κ Editing Rescues Autoreactive B Cells Destined for Deletion in Mice Transgenic for a Dual Specific Anti-Laminin Ig

Brady, Graham F.; Congdon, Kendra L.; Clark, Amy G.; Sackey, Faustina N. A.; Rudolph, Earl H.; Radic, Marko; Foster, Mary H.

doi:10.4049/jimmunol.172.9.5313

Cited by 14 publications

(48 citation statements)

References 34 publications

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“…Detailed analysis of M6 and M29 lineage mice revealed that LamH transgenic anti-laminin B cells are regulated by central deletion, κ light-chain editing, and anergy [10,74]. Anti-laminin antibodies were not detected in serum or among monoclonal antibodies despite in vitro and in vivo strategies to activate B cells (Tables 3 and 4).…”

Section: Regulation Of B Cell Autoreactivity To Laminin: the Lamh Ig mentioning

confidence: 99%

“…Most B cells that escaped deletion in M29 mice did so by editing their κ light-chain receptors [10]. Receptor editing is an efficient and common salvage process by which an Ig receptor is replaced by a different receptor through continued Ig gene rearrangements.…”

Section: Regulation Of B Cell Autoreactivity To Laminin: the Lamh Ig mentioning

confidence: 99%

“…The V8R light chain generates anti-DNA Ig when combined with the lupus 3H9 heavy chain [14,72] and is similar to light chains expressed by a subset of anti-laminin monoclonal antibodies derived from M7 mice [24]. Transfection of a cell line producing the V8R light chain with the LamH heavy chain yields an antibody strongly crossreactive with laminin and ssDNA [10], a specificity observed among a subset of LamH M7 transgenic antibodies [24]. M29 LamH transgenic mice were bred with V8R mice to generate H+L and H+LL double-and triple--transgenic mice in which one or both light-chain loci were replaced with the V8R light-chain.…”

Section: Regulation Of B Cell Autoreactivity To Laminin: the Lamh Ig mentioning

confidence: 99%

“…Because V8R uses Jk5, the most downstream Jk gene, further editing at the targeted κ allele is thus prevented. Characterization of the new double-mutant mice revealed a key role for κ editing in rescuing LamH heavy-chain transgenic B cells [10]. Neither anti-DNA nor anti-laminin transgenic Ig were recovered from serum, nor were autoantibodies recovered among the few monoclonal antibodies derived from endotoxin-stimulated splenocytes of H+L mice.…”

Section: Regulation Of B Cell Autoreactivity To Laminin: the Lamh Ig mentioning

confidence: 99%

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Deconstructing B cell tolerance to basement membranes

Foster

Zhang

Clark

2006

Arch. Immunol. Ther. Exp.

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Basement membrane antigens are frequent targets of autoantibody attack in systemic and organ-restricted autoimmunity. These specialized and highly organized matrices are composed of multiple components with restricted tissue distributions and limited epitope exposure. To dissect mechanisms controlling humoral autoimmunity to nephritogenic basement membrane antigens, we developed autoantibody transgenic models. In mice bearing the LamH Ig transgene encoding B cell receptors specific for laminin, autoreactive B cells are readily generated but actively regulated in vivo. In this model, anti-laminin B cells are immunologically censored by mechanisms that include central deletion, kappa light-chain editing, and anergy. Tolerance is maintained when the transgene is established in MRL and BXSB genetic backgrounds with inherited autoimmune susceptibility, and despite provocation with potent environmental stimulants. Collectively, these studies indicate that the pathogenic anti-laminin reactivity characteristic of systemic lupus is tightly regulated. A novel anti-collagen transgenic model is used to assess the tolerogenesis of a structurally distinct pathogenic basement membrane epitope and to determine if reactivity to putative cryptic epitopes targeted in organ-restricted disease is regulated. These studies should provide insight into the molecular mechanisms controlling basement membrane autoreactivity and ultimately facilitate the development of novel strategies to inactivate autoreactive cells and treat autoimmune disease.

