Key Points
-
Autoantibodies against post-translational modified citrullinated proteins, so-called anti-citrullinated protein antibodies (ACPAs), define a distinct clinical RA phenotype; this phenotype is characterized by an increased frequency of early inflammatory lung changes
-
The presence of ACPAs before signs of inflammation in joints suggests that immunity against citrullinated proteins is initiated outside the joint
-
Changes in the lung and enrichment of ACPAs in the lungs (bronchoalveolar lavage fluid) occur in both individuals at risk of developing RA as well as patients with early RA
-
The lung, therefore, might be a site of initiation of immunity to citrullinated proteins
-
Early targeting of the immune reactions in the lung might be a new approach to modulate disease
Abstract
Rheumatoid arthritis (RA) is a prototype for a criterion-defined inflammatory disease, for which the aetiology and initial molecular pathogenesis has been elusive for a long time. We describe in this Review how studies on the interplay between specific immunity, alongside genetic and environmental predisposing factors, provide new tools to understand the molecular basis of distinct subsets of the disease. A particular emphasis is on the possibility that pathogenic immune reactions might be initiated at other sites than the joints, and that the lungs could harbour such sites. New data strengthen this concept, showing that local immunity towards citrullinated proteins and accompanying inflammation might be present in the lungs early during disease development. This progress makes RA an interesting case for the future development of therapies that might be directed against disease-inducing immunity even before inflammation and destruction of joints has begun.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Weinblatt, M. E. et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. N. Engl. J. Med. 312, 818–822 (1985).
Feldmann, M. & Maini, R. N. Anti-TNFα therapy of rheumatoid arthritis: what have we learned? Annu. Rev. Immunol. 19, 163–196 (2001).
Nishimoto, N. & Kishimoto, T. Interleukin 6: from bench to bedside. Nat. Clin. Pract. Rheumatol. 2, 619–626 (2006).
Smolen, J. S., Aletaha, D., Koeller, M., Weisman, M. H. & Emery, P. New therapies for treatment of rheumatoid arthritis. Lancet 370, 1861–1874 (2007).
Arend, W. P. & Firestein, G. S. Pre-rheumatoid arthritis: predisposition and transition to clinical synovitis. Nat. Rev. Rheumatol. 8, 573–586 (2012).
Willemze, A., Trouw, L. A., Toes, R. E. & Huizinga, T. W. The influence of ACPA status and characteristics on the course of RA. Nat. Rev. Rheumatol. 8, 144–152 (2012).
Waaler, E. On the occurrence of a factor in human serum activating the specific agglutintion of sheep blood corpuscles. 1939. APMIS 115, 422–438 (2007).
Hoet, R. M., Boerbooms, A. M., Arends, M., Ruiter, D. J. & van Venrooij, W. J. Antiperinuclear factor, a marker autoantibody for rheumatoid arthritis: colocalisation of the perinuclear factor and profilaggrin. Ann. Rheum. Dis. 50, 611–618 (1991).
Burkhardt, H. et al. Epitope-specific recognition of type II collagen by rheumatoid arthritis antibodies is shared with recognition by antibodies that are arthritogenic in collagen-induced arthritis in the mouse. Arthritis Rheum. 46, 2339–2348 (2002).
Blass, S. et al. The stress protein BiP is overexpressed and is a major B and T cell target in rheumatoid arthritis. Arthritis Rheum. 44, 761–771 (2001).
Skriner, K. et al. Anti-A2/RA33 autoantibodies are directed to the RNA binding region of the A2 protein of the heterogeneous nuclear ribonucleoprotein complex. Differential epitope recognition in rheumatoid arthritis, systemic lupus erythematosus, and mixed connective tissue disease. J. Clin. Invest. 100, 127–135 (1997).
Matsumoto, I. et al. Low prevalence of antibodies to glucose-6-phosphate isomerase in patients with rheumatoid arthritis and a spectrum of other chronic autoimmune disorders. Arthritis Rheum. 48, 944–954 (2003).
Schellekens, G. A., de Jong, B. A., van den Hoogen, F. H., van de Putte, L. B. & van Venrooij, W. J. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J. Clin. Invest. 101, 273–281 (1998).
Girbal-Neuhauser, E. et al. The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues. J. Immunol. 162, 585–594 (1999).
Schellekens, G. A. et al. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum. 43, 155–163 (2000).
Verpoort, K. N. et al. Fine specificity of the anti-citrullinated protein antibody response is influenced by the shared epitope alleles. Arthritis Rheum. 56, 3949–3952 (2007).
