell Tolerance

2011 ◽  
Vol 186 (3) ◽  
pp. 1301-1302 ◽  
Author(s):  
Selvakumar Sukumar ◽  
Mark S. Schlissel
Keyword(s):  
B Cell ◽  
Receptor Editing ◽  
Cell Tolerance ◽  
B Cell Tolerance

scholarly journals Reduced receptor editing in lupus-prone MRL/lpr mice

2007 ◽  
Vol 204 (12) ◽  
pp. 2853-2864 ◽  
Author(s):  
Jennifer L. Lamoureux ◽  
Lisa C. Watson ◽  
Marie Cherrier ◽  
Patrick Skog ◽  
David Nemazee ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Messenger Rna ◽  
Immunoglobulin M ◽  
Considerable Proportion ◽  
Receptor Editing ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Immature B Cells

The initial B cell repertoire contains a considerable proportion of autoreactive specificities. The first major B cell tolerance checkpoint is at the stage of the immature B cell, where receptor editing is the primary mode of eliminating self-reactivity. The cells that emigrate from the bone marrow have a second tolerance checkpoint in the transitional compartment in the spleen. Although it is known that the second checkpoint is defective in lupus, it is not clear whether there is any breakdown in central B cell tolerance in the bone marrow. We demonstrate that receptor editing is less efficient in the lupus-prone strain MRL/lpr. In an in vitro system, when receptor-editing signals are given to bone marrow immature B cells by antiidiotype antibody or after in vivo exposure to membrane-bound self-antigen, MRL/lpr 3-83 transgenic immature B cells undergo less endogenous rearrangement and up-regulate recombination activating gene messenger RNA to a lesser extent than B10 transgenic cells. CD19, along with immunoglobulin M, is down-regulated in the bone marrow upon receptor editing, but the extent of down-regulation is fivefold less in MRL/lpr mice. Less efficient receptor editing could allow some autoreactive cells to escape from the bone marrow in lupus-prone mice, thus predisposing to autoimmunity.

Receptor editing is the main mechanism of B cell tolerance toward membrane antigens

2004 ◽  
Vol 5 (6) ◽  
pp. 645-650 ◽  
Author(s):  
Regina Halverson ◽  
Raul M Torres ◽  
Roberta Pelanda
Keyword(s):  
B Cell ◽  
Main Mechanism ◽  
Receptor Editing ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Membrane Antigens

Mechanisms of B Cell Tolerance after in Utero Hematopoietic Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4289-4289
Author(s):  
Lauren Elizabeth McClain ◽  
Grace Lee ◽  
Aimee G Kim ◽  
Patricia Tsao ◽  
Eline Luning Prak ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Hematopoietic Cell Transplantation ◽  
Donor Cell ◽  
Absolute Number ◽  
Receptor Editing ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
The Absolute ◽  
Functional Inactivation

