Spontaneous autoimmunity in mice that carry an IghV partial transgene: a required arginine in VHCDR3

Guth, Amanda; Detanico, Thiago; Smith, Diana S.; Tung, Kenneth S. K.; Bonorino, Cristina; Wysocki, Lawrence J.

doi:10.1177/0961203308097480

Cited by 4 publications

(4 citation statements)

References 62 publications

(117 reference statements)

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“…Concentrations of anti-chromatin IgG antibodies were determined using the protocol of Guth et al [11]. Briefly, 96-well microplates were coated overnight at 4 °C with mouse chromatin (10 μg/mL), followed by incubation with blocking buffer solution at 37 °C for 2 h. Mouse sera diluted in blocking buffer were added to the trays for 2 h. IgG anti-chromatin antibodies were detected with an alkaline phosphatase (AP)–conjugated goat anti-mouse IgG antibody (Southern Biotechnology Associates, Inc.).…”

Section: Methodsmentioning

confidence: 99%

TLR7 drives accumulation of ABCs and autoantibody production in autoimmune-prone mice

et al. 2012

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Although autoantibodies are the hallmarks of most autoimmune diseases, the mechanisms by which autoreactive B cells are generated and accumulate are still poorly understood. Overexpression of Toll-like receptor 7 (TLR7) that recognizes single-stranded RNAs has been implicated in systemic lupus erythematosus (SLE), although the cellular mechanism by which this receptor drives the disease is unknown. We recently identified a population of CD11c+ age-associated B cells (ABCs) which is driven by TLR7 signaling, secretes autoantibodies and appears in autoimmune-prone mice by the time of onset of autoimmunity. Mice lacking the Mer receptor develop autoantibodies and splenomegaly similar to other mouse models of SLE. Here, we show that Mer−/− mice that lack TLR7 fail to develop anti-chromatin IgG antibodies, perhaps because they also fail to develop ABCs. Moreover, depletion of CD11c+ ABCs from Mer−/− mice leads to rapid reduction in autoantibodies. Together, these data strongly suggest that ABCs and/or their descendants are the primary source of autoantibodies in Mer−/− mice and that TLR7 signaling is crucial for accumulation of ABCs and development of autoantibodies. These data demonstrate for the first time that TLR7, and not TLR9, is responsible for generation of anti-chromatin IgG antibodies in Mer−/− mice.

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Section: Methodsmentioning

confidence: 99%

TLR7 drives accumulation of ABCs and autoantibody production in autoimmune-prone mice

et al. 2012

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“…Concentrations of anti-chromatin immunoglobulin G (IgG) antibodies were determined using the protocol of Guth et al 11 For in vitro antibody production, ABCs and MZ, FO, and B1 B cells were incubated at 10 6 cells/mL in complete Dulbecco modified Eagle medium with or without TLR7 agonist 3M-012 (1 g/mL). Supernatants were harvested at day 7, and the concentration of total and anti-chromatin IgG was determined by ELISA.…”

Section: Chronic Immunization and Antibody Measurementmentioning

confidence: 99%

Toll-like receptor 7 (TLR7)–driven accumulation of a novel CD11c+ B-cell population is important for the development of autoimmunity

Rubtsov

Rubtsova

Fischer

et al. 2011

Blood

612

871

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“…Sera from experimental and control mice were tested for the presence of autoAbs or total Igk as described with the following modifications [47]. 96-well trays were coated overnight with calf-chromatin, ssDNA (Sigma–Aldrich), total histones (Roche), dsDNA/total histones or bovine serum albumin (BSA) at 10 μg/ml in PBS-1mM EDTA or goat anti-mouse Ig at 1 μg/ml (Sigma–Aldrich) in PBS.…”

Section: Methodsmentioning

confidence: 99%

Predominant role for activation-induced cytidine deaminase in generating IgG anti-nucleosomal antibodies of murine SLE

Detanico

Guo

Wysocki

2015

Journal of Autoimmunity

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Serum IgG anti-nuclear antibodies (ANA) directed to complexes of DNA and histones are a hallmark of systemic lupus erythematosus (SLE) and reflect a failure in lymphocyte self-tolerance. A prior study utilizing spontaneously autoimmune B6.Nba2 mice deficient in terminal deoxynucleotidyl transferase (TdT) and with heterozygous deficiencies in Jh and Igk loci underscored the importance of somatic hypermutation (SHM) as a major generator of SLE-associated ANA. This interpretation had to be qualified because of severely limited opportunities for receptor editing and restricted VHCDR3 diversity. Therefore, we performed the converse study using mice that carried functional Tdt genes and wild type Jh and Igk loci but that could not undergo SHM. Analyses of ANA and ANA-producing hybridomas from B6.Nba2 Aicda−/− mice revealed that few animals produced high titers of the prototypical ANA directed to complexes of histones and DNA, that this response was delayed and that those cells that did produce such antibody exhibited limited clonal expansion, unusual Jk use and only infrequent dual receptor expression. This, together with the additional finding of an intrinsic propensity for SHM to generate Arg codons selectively in CDRs, reinforce the view that most IgG autoimmune clones producing prototypical anti-nucleosome antibodies in wild type mice are created by SHM.

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Spontaneous autoimmunity in mice that carry an IghV partial transgene: a required arginine in VHCDR3

Cited by 4 publications

References 62 publications

TLR7 drives accumulation of ABCs and autoantibody production in autoimmune-prone mice

TLR7 drives accumulation of ABCs and autoantibody production in autoimmune-prone mice

Toll-like receptor 7 (TLR7)–driven accumulation of a novel CD11c+ B-cell population is important for the development of autoimmunity

Predominant role for activation-induced cytidine deaminase in generating IgG anti-nucleosomal antibodies of murine SLE

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