Shoda, H. et al. Detection of autoantibodies to citrullinated BiP in rheumatoid arthritis patients and pro-inflammatory role of citrullinated BiP in collagen-induced arthritis. Arthritis Res. Ther. 13, R191 (2011).
Snir, O. et al. Multiple antibody reactivities to citrullinated antigens in sera from patients with rheumatoid arthritis: association with HLA-DRB1 alleles. Ann. Rheum. Dis. 68, 736–743 (2009).
Shi, J. et al. Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc. Natl Acad. Sci. USA 108, 17372–17377 (2011).
Chandra, P. E. et al. Novel multiplex technology for diagnostic characterization of rheumatoid arthritis. Arthritis Res. Ther. 13, R102 (2011).
Lundberg, K. et al. Genetic and environmental determinants for disease risk in subsets of rheumatoid arthritis defined by the anticitrullinated protein/peptide antibody fine specificity profile. Ann. Rheum. Dis. 72, 652–658 (2013).
Shi, J. et al. Anti-carbamylated protein antibodies are present in arthralgia patients and predict the development of rheumatoid arthritis. Arthritis Rheum. 65, 911–915 (2013).
Snir, O. et al. Multifunctional T cell reactivity with native and glycosylated type II collagen in rheumatoid arthritis. Arthritis Rheum. 64, 2482–2488 (2012).
Trembleau, S. et al. Immunodominant T-cell epitopes of hnRNP-A2 associated with disease activity in patients with rheumatoid arthritis. Eur. J. Immunol. 40, 1795–1808 (2010).
Corrigall, V. M., Vittecoq, O. & Panayi, G. S. Binding immunoglobulin protein-treated peripheral blood monocyte-derived dendritic cells are refractory to maturation and induce regulatory T-cell development. Immunology 128, 218–226 (2009).
Auger, I. et al. Influence of HLA-DR genes on the production of rheumatoid arthritis-specific autoantibodies to citrullinated fibrinogen. Arthritis Rheum. 52, 3424–3432 (2005).
Snir, O. et al. Identification and functional characterization of T cells reactive to citrullinated vimentin in HLA-DRB1*0401-positive humanized mice and rheumatoid arthritis patients. Arthritis Rheum. 63, 2873–2883 (2011).
Aho, K., Heliovaara, M., Maatela, J., Tuomi, T. & Palosuo, T. Rheumatoid factors antedating clinical rheumatoid arthritis. J. Rheumatol. 18, 1282–1284 (1991).
Kurki, P., Aho, K., Palosuo, T. & Heliovaara, M. Immunopathology of rheumatoid arthritis. Antikeratin antibodies precede the clinical disease. Arthritis Rheum. 35, 914–917 (1992).
Rantapaa-Dahlqvist, S. et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 48, 2741–2749 (2003).
Nielen, M. M. et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 50, 380–386 (2004).
Chibnik, L. B., Mandl, L. A., Costenbader, K. H., Schur, P. H. & Karlson, E. W. Comparison of threshold cutpoints and continuous measures of anti-cyclic citrullinated peptide antibodies in predicting future rheumatoid arthritis. J. Rheumatol. 36, 706–711 (2009).
Majka, D. S. et al. Duration of preclinical rheumatoid arthritis-related autoantibody positivity increases in subjects with older age at time of disease diagnosis. Ann. Rheum. Dis. 67, 801–807 (2008).
Shi, J. et al. Anti-carbamylated protein (anti-CarP) antibodies precede the onset of rheumatoid arthritis. Ann. Rheum. Dis. 73, 780–783 (2014).
Brink, M. et al. Multiplex analyses of antibodies against citrullinated peptides in individuals prior to development of rheumatoid arthritis. Arthritis Rheum. 65, 899–910 (2013).
Sokolove, J. et al. Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis. PLoS ONE 7, e35296 (2012).
van de Stadt, L. A., Witte, B. I., Bos, W. H. & van Schaardenburg, D. A prediction rule for the development of arthritis in seropositive arthralgia patients. Ann. Rheum. Dis. 72, 1920–1926 (2012).
van de Stadt, L. A. et al. Development of the anti-citrullinated protein antibody repertoire prior to the onset of rheumatoid arthritis. Arthritis Rheum. 63, 3226–3233 (2011).
Coulie, P. G. & Van Snick, J. Rheumatoid factor (RF) production during anamnestic immune responses in the mouse. III. Activation of RF precursor cells is induced by their interaction with immune complexes and carrier-specific helper T cells. J. Exp. Med. 161, 88–97 (1985).