Abstract Background: In utero hematopoietic cell transplantation (IUHCT) is a nonmyeloablative, nonimmunosuppressive transplant approach that results in donor cell engraftment across immune barriers. Although a significant amount of work has investigated the fate of T cells following IUHCT, little attention has been paid to B cell tolerance and the fate of donor derived host reactive or host derived donor reactive B cells following IUHCT. B cell tolerance is broadly believed to occur by a combination of 3 mechanisms: deletion, receptor editing, and functional inactivation (anergy). In the current study we attempt to elucidate the mechanism(s) by which B cell tolerance occurs following IUHCT. Methods: 10x106 donor bone marrow (BM) cells were injected intravenously via the vitelline vein into gestational day 14 murine fetuses. IUHCT was performed in the congenic (C57Bl/6-GFP [H2Kb ] into C57Bl/6 [H2Kb ]) and allogeneic (C57Bl/6-GFP into Balb/c [H2Kd ]) strain combinations. Naive Balb/c and C57Bl/6 mice served as controls. Mice were sacrificed at day of life 3 (P3), 1 month and 4 months of age at which time their BM, spleen, and serum were harvested. To assess B cell deletion, flow cytometry was used to determine the absolute # and % of host and donor immature and pre B cells in the BM. Additionally, apoptosis of host and donor BM derived B cells was determined by annexin staining. Central receptor editing was evaluated using RT qPCR to measure the amount of Vκ-RS rearrangments in BM pre-B cells. Peripheral receptor editing was studied by calculating the % of λ light chains in mature splenocytes identified by flow cytometry. Finally, functional inactivation of donor reactive host B cells was assessed by measuring anti-H2Kb serum antibodies (ab) of allogeneic chimeras, naive, and immunized mice at 1 month of age. Results: The absolute number of BM immature B cells was decreased in allogeneic recipients of IUHCT compared to noninjected Balb/c controls at 1 month of age (fig 1). This effect was lost by 4 months of age. The decrease in B cells resulted primarily from a decrease in immature donor as opposed to host B cells compared to controls (% immature donor B cells in allogeneic recipients vs. controls: 16.2% vs. 39.9%; p<0.0005). Donor B cells in allogeneic chimeras also demonstrated a trend toward increased apoptosis compared to controls (24.8 vs. 18.7%; p=0.2) which was not seen in immature host B cells (18.3 vs. 18.6%; p=0.9). There was no significant decrease in the absolute number of immature B cells or increased apoptosis in congenic recipients compared to uninjected controls. These findings suggest deletion of autoreactivedonor B cells. Light chain receptor editing involves rearrangements within the κ and λ gene loci and may occur in BM pre-B cells or mature B cells in the spleen. We found no difference in the Vκ-RS rearrangements of pre B cells in allogeneic chimeras and controls at 1 month. In contrast, the quantity of total λ+ mature splenic B cells was increased in allogeneic chimeras at P3 (10.8 vs. 8.4%; p=0.02) and resulted from an increased host λ+ % compared to controls (10.8 vs. 8.4% p=0.03) suggesting peripheral receptor editing of host cells (fig.2). The λ+ % increase in allogeneic chimeras was lost by 1 month. Autoreactive B cells that escape deletion and receptor editing can be functionally inactivated. Neither allogeneic nor naive mice developed ab to H2Kb splenocytes, however, Balb/c mice immunized to H2kb antigen showed high ablevels (MFI fold change: allo-0.89 naive-1.37 imm-2.77; p<0.05). Conclusion: B cell tolerance after IUHCT is achieved by distinct mechanisms for host and donor cell populations. Donor derived host reactive B cells undergo deletion and apoptosis while receptor editing and functional inactivation are the primary mechanisms of B cell tolerance of host derived donor reactive B cells. We hope use this and future studies of antigen specific B cell tolerance to harness the immunologic potential of IUHCT for many hematopoietic and immunologic congenital diseases. Disclosures No relevant conflicts of interest to declare.

scholarly journals Liver-expressed Igκ superantigen induces tolerance of polyclonal B cells by clonal deletion not κ to λ receptor editing

2011 ◽  
Vol 208 (3) ◽  
pp. 617-629 ◽  
Author(s):  
Takayuki Ota ◽  
Miyo Ota ◽  
Bao Hoa Duong ◽  
Amanda L. Gavin ◽  
David Nemazee
Keyword(s):  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Tolerance Induction ◽  
Cell Receptor ◽  
Mature Stage ◽  
Receptor Editing ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Clonal Deletion

Little is know about the nature of peripheral B cell tolerance or how it may vary in distinct lineages. Although autoantibody transgenic studies indicate that anergy and apoptosis are involved, some studies claim that receptor editing occurs. To model peripheral B cell tolerance in a normal, polyclonal immune system, we generated transgenic mice expressing an Igκ–light chain–reactive superantigen targeted to the plasma membrane of hepatocytes (pAlb mice). In contrast to mice expressing κ superantigen ubiquitously, in which κ cells edit efficiently to λ, in pAlb mice, κ B cells underwent clonal deletion. Their κ cells failed to populate lymph nodes, and the remaining splenic κ cells were anergic, arrested at a semi-mature stage without undergoing receptor editing. In the liver, κ cells recognized superantigen, down-regulated surface Ig, and expressed active caspase 3, suggesting ongoing apoptosis at the site of B cell receptor ligand expression. Some, apparently mature, κ B1 and follicular B cells persisted in the peritoneum. BAFF (B cell–activating factor belonging to the tumor necrosis factor family) overexpression rescued splenic κ B cell maturation and allowed κ cells to populate lymph nodes. Our model facilitates analysis of tissue-specific autoimmunity, tolerance, and apoptosis in a polyclonal B cell population. The results suggest that deletion, not editing, is the major irreversible pathway of tolerance induction among peripheral B cells.

