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B-cell involvement in the pathogenesis of RA–is there a contribution of the sympathetic nervous system?

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Abstract

The pathogenesis of rheumatoid arthritis (RA), the most common rheumatic disease, is still an unsolved puzzle. For many years, T-cells were the main focus of research, but recently, the B-cell drew more and more attention not least, due to the observation in humans that the anti-CD20 antibody Retuximab®, which selectively depletes subsets of B-cells, lessens disease symptoms. A second novel approach to understand pathomechanisms that contribute to the development and progression of arthritis focuses on the sympathetic nervous system, which is known to moderate the function of immune cells, e.g., the B-cell, and therefore, is tied into a complex neuroimmune network that influences the course of the disease. This review first discusses current research that shows the significance of B-cells in the pathogenesis of RA. It then gives a short review of knowledge regarding the role of the sympathetic nervous system (1) in RA pathogenesis and (2) in modulating B-cell responses. Finally, the hypothesis is introduced that the sympathetic nervous system via modulating B-cell function, e.g., antibody production, influences the development and progression of RA.

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References

  1. Edwards JC, Szczepanski L, Szechinski J, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572–81

    PubMed  CAS  Google Scholar 

  2. 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

    PubMed  CAS  Google Scholar 

  3. Magalhaes R, Stiehl P, Morawietz L, Berek C, Krenn V. Morphological and molecular pathology of the B-cell response in synovitis of rheumatoid arthritis. Virchows Arch 2002;441:415–27

    PubMed  CAS  Google Scholar 

  4. Ruschpler P, Stiehl P. Shift in Th1 (IL-2 and IFN-gamma) and Th2 (IL-10 and IL-4) cytokine mRNA balance within two new histological main-types of rheumatoid-arthritis (RA). Cell Mol Biol (Noisy -le-grand) 2002;48:285–93

    CAS  Google Scholar 

  5. Aho K, Heliovaara M, Maatela J, Tuomi T, Palosuo T. Rheumatoid factors antedating clinical rheumatoid arthritis. J Rheumatol 1991;18:1282–4

    PubMed  CAS  Google Scholar 

  6. 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;31:1239–44

    PubMed  Google Scholar 

  7. Halldorsdottir HD, Jonsson T, Thorsteinsson J, Valdimarsson H. A prospective study on the incidence of rheumatoid arthritis among people with persistent increase of rheumatoid factor. Ann Rheum Dis 2000;59:149–51

    PubMed  CAS  Google Scholar 

  8. Nielen MM, van SD, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum 2004;50:380–6

  9. Scofield RH. Autoantibodies as predictors of disease. Lancet 2004;363:1544–6

    PubMed  CAS  Google Scholar 

  10. Newkirk MM. Rheumatoid factors: host resistance or autoimmunity? Clin Immunol 2002;104:1–13

    PubMed  CAS  Google Scholar 

  11. Burkhardt H, Koller T, Engstrom A, 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 2002;46:2339–48

    PubMed  CAS  Google Scholar 

  12. Bas S, Genevay S, Meyer O, Gabay C. Anti-cyclic citrullinated peptide antibodies, IgM and IgA rheumatoid factors in the diagnosis and prognosis of rheumatoid arthritis. Rheumatology (Oxford) 2003;42:677–80

    CAS  Google Scholar 

  13. Moore S, Ruska K, Peters L, Olsen NJ. Associations of IgA and IgA-rheumatoid factor with disease features in patients with rheumatoid arthritis. Immunol Invest 1994;23:355–65

    PubMed  CAS  Google Scholar 

  14. Teitsson I, Withrington RH, Seifert MH, Valdimarsson H. Prospective study of early rheumatoid arthritis. I. Prognostic value of IgA rheumatoid factor. Ann Rheum Dis 1984;43:673–8

    PubMed  CAS  Google Scholar 

  15. Lee DM, Friend DS, Gurish MF, Benoist C, Mathis D, Brenner MB. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science 2002;297:1689–92

    PubMed  CAS  Google Scholar 

  16. Crisp AJ, Chapman CM, Kirkham SE, Schiller AL, Krane SM. Articular mastocytosis in rheumatoid arthritis. Arthritis Rheum 1984;27:845–51

