Top

Published in:

01-10-2009 | Review

Developments in the scientific understanding of rheumatoid arthritis

Authors: Jörg J Goronzy, Cornelia M Weyand

Published in: Arthritis Research & Therapy | Issue 5/2009

Abstract

Rheumatoid arthritis (RA) is recognized to be an autoimmune disease that causes preclinical systemic abnormalities and eventually leads to synovial inflammation and destruction of the joint architecture. Recently identified genetic risk factors and novel insights from animal models of spontaneous arthritis have lent support to the concept that thymic selection of an autoreactive T-cell repertoire is an important risk factor for this disease. With advancing age, defects in the homeostatic control of the T-cell pool and in the setting of signaling thresholds lead to the accumulation of pro-inflammatory T-effector cell populations and loss of tolerance to neo-antigens, such as citrullinated peptides. As the breakdown of tolerance to modified self-antigens can precede synovitis by decades, repair of homeostatic defects may open a unique window of opportunity for preventive interventions in RA. The end result of RA, destruction of cartilage and bone, appears to be driven by cytokine- and cell contact-induced activation of synoviocytes and monocytic cells, some of which differentiate into tissue-destructive osteoclasts. Targeting mediators involved in this process has greatly improved the management of this chronic inflammatory syndrome.

Available only for authorised users

Smolen JS, Aletaha D: Developments in the clinical understanding of rheumatoid arthritis. Arthritis Res Ther. 2009, 11: 204-10.1186/ar2535.PubMedCentralPubMed

McInnes IB, Schett G: Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007, 7: 429-442. 10.1038/nri2094.PubMed

Brennan FM, McInnes IB: Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest. 2008, 118: 3537-3545. 10.1172/JCI36389.PubMedCentralPubMed

Feldmann M, Maini RN: Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned?. Annu Rev Immunol. 2001, 19: 163-196. 10.1146/annurev.immunol.19.1.163.PubMed

Nishimoto N, Kishimoto T: Interleukin 6: from bench to bedside. Nat Clin Pract Rheumatol. 2006, 2: 619-626. 10.1038/ncprheum0338.PubMed

Waldburger JM, Firestein GS: Garden of therapeutic delights: new targets in rheumatic diseases. Arthritis Res Ther. 2009, 11: 206-10.1186/ar2556.PubMedCentralPubMed

Nielen MM, van Schaardenburg D, Reesink HW, Stadt van de RJ, Horst-Bruinsma van der IE, de Koning MH, Habibuw MR, Vandenbroucke JP, Dijkmans BA: Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 2004, 50: 380-386. 10.1002/art.20018.PubMed

Rantapaa-Dahlqvist S, de Jong BA, Berglin E, Hallmans G, Wadell G, Stenlund H, Sundin U, van Venrooij WJ: Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003, 48: 2741-2749. 10.1002/art.11223.PubMed

Turesson C, Matteson EL: Vasculitis in rheumatoid arthritis. Curr Opin Rheumatol. 2009, 21: 35-40. 10.1097/BOR.0b013e32831c5303.PubMed

10.

Silman AJ, MacGregor AJ, Thomson W, Holligan S, Carthy D, Farhan A, Ollier WE: Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br J Rheumatol. 1993, 32: 903-907. 10.1093/rheumatology/32.10.903.PubMed

11.

Seldin MF, Amos CI, Ward R, Gregersen PK: The genetics revolution and the assault on rheumatoid arthritis. Arthritis Rheum. 1999, 42: 1071-1079. 10.1002/1529-0131(199906)42:6<1071::AID-ANR1>3.0.CO;2-8.PubMed

12.

Plenge RM, Criswell LA: Genetic variants that predict response to anti-tumor necrosis factor therapy in rheumatoid arthritis: current challenges and future directions. Curr Opin Rheumatol. 2008, 20: 145-152. 10.1097/BOR.0b013e3282f5135b.PubMed

13.

Fernando MM, Stevens CR, Walsh EC, De Jager PL, Goyette P, Plenge RM, Vyse TJ, Rioux JD: Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genet. 2008, 4: e1000024-10.1371/journal.pgen.1000024.PubMedCentralPubMed

14.

Yamada R, Yamamoto K: Mechanisms of disease: genetics of rheumatoid arthritis: ethnic differences in disease-associated genes. Nat Clin Pract Rheumatol. 2007, 3: 644-650. 10.1038/ncprheum0592.PubMed

15.

Gregersen PK, Silver J, Winchester RJ: The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987, 30: 1205-1213. 10.1002/art.1780301102.PubMed

16.

Huizinga TW, Amos CI, Helm-van Mil van der AH, Chen W, van Gaalen FA, Jawaheer D, Schreuder GM, Wener M, Breedveld FC, Ahmad N, Lum RF, de Vries RR, Gregersen PK, Toes RE, Criswell LA: Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins. Arthritis Rheum. 2005, 52: 3433-3438. 10.1002/art.21385.PubMed

17.

Helm-van Mil van der AH, Verpoort KN, Breedveld FC, Huizinga TW, Toes RE, de Vries RR: The HLA-DRB1 shared epitope alleles are primarily a risk factor for anti-cyclic citrullinated peptide antibodies and are not an independent risk factor for development of rheumatoid arthritis. Arthritis Rheum. 2006, 54: 1117-1121. 10.1002/art.21739.PubMed

18.

MacGregor AJ, Snieder H, Rigby AS, Koskenvuo M, Kaprio J, Aho K, Silman AJ: Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum. 2000, 43: 30-37. 10.1002/1529-0131(200001)43:1<30::AID-ANR5>3.0.CO;2-B.PubMed

19.

Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, Ardlie KG, Huang Q, Smith AM, Spoerke JM, Conn MT, Chang M, Chang SY, Saiki RK, Catanese JJ, Leong DU, Garcia VE, McAllister LB, Jeffery DA, Lee AT, Batliwalla F, Remmers E, Criswell LA, Seldin MF, Kastner DL, Amos CI, Sninsky JJ, Gregersen PK: A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet. 2004, 75: 330-337. 10.1086/422827.PubMedCentralPubMed

20.

van Oene M, Wintle RF, Liu X, Yazdanpanah M, Gu X, Newman B, Kwan A, Johnson B, Owen J, Greer W, Mosher D, Maksymowych W, Keystone E, Rubin LA, Amos CI, Siminovitch KA: Association of the lymphoid tyrosine phosphatase R620W variant with rheumatoid arthritis, but not Crohn's disease, in Canadian populations. Arthritis Rheum. 2005, 52: 1993-1998. 10.1002/art.21123.PubMed

21.

Wesoly J, Helm-van Mil van der AH, Toes RE, Chokkalingam AP, Carlton VE, Begovich AB, Huizinga TW: Association of the PTPN22 C1858T single-nucleotide polymorphism with rheumatoid arthritis phenotypes in an inception cohort. Arthritis Rheum. 2005, 52: 2948-2950. 10.1002/art.21294.PubMed

22.

Gregersen PK: Pathways to gene identification in rheumatoid arthritis: PTPN22 and beyond. Immunol Rev. 2005, 204: 74-86. 10.1111/j.0105-2896.2005.00243.x.PubMed

23.

Ikari K, Momohara S, Inoue E, Tomatsu T, Hara M, Yamanaka H, Kamatani N: Haplotype analysis revealed no association between the PTPN22 gene and RA in a Japanese population. Rheumatology (Oxford). 2006, 45: 1345-1348. 10.1093/rheumatology/kel169.

24.

Mori M, Yamada R, Kobayashi K, Kawaida R, Yamamoto K: Ethnic differences in allele frequency of autoimmune-disease-associated SNPs. J Hum Genet. 2005, 50: 264-266. 10.1007/s10038-005-0246-8.PubMed

25.

Wu J, Katrekar A, Honigberg LA, Smith AM, Conn MT, Tang J, Jeffery D, Mortara K, Sampang J, Williams SR, Buggy J, Clark JM: Identification of substrates of human protein-tyrosine phosphatase PTPN22. J Biol Chem. 2006, 281: 11002-11010. 10.1074/jbc.M600498200.PubMed

26.

Cloutier JF, Veillette A: Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase. J Exp Med. 1999, 189: 111-121. 10.1084/jem.189.1.111.PubMedCentralPubMed

27.

Vang T, Congia M, Macis MD, Musumeci L, Orrú V, Zavattari P, Nika K, Tautz L, Taskén K, Cucca F, Mustelin T, Bottini N: Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat Genet. 2005, 37: 1317-1319. 10.1038/ng1673.PubMed

28.

Bottini N, Vang T, Cucca F, Mustelin T: Role of PTPN22 in type 1 diabetes and other autoimmune diseases. Semin Immunol. 2006, 18: 207-213. 10.1016/j.smim.2006.03.008.PubMed

29.

Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, Nagasaki M, Nakayama-Hamada M, Kawaida R, Ono M, Ohtsuki M, Furukawa H, Yoshino S, Yukioka M, Tohma S, Matsubara T, Wakitani S, Teshima R, Nishioka Y, Sekine A, Iida A, Takahashi A, Tsunoda T, Nakamura Y, Yamamoto K: Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet. 2003, 34: 395-402. 10.1038/ng1206.PubMed

30.

Iwamoto T, Ikari K, Nakamura T, Kuwahara M, Toyama Y, Tomatsu T, Momohara S, Kamatani N: Association between PADI4 and rheumatoid arthritis: a meta-analysis. Rheumatology (Oxford). 2006, 45: 804-807. 10.1093/rheumatology/kel023.

31.

Kang CP, Lee HS, Ju H, Cho H, Kang C, Bae SC: A functional haplotype of the PADI4 gene associated with increased rheumatoid arthritis susceptibility in Koreans. Arthritis Rheum. 2006, 54: 90-96. 10.1002/art.21536.PubMed

32.

Barton A, Bowes J, Eyre S, Spreckley K, Hinks A, John S, Worthington J: A functional haplotype of the PADI4 gene associated with rheumatoid arthritis in a Japanese population is not associated in a United Kingdom population. Arthritis Rheum. 2004, 50: 1117-1121. 10.1002/art.20169.PubMed

33.

Caponi L, Petit-Teixeira E, Sebbag M, Bongiorni F, Moscato S, Pratesi F, Pierlot C, Osorio J, Chapuy-Regaud S, Guerrin M, Cornelis F, Serre G, Migliorini P, ECRAF: A family based study shows no association between rheumatoid arthritis and the PADI4 gene in a white French population. Ann Rheum Dis. 2005, 64: 587-593. 10.1136/ard.2004.026831.PubMedCentralPubMed

34.

Martinez A, Valdivia A, Pascual-Salcedo D, Lamas JR, Fernandez-Arquero M, Balsa A, Fernandez-Gutierrez B, de la Concha EG, Urcelay E: PADI4 polymorphisms are not associated with rheumatoid arthritis in the Spanish population. Rheumatology (Oxford). 2005, 44: 1263-1266. 10.1093/rheumatology/kei008.

35.