scholarly journals Receptor editing in peripheral B cell tolerance

2005 ◽  
Vol 102 (5) ◽  
pp. 1608-1613 ◽  
Author(s):  
J. S. Rice ◽  
J. Newman ◽  
C. Wang ◽  
D. J. Michael ◽  
B. Diamond
Keyword(s):  
B Cell ◽  
Receptor Editing ◽  
Cell Tolerance ◽  
B Cell Tolerance

scholarly journals Receptor editing: How B cells stay tolerant

2007 ◽  
Vol 204 (8) ◽  
pp. 1735-1735
Author(s):  
Hema Bashyam
Keyword(s):  
B Cells ◽  
B Cell ◽  
Main Mechanism ◽  
Receptor Editing ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Autoreactive B Cells

In 1993, David Nemazee and Martin Weigert independently showed that autoreactive B cells could proofread, alter, and reexpress modified receptors to become nonautoreactive. This process, called “receptor editing,” has since gained prominence as the main mechanism of B cell tolerance.

scholarly journals An immunoglobulin Cκ-reactive single chain antibody fusion protein induces tolerance through receptor editing in a normal polyclonal immune system

2005 ◽  
Vol 201 (5) ◽  
pp. 817-828 ◽  
Author(s):  
Djemel Ait-Azzouzene ◽  
Laurent Verkoczy ◽  
Jorieke Peters ◽  
Amanda Gavin ◽  
Patrick Skog ◽  
...  
Keyword(s):  
Immune System ◽  
B Cell ◽  
Immune Tolerance ◽  
Receptor Editing ◽  
Cell Tolerance ◽  
Single Chain ◽  
Single Chain Antibody ◽  
B Cell Tolerance ◽  
Cellular Analysis

Understanding immune tolerance mechanisms is a major goal of immunology research, but mechanistic studies have generally required the use of mouse models carrying untargeted or targeted antigen receptor transgenes, which distort lymphocyte development and therefore preclude analysis of a truly normal immune system. Here we demonstrate an advance in in vivo analysis of immune tolerance that overcomes these shortcomings. We show that custom superantigens generated by single chain antibody technology permit the study of tolerance in a normal, polyclonal immune system. In the present study we generated a membrane-tethered anti-Igκ–reactive single chain antibody chimeric gene and expressed it as a transgene in mice. B cell tolerance was directly characterized in the transgenic mice and in radiation bone marrow chimeras in which ligand-bearing mice served as recipients of nontransgenic cells. We find that the ubiquitously expressed, Igκ-reactive ligand induces efficient B cell tolerance primarily or exclusively by receptor editing. We also demonstrate the unique advantages of our model in the genetic and cellular analysis of immune tolerance.

scholarly journals Receptor Editing in a Transgenic Mouse Model: Site, Efficiency, and Role in B Cell Tolerance and Antibody Diversification

Immunity ◽  
1997 ◽  
Vol 7 (6) ◽  
pp. 765-775 ◽  
Author(s):  
Roberta Pelanda ◽  
Stephan Schwers ◽  
Eiichiro Sonoda ◽  
Raul M Torres ◽  
David Nemazee ◽  
...  
Keyword(s):  
Mouse Model ◽  
B Cell ◽  
Transgenic Mouse ◽  
Transgenic Mouse Model ◽  
Receptor Editing ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Antibody Diversification
Sign in / Sign up

Export Citation Format

Share Document