    PubMed  CAS  Google Scholar 

  17. Permin H, Skov PS, Norn S, et al. Possible role of histamine in rheumatoid arthritis. Treatment with cimetidine and mepyramine. Allergy 1981;36:435–6

    PubMed  CAS  Google Scholar 

  18. Tanaka S, Sohen S, Fukuda K. A role for histamine receptors in rheumatoid arthritis. Semin Arthritis Rheum 1997;26:824–33

    PubMed  CAS  Google Scholar 

  19. Yamaura K, Yonekawa T, Nakamura T, Yano S, Ueno K. The histamine H2-receptor antagonist, cimetidine, inhibits the articular osteopenia in rats with adjuvant-induced arthritis by suppressing the osteoclast differentiation induced by histamine. J Pharmacol Sci 2003 May; 92(1):43–992:43–9

    Google Scholar 

  20. De Clerck LS, Westedt ML, Cats A, et al. IgE deposition in normal skin of patients with rheumatoid arthritis in relation to clinical and laboratory findings. Ann Rheum Dis 1985;44:772–7

    PubMed  Google Scholar 

  21. Eisenberg R. Do autoantigens define autoimmunity or vice versa? Eur J Immunol 2005;35:367–70

    PubMed  CAS  Google Scholar 

  22. Blass S, Engel JM, Burmester GR. The immunologic homunculus in rheumatoid arthritis. Arthritis Rheum 1999;42:2499–506

    PubMed  CAS  Google Scholar 

  23. O’Garra A, Stapleton G, Dhar V, et al. Production of cytokines by mouse B-cells: B lymphomas and normal B-cells produce interleukin 10. Int Immunol 1990;2:821–32

    PubMed  CAS  Google Scholar 

  24. Pistoia V. Production of cytokines by human B-cells in health and disease. Immunol Today 1997;18:343–50

    PubMed  CAS  Google Scholar 

  25. Harris DP, Haynes L, Sayles PC, et al. Reciprocal regulation of polarized cytokine production by effector B and T-cells. Nat Immunol 2000;1:475–82

    PubMed  CAS  Google Scholar 

  26. Lund FE, Garvy BA, Randall TD, Harris DP. Regulatory roles for cytokine-producing B-cells in infection and autoimmune disease. Curr Dir Autoimmune 2005;8:25–54

    Article  CAS  Google Scholar 

  27. Harris DP, Goodrich S, Gerth AJ, Peng SL, Lund FE. Regulation of IFN-gamma production by B effector 1 cells: essential roles for T-bet and the IFN-gamma receptor. J Immunol 2005;174:6781–90

    PubMed  CAS  Google Scholar 

  28. Harris DP, Goodrich S, Mohrs K, Mohrs M, Lund FE. Cutting edge: the development of IL-4-producing B-cells (B effector 2 cells) is controlled by IL-4, IL-4 receptor alpha, and Th2 cells. J Immunol 2005;175:7103–7

    PubMed  CAS  Google Scholar 

  29. Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 1996;14:397–440

    PubMed  CAS  Google Scholar 

  30. Williams RO, Feldmann M, Maini RN. Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc Natl Acad Sci USA 1992;89:9784–8

    PubMed  CAS  Google Scholar 

  31. Keffer J, Probert L, Cazlaris H, et al. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J 1991;10:4025–31

    PubMed  CAS  Google Scholar 

  32. Lipsky PE, van der Heijde DM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 2000;343:1594–602

    PubMed  CAS  Google Scholar 

  33. Vassalli P. The pathophysiology of tumor necrosis factors. Annu Rev Immunol 1992;10:411–52

    PubMed  CAS  Google Scholar 

  34. Wang JM, Walter S, Mantovani A. Re-evaluation of the chemotactic activity of tumour necrosis factor for monocytes. Immunology 1990;71:364–7

    PubMed  CAS  Google Scholar 

  35. Hirano T, Matsuda T, Turner M, et al. Excessive production of interleukin 6/B-cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol 1988;18:1797–801

