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Current Osteoporosis Reports
Published in: Current Osteoporosis Reports 1/2014

01-03-2014 | Osteoimmunology (D Novack and G Schett, Section Editors)

Autoantibody-Mediated Bone Loss

Authors: Ulrike Harre, Nicolai A. Kittan, Georg Schett

Published in: Current Osteoporosis Reports | Issue 1/2014

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Abstract

In rheumatoid arthritis (RA), the presence of autoantibodies such as the rheumatoid factor and antibodies against citrullinated proteins is highly correlated with the severity of disease and bone loss. For many years, the involvement of autoantibodies in bone resorption has merely been attributed to enhanced tissue infiltration and the production of inflammatory cytokines that promote osteoclastogenesis. However, recent research provides evidence for a direct activation of osteoclasts and their precursors by autoantibodies, which is independent of inflammation. The depletion of B-cells with rituximab that substantially reduces autoantibody levels seems to be as effective as the well-established treatment with tumor necrosis factor-antagonists in RA patients that do not respond to methotrexate, highlighting the significance of autoantibodies for RA and bone loss.
Literature
1.
Nakahama K. Cellular communications in bone homeostasis and repair. Cell Mol Life Sci. 2010;67(23):4001–9.PubMedCrossRef
2.
Hayashi M, Nakashima T, Taniguchi M, Kodama T, Kumanogoh A, Takayanagi H. Osteoprotection by semaphorin 3A. Nature. 2012;485(7396):69–74.PubMedCrossRef
3.
Willemze A, Toes RE, Huizinga TW, Trouw LA. New biomarkers in rheumatoid arthritis. Neth J Med. 2012;70(9):392–9.PubMed
4.
Modi S, Soejima M, Levesque MC. The effect of targeted rheumatoid arthritis therapies on anti-citrullinated protein autoantibody levels and B cell responses. Clin Exp Immunol. 2013;173(1):8–17.PubMedCrossRef
5.
Schett G, Gravallese E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol. 2012;8(11):656–64.PubMedCrossRef
6.
Aho K, Palusuo T, Kurki P. Marker antibodies of rheumatoid arthritis: diagnostic and pathogenetic implications. Semin Arthritis Rheum. 1994;23(6):379–87.PubMedCrossRef
7.
Arnett FC. Revised criteria for the classification of rheumatoid arthritis. Bull Rheum Dis. 1989;38(5):1–6.PubMed
8.
Conrad K, Roggenbuck D, Reinhold D, Dorner T. Profiling of rheumatoid arthritis associated autoantibodies. Autoimmun Rev. 2010;9(6):431–5.PubMedCrossRef
9.
Ferraccioli G, Tolusso B, Bobbio-Pallavicini F, et al. Biomarkers of good EULAR response to the B cell depletion therapy in all seropositive rheumatoid arthritis patients: clues for the pathogenesis. PLoS One. 2012;7(7):e40362.PubMedCentralPubMedCrossRef
10.
Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69(9):1580–8.PubMedCrossRef
11.
Nienhuis RL, Mandema E. A new serum factor in patients with rheumatoid arthritis; the antiperinuclear factor. Ann Rheum Dis. 1964;23:302–5.PubMedCrossRef
12.
Saeki Y, Kudo-Tanaka E, Ohshima S, et al. Baseline anti-citrullinated peptide antibody (ACPA) titers and serum interleukin-6 (IL-6) levels possibly predict progression of bone destruction in early stages of rheumatoid arthritis (ERA). Rheumatol Int. 2012;33(2):451–6.PubMedCrossRef
13.
Zendman AJ, van Venrooij WJ, Pruijn GJ. Use and significance of anti-CCP autoantibodies in rheumatoid arthritis. Rheumatology. 2006;45(1):20–5.PubMedCrossRef
14.
van Gaalen FA, Linn-Rasker SP, van Venrooij WJ, et al. Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients with undifferentiated arthritis: a prospective cohort study. Arthritis Rheum. 2004;50(3):709–15.PubMedCrossRef
15.
van der Woude D, Rantapaa-Dahlqvist S, Ioan-Facsinay A, et al. Epitope spreading of the anti-citrullinated protein antibody response occurs before disease onset and is associated with the disease course of early arthritis. Ann Rheum Dis. 2010;69(8):1554–61.PubMedCrossRef
