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 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.

The expression of Vpre-B/λ5 surrogate light chain in early bone marrow precursor B cells of normal and B cell-deficient mutant mice

Cell ◽  
1994 ◽  
Vol 77 (1) ◽  
pp. 133-143 ◽  
Author(s):  
Hajime Karasuyama ◽  
Antonius Rolink ◽  
Yoichi Shinkal ◽  
Faith Young ◽  
Frederick W. Alt ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Light Chain ◽  
Mutant Mice ◽  
Deficient Mutant ◽  
Surrogate Light Chain ◽  
Bone Marrow Precursor ◽  
Precursor B Cells

scholarly journals Fate of surrogate light chains in B lineage cells.

1996 ◽  
Vol 183 (2) ◽  
pp. 421-429 ◽  
Author(s):  
K Lassoued ◽  
H Illges ◽  
K Benlagha ◽  
M D Cooper
Keyword(s):  
B Cells ◽  
Cell Surface ◽  
Light Chain ◽  
Light Chains ◽  
Receptor Complex ◽  
Surrogate Light Chain ◽  
Heavy Chains ◽  
Receptor Component ◽  
B Lineage ◽  
Receptor Assembly

Biosynthesis of the immunoglobulin (Ig) receptor components and their assembly were examined in cell lines representative of early stages in human B lineage development. In pro-B cells, the nascent surrogate light chain proteins form a complex that transiently associates in the endoplasmic reticulum with a spectrum of unidentified proteins (40, 60, and 98 kD) and Bip, a heat shock protein family member. Lacking companion heavy chains, the surrogate light chains in pro-B cells do not associate with either the Ig(alpha) or Ig(beta) signal transduction units, undergo rapid degradation, and fail to reach the pro-B cell surface. In pre-B cells, by contrast, a significant portion of the surrogate light chain proteins associate with mu heavy chains, Ig(alpha), and Ig(beta) to form a stable receptor complex with a relatively long half-life. Early in this assembly process, Bip/GRP78, calnexin, GRP94, and a protein of approximately 17 kD differentially bind to the nascent mu heavy chains. The 17-kD intermediate is gradually replaced by the surrogate light chain protein complex, and the Ig(alpha) and Ig(beta) chains bind progressively to the mu heavy chains during the complex and relatively inefficient process of pre-B receptor assembly. The results suggest that, in humans, heavy chain association is essential for surrogate light chain survival and transport to the cell surface as an integral receptor component.

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.

Interferon-γ induces light chain synthesis in interleukin 2 stimulated human B cells

1986 ◽  
Vol 16 (5) ◽  
pp. 547-550 ◽  
Author(s):  
Lě Thi Bieh-Thuy ◽  
Cary Queen ◽  
Anthony S. Fauci
Keyword(s):  
B Cells ◽  
Light Chain ◽  
Interleukin 2 ◽  
Interferon Γ ◽  
Human B Cells ◽  
Chain Synthesis

scholarly journals In aged mice, low surrogate light chain promotes pro‐ B ‐cell apoptotic resistance, compromises the P re BCR checkpoint, and favors generation of autoreactive, phosphorylcholine‐specific B cells

Aging Cell ◽  
2015 ◽  
Vol 14 (3) ◽  
pp. 382-390 ◽  
Author(s):  
Michelle Ratliff ◽  
Sarah Alter ◽  
Kelly McAvoy ◽  
Daniela Frasca ◽  
Jacqueline A. Wright ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Light Chain ◽  
Aged Mice ◽  
Surrogate Light Chain

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 B cells are exquisitely sensitive to central tolerance and receptor editing induced by ultralow affinity, membrane-bound antigen.

1996 ◽  
Vol 184 (5) ◽  
pp. 1685-1697 ◽  
Author(s):  
J Lang ◽  
M Jackson ◽  
L Teyton ◽  
A Brunmark ◽  
K Kane ◽  
...  
Keyword(s):  
B Cells ◽  
Transgenic Mice ◽  
Peripheral Tolerance ◽  
Class I ◽  
Lymphoid Tissues ◽  
Mrna Levels ◽  
Receptor Editing ◽  
Central Tolerance ◽  
Affinity Ligands ◽  
Affinity Ligand

To assess the sensitivity of B cell tolerance with respect to receptor/autoantigen affinity, we identified low affinity ligands to the 3-83 (anti-major histocompatibility complex class I) antibody and tested the ability of these ligands to induce central and peripheral tolerance in 3-83 transgenic mice. Several class I protein alloforms, including Kbm3 and Dk, showed remarkably low, but detectable, affinity to 3-83. The 3-83 antibody bound Kb with K lambda approximately 2 x 10(5) M-1 and bound 10-fold more weakly to the Kbm3 (K lambda approximately 2 x 10(4) M-1) and Dk antigens. Breeding 3-83 immunoglobulin transgenic mice with mice expressing these ultralow affinity Kbm3 and Dk ligands resulted in virtually complete deletion of the autoreactive B cells from the peripheral lymphoid tissues. These low affinity antigens also induced receptor editing, as measured by elevated RAG mRNA levels in the bone marrow and excess levels of id- variant B cells bearing lambda light chains in the spleen. Reactive class I antigens were also able to mediate deletion of mature B cells when injected into the peritoneal cavity of 3-83 transgenic mice. Although the highest affinity ligand, Kk, was consistently able to induce elimination of the 3-83 peritoneal B cells, the lower affinity ligands were only partially effective. These results demonstrate the remarkable sensitivity of the deletion and receptor-editing mechanisms in immature B cells, and may suggest a higher affinity threshold for deletion of peripheral, mature B cells.

scholarly journals Phospholipase Cγ2 Contributes to Light-Chain Gene Activation and Receptor Editing

2007 ◽  
Vol 27 (17) ◽  
pp. 5957-5967 ◽  
Author(s):  
Li Bai ◽  
Yuhong Chen ◽  
Yinghong He ◽  
Xuezhi Dai ◽  
Xueyan Lin ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Light Chain ◽  
Gene Activation ◽  
Chain Gene ◽  
Receptor Editing ◽  
Light Chain Gene ◽  
Transitional Type

ABSTRACT Phospholipase Cγ2 (PLCγ2) is critical for pre-B-cell receptor (pre-BCR) and BCR signaling. Current studies discovered that PLCγ2-deficient mice had reduced immunoglobulin λ (Igλ) light-chain usage throughout B-cell maturation stages, including transitional type 1 (T1), transitional type 2 (T2), and mature follicular B cells. The reduction of Igλ rearrangement by PLCγ2 deficiency was not due to specifically increased apoptosis or decreased proliferation of mutant Igλ+ B cells, as lack of PLCγ2 exerted a similar effect on apoptosis and proliferation of both Igλ+ and Igκ+ B cells. Moreover, PLCγ2-deficient IgHEL transgenic B cells exhibited an impairment of antigen-induced receptor editing among both the endogenous λ and κ loci in vitro and in vivo. Importantly, PLCγ2 deficiency impaired BCR-induced expression of IRF-4 and IRF-8, the two transcription factors critical for λ and κ light-chain rearrangements. Taken together, these data demonstrate that the PLCγ2 signaling pathway plays a role in activation of light-chain loci and contributes to receptor editing.

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