Imaging B lymphocytes in autoimmune inflammatory diseases

Quarterly Journal of Nuclear Medicine and Molecular Imaging

Volumn 58, Issue 3, 2014, Pages 258-268

  Iodice, V ^a   Lagana B ^b   Lauri, C ^a   Capriotti, G ^a   Germano, V ^b   D'Amelio, R ^b   Picchianti Diamanti, A ^b  

^a SAPIENZA UNIVERSITY OF ROME   (Italy)

^b SAPIENZA UNIVERSITY OF ROME   (Italy)

Author keywords

Autoimmunity; B lymphocytes; Radiopharmaceuticals; Rituximab

Indexed keywords

B LYMPHOCYTE ANTIGEN; MONOCLONAL ANTIBODY; RADIOPHARMACEUTICAL AGENT; RITUXIMAB;

AUTOIMMUNE DISEASE; AUTOIMMUNE INFLAMMATORY DISEASE; AUTOIMMUNITY; B LYMPHOCYTE; BINDING SITE; CELL MATURATION; CLINICAL EVALUATION; DISEASE ACTIVITY; DRUG MONITORING; DRUG TARGETING; HUMAN; HUMAN CELL; IMMUNOLOGICAL TOLERANCE; IMMUNOTHERAPY; IN VITRO STUDY; IN VIVO STUDY; INFLAMMATORY DISEASE; ISOTOPE LABELING; MOLECULAR IMAGING; NONHUMAN; ONTOGENY; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; ANIMAL; CELL TRACKING; COMPUTER ASSISTED EMISSION TOMOGRAPHY; DIAGNOSTIC USE; IMMUNOLOGY; INFLAMMATION; PATHOLOGY; PROCEDURES; SCINTISCANNING;

ANIMALS; AUTOIMMUNE DISEASES; B-LYMPHOCYTES; CELL TRACKING; HUMANS; INFLAMMATION; RADIOPHARMACEUTICALS; TOMOGRAPHY, EMISSION-COMPUTED;

EID: 84925223292     PISSN: 18244785     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (103)

