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Impaired ATM activation in B cells is associated with bone resorption in rheumatoid arthritis.

ABSTRACT: Patients with rheumatoid arthritis (RA) may display atypical CD21-/lo B cells in their blood, but the implication of this observation remains unclear. We report here that the group of patients with RA and elevated frequencies of CD21-/lo B cells shows decreased ataxia telangiectasia-mutated (ATM) expression and activation in B cells compared with other patients with RA and healthy donor controls. In agreement with ATM involvement in the regulation of V(D)J recombination, patients with RA who show defective ATM function displayed a skewed B cell receptor (BCR) Ig? repertoire, which resembled that of patients with ataxia telangiectasia (AT). This repertoire was characterized by increased J?1 and decreased upstream V? gene segment usage, suggesting improper secondary recombination processes and selection. In addition, altered ATM function in B cells was associated with decreased osteoprotegerin and increased receptor activator of nuclear factor ?B ligand (RANKL) production. These changes favor bone loss and correlated with a higher prevalence of erosive disease in patients with RA who show impaired ATM function. Using a humanized mouse model, we also show that ATM inhibition in vivo induces an altered Ig? repertoire and RANKL production by immature B cells in the bone marrow, leading to decreased bone density. We conclude that dysregulated ATM function in B cells promotes bone erosion and the emergence of circulating CD21-/lo B cells, thereby contributing to RA pathophysiology.

SUBMITTER: Mensah KA

PROVIDER: S-EPMC7167286 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Impaired ATM activation in B cells is associated with bone resorption in rheumatoid arthritis.

Mensah Kofi A KA Chen Jeff W JW Schickel Jean-Nicolas JN Isnardi Isabelle I Yamakawa Natsuko N Vega-Loza Andrea A Anolik Jennifer H JH Gatti Richard A RA Gelfand Erwin W EW Montgomery Ruth R RR Horowitz Mark C MC Craft Joe E JE Meffre Eric E

Science translational medicine 20191101 519

Patients with rheumatoid arthritis (RA) may display atypical CD21<sup>-/lo</sup> B cells in their blood, but the implication of this observation remains unclear. We report here that the group of patients with RA and elevated frequencies of CD21<sup>-/lo</sup> B cells shows decreased ataxia telangiectasia-mutated (ATM) expression and activation in B cells compared with other patients with RA and healthy donor controls. In agreement with ATM involvement in the regulation of V(D)J recombination, pa ...[more]

PMID: 31748230

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Project description:BackgroundThe complement system plays an important role in pathophysiology of cardiovascular disease (CVD), and might be involved in accelerated atherogenesis in rheumatoid arthritis (RA). The role of complement activation in response to treatment, and in development of premature CVD in RA, is limited. Therefore, we examined the effects of methotrexate (MTX) and tumor necrosis factor inhibitors (TNFi) on complement activation using soluble terminal complement complex (TCC) levels in RA; and assessed associations between TCC and inflammatory and cardiovascular biomarkers.MethodsWe assessed 64 RA patients starting with MTX monotherapy (n = 34) or TNFi with or without MTX co-medication (TNFi±MTX, n = 30). ELISA was used to measure TCC in EDTA plasma. The patients were examined at baseline, after 6 weeks and 6 months of treatment.ResultsMedian TCC was 1.10 CAU/mL, and 57 (89%) patients had TCC above the estimated upper reference limit (<0.70). Compared to baseline, TCC levels were significantly lower at 6-week visit (0.85 CAU/mL, p<0.0001), without significant differences between the two treatment regimens. Notably, sustained reduction in TCC was only achieved after 6 months on TNFi±MTX (0.80 CAU/mL, p = 0.006). Reductions in TCC after treatment were related to decreased C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and interleukin 6, and increased levels of total, high and low-density lipoprotein cholesterol. Similarly, baseline TCC was significantly related to baseline CRP, ESR and interleukin 6. Patients with endothelial dysfunction had higher baseline TCC than those without (median 1.4 versus 1.0 CAU/mL, p = 0.023).ConclusionsPatients with active RA had elevated TCC, indicating increased complement activation. TCC decreased with antirheumatic treatment already after 6 weeks. However, only treatment with TNFi±MTX led to sustained reduction in TCC during the 6-month follow-up period. RA patients with endothelial dysfunction had higher baseline TCC compared to those without, possibly reflecting involvement of complement in the atherosclerotic process in RA.

Dataset Information

Impaired ATM activation in B cells is associated with bone resorption in rheumatoid arthritis.

Publications

Impaired ATM activation in B cells is associated with bone resorption in rheumatoid arthritis.

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