Plenge RM, Padyukov L, Remmers EF, Purcell S, Lee AT, Karlson EW, Wolfe F, Kastner DL, Alfredsson L, Altshuler D, Gregersen PK, Klareskog L, Rioux JD: Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. Am J Hum Genet. 2005, 77: 1044-1060. 10.1086/498651.PubMedCentralPubMed

36.

Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, de Bakker PI, Le JM, Lee HS, Batliwalla F, Li W, Masters SL, Booty MG, Carulli JP, Padyukov L, Alfredsson L, Klareskog L, Chen WV, Amos CI, Criswell LA, Seldin MF, Kastner DL, Gregersen PK: STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med. 2007, 357: 977-986. 10.1056/NEJMoa073003.PubMedCentralPubMed

37.

Lee HS, Remmers EF, Le JM, Kastner DL, Bae SC, Gregersen PK: Association of STAT4 with rheumatoid arthritis in the Korean population. Mol Med. 2007, 13: 455-460.PubMedCentralPubMed

38.

Thomson W, Barton A, Ke X, Eyre S, Hinks A, Bowes J, Donn R, Symmons D, Hider S, Bruce IN, Wellcome Trust Case Control Consortium, Wilson AG, Marinou I, Morgan A, Emery P, YEAR Consortium, Carter A, Steer S, Hocking L, Reid DM, Wordsworth P, Harrison P, Strachan D, Worthington J: Rheumatoid arthritis association at 6q23. Nat Genet. 2007, 39: 1431-1433. 10.1038/ng.2007.32.PubMedCentralPubMed

39.

Plenge RM, Cotsapas C, Davies L, Price AL, de Bakker PI, Maller J, Pe'er I, Burtt NP, Blumenstiel B, DeFelice M, Parkin M, Barry R, Winslow W, Healy C, Graham RR, Neale BM, Izmailova E, Roubenoff R, Parker AN, Glass R, Karlson EW, Maher N, Hafler DA, Lee DM, Seldin MF, Remmers EF, Lee AT, Padyukov L, Alfredsson L, Coblyn J, et al: Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat Genet. 2007, 39: 1477-1482. 10.1038/ng.2007.27.PubMedCentralPubMed

40.

Boone DL, Turer EE, Lee EG, Ahmad RC, Wheeler MT, Tsui C, Hurley P, Chien M, Chai S, Hitotsumatsu O, McNally E, Pickart C, Ma A: The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol. 2004, 5: 1052-1060. 10.1038/ni1110.PubMed

41.

Wertz IE, O'Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S, Wu P, Wiesmann C, Baker R, Boone DL, Ma A, Koonin EV, Dixit VM: De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature. 2004, 430: 694-699. 10.1038/nature02794.PubMed

42.

Lee EG, Boone DL, Chai S, Libby SL, Chien M, Lodolce JP, Ma A: Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science. 2000, 289: 2350-2354. 10.1126/science.289.5488.2350.PubMedCentralPubMed

43.

Kurreeman FA, Padyukov L, Marques RB, Schrodi SJ, Seddighzadeh M, Stoeken-Rijsbergen G, Helm-van Mil van der AH, Allaart CF, Verduyn W, Houwing-Duistermaat J, Alfredsson L, Begovich AB, Klareskog L, Huizinga TW, Toes RE: A candidate gene approach identifies the TRAF1/C5 region as a risk factor for rheumatoid arthritis. PLoS Med. 2007, 4: e278-10.1371/journal.pmed.0040278.PubMedCentralPubMed

44.

Plenge RM, Seielstad M, Padyukov L, Lee AT, Remmers EF, Ding B, Liew A, Khalili H, Chandrasekaran A, Davies LR, Li W, Tan AK, Bonnard C, Ong RT, Thalamuthu A, Pettersson S, Liu C, Tian C, Chen WV, Carulli JP, Beckman EM, Altshuler D, Alfredsson L, Criswell LA, Amos CI, Seldin MF, Kastner DL, Klareskog L, Gregersen PK: TRAF1-C5 as a risk locus for rheumatoid arthritis: a genomewide study. N Engl J Med. 2007, 357: 1199-1209. 10.1056/NEJMoa073491.PubMedCentralPubMed

45.

Chang M, Rowland CM, Garcia VE, Schrodi SJ, Catanese JJ, Helm-van Mil van der AH, Ardlie KG, Amos CI, Criswell LA, Kastner DL, Gregersen PK, Kurreeman FA, Toes RE, Huizinga TW, Seldin MF, Begovich AB: A large-scale rheumatoid arthritis genetic study identifies association at chromosome 9q33.2. PLoS Genet. 2008, 4: e1000107-10.1371/journal.pgen.1000107.PubMedCentralPubMed

46.

Raychaudhuri S, Remmers EF, Lee AT, Hackett R, Guiducci C, Burtt NP, Gianniny L, Korman BD, Padyukov L, Kurreeman FA, Chang M, Catanese JJ, Ding B, Wong S, Helm-van Mil van der AH, Neale BM, Coblyn J, Cui J, Tak PP, Wolbink GJ, Crusius JB, Horst-Bruinsma van der IE, Criswell LA, Amos CI, Seldin MF, Kastner DL, Ardlie KG, Alfredsson L, Costenbader KH, Altshuler D, et al: Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat Genet. 2008, 40: 1216-1223. 10.1038/ng.233.PubMedCentralPubMed

47.

Holmdahl R, Andersson M, Goldschmidt TJ, Gustafsson K, Jansson L, Mo JA: Type II collagen autoimmunity in animals and provocations leading to arthritis. Immunol Rev. 1990, 118: 193-232. 10.1111/j.1600-065X.1990.tb00817.x.PubMed

48.