Tarkowski, A., Czerkinsky, C. & Nilsson, L. A. Simultaneous induction of rheumatoid factor- and antigen-specific antibody-secreting cells during the secondary immune response in man. Clin. Exp. Immunol. 61, 379–387 (1985).
Padyukov, L., Silva, C., Stolt, P., Alfredsson, L. & Klareskog, L. A gene–environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum. 50, 3085–3092 (2004).
Klareskog, L. 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. 54, 38–46 (2006).
Huizinga, T. W. et al. Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins. Arthritis Rheum. 52, 3433–3438 (2005).
Pedersen, M. et al. Environmental risk factors differ between rheumatoid arthritis with and without auto-antibodies against cyclic citrullinated peptides. Arthritis Res. Ther. 8, R133 (2006).
Karlson, E. W. et al. Gene-environment interaction between HLA-DRB1 shared epitope and heavy cigarette smoking in predicting incident rheumatoid arthritis. Ann. Rheum. Dis. 69, 54–60 (2010).
Too, C. L. et al. Smoking interacts with HLA-DRB1 shared epitope in the development of anti-citrullinated protein antibody-positive rheumatoid arthritis: results from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA). Arthritis Res. Ther. 14, R89 (2012).
Stolt, P. et al. Silica exposure among male current smokers is associated with a high risk of developing ACPA-positive rheumatoid arthritis. Ann. Rheum. Dis. 69, 1072–1076 (2010).
Too, C. L. et al. Gene–environment interaction between HLA-DRB1 shared epitope and occupational textile dust exposure in the risk of ACPA-positive rheumatoid arthritis in female patients: evidence from the Malaysian Epidemiological Investigation Of Rheumatoid Arthritis Case–Control Study [abstract]. Arthritis Rheum. 65, S457–S458 (2013).
Hart, J. E., Laden, F., Puett, R. C., Costenbader, K. H. & Karlson, E. W. Exposure to traffic pollution and increased risk of rheumatoid arthritis. Environ. Health Perspect. 117, 1065–1069 (2009).
Hart, J. E. et al. Ambient air pollution exposures and risk of rheumatoid arthritis: results from the Swedish EIRA case-control study. Ann. Rheum. Dis. 72, 888–894 (2013).
Hart, J. E. et al. Ambient air pollution exposures and risk of rheumatoid arthritis. Arthritis Care Res. (Hoboken) 65, 1190–1196 (2013).
Carlens, C. et al. Smoking, use of moist snuff, and risk of chronic inflammatory diseases. Am. J. Respir. Crit. Care Med. 181, 1217–1222 (2010).
Stolt, P. et al. Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases. Ann. Rheum. Dis. 62, 835–841 (2003).
Haj Hensvold, A. et al. Environmental and genetic factors in the development of anticitrullinated protein antibodies (ACPAs) and ACPA-positive rheumatoid arthritis: an epidemiological investigation in twins. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2013-203947.
Rangel-Moreno, J. et al. Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis. J. Clin. Invest. 116, 3183–3194 (2006).
Reynisdottir, G. et al. Structural lung changes and local anti-citrulline immunity are early features of anti citrullinated-proteins antibodies positive rheumatoid arthritis. Arthritis Rheum. 66, 31–39 (2013).
Joshua, V. et al. Characterization of lung inflammation and identification of shared citrullinated targets in the lungs and joints of early RA [abstract]. Arthritis Rheum. 65, S392–S392 (2013).
Fischer, A. et al. Lung disease with anti-CCP antibodies but not rheumatoid arthritis or connective tissue disease. Respir. Med. 106, 1040–1047 (2012).
Demoruelle, M. K. et al. Brief report: airways abnormalities and rheumatoid arthritis-related autoantibodies in subjects without arthritis: early injury or initiating site of autoimmunity? Arthritis Rheum. 64, 1756–1761 (2012).
Makrygiannakis, D. et al. Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann. Rheum. Dis. 67, 1488–1492 (2008).
Willis, V. C. et al. Sputum autoantibodies in patients with established rheumatoid arthritis and subjects at risk of future clinically apparent disease. Arthritis Rheum. 65, 2545–2554 (2013).
Ytterberg, A. J. et al. Shared immunological targets in the lungs and joints of patients with rheumatoid arthritis: identification and validation. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2013-204912.
Harlow, L. et al. Identification of citrullinated hsp90 isoforms as novel autoantigens in rheumatoid arthritis-associated interstitial lung disease. Arthritis Rheum. 65, 869–879 (2013).
Mohamed, B. M. et al. Citrullination of proteins: a common post-translational modification pathway induced by different nanoparticles in vitro and in vivo. Nanomedicine 7, 1181–1195 (2012).