1. Hiepe F, Radbruch A. B cells in autoimmunity: More than antibodies? Blood 2005;106:2227.
2. Mitchison NA, Wedderbum LR. B cells in autoimmunity. Proc Natl Acad Sci USA 2000;97:8750-1.
3. Gause A, Berek C. The role of B cells in the pathogenesis of rheumatoid arthritis. Potential implications for treatment. BioD-rugs 2001;15:73-9.
4. Takemura S, Klimiuk PA, Braun A, Goronzy JJ, Weyand CM. T cell activation in rheumatoid synovium is B cell dependent. J Immunol 2001;167:4710-8.
5. Dörner T, Burmester GR. The role of B cells in rheumatoid arthritis: Mechanisms and therapeutic targets. Curr Opin Rheumatol 2003;15:246-52.
6. Stashenko P, Nadler LM, Hardy R, Schlossman SF. Characterization of a human B-lymphocyte-specific antigen. J Immunol 1980;125:1678-85.
7. Tedder TF, Boyd AW, Freedman AS, Nadler LM, Schlossman SF. The B cell surface molecule Bl is functionally linked with B-cell activation and differentiation. J Immunol 1985;135:973-9.
8. van Zelm MC, Szczepanski T, van der Burg M, van Dongen JJ. Replication history of B lymphocytes reveals homeostatic proliferation and extensive antigen-induced B cell expansion. J Exp Med 2007;204:645-55.
9. Malchers F. The pre-B-cell receptor: Selector of fitting immunoglobulin heavy chains for the B-cell repertoire. Nat Rev Immunol 2005;5:578-84.
10. Pieper K, Grimbacher B, Eibel H. B-cell biology and development. J Allergy Clin Immunol 2013;131:959-71.
11. Carsetti R, Rosado MM, Wardemann H. Peripheral development of B cells in mouse and man. Immunology Reviews 2004;197:179-91.
12. Capolunghi F, Cascioli S, Giorda E, Rosado MM, Plebani A, Auriti C et al. CpG Drives human transitional B cells to terminal differentiation and production of natural antibodies. J Immunol 2008;180:800-8.
13. Loder F, Mutschier B, Ray RJ, Paige CJ, Sidéras P, Torres R et al. B cell development in the spleen takes place in discrete steps and is determined by the quality of B cell receptor-derived signals. J Exp Med 1999;190:75-89.
14. Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T. Class switch recombination and hypermutation require activation-induced cyitidine deaminase (AID) and potential RNA editing enzymes. Cell 2000;102:553-63.
15. Chappel CP, Jacob J. Germinal-center-derived B-cell memory. Adv Exp Med Biol 2007;590; 139-48.
16. Kunkel EJ, Butcher EC. Plasma cell homing. Nat Rev 2003;3:822-9.
17. Caraux A, Klein B, Paiva B, Bret C, Schmitz A, Fühler GM et al. Circulating human B and plasma cells. Age associated changes in counts and detailed characterization of circulating normal Cd138- and Cd138+ plasma cells. Hematologica 2010;95:1016-20.
18. Capolunghi F, Rosado MM, Sinibaldi M, Aranburu A, Carestti R. Why do we need IgM memory B cells? Immunology Letters 2013;152:114-20.
19. Klein U, Kuppers R, Rajewsky K. Evidence for a large compartment of IgM expressing memory B cells in humans. Blood 1997;89:1288-98.
20. Weller S, Bonnet M, Delagreverie H, Israel L, Chrabieh M, Marodi L et al. IgM+ IgD+Cd27+ B cells are markedly reduced in IRAK, Myd88 and TIRAP but not UNC93B deficient patients. Blood 2012;120:4992-5001.
21. Tedder TF, Isaacs CM. Isolation of cDNA encoding the Cd19 human and mouse B lymphocites. A new member of the immunoglobulin superfamily. J Immunol 1989;143:712-7.
22. Klein U, Rajewsky K, Kuppers R. Human immunoglobulin IgM IgD+ peripheral B cells expressing the Cd27 surface antigen carry somatically mutated variable regions genes: Cd27 as a general marker for somatically mutated memory B cells. J Exp Med 1998;188:1679-89.
23. Alman DM, Ferguson SE. Cancro MP. Peripheral B cell maturation. Immature peripheral B cells in adults are heat-stable anti-genhi and exhibit unique signalling characteristics. J Immunol 1992;149:2533-40.
