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

Defective ATM activation skews the B cell repertoire and increases RANKL production, promoting joint erosion in patients with rheumatoid arthritis. 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.

[1]  G. Gibson,et al.  Distinct Effector B Cells Induced by Unregulated Toll‐like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus , 2018, Immunity.

[2]  R. Salomão,et al.  B-cell subsets imbalance and reduced expression of CD40 in ataxia-telangiectasia patients. , 2018, Allergologia et immunopathologia.

[3]  D. Ramsköld,et al.  B cells expressing the IgA receptor FcRL4 participate in the autoimmune response in patients with rheumatoid arthritis , 2017, Journal of autoimmunity.

[4]  G. Schett,et al.  Pathogenetic insights from the treatment of rheumatoid arthritis , 2017, The Lancet.

[5]  A. Gagro,et al.  Ataxia Telangiectasia and Juvenile Idiopathic Arthritis , 2017, Pediatrics.

[6]  T. Crawford,et al.  Ataxia telangiectasia: a review , 2016, Orphanet Journal of Rare Diseases.

[7]  S. Goodman,et al.  Deficient Activity of the Nuclease MRE11A Induces T Cell Aging and Promotes Arthritogenic Effector Functions in Patients with Rheumatoid Arthritis. , 2016, Immunity.

[8]  K. Horiuchi,et al.  Conditional abrogation of Atm in osteoclasts extends osteoclast lifespan and results in reduced bone mass , 2016, Scientific Reports.

[9]  E. Wherry,et al.  Cutting Edge: IL-4, IL-21, and IFN-γ Interact To Govern T-bet and CD11c Expression in TLR-Activated B Cells , 2016, The Journal of Immunology.

[10]  Y. Maeda,et al.  RANK‐Independent Osteoclast Formation and Bone Erosion in Inflammatory Arthritis , 2016, Arthritis & rheumatology.

[11]  E. Meffre,et al.  PTPN22 inhibition resets defective human central B cell tolerance , 2016, Science Immunology.

[12]  L. Xing,et al.  Production of RANKL by Memory B Cells: A Link Between B Cells and Bone Erosion in Rheumatoid Arthritis , 2016, Arthritis & rheumatology.

[13]  L. Tian,et al.  Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis , 2016, Science Translational Medicine.

[14]  T. Chun,et al.  Maturational characteristics of HIV-specific antibodies in viremic individuals. , 2016, JCI insight.

[15]  K. Akashi,et al.  Generation mechanism of RANKL+ effector memory B cells: relevance to the pathogenesis of rheumatoid arthritis , 2016, Arthritis Research & Therapy.

[16]  J. Tarín,et al.  The role of CD40 and CD40L in bone mineral density and in osteoporosis risk: A genetic and functional study. , 2016, Bone.

[17]  J. Cyster,et al.  CXCR4 and a cell-extrinsic mechanism control immature B lymphocyte egress from bone marrow , 2014, The Journal of experimental medicine.

[18]  M. Mottolese,et al.  ATM kinase sustains HER2 tumorigenicity in breast cancer , 2014, Nature Communications.

[19]  P. Visscher,et al.  Genetics of rheumatoid arthritis contributes to biology and drug discovery , 2013, Nature.

[20]  R. Gatti,et al.  Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions. , 2013, Blood.

[21]  E. Meffre,et al.  Expansion of autoreactive unresponsive CD21-/low B cells in Sjögren's syndrome-associated lymphoproliferation. , 2013, Arthritis and rheumatism.

[22]  Katherine S. Yang-Iott,et al.  The Ataxia Telangiectasia mutated kinase controls Igκ allelic exclusion by inhibiting secondary Vκ-to-Jκ rearrangements , 2013, The Journal of experimental medicine.

[23]  A. Gibofsky,et al.  Overview of epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis. , 2012, The American journal of managed care.

[24]  R. Toes,et al.  Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. , 2012, The Journal of clinical investigation.

[25]  P. Marrack,et al.  Toll-like receptor 7 (TLR7)-driven accumulation of a novel CD11c⁺ B-cell population is important for the development of autoimmunity. , 2011, Blood.

[26]  D. Schatz,et al.  Recombination centres and the orchestration of V(D)J recombination , 2011, Nature Reviews Immunology.

[27]  K. Toellner,et al.  Cytokine mRNA profiling identifies B cells as a major source of RANKL in rheumatoid arthritis , 2011, Annals of the rheumatic diseases.

[28]  E. L. Luning Prak,et al.  B cell receptor editing in tolerance and autoimmunity , 2011, Annals of the New York Academy of Sciences.

[29]  M. Horowitz,et al.  How B cells influence bone biology in health and disease. , 2010, Bone.

[30]  D. Symmons,et al.  2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. , 2010, Arthritis and rheumatism.

[31]  M. Schlissel,et al.  Allelic exclusion of immunoglobulin genes: models and mechanisms , 2010, Immunological reviews.

[32]  C. Cunningham-Rundles,et al.  Complement receptor 2/CD21- human naive B cells contain mostly autoreactive unresponsive clones. , 2010, Blood.

[33]  R. Proia,et al.  S1P1 receptor directs the release of immature B cells from bone marrow into blood , 2010, The Journal of experimental medicine.

