The Lupus Susceptibility Locus <i>Sle1</i> Facilitates the Peripheral Development and Selection of Anti-DNA B Cells through Impaired Receptor Editing

Chang, Soog Hee; Kim, Tae Joo; Kim, Young Joo; Yang, Liu; Min, Sung−Wook; Park, Min Jung; Park, Hyun Sil; Lee, Sun Kyung; Nam, Ki Hoan; Kim, Ho Youn; Mohan, Chandra; Kim, Hang Rae

doi:10.4049/jimmunol.1201558

Cited by 5 publications

(5 citation statements)

References 35 publications

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“…To assess receptor editing more directly, we quantified the frequency of the VκRS rearrangement sequence within pre–B cells, which forms within the Igκ light chain locus following exhaustive editing (15). Compared to empty vector treatment, IFNα‐treated mice displayed a significant decrease in the relative abundance of the VκRS rearrangement sequence (Figure 2D), consistent with impaired receptor editing.…”

Section: Resultsmentioning

confidence: 99%

“…Briefly, purified genomic DNA (15–25 ng) was mixed with SYBR‐green master mix (Thermo Fisher Scientific) and 1 μ M primers in a 20 μl reaction volume. Cycling conditions were as follows: 95°C for 15 minutes, followed by 50 cycles at 95°C for 15 seconds, 60°C for 15 seconds, and 72°C for 30 seconds, using the same primers as previously reported (15). The amount of VκRS product in each sample was normalized to the amount of β‐actin product and then compared with the normalized value for uninfected B6 B220+IgM+Igκ+ B cells to determine relative quantity.…”

Section: Methodsmentioning

confidence: 99%

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Elevated Levels of Interferon‐α Act Directly on B Cells to Breach Multiple Tolerance Mechanisms Promoting Autoantibody Production

Ferri

Nassar

Manion

et al. 2023

Arthritis & Rheumatology

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ObjectiveElevated levels of serum interferon‐α (IFNα) and the disruption of B cell tolerance are central to systemic lupus erythematosus (SLE) immunopathogenesis; however, the relationship between these 2 processes remains unclear. The purpose of this study was to investigate the impact of elevated IFNα levels on B cell tolerance mechanisms in vivo and determine whether any changes observed were due to the direct effect of IFNα on B cells.MethodsTwo classical mouse models of B cell tolerance were used in conjunction with an adenoviral vector encoding IFNα to mimic the sustained elevations of IFNα seen in SLE. The role of B cell IFNα signaling, T cells, and Myd88 signaling was determined using B cell–specific IFNα receptor–knockout, CD4+ T cell–depleted, or Myd88‐knockout mice, respectively. Flow cytometry, enzyme‐linked immunosorbent assay, real‐time quantitative polymerase chain reaction, and cell cultures were used to study the effects of elevated IFNα on the immunologic phenotype.ResultsElevation of serum IFNα disrupts multiple B cell tolerance mechanisms and leads to autoantibody production. This disruption was dependent upon B cell expression of IFNα receptor. Many of the IFNα‐mediated alterations also required the presence of CD4+ T cells as well as Myd88, suggesting that IFNα acts directly on B cells to modify their response to Myd88 signaling and their ability to interact with T cells.ConclusionThe results provide evidence that elevated IFNα levels act directly on B cells to facilitate autoantibody production and further highlight the importance of IFN signaling as a potential therapeutic target in SLE.image

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Elevated Levels of Interferon‐α Act Directly on B Cells to Breach Multiple Tolerance Mechanisms Promoting Autoantibody Production

Ferri

Nassar

Manion

et al. 2023

Arthritis & Rheumatology

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“…This has been observed in multiple animal models and can be inferred in humans and mice by the loss of some, though not all, autoAbs after B cell depletion therapy (7-10). Most prominently, anti-DNA and anti-self-IgG (rheumatoid factor, RF) responses use the EF pathway (11, 12). In contrast to the GC, how these EF responses are promoted and regulated is poorly defined, both in immunity and autoimmunity.…”

Section: Introductionmentioning

confidence: 99%

B Cell–Extrinsic Myd88 and Fcer1g Negatively Regulate Autoreactive and Normal B Cell Immune Responses

