Impaired ATM Activation in B Cells is Associated with Bone Resorption in Rheumatoid Arthritis
| Autor: | Jeff W. Chen, Andrea Vega-Loza, Eric Meffre, Natsuko Yamakawa, Kofi A. Mensah, Jennifer H. Anolik, Ruth R. Montgomery, Jean-Nicolas Schickel, Erwin W. Gelfand, Mark C. Horowitz, Joe Craft, Isabelle Isnardi, Richard A. Gatti |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Cell Survival
B-cell receptor Arthritis Immunoglobulins Ataxia Telangiectasia Mutated Proteins Bone resorption Article Arthritis Rheumatoid Mice Osteoprotegerin Bone Density Osteogenesis medicine Animals Humans Lymphocyte Count Bone Resorption Receptor Recombination Genetic B-Lymphocytes biology Chemistry RANK Ligand General Medicine Middle Aged medicine.disease medicine.anatomical_structure Phenotype RANKL Ataxia-telangiectasia biology.protein Cancer research Joints Receptors Complement 3d Bone marrow |
| Zdroj: | Sci Transl Med |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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