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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) Igκ repertoire, which resembled that of patients with ataxia telangiectasia (AT). This repertoire was characterized by increased Jκ1 and decreased upstream Vκ 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 κB 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 Igκ 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:BackgroundRheumatoid arthritis (RA) is a chronic disease with worldwide representation that impacts every domain of a patient´s life, extending to sexual and reproductive domains. The study characterized sexual health (SH) and reproductive health (RH) in Mexican RA outpatients and identified factors associated with impaired sexual function (ISF).MethodsFrom September 1, 2020-January 31, 2022, consecutive RA participants had semi-structured interviews focusing on their SH and RH biographies, and self-administered questionnaires were applied to assess patient-reported outcomes, including fatigue with the Functional Assessment of Chronic Illness Therapy-Fatigue scale (FACIT-F). ISF was defined based on published cut-offs of the International Index of Erectile Function (IIEF) in males and the Female Sexual Function Index (FSFI) in females (≥1 sexual intercourse in the last four weeks was required for index scoring). Multivariable logistic regression analysis was used to identify the factors associated with ISF.ResultsThere were 268 participants, and 246 (91.8%) were females. Participants had 13 years of disease duration. Among females, 151 (61.4%) had FSFI applied, and the satisfaction domain was impaired in 111 (73.5%). Among males (N = 22), 17 (77.3%) had IIEF applied, and erectile dysfunction was present in 5 (29.4%). Almost half of the participants denied using a family planning method, were in their 50s, and receiving teratogenic drugs; 89.7% of the participants had children. ISF was detected in 94 (62.3%) females and 3 (17.6%) males. Male sex (aOR: 0.07, 95%CI: 0.01-0.36, p = 0.001), FACIT-F score (aOR: 0.96, 95%CI: 0.92-1.00, p = 0.03), and cohabitation with the couple (aOR: 0.32, 95%CI: 0.11-0.96, p = 0.04) were associated with ISF.ConclusionsWe observed a disproportionate burden of ISF among women with RA compared to male participants. Male sex, lesser fatigue, and cohabitation with the couple were protective against ISF. Regardless of the prevalent use of teratogenic medications, contraceptive use was suboptimal among the participants.

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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