24. Morbach H, Eichhorn EM, Liese JG, Girschick HJ. Reference values for B cell subpopulations from infancy to adulthood. Clin Exp Immunol 2010;162:271-9.
25. Rodriguez-Alba JC, Moreno-Garcia ME, Sandoval-Montes C, Rosales-Garcia VH, Santos-Argumedo L. CD38 induces differentiation of immature transitional 2 B lymphocytes. Blood 2008;111:3644-52.
26. Kalampokis I, Yoshizaki A, Tedder FT. IL-10-producing regulatory B cells (BIO cells) in autoimmune disease. Arthritis Res & Ther 2013;15(Suppl 1).
27. Mauri C, Ehrenstein MR. The 'short' history of regulatory B cells. Trends in Immunology 2007;29:34-40.
28. Meffre E. The establishment of early B cell tolerance in humans: Lessons from primary immunodeficiency diseases. Ann N Y Aca Sci 2011;1246:1-10.
29. Meffre E, Wardermann H. B cell tolerance checkpoints in health and autoimmunity. Curr Opin Immunol 2008;20:632-8.
30. Pillai S, Mattoo H, Cariappa A. B cells and autoimmunity. Curr Opin Immunol 2011;23:721-31.
31. Menard L, Saadoun D, Isnardi I, Ng YS, Meyers G, Massad C et al. The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans. J Clin Invest 2011;121:3635-44.
32. Fukui R, Saitoh S, Kanno A, Onji M, Shibata T, Ito A et al. Un-c93Bl restricts systemic lethal inflammation by orchestrating Toll-like receptor 7 and 9 trafficking. Immunity 2011;35:69-81.
33. Moore PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P et al. BLyS: Member of the tumor necrosis factor family and B lymphocyte stimulator. Science 1999;285:260.
34. Gross JA, Dillon SR, Mudri S, Johnston J, Linau A, Roque R et al. TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease, impaired B cell maturation in mice lacking BLyS. Immunity 2001;15:289-302.
35. Schiemann B, Gommerman JL, Vora K, Cachero TG, Shulga-Morskaya S, Dobles M et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 2001;293:2111-4.
36. Mackay F, Woodcock SA, Lawton P, Ambrose C, Baetscher M, Schneider P et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med 1999;190:1697-710.
37. Cheema GS, Roschke V, Hilbert DM, Stohl W. Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum 2001;44:1313-9.
38. Rosado MM, Picchiami Diamanti A, Cascioli S, Ceccarelli S, Ca-poruscio S, D'Amelio R et al. Hyper-IgM, neutropenia, mild infections and low response to polyclonal stimulation: Hyper-IgM syndrome or common variable immunodeficiency? Int J Immu-nopathol Pharmacol 2011;24:983-91.
39. Yoshizaki A, Miyagaki T, DiLillo DJ, Matsushita T, Horikawa M, Kountikov EI et al. Regulatory B cells control T cell autoimmunity through IL-21-dependent cognate interactions. Nature 2012;491:264-8.
40. Dörner T, Jacobi AM, Lipsky PE. B cells in autoimmunity. Arthritis Res Ther 2009; 11:247.
41. Odendahl M, Jacobi A, Hansen A, Feist E, Hiepe F, Burmester GR et al. Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J Immunol 2000;165:5970-9.
42. Jacobi AM, Odendahl M, Reiter K, Bruns A, Burmester GR, Radbruch A et al. Correlation between circulating CD27 high plasma cells and disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 2003;48:1332-42.
43. Moser K, Tokoyoda K, Radbruch A, MacLennan I, Manz RA. Stromal niches, plasma cell differentiation and survival. Curr Opin Immunol 2006;18:265-70.
44. Zhang J, Roschke V, Baker KP, Wang Z, Alarcón GS, Fessier BJ et al. Cutting edge: A role for B lymphocyte stimulator in systemic lupus erythematosus. J Immunol 2001;166:6-10.
45. Grammer AC, Slota R, Fischer R, Gur H, Girschick H, Yarboro C et al. Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions. J Clin Invest 2003;112:1506-20.
46. Rönnblom L, Alm GV. A pivotal role for the natural interferon alpha-producing cells (plasmacytoid dendritic cells) in the pathogenesis of lupus. J Exp Med 2001;194:F59-63.
