scholarly journals Light chain editors of anti-DNA receptors in human B cells

2014 ◽  
Vol 211 (2) ◽  
pp. 357-364 ◽  
Author(s):  
Olga Kalinina ◽  
Yue Wang ◽  
Kevin Sia ◽  
Marko Radic ◽  
Pierre-André Cazenave ◽  
...  
Keyword(s):  
B Cells ◽  
Dna Binding ◽  
Mouse Models ◽  
Protein Sequences ◽  
Receptor Editing ◽  
Transgenic Mouse Models ◽  
Human B Cells ◽  
Self Tolerance ◽  
V Genes ◽  
Complementarity Determining Region

Receptor editing is a mechanism of self-tolerance used in newly generated B cells. The expressed heavy (H) or light (L) chain of an autoreactive receptor is replaced by upstream V genes which eliminate or modify autoreactivity. Editing of anti-DNA receptors has been characterized in anti-DNA transgenic mouse models including 3H9, 3H9/56R, and their revertant 3H9GL. Certain L chains, termed editors, rescue anti-DNA B cells by neutralizing or modifying DNA binding of the H chain. This editing mechanism acts on the natural H chain repertoire; endogenous H chains with anti-DNA features are expressed primarily in combination with editor L chains. We ask whether a similar set of L chains exists in the human repertoire, and if so, do they edit H chains with anti-DNA signatures? We compared the protein sequences of mouse editors to all human L chains and found several human L chains similar to mouse editors. These L chains diminish or veto anti-DNA binding when expressed with anti-DNA H chains. The human H chains expressed with these L chains also have relatively high arginine (Arg) content in the H chain complementarity determining region (H3), suggesting that receptor editing plays a role in establishing tolerance to DNA in humans.

scholarly journals Enforced Bcl-2 Expression Inhibits Antigen-mediated Clonal Elimination of Peripheral B Cells in an Antigen Dose–dependent Manner and Promotes Receptor Editing in Autoreactive, Immature B Cells

1997 ◽  
Vol 186 (9) ◽  
pp. 1513-1522 ◽  
Author(s):  
Julie Lang ◽  
B. Arnold ◽  
G. Hammerling ◽  
Alan W. Harris ◽  
Stanley Korsmeyer ◽  
...  
Keyword(s):  
B Cells ◽  
Tolerance Induction ◽  
Antigen Expression ◽  
Dependent Manner ◽  
Receptor Editing ◽  
B Cell Tolerance ◽  
Antigen Dose ◽  
Central Tolerance ◽  
Self Tolerance ◽  
Immature B Cells

The mechanisms that establish immune tolerance in immature and mature B cells appear to be distinct. Membrane-bound autoantigen is thought to induce developmental arrest and receptor editing in immature B cells, whereas mature B cells have shortened lifespans when exposed to the same stimulus. In this study, we used Eμ–bcl-2-22 transgenic (Tg) mice to test the prediction that enforced expression of the Bcl-2 apoptotic inhibitor in B cells would rescue mature, but not immature, B cells from tolerance induction. To monitor tolerance to the natural membrane autoantigen H-2Kb, we bred 3–83μδ (anti-Kk,b) Ig Tg mice to H-2b mice or to mice expressing transgene-driven Kb in the periphery. In 3–83μδ/bcl-2 Tg mice, deletion of autoreactive B cells induced by peripheral Kb antigen expression in the liver (MT-Kb Tg) or epithelia (KerIV-Kb Tg), was partly or completely inhibited, respectively. Furthermore, Bcl-2 protected peritoneal B-2 B cells from deletion mediated by acute antigen exposure, but this protection could be overcome by higher antigen dose. In contrast to its ability to block peripheral self-tolerance, Bcl-2 overexpression failed to inhibit central tolerance induced by bone marrow antigen expression, but instead, enhanced the receptor editing process. These studies indicate that apoptosis plays distinct roles in central and peripheral B cell tolerance.

scholarly journals Clonal redemption of autoantibodies by somatic hypermutation away from self-reactivity during human immunization