Matsuo, K. et al. Identification of novel citrullinated autoantigens of synovium in rheumatoid arthritis using a proteomic approach. Arthritis Res. Ther. 8, R175 (2006).
van Beers, J. J. et al. The rheumatoid arthritis synovial fluid citrullinome reveals novel citrullinated epitopes in apolipoprotein E, myeloid nuclear differentiation antigen, and beta-actin. Arthritis Rheum. 65, 69–80 (2013).
Makrygiannakis, D. et al. Citrullination is an inflammation-dependent process. Ann. Rheum. Dis. 65, 1219–1222 (2006).
Arnson, Y., Shoenfeld, Y. & Amital, H. Effects of tobacco smoke on immunity, inflammation and autoimmunity. J. Autoimmun 34, J258–265 (2010).
Larsen, J. M. et al. Divergent pro-inflammatory profile of human dendritic cells in response to commensal and pathogenic bacteria associated with the airway microbiota. PLoS ONE 7, e31976 (2012).
Demoruelle, M. K., Norris, J. M., Holers, V. M., Harris, J. K. & Deane, K. D. The lung microbiome differs in asymptomatic subjects at elevated risk of future rheumatoid arthritis compared with healthy control subjects. Ann. Am. Thorac. Soc. 11 (Suppl. 1), S74 (2014).
Sokolove, J., Zhao, X., Chandra, P. E. & Robinson, W. H. Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fcγ receptor. Arthritis Rheum. 63, 53–62 (2011).
Wegner, N. et al. Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and alpha-enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum. 62, 2662–2672 (2010).
Mikuls, T. R. et al. Porphyromonas gingivalis and disease-related autoantibodies in individuals at increased risk of rheumatoid arthritis. Arthritis Rheum. 64, 3522–3530 (2012).
Nesse, W. et al. The periodontium of periodontitis patients contains citrullinated proteins which may play a role in ACPA (anti-citrullinated protein antibody) formation. J. Clin. Periodontol. 39, 599–607 (2012).
Scher, J. U. et al. Periodontal disease and the oral microbiota in new-onset rheumatoid arthritis. Arthritis Rheum. 64, 3083–3094 (2012).
Harvey, G. P. et al. Expression of peptidylarginine deiminase-2 and -4, citrullinated proteins and anti-citrullinated protein antibodies in human gingiva. J. Periodontal Res. 48, 252–261 (2013).
Vaahtovuo, J., Munukka, E., Korkeamaki, M., Luukkainen, R. & Toivanen, P. Fecal microbiota in early rheumatoid arthritis. J. Rheumatol. 35, 1500–1505 (2008).
Liu, X., Zou, Q., Zeng, B., Fang, Y. & Wei, H. Analysis of fecal Lactobacillus community structure in patients with early rheumatoid arthritis. Curr. Microbiol. 67, 170–176 (2013).
Gregersen, P. K., Silver, J. & Winchester, R. J. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 30, 1205–1213 (1987).
Raychaudhuri, S. et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat. Genet. 44, 291–296 (2012).
Scally, S. W. et al. A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J. Exp. Med. 210, 2569–2582 (2013).
Begovich, A. B. et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am. J. Hum. Genet. 75, 330–337 (2004).
Kallberg, H. et al. Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. Am. J. Hum. Genet. 80, 867–875 (2007).
Costenbader, K. H., Chang, S. C., De Vivo, I., Plenge, R. & Karlson, E. W. Genetic polymorphisms in PTPN22, PADI-4, and CTLA-4 and risk for rheumatoid arthritis in two longitudinal cohort studies: evidence of gene–environment interactions with heavy cigarette smoking. Arthritis Res. Ther. 10, R52 (2008).
Rieck, M. et al. Genetic variation in PTPN22 corresponds to altered function of T and B lymphocytes. J. Immunol. 179, 4704–4710 (2007).
Menard, L. et al. The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans. J. Clin. Invest. 121, 3635–3644 (2011).
Arechiga, A. F. et al. Cutting edge: the PTPN22 allelic variant associated with autoimmunity impairs B cell signaling. J. Immunol. 182, 3343–3347 (2009).
Vang, T. et al. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat. Genet. 37, 1317–1319 (2005).
Swanberg, M. et al. MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction. Nat. Genet. 37, 486–494 (2005).
Suzuki, A. et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat. Genet. 34, 395–402 (2003).
Kang, C. P. et al. A functional haplotype of the PADI4 gene associated with increased rheumatoid arthritis susceptibility in Koreans. Arthritis Rheum. 54, 90–96 (2006).