    PubMed  CAS  Google Scholar 

  36. Houssiau FA, Devogelaer JP, Van DJ, de Deuxchaisnes CN, Van SJ. Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum 1988;31:784–8

    Google Scholar 

  37. Takai Y, Seki N, Senoh H, et al. Enhanced production of interleukin-6 in mice with type II collagen-induced arthritis. Arthritis Rheum 1989;32:594–600

    PubMed  CAS  Google Scholar 

  38. Hermann E, Fleischer B, Mayet WJ, Poralla T, Meyer zum Buschenfelde KH. Correlation of synovial fluid interleukin 6 (IL-6) activities with IgG concentrations in patients with inflammatory joint disease and osteoarthritis. Clin Exp Rheumatol 1989;7:411–4

    PubMed  CAS  Google Scholar 

  39. Sawada T, Hirohata S, Inoue T, Ito K. Correlation between rheumatoid factor and IL-6 activity in synovial fluids from patients with rheumatoid arthritis. Clin Exp Rheumatol 1991;9:363–8

    PubMed  CAS  Google Scholar 

  40. Alonzi T, Fattori E, Lazzaro D, et al. Interleukin 6 is required for the development of collagen-induced arthritis. J Exp Med 1998;187:461–8

    PubMed  CAS  Google Scholar 

  41. Sasai M, Saeki Y, Ohshima S, et al. Delayed onset and reduced severity of collagen-induced arthritis in interleukin-6-deficient mice. Arthritis Rheum 1999;42:1635–43

    PubMed  CAS  Google Scholar 

  42. De BF, Massa M, Robbioni P, Ravelli A, Burgio GR, Martini A. Correlation of serum interleukin-6 levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid arthritis. Arthritis Rheum 1991;34:1158–63

    Google Scholar 

  43. Mihara M, Nishimoto N, Ohsugi Y. The therapy of autoimmune diseases by anti-interleukin-6 receptor antibody. Expert Opin Biol Ther 2005;5:683–90

    PubMed  CAS  Google Scholar 

  44. Hirano T. Interleukin-6 and its relation to inflammation and disease. Clin Immunol Immunopathol 1992;62:S60–S65

    PubMed  CAS  Google Scholar 

  45. Cush JJ, Splawski JB, Thomas R, et al. Elevated interleukin-10 levels in patients with rheumatoid arthritis. Arthritis Rheum 1995;38:96–104

    PubMed  CAS  Google Scholar 

  46. Katsikis PD, Chu CQ, Brennan FM, Maini RN, Feldmann M. Immunoregulatory role of interleukin 10 in rheumatoid arthritis. J Exp Med 1994;179:1517–27

    PubMed  CAS  Google Scholar 

  47. Go NF, Castle BE, Barrett R, et al. Interleukin 10, a novel B-cell stimulatory factor: unresponsiveness of X chromosome-linked immunodeficiency B-cells. J Exp Med 1990;172:1625–31

    PubMed  CAS  Google Scholar 

  48. Persson S, Mikulowska A, Narula S, O’Garra A, Holmdahl R. Interleukin-10 suppresses the development of collagen type II-induced arthritis and ameliorates sustained arthritis in rats. Scand J Immunol 1996;44:607–14

    PubMed  CAS  Google Scholar 

  49. Walmsley M, Katsikis PD, Abney E, et al. Interleukin-10 inhibition of the progression of established collagen-induced arthritis. Arthritis Rheum 1996;39:495–503

    PubMed  CAS  Google Scholar 

  50. Tanaka Y, Otsuka T, Hotokebuchi T, et al. Effect of IL-10 on collagen-induced arthritis in mice. Inflamm Res 1996;45:283–8

    PubMed  CAS  Google Scholar 

  51. Apparailly F, Verwaerde C, Jacquet C, Auriault C, Sany J, Jorgensen C. Adenovirus-mediated transfer of viral IL-10 gene inhibits murine collagen-induced arthritis. J Immunol 1998;160:5213–20

    PubMed  CAS  Google Scholar 

  52. Mauri C, Gray D, Mushtaq N, Londei M. Prevention of arthritis by interleukin 10-producing B-cells. J Exp Med 2003;197:489–501