Glant TT, Finnegan A, Mikecz K: Proteoglycan-induced arthritis: immune regulation, cellular mechanisms, and genetics. Crit Rev Immunol. 2003, 23: 199-250. 10.1615/CritRevImmunol.v23.i3.20.PubMed

49.

Keffer J, Probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D, Kollias G: Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 1991, 10: 4025-4031.PubMedCentralPubMed

50.

Kouskoff V, Korganow AS, Duchatelle V, Degott C, Benoist C, Mathis D: Organ-specific disease provoked by systemic autoimmunity. Cell. 1996, 87: 811-822. 10.1016/S0092-8674(00)81989-3.PubMed

51.

Matsumoto I, Maccioni M, Lee DM, Maurice M, Simmons B, Brenner M, Mathis D, Benoist C: How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease. Nat Immunol. 2002, 3: 360-365. 10.1038/ni772.PubMed

52.

Caton AJ, Stark SE, Kavaler J, Staudt LM, Schwartz D, Gerhard W: Many variable region genes are utilized in the antibody response of BALB/c mice to the influenza virus A/PR/8/34 hemagglutinin. J Immunol. 1991, 147: 1675-1686.PubMed

53.

Rankin AL, Reed AJ, Oh S, Cozzo Picca C, Guay HM, Larkin J, Panarey L, Aitken MK, Koeberlein B, Lipsky PE, Tomaszewski JE, Naji A, Caton AJ: CD4⁺ T cells recognizing a single self-peptide expressed by APCs induce spontaneous autoimmune arthritis. J Immunol. 2008, 180: 833-841.PubMed

54.

Atsumi T, Ishihara K, Kamimura D, Ikushima H, Ohtani T, Hirota S, Kobayashi H, Park SJ, Saeki Y, Kitamura Y, Hirano T: A point mutation of Tyr-759 in interleukin 6 family cytokine receptor subunit gp130 causes autoimmune arthritis. J Exp Med. 2002, 196: 979-990. 10.1084/jem.20020619.PubMedCentralPubMed

55.

Sakaguchi N, Takahashi T, Hata H, Nomura T, Tagami T, Yamazaki S, Sakihama T, Matsutani T, Negishi I, Nakatsuru S, Sakaguchi S: Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature. 2003, 426: 454-460. 10.1038/nature02119.PubMed

56.

Hirota K, Hashimoto M, Yoshitomi H, Tanaka S, Nomura T, Yamaguchi T, Iwakura Y, Sakaguchi N, Sakaguchi S: T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17⁺ Th cells that cause autoimmune arthritis. J Exp Med. 2007, 204: 41-47. 10.1084/jem.20062259.PubMedCentralPubMed

57.

King C, Ilic A, Koelsch K, Sarvetnick N: Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell. 2004, 117: 265-277. 10.1016/S0092-8674(04)00335-6.PubMed

58.

Calzascia T, Pellegrini M, Lin A, Garza KM, Elford AR, Shahinian A, Ohashi PS, Mak TW: CD4 T cells, lymphopenia, and IL-7 in a multistep pathway to autoimmunity. Proc Natl Acad Sci USA. 2008, 105: 2999-3004. 10.1073/pnas.0712135105.PubMedCentralPubMed

59.

Cope AP: Altered signalling thresholds in T lymphocytes cause autoimmune arthritis. Arthritis Res Ther. 2004, 6: 112-116. 10.1186/ar1185.PubMedCentralPubMed

60.

Thomas R, Turner M, Cope AP: High avidity autoreactive T cells with a low signalling capacity through the T-cell receptor: central to rheumatoid arthritis pathogenesis?. Arthritis Res Ther. 2008, 10: 210-10.1186/ar2446.PubMedCentralPubMed

61.

Goronzy JJ, Weyand CM: Rheumatoid arthritis. Immunol Rev. 2005, 204: 55-73. 10.1111/j.0105-2896.2005.00245.x.PubMed

62.

Goronzy JJ, Weyand CM: Aging, autoimmunity and arthritis: T-cell senescence and contraction of T-cell repertoire diversity-catalysts of autoimmunity and chronic inflammation. Arthritis Res Ther. 2003, 5: 225-234. 10.1186/ar974.PubMedCentralPubMed

63.

Hodes RJ, Hathcock KS, Weng NP: Telomeres in T and B cells. Nat Rev Immunol. 2002, 2: 699-706. 10.1038/nri890.PubMed

64.

Koetz K, Bryl E, Spickschen K, O'Fallon WM, Goronzy JJ, Weyand CM: T cell homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci USA. 2000, 97: 9203-9208. 10.1073/pnas.97.16.9203.PubMedCentralPubMed

65.

Colmegna I, Diaz-Borjon A, Fujii H, Schaefer L, Goronzy JJ, Weyand CM: Defective proliferative capacity and accelerated telomeric loss of hematopoietic progenitor cells in rheumatoid arthritis. Arthritis Rheum. 2008, 58: 990-1000. 10.1002/art.23287.PubMedCentralPubMed

66.

Schonland SO, Lopez C, Widmann T, Zimmer J, Bryl E, Goronzy JJ, Weyand CM: Premature telomeric loss in rheumatoid arthritis is genetically determined and involves both myeloid and lymphoid cell lineages. Proc Natl Acad Sci USA. 2003, 100: 13471-13476. 10.1073/pnas.2233561100.PubMedCentralPubMed

67.

Fujii H, Shao L, Colmegna I, Goronzy JJ, Weyand CM: Telomerase insufficiency in rheumatoid arthritis. Proc Natl Acad Sci USA. 2009, 106: 4360-4365. 10.1073/pnas.0811332106.PubMedCentralPubMed

68.