Eyre, S. et al. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat. Genet. 44, 1336–1340 (2012).
Darrah, E. et al. Erosive rheumatoid arthritis is associated with antibodies that activate PAD4 by increasing calcium sensitivity. Sci. Transl. Med. 5, 186ra65 (2013).
Uysal, H. et al. Structure and pathogenicity of antibodies specific for citrullinated collagen type II in experimental arthritis. J. Exp. Med. 206, 449–462 (2009).
Harre, U. et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J. Clin. Invest. 122, 1791–1802 (2012).
Kleyer, A. et al. Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies. Ann. Rheum. Dis. 73, 854–860 (2014).
Kinloch, A. J. et al. Immunization with Porphyromonas gingivalis enolase induces autoimmunity to mammalian α-enolase and arthritis in DR4-I E-transgenic mice. Arthritis Rheum. 63, 3818–3823 (2011).
Haag, S., Uysal, H., Backlund, J., Tuncel, J. & Holmdahl, R. Human α-enolase is immunogenic, but not arthritogenic, in HLA-DR4-transgenic mice: comment on the article by Kinloch et al. Arthritis Rheum. 64, 1689–1691; author reply 1691–1692 (2012).
Trouw, L. A. et al. Anti-cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways. Arthritis Rheum. 60, 1923–1931 (2009).
Wright, H. L., Moots, R. J., Bucknall, R. C. & Edwards, S. W. Neutrophil function in inflammation and inflammatory diseases. Rheumatology (Oxford) 49, 1618–1631 (2010).
De Rycke, L. et al. Synovial intracellular citrullinated proteins colocalizing with peptidyl arginine deiminase as pathophysiologically relevant antigenic determinants of rheumatoid arthritis-specific humoral autoimmunity. Arthritis Rheum. 52, 2323–2330 (2005).
Snir, O. et al. Antibodies to several citrullinated antigens are enriched in the joints of rheumatoid arthritis patients. Arthritis Rheum. 62, 44–52 (2010).
Humby, F. et al. Ectopic lymphoid structures support ongoing production of class-switched autoantibodies in rheumatoid synovium. PLoS Med. 6, e1 (2009).
Amara, K. 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. 210, 445–455 (2013).
Hedstrom, A. K. et al. Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis. Brain 134, 653–664 (2011).
Chinoy, H. et al. Interaction of HLA-DRB1*03 and smoking for the development of anti-Jo-1 antibodies in adult idiopathic inflammatory myopathies: a European-wide case study. Ann. Rheum. Dis. 71, 961–965 (2012).
Acknowledgements
A.I.C. acknowledges support from the Swedish Foundation for Strategic Research, the Initial Training Networks 7th framework programme Osteoimmune (289150), the European 7th framework programme (FP7/2007–2013) Euro-TEAM (305549), the Innovative Medicine Initiative Be The Cure (115142-2) and the Swedish Research Council. A.J.Y. acknowledges grant support from the Swedish Foundation for Strategic Research. L.K. acknowledges support from the Swedish Foundation for Strategic Research, the European 7th framework programme (FP7/2007–2013) Euro-TEAM (305549), the Innovative Medicine Initiative Be The Cure (115142-2) and the Swedish Research Council.
Author information
Authors and Affiliations
Contributions
All authors made substantial contributions to researching data for the article and made substantial contributions to discussions of content and writing the article. A.I.C. and L.K. had the main responsibility for reviewing and/or editing of the article before submission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
PowerPoint slides
Rights and permissions
About this article
Cite this article
Catrina, A., Ytterberg, A., Reynisdottir, G. et al. Lungs, joints and immunity against citrullinated proteins in rheumatoid arthritis. Nat Rev Rheumatol 10, 645–653 (2014). https://doi.org/10.1038/nrrheum.2014.115
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrrheum.2014.115
This article is cited by
-
Protein citrullination and NET formation do not contribute to the pathology of A20/TNFAIP3 mutant mice
Scientific Reports (2023)
-
Exhaled nitric oxide in early rheumatoid arthritis and effects of methotrexate treatment
Scientific Reports (2022)
-
Thoracic Involvement in Systemic Autoimmune Rheumatic Diseases: Pathogenesis and Management
Clinical Reviews in Allergy & Immunology (2022)
-
Systematic Review and Meta-analysis on the Association of Occupational Exposure to Free Crystalline Silica and Rheumatoid Arthritis
Clinical Reviews in Allergy & Immunology (2022)
-
Effect of Porphyromonas gingivalis infection on gut dysbiosis and resultant arthritis exacerbation in mouse model
Arthritis Research & Therapy (2020)