    PubMed  CAS  Google Scholar 

  53. Gommerman JL, Browning JL. Lymphotoxin/light, lymphoid microenvironments and autoimmune disease. Nat Rev Immunol 2003;3:642–55

    PubMed  CAS  Google Scholar 

  54. Koni PA, Sacca R, Lawton P, Browning JL, Ruddle NH, Flavell RA. Distinct roles in lymphoid organogenesis for lymphotoxins alpha and beta revealed in lymphotoxin beta-deficient mice. Immunity 1997;6:491–500

    PubMed  CAS  Google Scholar 

  55. Fu YX, Huang G, Matsumoto M, Molina H, Chaplin DD. Independent signals regulate development of primary and secondary follicle structure in spleen and mesenteric lymph node. Proc Natl Acad Sci USA 1997;94:5739–43

    PubMed  CAS  Google Scholar 

  56. Matsumoto M, Lo SF, Carruthers CJ, et al. Affinity maturation without germinal centres in lymphotoxin-alpha-deficient mice. Nature 1996;382:462–6

    PubMed  CAS  Google Scholar 

  57. Futterer A, Mink K, Luz A, Kosco-Vilbois MH, Pfeffer K. The lymphotoxin beta receptor controls organogenesis and affinity maturation in peripheral lymphoid tissues. Immunity 1998;9:59–70

    PubMed  CAS  Google Scholar 

  58. Rennert PD, James D, Mackay F, Browning JL, Hochman PS. Lymph node genesis is induced by signaling through the lymphotoxin beta receptor. Immunity 1998;9:71–9

    PubMed  CAS  Google Scholar 

  59. Mebius RE. Organogenesis of lymphoid tissues. Nat Rev Immunol 2003;3:292–303

    PubMed  CAS  Google Scholar 

  60. Luther SA, Lopez T, Bai W, Hanahan D, Cyster JG. BLC expression in pancreatic islets causes B-cell recruitment and lymphotoxin-dependent lymphoid neogenesis. Immunity 2000;12:471–81

    PubMed  CAS  Google Scholar 

  61. Koni PA, Flavell RA. Lymph node germinal centers form in the absence of follicular dendritic cell networks. J Exp Med 1999;189:855–64

    PubMed  CAS  Google Scholar 

  62. Aloisi F, Pujol-Borrell R. Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol 2006;6:205–17

    PubMed  CAS  Google Scholar 

  63. Schroder AE, Greiner A, Seyfert C, Berek C. Differentiation of B-cells in the non-lymphoid tissue of the synovial membrane of patients with rheumatoid arthritis. Proc Natl Acad Sci USA 1996;93:221–5

    PubMed  CAS  Google Scholar 

  64. Weyand CM, Goronzy JJ. Ectopic germinal center formation in rheumatoid synovitis. Ann N Y Acad Sci 2003;987:140–9

    Google Scholar 

  65. Fava RA, Notidis E, Hunt J, et al. A role for the lymphotoxin/LIGHT axis in the pathogenesis of murine collagen-induced arthritis. J Immunol 2003;171:115–26

    PubMed  CAS  Google Scholar 

  66. Braun A, Takemura S, Vallejo AN, Goronzy JJ, Weyand CM. Lymphotoxin beta-mediated stimulation of synoviocytes in rheumatoid arthritis. Arthritis Rheum 2004;50:2140–50

    PubMed  CAS  Google Scholar 

  67. Pap T, Meinecke I, Muller-Ladner U, Gay S. Are fibroblasts involved in joint destruction? Ann Rheum Dis 2005;64 Suppl 4:iv52–4

    PubMed  CAS  Google Scholar 

  68. Snider DP, Segal DM. Efficiency of antigen presentation after antigen targeting to surface IgD, IgM, MHC, Fc gamma RII, and B220 molecules on murine splenic B-cells. J Immunol 1989;143:59–65

    PubMed  CAS  Google Scholar 

  69. Batista FD, Neuberger MS. Affinity dependence of the B-cell response to antigen: a threshold, a ceiling, and the importance of off-rate. Immunity 1998;8:751–9