Shao L, Fujii H, Colmegna I, Oishi H, Goronzy JJ, Weyand CM: Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis. J Exp Med. 2009, 206: 1435-1449. 10.1084/jem.20082251.PubMedCentralPubMed

69.

Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, Polis MA, Haase AT, Feinberg MB, Sullivan JL, Jamieson BD, Zack JA, Picker LJ, Koup RA: Changes in thymic function with age and during the treatment of HIV infection. Nature. 1998, 396: 690-695. 10.1038/25374.PubMed

70.

Dool van den C, de Boer RJ: The effects of age, thymectomy, and HIV Infection on alpha and beta TCR excision circles in naive T cells. J Immunol. 2006, 177: 4391-4401.PubMed

71.

Goronzy JJ, Weyand CM: Thymic function and peripheral T-cell homeostasis in rheumatoid arthritis. Trends Immunol. 2001, 22: 251-255. 10.1016/S1471-4906(00)01841-X.PubMed

72.

Wagner UG, Koetz K, Weyand CM, Goronzy JJ: Perturbation of the T cell repertoire in rheumatoid arthritis. Proc Natl Acad Sci USA. 1998, 95: 14447-14452. 10.1073/pnas.95.24.14447.PubMedCentralPubMed

73.

van Boekel MA, Vossenaar ER, Hoogen van den FH, van Venrooij WJ: Autoantibody systems in rheumatoid arthritis: specificity, sensitivity and diagnostic value. Arthritis Res. 2002, 4: 87-93. 10.1186/ar395.PubMedCentralPubMed

74.

Alavi A, Axford JS: Sweet and sour: the impact of sugars on disease. Rheumatology (Oxford). 2008, 47: 760-770. 10.1093/rheumatology/ken081.

75.

Stefanova I, Hemmer B, Vergelli M, Martin R, Biddison WE, Germain RN: TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nat Immunol. 2003, 4: 248-254. 10.1038/ni895.PubMed

76.

Altan-Bonnet G, Germain RN: Modeling T cell antigen discrimination based on feedback control of digital ERK responses. PLoS Biol. 2005, 3: e356-10.1371/journal.pbio.0030356.PubMedCentralPubMed

77.

Singh K, Deshpande P, Pryshchep S, Weyand CM, Goronzy JJ: Increased signal amplification in the Raf-MEK-ERK module of RA T cells. Arthritis Rheum. 2008, 58: S293-

78.

Churchman SM, Ponchel F: Interleukin-7 in rheumatoid arthritis. Rheumatology (Oxford). 2008, 47: 753-759. 10.1093/rheumatology/ken053.

79.

McInnes IB, Leung BP, Sturrock RD, Field M, Liew FY: Inter-leukin-15 mediates T cell-dependent regulation of tumor necrosis factor-alpha production in rheumatoid arthritis. Nat Med. 1997, 3: 189-195. 10.1038/nm0297-189.PubMed

80.

Ettinger R, Kuchen S, Lipsky PE: Interleukin 21 as a target of intervention in autoimmune disease. Ann Rheum Dis. 2008, 67 (suppl 3): iii83-iii86. 10.1136/ard.2008.098400.PubMed

81.

Fitzgerald JE, Ricalton NS, Meyer AC, West SG, Kaplan H, Behrendt C, Kotzin BL: Analysis of clonal CD8⁺ T cell expansions in normal individuals and patients with rheumatoid arthritis. J Immunol. 1995, 154: 3538-3547.PubMed

82.

Waase I, Kayser C, Carlson PJ, Goronzy JJ, Weyand CM: Oligoclonal T cell proliferation in patients with rheumatoid arthritis and their unaffected siblings. Arthritis Rheum. 1996, 39: 904-913. 10.1002/art.1780390606.PubMed

83.

Schmidt D, Martens PB, Weyand CM, Goronzy JJ: The repertoire of CD4⁺ CD28^- T cells in rheumatoid arthritis. Mol Med. 1996, 2: 608-618.PubMedCentralPubMed

84.

Schmidt D, Goronzy JJ, Weyand CM: CD4⁺ CD7^- CD28^- T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity. J Clin Invest. 1996, 97: 2027-2037. 10.1172/JCI118638.PubMedCentralPubMed

85.

Singh K, Colmegna I, He X, Weyand CM, Goronzy JJ: Synoviocyte stimulation by the LFA-1-intercellular adhesion molecule-2-Ezrin-Akt pathway in rheumatoid arthritis. J Immunol. 2008, 180: 1971-1978.PubMed

86.

Zhang X, Nakajima T, Goronzy JJ, Weyand CM: Tissue trafficking patterns of effector memory CD4⁺ T cells in rheumatoid arthritis. Arthritis Rheum. 2005, 52: 3839-3849. 10.1002/art.21482.PubMed

87.

Sawai H, Park YW, Roberson J, Imai T, Goronzy JJ, Weyand CM: T cell costimulation by fractalkine-expressing synoviocytes in rheumatoid arthritis. Arthritis Rheum. 2005, 52: 1392-1401. 10.1002/art.21140.PubMed

88.

Groh V, Bruhl A, El-Gabalawy H, Nelson JL, Spies T: Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis. Proc Natl Acad Sci USA. 2003, 100: 9452-9457. 10.1073/pnas.1632807100.PubMedCentralPubMed

89.

Namekawa T, Snyder MR, Yen JH, Goehring BE, Leibson PJ, Weyand CM, Goronzy JJ: Killer cell activating receptors function as costimulatory molecules on CD4⁺ CD28^null T cells clonally expanded in rheumatoid arthritis. J Immunol. 2000, 165: 1138-1145.PubMed

90.

