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- Title
Impaired ATM activation in B cells is associated with bone resorption in rheumatoid arthritis.
- Authors
Mensah, Kofi A.; Chen, Jeff W.; Schickel, Jean-Nicolas; Isnardi, Isabelle; Yamakawa, Natsuko; Vega-Loza, Andrea; Anolik, Jennifer H.; Gatti, Richard A.; Gelfand, Erwin W.; Montgomery, Ruth R.; Horowitz, Mark C.; Craft, Joe E.; Meffre, Eric
- Abstract
When B cells are bad to the bone: B cells may contribute to rheumatoid arthritis pathogenesis through additional mechanisms beyond autoantibodies. Mensah et al. observed that a subset of patients with rheumatoid arthritis had defective ataxia telangiectasia–mutated (ATM) expression, which among other pathways controls gene rearrangements in B cells. This group of patients had a skewed B cell repertoire and erosive bone lesions. In vitro experiments revealed that ATM-deficient B cells expressed factors that would promote bone resorption. An ATM inhibitor in humanized mice recapitulated the B cell defects and bone erosion observed in patients. These results identify a pathogenic B cell axis in rheumatoid arthritis that could potentially be targeted with B cell–depleting therapies. 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.
- Subjects
B cell receptors; BONE resorption; B cells; RHEUMATOID arthritis; T cell receptors; BONE marrow cells; BONE cells
- Publication
Science Translational Medicine, 2019, Vol 11, Issue 519, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aaw4626