    PubMed  CAS  Google Scholar 

  70. Roth R, Nakamura T, Mamula MJ. B7 costimulation and autoantigen specificity enable B-cells to activate autoreactive T-cells. J Immunol 1996;157:2924–31

    PubMed  CAS  Google Scholar 

  71. Lee BO, Moyron-Quiroz J, Rangel-Moreno J, et al. CD40, but not CD154, expression on B-cells is necessary for optimal primary B-cell responses. J Immunol 2003;171:5707–17

    PubMed  CAS  Google Scholar 

  72. Ozaki ME, Coren BA, Huynh TN, Redondo DJ, Kikutani H, Webb SR. CD4+ T-cell responses to CD40-deficient APCs: defects in proliferation and negative selection apply only with B-cells as APCs. J Immunol 1999;163:5250–6

    PubMed  CAS  Google Scholar 

  73. Hollander GA, Castigli E, Kulbacki R, et al. Induction of alloantigen-specific tolerance by B-cells from CD40-deficient mice. Proc Natl Acad Sci USA 1996;93:4994–8

    PubMed  CAS  Google Scholar 

  74. Buhlmann JE, Foy TM, Aruffo A, et al. In the absence of a CD40 signal, B-cells are tolerogenic. Immunity 1995;2:645–53

    PubMed  CAS  Google Scholar 

  75. Rodriguez-Pinto D. B-cells as antigen presenting cells. Cell Immunol 2005;238:67–75

    PubMed  CAS  Google Scholar 

  76. Lehmann PV, Sercarz EE, Forsthuber T, Dayan CM, Gammon G. Determinant spreading and the dynamics of the autoimmune T-cell repertoire. Immunol Today 1993;14:203–8

    PubMed  CAS  Google Scholar 

  77. Watts C, Lanzavecchia A. Suppressive effect of antibody on processing of T-cell epitopes. J Exp Med 1993;178:1459–63

    PubMed  CAS  Google Scholar 

  78. Davidson HW, Watts C. Epitope-directed processing of specific antigen by B lymphocytes. J Cell Biol 1989;109:85–92

    PubMed  CAS  Google Scholar 

  79. Liang B, Mamula MJ. Molecular mimicry and the role of B lymphocytes in the processing of autoantigens. Cell Mol Life Sci 2000;57:561–8

    PubMed  CAS  Google Scholar 

  80. Brennan FR, Mikecz K, Buzas EI, et al Antigen-specific B-cells present cartilage proteoglycan (aggrecan) to an autoreactive T-cell hybridoma derived from a mouse with proteoglycan-induced arthritis. Clin Exp Immunol 1995;101:414–21

    Article  PubMed  CAS  Google Scholar 

  81. O’Neill SK, Shlomchik MJ, Glant TT, Cao Y, Doodes PD, Finnegan A. Antigen-specific B-cells are required as APCs and autoantibody-producing cells for induction of severe autoimmune arthritis. J Immunol 2005;174:3781–8

    PubMed  CAS  Google Scholar 

  82. Constant S, Schweitzer N, West J, Ranney P, Bottomly K. B lymphocytes can be competent antigen-presenting cells for priming CD4+ T-cells to protein antigens in vivo. J Immunol 1995;155:3734–41

    PubMed  CAS  Google Scholar 

  83. Ron Y, Sprent J. T-cell priming in vivo: a major role for B-cells in presenting antigen to T-cells in lymph nodes. J Immunol 1987;138:2848–56

    PubMed  CAS  Google Scholar 

  84. Kurt-Jones EA, Liano D, HayGlass KA, Benacerraf B, Sy MS, Abbas AK. The role of antigen-presenting B-cells in T-cell priming in vivo. Studies of B-cell-deficient mice. J Immunol 1988;140:3773–8

    PubMed  CAS  Google Scholar 

  85. Janeway CA Jr., Ron J, Katz ME. The B-cell is the initiating antigen-presenting cell in peripheral lymph nodes. J Immunol 1987;138:1051–5