47. Christensen SR, Kashgarian M, Alexopoulou L, Flavell RA, Akira S, Shlomchik MJ. Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus. J Exp Med 2005;202:321-31.
48. Blair PA, Noreña LY, Flores-Borja F, Rawlings DJ, Isenberg DA, Ehrenstein MR et al. (CD19C+) CD24(hi) CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity 2010;32:129-40.
49. Hamza N, Bos NA, Kallenberg CG. B-cell populations and sub-populations in Sjögren's syndrome. Presse Med 2012;41(9 Pt 2):e475-83.
50. Bohnhorst JO, Bjorgan MB, Thoen JE, Natvig JB, Thompson KM. Bm1-Bm5 classification of peripheral blood B cells reveals circulating germinal center founder cells in healthy individuals and disturbance in the b cell subpopulations in patients with primary Sjogren's syndrome. J Immunol 2001;167:3610-8.
51. Abdulahad WH, Meijer JM, Kroese FG, Meiners I'M, Vissink A, Spijkervet FK et al. B cell reconstitution and T helper cell balance after rituximab treatment of active primary Sjogren's syndrome: A double-blind, placebo-controlled study. Arthritis Rheum 2011;63:1116-23.
52. Szyszko EA, Brun JG, Skarstein K, Peck AB, Jonsson R, Brokstad KA. Phenotypic diversity of peripheral blood plasma cells in primary Sjogren's syndrome. Scand J Immunol 2011;73:18-28.
53. Quartuccio L, Salvin S, Fabris M, Maset M, Pontarini E, Isola M et al. BLyS upregulation in Sjogren's syndrome associated with lymphoproliferative disorders, higher ESSDAI score and B-cell clonal expansion in the salivary glands. Rheumatology (Oxford) 2013;52:276-81.
54. Huang YF, Cheng Q, Jiang CM, An S, Xiao L, Gou YC et al. The immune factors involved in the pathogenesis, diagnosis, and treatment of Sjogren's syndrome. Clin Dev Immunol 2013;2013:160491.
55. Souto-Carneiro MM, Mahadevan V, Takada K, Fritsch-Stork R, Nanki T, Brown M et al. Alterations in peripheral blood memory B cells in patients with active rheumatoid arthritis are dependent on the action of tumor necrosis factor. Arthritis Res & Ther 2009;11:R84.
56. Humby F, Bombardieri M, Manzo A, Kelly S, Blades MC, Kirkham B et al. Ectopic lymphoid structures support ongoing production of class-switched autoantibodies in rheumatoid synovium. PLoS Med 2009;6:el.
57. Takemura S, Klimiuk PA, Braun A, Goronzy JJ, Weyand CM. T cell activation in rheumatoid synovium is B cell dependent. J Immunol 2001;167:4710-8.
58. Moura RA, Cascao R, Perpetuo I, Canhao H, Vieria-Sousa E, Mourao AF et al. Cytokine pattern in very early rheumatoid arthritis favours B cell activation and survival. Rheumatology 2011;50:278-82.
59. Masson-Bessière C, Sebbag M, Durieux JJ, Nogueira L, Vincent C, Girbal-Neuhauser E et al. In the rheumatoid pannus, anti-filaggrin autoantibodies are produced by local plasma cells and constitute a higher proportion of IgG than in synovial fluid and serum. Clin Exp Immunol 2000;119:544-52.
60. Ma L, Liu B, Jiang Z, Jiang Y. Reduced numbers of regulatory B cells are negatively correlated with disease activity in patients with new-onset rheumatoid arthritis. Clin Rheumatol 2014;33:187-95.
61. Lee NS, Barber L, Akula SM, Sigounas G, Kataria YP, Arce S. Disturbed homeostasis and multiple signaling defects in the peripheral blood B-cell compartment of patients with severe chronic sarcoidosis. Clin Vaccine Immunol 2011;18:1306-16.
62. Busuttil A, Weigt SS, Keane MP, Xue YY, Palchevskiy V, Burdick MD et al. CXCR3 ligands are augmented during the pathogenesis of pulmonary sarcoidosis. Eur Respir J 2009;34:676-86.
63. Saussine A, Tazi A, Feuillet S, Rybojad M, Juillard C, Bergeron A et al. Active chronic sarcoidosis is characterized by increased transitional blood B cells, increased IL-10-producing regulatory B cells and high BAFF levels. PLoS One 2012;7:e43588.