Yen JH, Moore BE, Nakajima T, Scholl D, Schaid DJ, Weyand CM, Goronzy JJ: Major histocompatibility complex class I-recognizing receptors are disease risk genes in rheumatoid arthritis. J Exp Med. 2001, 193: 1159-1167. 10.1084/jem.193.10.1159.PubMedCentralPubMed

91.

Park W, Weyand CM, Schmidt D, Goronzy JJ: Co-stimulatory pathways controlling activation and peripheral tolerance of human CD4⁺ CD28^- T cells. Eur J Immunol. 1997, 27: 1082-1090. 10.1002/eji.1830270507.PubMed

92.

Nakajima T, Goek O, Zhang X, Kopecky SL, Frye RL, Goronzy JJ, Weyand CM: De novo expression of killer immunoglobulin-like receptors and signaling proteins regulates the cytotoxic function of CD4 T cells in acute coronary syndromes. Circ Res. 2003, 93: 106-113. 10.1161/01.RES.0000082333.58263.58.PubMed

93.

Goronzy JJ, Matteson EL, Fulbright JW, Warrington KJ, Chang-Miller A, Hunder GG, Mason TG, Nelson AM, Valente RM, Crowson CS, Erlich HA, Reynolds RL, Swee RG, O'Fallon WM, Weyand CM: Prognostic markers of radiographic progression in early rheumatoid arthritis. Arthritis Rheum. 2004, 50: 43-54. 10.1002/art.11445.PubMed

94.

Martens PB, Goronzy JJ, Schaid D, Weyand CM: Expansion of unusual CD4+ T cells in severe rheumatoid arthritis. Arthritis Rheum. 1997, 40: 1106-1114. 10.1002/art.1780400615.PubMed

95.

Warrington KJ, Kent PD, Frye RL, Lymp JF, Kopecky SL, Goronzy JJ, Weyand CM: Rheumatoid arthritis is an independent risk factor for multi-vessel coronary artery disease: a case control study. Arthritis Res Ther. 2005, 7: R984-R991. 10.1186/ar1775.PubMedCentralPubMed

96.

Andersson AK, Li C, Brennan FM: Recent developments in the immunobiology of rheumatoid arthritis. Arthritis Res Ther. 2008, 10: 204-10.1186/ar2370.PubMedCentralPubMed

97.

Zhang Z, Gorman CL, Vermi AC, Monaco C, Foey A, Owen S, Amjadi P, Vallance A, McClinton C, Marelli-Berg F, et al: TCRzetadim lymphocytes define populations of circulating effector cells that migrate to inflamed tissues. Blood. 2007, 109: 4328-4335. 10.1182/blood-2006-12-064170.PubMedCentralPubMed

98.

Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R: Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006, 439: 682-687. 10.1038/nature04444.PubMed

99.

Cope AP: Studies of T-cell activation in chronic inflammation. Arthritis Res. 2002, 4 (suppl 3): S197-S211. 10.1186/ar557.PubMedCentralPubMed

100.

Allen ME, Young SP, Michell RH, Bacon PA: Altered T lymphocyte signaling in rheumatoid arthritis. Eur J Immunol. 1995, 25: 1547-1554. 10.1002/eji.1830250612.PubMed

101.

Brennan FM, Hayes AL, Ciesielski CJ, Green P, Foxwell BM, Feldmann M: Evidence that rheumatoid arthritis synovial T cells are similar to cytokine-activated T cells: involvement of phosphatidylinositol 3-kinase and nuclear factor kappaB pathways in tumor necrosis factor alpha production in rheumatoid arthritis. Arthritis Rheum. 2002, 46: 31-41. 10.1002/1529-0131(200201)46:1<31::AID-ART10029>3.0.CO;2-5.PubMed

102.

Bryl E, Vallejo AN, Matteson EL, Witkowski JM, Weyand CM, Goronzy JJ: Modulation of CD28 expression with anti-tumor necrosis factor alpha therapy in rheumatoid arthritis. Arthritis Rheum. 2005, 52: 2996-3003. 10.1002/art.21353.PubMed

103.

Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, Kalia V, Subramaniam S, Blattman JN, Barber DL, Ahmed R: Molecular signature of CD8⁺ T cell exhaustion during chronic viral infection. Immunity. 2007, 27: 670-684. 10.1016/j.immuni.2007.09.006.PubMed

104.

Schellekens GA, de Jong BA, Hoogen van den FH, Putte van de LB, van Venrooij WJ: Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest. 1998, 101: 273-281. 10.1172/JCI1316.PubMedCentralPubMed

105.

Vossenaar ER, Despres N, Lapointe E, Heijden van der A, Lora M, Senshu T, van Venrooij WJ, Menard HA: Rheumatoid arthritis specific anti-Sa antibodies target citrullinated vimentin. Arthritis Res Ther. 2004, 6: R142-R150. 10.1186/ar1149.PubMedCentralPubMed

106.

Axford JS, Sumar N, Alavi A, Isenberg DA, Young A, Bodman KB, Roitt IM: Changes in normal glycosylation mechanisms in autoimmune rheumatic disease. J Clin Invest. 1992, 89: 1021-1031. 10.1172/JCI115643.PubMedCentralPubMed

107.

Klareskog L, Stolt P, Lundberg K, Källberg H, Bengtsson C, Grunewald J, Rönnelid J, Harris HE, Ulfgren AK, Rantapää-Dahlqvist S, Eklund A, Padyukov L, Alfredsson L: 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: 38-46. 10.1002/art.21575.PubMed

108.