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Section: Regulation Of B Cell Autoreactivity To Laminin: the Lamh Ig mentioning

confidence: 99%

Section: Regulation Of B Cell Autoreactivity To Laminin: the Lamh Ig mentioning

confidence: 99%

Section: Regulation Of B Cell Autoreactivity To Laminin: the Lamh Ig mentioning

confidence: 99%

Section: Regulation Of B Cell Autoreactivity To Laminin: the Lamh Ig mentioning

confidence: 99%

See 2 more Smart Citations

Deconstructing B cell tolerance to basement membranes

Foster

Zhang

Clark

2006

Arch. Immunol. Ther. Exp.

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“…Autoimmune diseases afflict most organ systems and impose an enormous burden on the health care system (1).…”

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confidence: 99%

Antibodies as Predictors of Complex Autoimmune Diseases

Vojdani

2008

Int J Immunopathol Pharmacol

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Emerging evidence has suggested environmental factors such as infections and xenobiotics and some dietary proteins and peptides in the pathogenesis of many autoimmune diseases. Considering the fact that autoantibodies can often be detected prior to the onset of a disease, in this study an enzyme immunoassay was used for measurement of antibodies against different highly purified antigens or synthetic peptides originating not only from human tissue, but also from cross-reactive epitopes of infectious agents, dietary proteins and xenobiotics. The measurement of antibodies against a panel of antigens allows for identification of patterns or antibody signatures, rather than just one or two markers of autoimmunity, thus establishing the premise for increased sensitivity and specificity of prediction, as well as positive predictive values. This panel of different autoantibodies was applied to 420 patients with different autoimmune diseases, including pernicious anemia, celiac disease, thyroiditis, lupus, rheumatoid arthritis, osteoarthritis, Addison's disease, type 1 diabetes, cardiovascular disease and autoimmunity, which are presented in this article. In all cases, the levels of these antibodies were significantly elevated in patients versus controls. Antibody patterns related to neuroautoimmune disorders, cancer, and patients with somatic hypermutation will be shown in a subsequent article. We believe that this novel 96 antigen-specific autoantibody or predictive antibody screen should be studied for its incorporation into routine medical examinations. Clinicians should be aware that the detection of antibodies should not automatically mean that a patient will definitely become ill, but would rather give a percentage of risk for autoimmune disease over subsequent months or years.

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Altered toll‐like receptor responsiveness underlies a dominant heritable defect in B cell tolerance in autoimmune New Zealand Black mice

2018

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Systemic lupus erythematosus is a debilitating autoimmune disease in which autoantibodies and autoreactive T cells destroy kidneys and other organs. Disease is clinically and genetically heterogeneous, suggesting that underlying mechanisms vary between patients. We previously used an autoantibody transgenic mouse reporter system to examine the effect of different autoimmune backgrounds on B-cell tolerance, failure of which is a fundamental defect in lupus. We identified a defect consistent with reversible anergy induced by endotoxin stimulation of B cells from Ig transgenic New Zealand Black (NZB) mice. Herein we report that the tolerance defect is revealed by TLR7 and TLR9 as well as TLR4 ligands, with additive effect, and is partially reversed by Mek inhibition. Gene expression analysis reveals significant differences in transcription of multiple TLR pathway genes and ptpn22 in stimulated NZB compared to B6 B cells. Additionally, the defect is detected in Ig transgenic NZB F1 hybrid strains (NZBxNZW)F1 and (B6xNZB)F1. These results implicate an inherited defect wherein NZB anergic B cells maintain coordinated TLR/BCR signaling that permits autoantibody production. Agents targeting these pathways may have therapeutic benefit in the subset of lupus patients that manifest similar defects in B-cell regulation.

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κ Editing Rescues Autoreactive B Cells Destined for Deletion in Mice Transgenic for a Dual Specific Anti-Laminin Ig

Cited by 14 publications

References 34 publications

Deconstructing B cell tolerance to basement membranes

Deconstructing B cell tolerance to basement membranes

Antibodies as Predictors of Complex Autoimmune Diseases

Altered toll‐like receptor responsiveness underlies a dominant heritable defect in B cell tolerance in autoimmune New Zealand Black mice

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