64. Witko-Sarsat V, Daniel S, Noël LH, Mouthon L. Neutrophils and B lymphocytes in ANCA-associated vasculitis. APMIS Suppl 2009;127:27-31.
65. Culton DA, Nicholas MW, Bunch DO, Zhen QL, Kepler TB, Dooley MA et al. Similar CD 19 dysregulation in two autoantibody-associated autoimmune diseases suggests a shared mechanism of B-cell tolerance loss. J Clin Immunol 2007;27:53-68.
66. Wilde B, Thewissen M, Damoiseaux J, Knippenberg S, Hilhorst M, van Paassen P et al. Regulatory B cells in ANCA-associated vasculitis. Ann Rheum Dis 2013;72:1416-9.
67. Tsurikisawa N, Saito H, Oshikata C, Tsuburai T, Akiyama K. Decreases in the numbers of peripheral blood regulatory T cells, and increases in the levels of memory and activated B cells, in patients with active eosinophilic granulomatosis and polyangi-itis. J Clin Immunol 2013;33:965-76.
68. Hoyer BF, Mumtaz IM, Loddenkemper K, Bruns A, Sengler C, Hermann KG et al. Takayasu arteritis is characterised by disturbances of B cell homeostasis and responds to B cell depletion therapy with rituximab. Ann Rheum Dis 2012;71:75-9.
69. Krumbholz M, Specks U, Wick M, Railed SL, Jenne D, Meinl E. BAFF is elevated in serum of patients with Wegener's granulomatosis. J Autoimmun 2005;25:298-302.
70. Scott JL, McMillan R, Marino JV, Davidson JG. Leukocyte labeling with 51 chromium. IV. The kinetics of chronic lymphocytic leukemic lymphocytes. Blood 1973;41:155-62.
71. Rankin EM, Hekman A, Hardeman MR, Hoefnagel CA. Dynamic studies of lymphocytes labelled with indium-111 during and after treatment with monoclonal anti-idiotype antibody in advanced B cell lymphoma. Br Med J (Clin Res Ed) 1984;289:1097-100.
72. McAfee JG, Thakur ML. Survey of radioactive agents for in vitro labeling of phagocytic leukocytes. I. Soluble agents. J Nucl Med 1976;17:480-7.
73. 73- McAfee JG, Thakur ML. Survey of radioactive agents for in vitro labeling of phagocytic leukocytes. II. Particles. J Nucl Med 1976;17:488-92.
74. Wagstaff J, Gibson C, Thatcher N, Ford WL, Sharma H, Crowther D. Human lymphocyte traffic assessed by indium-111 oxine labelling: Clinical observations. Clin Exp Immunol 1981;43:443-9.
75. Malviya G, Galli F, Sonni I, Pacilio M, Signore A. Targeting T and B lymphocytes with radiolabelled antibodies for diagnostic and therapeutic applications. Q J Nucl Med Mol Imaging 2010;54:654-76.
76. Thakur ML. Cell labeling: Achievements, challenges, and prospects. J Nucl Med 1981;22:1011-4.
77. Lavender JP, Goldman JM, Arnot RN, Thakur ML. Kinetics of indium-III labelled lymphocytes in normal subjects and patients with Hodgkin's disease. Br Med J 1977;2:797-9.
78. Wagstaff J, Gibson C, Thatcher N, Ford WL, Sharma H, Benson W et al. A method for following human lymphocyte traffic using indium-111 oxine labelling. Clin Exp Immunol 1981;43:435-42.
79. Pozzilli P, Pozzilli C, Pantano P, Negri M, Andreani D, Cudworth G. Tracking of indium-111-oxine labelled lymphocytes in autoimmune thyroid disease. Clin Endocrinol (Oxf) 1983;19:111-6.
80. Wagstaff J, Gibson C, Thatcher N, Crowther D. The migratory properties of indium-111 oxine labelled lymphocytes in patients with chronic lymphocytic leukaemia. Br J Haematol 1981;49:283-91.
81. De Vita S, Zaja F, Sacco S, De Candia A, Fanin R, Ferraccioli G. Efficacy of selective B-Cell blockade in the treatment of rheumatoid arthritis, evidence for a pathogenic role of B-cells. Arthritis Rheumatism 2002;46:2029-33.
82. Marston B, Palanichamy A, Anolik JH. B-cells in the pathogenesis and treatment of rheumatoid arthritis. Current Opinion in Rheumatology 2010;22:307-15.
83. Dörner T, Kinnman N, Tak PP. Targeting B cells in immune-mediated inflammatory disease: A comprehensive review of mechanisms of action and identification of biomarkers. Pharmacol Ther 2010;125:464-75.
84. Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994;83:435-45.
85. Uchida J, Lee Y, Hasegawa M. Mouse CD20 expression and function. Int Immunol 2004;16:119-29.
86. Beers SA, Chan CH, French RR, Cragg MS, Glennie MJ. CD20 as a target for therapeutic type I and II monoclonal antibodies. Semin Hematol 2010;47:107-14.
87. Tedder TF, Streuli M, Schlossman SF, Saito H. Isolation and structure of a cDNA encoding the B1 (CD20) cell-surface antigen of human B lymphocytes. Proc Natl Acad Sci U S A 1988;85:208-12.
88. Maloney DG. Anti-CD20 antibody therapy for B-cell lymphomas. N Engl J Med 2012;366:2008-16.
89. Mease PJ, Cohen S, Gaylis NB, Chubick A, Kaell AT, Green-wald M et al. Efficacy and safety of retreatment in patients with rheumatoid arthritis with previous inadequate response to tumor necrosis factor inhibitors: Results from the SUNRISE Trial. J Rheumatol 2010;37:917-27.
90. Cianchini G, Lupi F, Masini C, Corona R, Puddu P, De Pità O. Therapy with rituximah for autoimmune pemphigus: Results from a single-center observational study on 42 cases with long-term follow-up. J Am Acad Dermatol 2012;67:617-22.
91. Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: The randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 2010;62:222-33.
92. Townsend MJ, Monroe JG, Chan AC. B-cell targeted therapies in human autoimmune diseases: An updated perspective. Immunol Rev 2010;237:264-83.
93. Gottenberg JE, Cinquetti G, Larroche C, Combe B, Hachulla E, Meyer O et al. Club Rhumatismes et Inflammations and the French Society of Rheumatology. Efficacy of rituximab in systemic manifestations of primary Sjogren's syndrome: Results in 78 patients of the autoimmune and rituximab registry. Ann Rheum Dis 2013;72:1026-31.
94. Vanhille P, Vrigneaud L, Quéméneur T. Renal disease in ANCA-associated vasculitis. Presse Med 2012,41(3 Pt 1):247-53.
95. Malviya G, Anzola KL, Podestà E, Lagana B, Del Mastro C, Dier-ckx RA et al. (99m)Tc-labeled rituximab for imaging B lymphocyte infiltration in inflammatory autoimmune disease patients. Mol Imaging Biol 2012;14:637-46.
96. Kurdziel KA. The panda sign. Radiology 2000;215:884-5.
97. Tran L, Huitema ADR, van Rijswijk MH, Dinant HJ, Baars JW, Beijnen JH et al. CD20 antigen imaging with 124I rituximab PET/ CT in patients with rheumatoid arthritis. Human Antibodies 2011;20:29-35.
98. Kausar F, Mustafa K, Sweis G, Sawaqed R, Alawneh K, Salloum R et al. Ocrelizumab: A step forward in the evolution of B-cell therapy. Expert Opin Biol Ther 2009;9:889-95.
99. Stohl W, Gomez-Reino J, Olech E, Dudler J, Fleischmann RM, Zerbini CA et al. Safety and efficacy of ocrelizumab in combination with methotrexate in MTX-naive subjects with rheumatoid arthritis: The phase III FILM trial. Ann Rheum Dis 2012;71:1289-96.
100. Morschhauser F, Leonard JP, Fayad L, Coiffier B, Petillon MO, Coleman M et al. Humanized anti-CD20 antibody, veltuzumab, in refractory/recurrent non-Hodgkin's lymphoma: Phase I/II results. J Clin Oncol 2009;27:3346-53.
101. Carnahan J, Stein R, Qu Z, Hess K, Cesano A, Hansen HJ et al. Epratuzumab, a CD22-targeting recombinant humanized antibody with a different mode of action from rituximab. Mol Immunol 2007;44:1331-41.
102. Halpern WG, Lappin P, Zanardi T, Cai W, Corcoran M, Zhong J, Baker KP. Chronic administration of belimumab, a BLyS antagonist, decreases tissue and peripheral blood B-lymphocyte populations in cynomolgus monkeys: Pharmacokinetic, pharmacodynamic, and toxicologic effects. Toxicol Sci 2006;91:586-99.
103. Hashizume M, Mihara M: The roles of interleukin-6 in the pathogenesis of rheumatoid arthritis. Arthritis 2011, 2011:765624.