Klareskog L, Catrina AI, Paget S: Rheumatoid arthritis. Lancet. 2009, 373: 659-672. 10.1016/S0140-6736(09)60008-8.PubMed

109.

Lee HS, Irigoyen P, Kern M, Lee A, Batliwalla F, Khalili H, Wolfe F, Lum RF, Massarotti E, Weisman M, Bombardier C, Karlson EW, Criswell LA, Vlietinck R, Gregersen PK: Interaction between smoking, the shared epitope, and anti-cyclic citrullinated peptide: a mixed picture in three large North American rheumatoid arthritis cohorts. Arthritis Rheum. 2007, 56: 1745-1753. 10.1002/art.22703.PubMed

110.

Linn-Rasker SP, Helm-van Mil van der AH, van Gaalen FA, Kloppenburg M, de Vries RR, le Cessie S, Breedveld FC, Toes RE, Huizinga TW: Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles. Ann Rheum Dis. 2006, 65: 366-371. 10.1136/ard.2005.041079.PubMedCentralPubMed

111.

Auger I, Balandraud N, Rak J, Lambert N, Martin M, Roudier J: New autoantigens in rheumatoid arthritis (RA): screening 8268 protein arrays with sera from patients with RA. Ann Rheum Dis. 2009, 68: 591-594. 10.1136/ard.2008.096917.PubMed

112.

Goeb V, Thomas-L'Otellier M, Daveau R, Charlionet R, Fardellone P, Le Loet X, Tron F, Gilbert D, Vittecoq O: Candidate autoantigens identified by mass spectrometry in early rheumatoid arthritis are chaperones and citrullinated glycolytic enzymes. Arthritis Res Ther. 2009, 11: R38-10.1186/ar2644.PubMedCentralPubMed

113.

del Puente A, Knowler WC, Pettitt DJ, Bennett PH: The incidence of rheumatoid arthritis is predicted by rheumatoid factor titer in a longitudinal population study. Arthritis Rheum. 1988, 31: 1239-1244. 10.1002/art.1780311004.PubMed

114.

Majka DS, Deane KD, Parrish LA, Lazar AA, Baron AE, Walker CW, Rubertone MV, Gilliland WR, Norris JM, Holers VM: Duration of preclinical rheumatoid arthritis-related autoantibody positivity increases in subjects with older age at time of disease diagnosis. Ann Rheum Dis. 2008, 67: 801-807. 10.1136/ard.2007.076679.PubMedCentralPubMed

115.

Karlson EW, Chibnik LB, Tworoger SS, Lee IM, Buring JE, Shadick NA, Manson JE, Costenbader KH: Biomarkers of inflammation and development of rheumatoid arthritis in women from two prospective cohort studies. Arthritis Rheum. 2009, 60: 641-652. 10.1002/art.24350.PubMedCentralPubMed

116.

Hill JA, Bell DA, Brintnell W, Yue D, Wehrli B, Jevnikar AM, Lee DM, Hueber W, Robinson WH, Cairns E: Arthritis induced by posttranslationally modified (citrullinated) fibrinogen in DR4-IE transgenic mice. J Exp Med. 2008, 205: 967-979. 10.1084/jem.20072051.PubMedCentralPubMed

117.

Kuhn KA, Kulik L, Tomooka B, Braschler KJ, Arend WP, Robinson WH, Holers VM: Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis. J Clin Invest. 2006, 116: 961-973. 10.1172/JCI25422.PubMedCentralPubMed

118.

Uysal H, Bockermann R, Nandakumar KS, Sehnert B, Bajtner E, Engstrom A, Serre G, Burkhardt H, Thunnissen MM, Holmdahl R: Structure and pathogenicity of antibodies specific for citrullinated collagen type II in experimental arthritis. J Exp Med. 2009, 206: 449-462. 10.1084/jem.20081862.PubMedCentralPubMed

119.

Lutzky V, Hannawi S, Thomas R: Cells of the synovium in rheumatoid arthritis. Dendritic cells. Arthritis Res Ther. 2007, 9: 219-10.1186/ar2200.PubMedCentralPubMed

120.

Thomas R, Lipsky PE: Human peripheral blood dendritic cell subsets. Isolation and characterization of precursor and mature antigen-presenting cells. J Immunol. 1994, 153: 4016-4028.PubMed

121.

Takemura S, Braun A, Crowson C, Kurtin PJ, Cofield RH, O'Fallon WM, Goronzy JJ, Weyand CM: Lymphoid neogenesis in rheumatoid synovitis. J Immunol. 2001, 167: 1072-1080.PubMed

122.

Weyand CM, Kurtin PJ, Goronzy JJ: Ectopic lymphoid organogenesis: a fast track for autoimmunity. Am J Pathol. 2001, 159: 787-793.PubMedCentralPubMed

123.

Seyler TM, Park YW, Takemura S, Bram RJ, Kurtin PJ, Goronzy JJ, Weyand CM: BLyS and APRIL in rheumatoid arthritis. J Clin Invest. 2005, 115: 3083-3092. 10.1172/JCI25265.PubMedCentralPubMed

124.

Schroder AE, Greiner A, Seyfert C, Berek C: Differentiation of B cells in the nonlymphoid tissue of the synovial membrane of patients with rheumatoid arthritis. Proc Natl Acad Sci USA. 1996, 93: 221-225. 10.1073/pnas.93.1.221.PubMedCentralPubMed

125.