2016 ◽  
Vol 213 (7) ◽  
pp. 1255-1265 ◽  
Author(s):  
Joanne H. Reed ◽  
Jennifer Jackson ◽  
Daniel Christ ◽  
Christopher C. Goodnow
Keyword(s):  
B Cells ◽  
Somatic Hypermutation ◽  
Human Antibody ◽  
Tolerance Mechanism ◽  
Heavy Chains ◽  
Human B Cells ◽  
Healthy Donors ◽  
Self Tolerance ◽  
Normal Human ◽  
Clonal Anergy

Clonal anergy is an enigmatic self-tolerance mechanism because no apparent purpose is served by retaining functionally silenced B cells bearing autoantibodies. Human autoantibodies with IGHV4-34*01 heavy chains bind to poly-N-acetyllactosamine carbohydrates (I/i antigen) on erythrocytes and B lymphocytes, cause cold agglutinin disease, and are carried by 5% of naive B cells that are anergic. We analyzed the specificity of three IGHV4-34*01 IgG antibodies isolated from healthy donors immunized against foreign rhesus D alloantigen or vaccinia virus. Each IgG was expressed and analyzed either in a hypermutated immune state or after reverting each antibody to its unmutated preimmune ancestor. In each case, the preimmune ancestor IgG bound intensely to normal human B cells bearing I/i antigen. Self-reactivity was removed by a single somatic mutation that paradoxically decreased binding to the foreign immunogen, whereas other mutations conferred increased foreign binding. These data demonstrate the existence of a mechanism for mutation away from self-reactivity in humans. Because 2.5% of switched memory B cells use IGHV4-34*01 and >43% of these have mutations that remove I/i binding, clonal redemption of anergic cells appears efficient during physiological human antibody responses.

scholarly journals Receptor editing: an approach by autoreactive B cells to escape tolerance.

1993 ◽  
Vol 177 (4) ◽  
pp. 999-1008 ◽  
Author(s):  
D Gay ◽  
T Saunders ◽  
S Camper ◽  
M Weigert
Keyword(s):  
B Cells ◽  
B Cell ◽  
Chain Gene ◽  
Receptor Editing ◽  
Immunoglobulin Receptor ◽  
Autoreactive B Cells ◽  
Surface Receptors ◽  
Double Stranded Dna ◽  
V Genes ◽  
Dna Antibodies

To determine the fate of anti-DNA antibody-bearing B cells in normal mice, we generated transgenic mice bearing the heavy (H) and light (L) chain genes of a well-characterized anti-double-stranded DNA antibody. This antibody was originally isolated from a diseased MRL/lpr mouse and has characteristics common to spontaneously arising anti-DNA antibodies. Results show that the H/L transgene (tg) immunoglobulin receptor is not expressed by animals bearing both tgs, although single tg animals (H or L) express their transgenes. Young H/L tg animals express few B cells, whereas adult H/L tg animals maintain almost normal B cell numbers. Analysis of the immunoglobulin receptors used by adult B cells shows that all contain the tg H chain in association with endogenous L chains. These B cells transcribe the L tg as well as the rearranged endogenous L chain gene, and loss of endogenous L chain gene transcription results in resurrection of the 3H9 H/L tg product. Examination of the endogenous L chains used by these cells shows that they represent a highly restricted subset of V genes. Taken together, these data suggest that autoreactive transgenic B cells can rearrange endogenous L chain genes to alter surface receptors. Those L chains that compete successfully with the L tg for H chain binding, and that create a nonautoreactive receptor, allow the B cell to escape deletion. We suggest that this receptor editing is a mechanism used by immature autoreactive B cells to escape tolerance.

scholarly journals Receptor editing and genetic variability in human autoreactive B cells

2015 ◽  
Vol 213 (1) ◽  
pp. 93-108 ◽  
Author(s):  
Julie Lang ◽  
Takayuki Ota ◽  
Margot Kelly ◽  
Pamela Strauch ◽  
Brian M. Freed ◽  
...  
Keyword(s):  
B Cells ◽  
Human Populations ◽  
Receptor Editing ◽  
Human Immune System ◽  
B Cell Tolerance ◽  
Clonal Deletion ◽  
Humanized Mouse Model ◽  
Central Tolerance ◽  
Autoreactive B Cells ◽  
Human B Cells