[34]  C. Weyand,et al.  Immune aging and rheumatoid arthritis. , 2010, Rheumatic diseases clinics of North America.

[35]  K. Schwarz,et al.  Circulating CD21low B cells in common variable immunodeficiency resemble tissue homing, innate-like B cells , 2009, Proceedings of the National Academy of Sciences.

[36]  C. Weyand,et al.  Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis , 2009, The Journal of experimental medicine.

[37]  D. Schatz,et al.  RAG1 and ATM coordinate monoallelic recombination and nuclear positioning of immunoglobulin loci , 2009, Nature Immunology.

[38]  E. Schwarz,et al.  The emerging field of osteoimmunology , 2009, Immunologic research.

[39]  C. Bassing,et al.  Aberrant V(D)J Recombination in Ataxia Telangiectasia Mutated-Deficient Lymphocytes Is Dependent on Nonhomologous DNA End Joining1 , 2008, The Journal of Immunology.

[40]  Wei-Ping Qian,et al.  B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo. , 2007, Blood.

[41]  M. Lavin,et al.  ATM Activation and DNA Damage Response , 2007, Cell cycle.

[42]  M. van der Burg,et al.  Replication history of B lymphocytes reveals homeostatic proliferation and extensive antigen-induced B cell expansion , 2007, The Journal of experimental medicine.

[43]  K. Nakachi,et al.  Short‐term culture and γH2AX flow cytometry determine differences in individual radiosensitivity in human peripheral T lymphocytes , 2007, Environmental and molecular mutagenesis.

[44]  T. Pandita,et al.  ATM stabilizes DNA double-strand-break complexes during V(D)J recombination , 2006, Nature.

[45]  Xueying Wang,et al.  Atm-deficient mice: an osteoporosis model with defective osteoblast differentiation and increased osteoclastogenesis. , 2006, Human molecular genetics.

[46]  E. Schwarz,et al.  Autoimmunity and Bone , 2006, Annals of the New York Academy of Sciences.

[47]  Frederick W. Alt,et al.  DNA Repair, Genome Stability, and Aging , 2005, Cell.

[48]  R. Kinne,et al.  Chaperonins and the regulation of immunity , 2005, Arthritis and rheumatism.

[49]  S. Lees-Miller,et al.  Doxorubicin Activates ATM-dependent Phosphorylation of Multiple Downstream Targets in Part through the Generation of Reactive Oxygen Species* , 2004, Journal of Biological Chemistry.

[50]  N. Curtin,et al.  Identification and Characterization of a Novel and Specific Inhibitor of the Ataxia-Telangiectasia Mutated Kinase ATM , 2004, Cancer Research.

[51]  M. Kotb,et al.  Human Lymphoid and Myeloid Cell Development in NOD/LtSz-scid IL2Rγnull Mice Engrafted with Mobilized Human Hemopoietic Stem Cells 12 , 2004, The Journal of Immunology.

[52]  F. Breedveld,et al.  Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis. , 2004, Arthritis and rheumatism.

[53]  P. Emery,et al.  Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. , 2004, The New England journal of medicine.

[54]  M. Duddy,et al.  Distinct Profiles of Human B Cell Effector Cytokines: A Role in Immune Regulation?1 , 2004, The Journal of Immunology.

[55]  M. Nussenzweig,et al.  Predominant Autoantibody Production by Early Human B Cell Precursors , 2003, Science.

[56]  G. Russo,et al.  Skewed T-cell receptor repertoire, decreased thymic output, and predominance of terminally differentiated T cells in ataxia telangiectasia. , 2002, Blood.

[57]  A. Koch,et al.  Selective lymphocyte chemokine receptor expression in the rheumatoid joint. , 2001, Arthritis and rheumatism.

[58]  M. van der Burg,et al.  Ordered recombination of immunoglobulin light chain genes occurs at the IGK locus but seems less strict at the IGL locus. , 2001, Blood.

[59]  S. Teitelbaum,et al.  Bone resorption by osteoclasts. , 2000, Science.

[60]  L. Hood,et al.  OPG/FDCR-1, a TNF receptor family member, is expressed in lymphoid cells and is up-regulated by ligating CD40. , 1998, Journal of immunology.

[61]  E. Rogakou,et al.  DNA Double-stranded Breaks Induce Histone H2AX Phosphorylation on Serine 139* , 1998, The Journal of Biological Chemistry.

[62]  W. Uttal.  On models and mechanisms , 1992, Behavioral and Brain Sciences.

[63]  David Brink,et al.  : A Review of the , 2018 .

[64]  Jun S. Liu,et al.  Genetics of rheumatoid arthritis contributes to biology and drug discovery , 2013 .

[65]  A. Silman,et al.  Rheumatoid arthritis classifi cation criteria : an American College of Rheumatology / European League Against Rheumatism collaborative initiative , 2010 .

[66]  G. R. Henshaw.  Biology in health and disease. , 1962, Journal of the American Institute of Homeopathy.

[67]  M. van der Burg,et al.  Immune deficiencies , infection , and systemic immune disorders Antibody deficiency in patients with ataxia telangiectasia is caused by disturbed Band T-cell homeostasis and reduced immune repertoire diversity , 2022 .