Chabaud M, Durand JM, Buchs N, Fossiez F, Page G, Frappart L, Miossec P: Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum. 1999, 42: 963-970. 10.1002/1529-0131(199905)42:5<963::AID-ANR15>3.0.CO;2-E.PubMed

126.

Miossec P: Interleukin-17 in fashion, at last: ten years after its description, its cellular source has been identified. Arthritis Rheum. 2007, 56: 2111-2115. 10.1002/art.22733.PubMed

127.

Klimiuk PA, Yang H, Goronzy JJ, Weyand CM: Production of cytokines and metalloproteinases in rheumatoid synovitis is T cell dependent. Clin Immunol. 1999, 90: 65-78. 10.1006/clim.1998.4618.PubMed

128.

Rezzonico R, Burger D, Dayer JM: Direct contact between T lymphocytes and human dermal fibroblasts or synoviocytes down-regulates types I and III collagen production via cell-associated cytokines. J Biol Chem. 1998, 273: 18720-18728. 10.1074/jbc.273.30.18720.PubMed

129.

Beech JT, Andreakos E, Ciesielski CJ, Green P, Foxwell BM, Brennan FM: T-cell contact-dependent regulation of CC and CXC chemokine production in monocytes through differential involvement of NFkappaB: implications for rheumatoid arthritis. Arthritis Res Ther. 2006, 8: R168-10.1186/ar2077.PubMedCentralPubMed

130.

Sawai H, Park YW, He X, Goronzy JJ, Weyand CM: Fractalkine mediates T cell-dependent proliferation of synovial fibroblasts in rheumatoid arthritis. Arthritis Rheum. 2007, 56: 3215-3225. 10.1002/art.22919.PubMed

131.

Burger D, Dayer JM: The role of human T-lymphocyte-monocyte contact in inflammation and tissue destruction. Arthritis Res. 2002, 4 (suppl 3): S169-S176. 10.1186/ar558.PubMedCentralPubMed

132.

Gravallese EM, Goldring SR: Cellular mechanisms and the role of cytokines in bone erosions in rheumatoid arthritis. Arthritis Rheum. 2000, 43: 2143-2151. 10.1002/1529-0131(200010)43:10<2143::AID-ANR1>3.0.CO;2-S.PubMed

133.

Noss EH, Brenner MB: The role and therapeutic implications of fibroblast-like synoviocytes in inflammation and cartilage erosion in rheumatoid arthritis. Immunol Rev. 2008, 223: 252-270. 10.1111/j.1600-065X.2008.00648.x.PubMed

134.

Lee DM, Kiener HP, Agarwal SK, Noss EH, Watts GF, Chisaka O, Takeichi M, Brenner MB: Cadherin-11 in synovial lining formation and pathology in arthritis. Science. 2007, 315: 1006-1010. 10.1126/science.1137306.PubMed

135.

Kiener HP, Lee DM, Agarwal SK, Brenner MB: Cadherin-11 induces rheumatoid arthritis fibroblast-like synoviocytes to form lining layers in vitro. Am J Pathol. 2006, 168: 1486-1499. 10.2353/ajpath.2006.050999.PubMedCentralPubMed

136.

Li X, Makarov SS: An essential role of NF-kappaB in the 'tumor-like' phenotype of arthritic synoviocytes. Proc Natl Acad Sci USA. 2006, 103: 17432-17437. 10.1073/pnas.0607939103.PubMedCentralPubMed

137.

Paniagua RT, Sharpe O, Ho PP, Chan SM, Chang A, Higgins JP, Tomooka BH, Thomas FM, Song JJ, Goodman SB, Lee DM, Genovese MC, Utz PJ, Steinman L, Robinson WH: Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis. J Clin Invest. 2006, 116: 2633-2642.PubMedCentralPubMed

138.

Miller MC, Manning HB, Jain A, Troeberg L, Dudhia J, Essex D, Sandison A, Seiki M, Nanchahal J, Nagase H, Itoh Y: Membrane type 1 matrix metalloproteinase is a crucial promoter of synovial invasion in human rheumatoid arthritis. Arthritis Rheum. 2009, 60: 686-697. 10.1002/art.24331.PubMedCentralPubMed

139.

Rutkauskaite E, Volkmer D, Shigeyama Y, Schedel J, Pap G, Müller-Ladner U, Meinecke I, Alexander D, Gay RE, Drynda S, Neumann W, Michel BA, Aicher WK, Gay S, Pap T: Retroviral gene transfer of an antisense construct against membrane type 1 matrix metalloproteinase reduces the invasiveness of rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 2005, 52: 2010-2014. 10.1002/art.21156.PubMed

140.

Schett G: Erosive arthritis. Arthritis Res Ther. 2007, 9 (suppl 1): S2-10.1186/ar2166.PubMedCentralPubMed

Title: Developments in the scientific understanding of rheumatoid arthritis
Authors: Jörg J Goronzy
Cornelia M Weyand
Publication date: 01-10-2009
Publisher: BioMed Central
Published in: Arthritis Research & Therapy / Issue 5/2009
Electronic ISSN: 1478-6362
DOI: https://doi.org/10.1186/ar2758

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Developments in the scientific understanding of rheumatoid arthritis

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2009

Mechanical effects of surgical procedures on osteochondral grafts elucidated by osmotic loading and real-time ultrasound

Progress in osteoporosis and fracture prevention: focus on postmenopausal women

Developments in the clinical understanding of lupus

Toll-like receptors and NOD-like receptors in rheumatic diseases

Microstructure and mineral composition of dystrophic calcification associated with the idiopathic inflammatory myopathies

The ITGAVrs3738919 variant and susceptibility to rheumatoid arthritis in four Caucasian sample sets

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page