16.
Klareskog L, Ronnelid J, Lundberg K, Padyukov L, Alfredsson L. Immunity to citrullinated proteins in rheumatoid arthritis. Ann Rev Immunol. 2008;26:651–75.CrossRef
17.
Amara K, Steen J, Murray F, et al. Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition. J Exp Med. 2013;210(3):445–55.PubMedCentralPubMedCrossRef
18.
Vossenaar ER, Zendman AJ, van Venrooij WJ, Pruijn GJ. PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. BioEssays. 2003;25(11):1106–18.PubMedCrossRef
19.
McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205–19.PubMedCrossRef
20.
Klareskog L, Stolt P, Lundberg K, et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006;54(1):38–46.PubMedCrossRef
21.
Mathsson L, Mullazehi M, Wick MC, et al. Antibodies against citrullinated vimentin in rheumatoid arthritis: higher sensitivity and extended prognostic value concerning future radiographic progression compared with antibodies against cyclic citrullinated peptides. Arthritis Rheum. 2008;58(1):36–45.PubMedCrossRef
22.••
Harre U, Georgess D, Bang H, et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J Clin Invest. 2012;122(5):1791–802. Provides the first report of direct osteoclast activation by ACPA.
23.
Fluckiger R, Harmon W, Meier W, Loo S, Gabbay KH. Hemoglobin carbamylation in uremia. N Engl J Med. 1981;304(14):823–7.PubMedCrossRef
24.•
Trouw LA, Huizinga TW, Toes RE. Autoimmunity in rheumatoid arthritis: different antigens — common principles. Ann Rheum Dis. 2013;72 Suppl 2:ii132–6. Introduces a new family of autoantbodies.
25.
Shi J, Willemze A, Janssen GM, et al. Recognition of citrullinated and carbamylated proteins by human antibodies: specificity, cross-reactivity and the 'AMC-Senshu' method. Ann Rheum Dis. 2013;72(1):148–50.PubMedCrossRef
26.
Van Steendam K, Tilleman K, De Ceuleneer M, De Keyser F, Elewaut D, Deforce D. Citrullinated vimentin as an important antigen in immune complexes from synovial fluid of rheumatoid arthritis patients with antibodies against citrullinated proteins. Arthritis Res Ther. 2010;12(4):R132.PubMedCentralPubMedCrossRef
27.
Zhao X, Okeke NL, Sharpe O, et al. Circulating immune complexes contain citrullinated fibrinogen in rheumatoid arthritis. Arthritis Res Ther. 2008;10(4):R94.PubMedCentralPubMedCrossRef
28.
Mathsson L, Lampa J, Mullazehi M, Ronnelid J. Immune complexes from rheumatoid arthritis synovial fluid induce Fcgamma RIIa dependent and rheumatoid factor correlated production of tumour necrosis factor-alpha by peripheral blood mononuclear cells. Arthritis Res Ther. 2006;8(3):R64.PubMedCentralPubMedCrossRef
29.
Nimmerjahn F, Ravetch JV. Antibody-mediated modulation of immune responses. Immunol Rev. 2010;236:265–75.PubMedCrossRef
30.
Clavel C, Nogueira L, Laurent L, et al. Induction of macrophage secretion of tumor necrosis factor alpha through Fcgamma receptor IIa engagement by rheumatoid arthritis-specific autoantibodies to citrullinated proteins complexed with fibrinogen. Arthritis Rheum. 2008;58(3):678–88.PubMedCrossRef
31.
Lu MC, Lai NS, Yu HC, Huang HB, Hsieh SC, Yu CL. Anti-citrullinated protein antibodies bind surface-expressed citrullinated Grp78 on monocyte/macrophages and stimulate tumor necrosis factor alpha production. Arthritis Rheum. 2010;62(5):1213–23.PubMedCrossRef
32.
33.
Keffer J, Probert L, Cazlaris H, et al. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 1991;10(13):4025–31.PubMed
34.•
Atzeni F, Benucci M, Salli S, Bongiovanni S, Boccassini L, Sarzi-Puttini P. Different effects of biological drugs in rheumatoid arthritis. Autoimmun Rev. 2013;12(5):575–9. Summarizes current knowledge on RA treatment with biologicals.
35.•