Sweet

Nickerson

Cullen

et al. 2017

The Journal of Immunology

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MyD88 and FcR common gamma chain (Fcer1g, FcRγ) elicit proinflammatory responses to exogenous antigens. Deletion of these receptors in autoimmune models has generally led to reduced overall disease. In B cells, Myd88 is required for anti-DNA and anti-RNA autoAb responses, while Fcer1g is not expressed in these cells. The roles of these receptors in myeloid cells during B cell autoimmune activation remain less clear. To investigate the roles of Myd88 and Fcer1g on non-B cells, we transferred anti-self IgG (rheumatoid factor) B cells and their physiologic target antigen, anti-chromatin Ab, into mice lacking Fcer1g, Myd88 or both and studied the extrafollicular plasmablast response. Surprisingly, we found a markedly higher and more prolonged response in the absence of either molecule, an effect that was accentuated in doubly-deficient recipients, with a 40-fold increase compared to WT recipients at d10. This enhancement was dependent on CD40L, indicating that Myd88 and FcRγ, presumably on myeloid APC, was required to downregulate T cell help for the EF response. To extend the generality we then investigated a classic T cell dependent response to NP-CGG and found a similar effect. These results thus reveal novel regulatory roles in the B cell response for receptors that are typically proinflammatory.

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“…Sle1 expression decreased the percentage and number of total B cells but favored the expansion of AM14 HC tg B cells over endogenous B cells, and this was independent of the expression of the autoAg. Consistent with this result, it has been shown that Sle1 locus favored the expansion of DNA-specific 56R HC tg B cells relative to the endogenous B cells [34]. In the AM14 model, the expansion of the tg B cells resulted in a relatively low production of antichromatin IgG2a a by endogenous B cells, thereby limiting autoAg availability for Id + RF B cells.…”

Section: Discussionmentioning

confidence: 63%

Genetic and cellular dissection of the activation of AM14 rheumatoid factor B cells in a mouse model of lupus

Sang

Zheng

Choi

et al. 2015

Journal of Leukocyte Biology

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The RF-specific AM14 tg BCR has been used as a model to dissect the mechanisms of B cell tolerance to ICs containing nucleic acids. We have shown previously that AM14 RF B cells break tolerance in the TC mouse model of lupus through the dual engagement of the AM14 BCR and TLR9. In this study, we showed that neither the expression of Sle1 or Sle2 susceptibility loci alone was sufficient to activate AM14 RF B cells, suggesting that the production of antichromatin IgG2a(a) autoAg mediated by Sle1 and an intrinsically higher B cell activation mediated by Sle2 were required. We also showed that the B6 genetic background enhanced the selection of AM14 RF B cells to the MZB cell compartment regardless of the expression of the Sle loci and therefore, of their activation into AFCs. Furthermore, some AM14 RF B cells were selected into the B-1a compartment, where they did not differentiate into AFCs. Therefore, it is unlikely that the selection of AM14 RF B cells to the MZB or B-1a cell compartments in TC.AM14(a) mice is responsible for their breach of tolerance. Finally, we showed that the presence of expression of Sle1 in non-tg cells, most likely T cells, is necessary for the activation of AM14 RF B cells into AFCs. Overall, these results suggest a threshold model of activation of AM14 RF B cells on the B6 background with additive genetic and cellular contribution of multiple sources.

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The Lupus Susceptibility Locus Sle1 Facilitates the Peripheral Development and Selection of Anti-DNA B Cells through Impaired Receptor Editing

Cited by 5 publications

References 35 publications

Elevated Levels of Interferon‐α Act Directly on B Cells to Breach Multiple Tolerance Mechanisms Promoting Autoantibody Production

Elevated Levels of Interferon‐α Act Directly on B Cells to Breach Multiple Tolerance Mechanisms Promoting Autoantibody Production

B Cell–Extrinsic Myd88 and Fcer1g Negatively Regulate Autoreactive and Normal B Cell Immune Responses

Genetic and cellular dissection of the activation of AM14 rheumatoid factor B cells in a mouse model of lupus

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