The mechanisms by which B cells undergo tolerance, such as receptor editing, clonal deletion, and anergy, have been established in mice. However, corroborating these mechanisms in humans remains challenging. To study how autoreactive human B cells undergo tolerance, we developed a novel humanized mouse model. Mice expressing an anti–human Igκ membrane protein to serve as a ubiquitous neo self-antigen (Ag) were transplanted with a human immune system. By following the fate of self-reactive human κ+ B cells relative to nonautoreactive λ+ cells, we show that tolerance of human B cells occurs at the first site of self-Ag encounter, the bone marrow, via a combination of receptor editing and clonal deletion. Moreover, the amount of available self-Ag and the genetics of the cord blood donor dictate the levels of central tolerance and autoreactive B cells in the periphery. Thus, this model can be useful for studying specific mechanisms of human B cell tolerance and to reveal differences in the extent of this process among human populations.

scholarly journals Surrogate Light Chain Expressing Human Peripheral B Cells Produce Self-reactive Antibodies

2003 ◽  
Vol 199 (1) ◽  
pp. 145-150 ◽  
Author(s):  
Eric Meffre ◽  
Anne Schaefer ◽  
Hedda Wardemann ◽  
Patrick Wilson ◽  
Eric Davis ◽  
...  
Keyword(s):  
B Cells ◽  
Light Chain ◽  
Antinuclear Antibodies ◽  
Receptor Editing ◽  
Tolerance Mechanisms ◽  
Central Tolerance ◽  
Surrogate Light Chain ◽  
Human B Cells ◽  
Autoreactive Antibodies ◽  
Light Chain Antibody

Human B cells that coexpress surrogate and conventional light chains (V-preB+L+) show an unusual heavy and light chain antibody repertoire that display evidence of receptor editing. However, it is unclear whether V-preB+L+ B cells have been silenced by receptor editing or still express autoreactive antibodies. Here we report that 68% of the antibodies expressed by V-preB+L+ B cells are autoreactive. A majority of these autoantibodies are true antinuclear antibodies (ANA), and 50% of the ANAs are also reactive with a diverse group of antigens that include dsDNA, ssDNA, immunoglobulin, insulin, and bacterial lipopolysaccharide. Such antibodies are rarely encountered among conventional B cells. We conclude that V-preB+L+ B cells are a unique subset of normal circulating human B cells that escape central tolerance mechanisms and express self-reactive antibodies including potentially harmful ANAs.

scholarly journals Editing Anti-DNA B Cells by Vλx

2004 ◽  
Vol 199 (3) ◽  
pp. 337-346 ◽  
Author(s):  
Yijin Li ◽  
Yoram Louzoun ◽  
Martin Weigert
Keyword(s):  
B Cells ◽  
Dna Binding ◽  
Transgenic Mice ◽  
Heavy Chain ◽  
Light Chain ◽  
Gene Replacement ◽  
Light Chains ◽  
Alternative Pathways ◽  
Self Tolerance ◽  
V Gene

Receptor editing is performed by replacement of Vκ genes that contribute to autoreactivity. In addition, the Cκ locus can be deleted by Vκ rearrangement to intronic or 3′ of Cκ RS sequences (also referred to as κ deletion elements). B cells that delete the Cκ can then express λ light chains. However, the λ locus, either of man or mouse, does not allow V gene replacement. Nor does it appear to be deleted. Therefore, editing of autoreactive λ B cells may require alternative pathways. We have found that in anti-DNA heavy chain transgenic mice (tgs) VH3H9/56R, B cells that express anti-DNA receptors comprised of λ1 in association with an anti-DNA heavy chain often coexpress a κ chain that prevents DNA binding. We speculate that such isotypically included cells may have low anti-DNA receptor densities, a feature that may lead to self-tolerance. Here we describe a mechanism of preventing DNA binding by expression of a rarely used member of the Vλ family, Vλx. The λx B cells of the tgs also express CD25 and may represent B cells that have exhausted light chain editing possibilities.

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