Buch MH, Rubbert-Roth A, Ferraccioli G. To switch or not to switch after a poor response to a TNFalpha blocker? It is not only a matter of ACR20 OR ACR50. Autoimmun Rev. 2012;11(8):558–62. Summarizes current knowledge on anti-TNF treatment.
36.
Mertens M, Singh JA. Anakinra for rheumatoid arthritis: a systematic review. J Rheumatol. 2009;36(6):1118–25.PubMedCrossRef
37.
Kellner H. Targeting interleukin-17 in patients with active rheumatoid arthritis: rationale and clinical potential. Ther Adv Dis. 2013;5(3):141–52.
38.•
Kleyer A, Finzel S, Rech J, et al. Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies. Ann Rheumat Dis. 2013. doi:10.​1136/​annrheumdis-2012-202958. Provides first evidence for ACPA driven bone loss before onset of disease.
39.••
Seeling M, Hillenhoff U, David JP, et al. Inflammatory monocytes and Fcgamma receptor IV on osteoclasts are critical for bone destruction during inflammatory arthritis in mice. Proc Natl Acad Sci U S A. 2013;110(26):10729–34. Shows that autoantibody-mediated activation of osteoclasts is critical for bone resorption in collagen induced arthritis.
40.
Grevers LC, de Vries TJ, Everts V, Verbeek JS, van den Berg WB, van Lent PL. Immune complex-induced inhibition of osteoclastogenesis is mediated via activating but not inhibitory Fcgamma receptors on myeloid precursor cells. Ann Rheum Dis. 2013;72(2):278–85.PubMedCrossRef
41.
MacLellan LM, Montgomery J, Sugiyama F, et al. Co-opting endogenous immunoglobulin for the regulation of inflammation and osteoclastogenesis in humans and mice. Arthritis Rheum. 2011;63(12):3897–907.PubMedCentralPubMedCrossRef
42.••
Scherer HU, van der Woude D, Ioan-Facsinay A, et al. Glycan profiling of anti-citrullinated protein antibodies isolated from human serum and synovial fluid. Arthritis Rheum. 2010;62(6):1620–9. Reveals different glycosylation patterns of ACPA and pooled IgG as well as between ACPA derived from serum or synovial fluid.
43.
Parekh RB, Dwek RA, Sutton BJ, et al. Association of rheumatoid arthritis and primary osteoarthritis with changes in the glycosylation pattern of total serum IgG. Nature. 1985;316(6027):452–7.PubMedCrossRef
44.
Arnold JN, Wormald MR, Sim RB, Rudd PM, Dwek RA. The impact of glycosylation on the biological function and structure of human immunoglobulins. Ann Rev Immunol. 2007;25:21–50.CrossRef
45.
Suwannalai P, Britsemmer K, Knevel R, et al. Low-avidity anticitrullinated protein antibodies (ACPA) are associated with a higher rate of joint destruction in rheumatoid arthritis. Ann Rheumat Dis. 2014;73(1):270-6.
46.
Leandro MJ, Becerra-Fernandez E. B-cell therapies in established rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2011;25(4):535–48.PubMedCrossRef
47.
Reff ME, Carner K, Chambers KS, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994;83(2):435–45.PubMed
48.
Thurlings RM, Vos K, Wijbrandts CA, Zwinderman AH, Gerlag DM, Tak PP. Synovial tissue response to rituximab: mechanism of action and identification of biomarkers of response. Ann Rheum Dis. 2008;67(7):917–25.PubMedCentralPubMedCrossRef
49.••
Teng YK, Wheater G, Hogan VE, et al. Induction of long-term B-cell depletion in refractory rheumatoid arthritis patients preferentially affects autoreactive more than protective humoral immunity. Arthritis Res Ther. 2012;14(2):R57. Suggests that autoantibody-pruducing plasma cells live shorter than plasma cells producing protective antibodies.
50.
Amanna IJ, Slifka MK. Mechanisms that determine plasma cell lifespan and the duration of humoral immunity. Immunol Rev. 2010;236:125–38.PubMedCrossRef
Metadata
Title
Autoantibody-Mediated Bone Loss
Authors
Ulrike Harre
Nicolai A. Kittan
Georg Schett
Publication date
01-03-2014
Publisher
Springer US
Published in
Current Osteoporosis Reports / Issue 1/2014
Print ISSN: 1544-1873
Electronic ISSN: 1544-2241
DOI
https://doi.org/10.1007/s11914-013-0185-9

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