    PubMed  Google Scholar 

  86. Reparon-Schuijt CC, Van Esch WJ, Van KC, Levarht EW, Breedveld FC, Verweij CL. Functional analysis of rheumatoid factor-producing B-cells from the synovial fluid of rheumatoid arthritis patients. Arthritis Rheum 1998;41:2211–20

    Google Scholar 

  87. Reparon-Schuijt CC, Van Esch WJ, Van KC, et al. Presence of a population of CD20+, CD38- B lymphocytes with defective proliferative responsiveness in the synovial compartment of patients with rheumatoid arthritis. Arthritis Rheum 2001;44:2029–37

    Google Scholar 

  88. Hanly JG, Pledger D, Parkhill W, Roberts M, Gross M. Phenotypic characteristics of dissociated mononuclear cells from rheumatoid synovial membrane. J Rheumatol 1990;17:1274–9

    PubMed  CAS  Google Scholar 

  89. Liu MF, Chao SC, Wang CR, Lei HY. Expression of CD40 and CD40 ligand among cell populations within rheumatoid synovial compartment. Autoimmunity 2001;34:107–13

    Article  PubMed  CAS  Google Scholar 

  90. Cho CS, Cho ML, Min SY, et al. CD40 engagement on synovial fibroblast up-regulates production of vascular endothelial growth factor. J Immunol 2000;164:5055–61

    PubMed  CAS  Google Scholar 

  91. Harigai M, Hara M, Kawamoto M, et al. Amplification of the synovial inflammatory response through activation of mitogen-activated protein kinases and nuclear factor kappaB using ligation of CD40 on CD14+ synovial cells from patients with rheumatoid arthritis. Arthritis Rheum 2004;50:2167–77

    PubMed  CAS  Google Scholar 

  92. Harigai M, Hara M, Nakazawa S, et al. Ligation of CD40 induced tumor necrosis factor-alpha in rheumatoid arthritis: a novel mechanism of activation of synoviocytes. J Rheumatol 1999;26:1035–43

    PubMed  CAS  Google Scholar 

  93. Berek C, Kim HJ. B-cell activation and development within chronically inflamed synovium in rheumatoid and reactive arthritis. Semin Immunol 1997;9:261–8

    PubMed  CAS  Google Scholar 

  94. Gause A, Gundlach K, Carbon G, Daus H, Trumper L, Pfreundschuh M. Analysis of VH gene rearrangements from synovial B-cells of patients with rheumatoid arthritis reveals infiltration of the synovial membrane by memory B-cells. Rheumatol Int 1997;17:145–50

    PubMed  CAS  Google Scholar 

  95. Kim HJ, Krenn V, Steinhauser G, Berek C. Plasma cell development in synovial germinal centers in patients with rheumatoid and reactive arthritis. J Immunol 1999;162:3053–62

    PubMed  CAS  Google Scholar 

  96. Takemura S, Braun A, Crowson C, et al. Lymphoid neogenesis in rheumatoid synovitis. J Immunol 2001;167:1072–80

    PubMed  CAS  Google Scholar 

  97. Krenn V, Hensel F, Kim HJ, et al. Molecular IgV(H) analysis demonstrates highly somatic mutated B-cells in synovialitis of osteoarthritis: a degenerative disease is associated with a specific, not locally generated immune response. Lab Invest 1999;79:1377–84

    PubMed  CAS  Google Scholar 

  98. Young CL, Adamson TC III, Vaughan JH, Fox RI. Immunohistologic characterization of synovial membrane lymphocytes in rheumatoid arthritis. Arthritis Rheum 1984;27:32–9

    Google Scholar 

  99. Randen I, Mellbye OJ, Forre O, Natvig JB. The identification of germinal centres and follicular dendritic cell networks in rheumatoid synovial tissue. Scand J Immunol 1995;41:481–6

    PubMed  CAS  Google Scholar 

  100. Krenn V, Morawietz L, Haupl T, Neidel J, Petersen I, Konig A. Grading of chronic synovitis-a histopathological grading system for molecular and diagnostic pathology. Pathol Res Pract 2002;198:317–25

    PubMed  CAS  Google Scholar 

  101. Hardy RR. B-1 B-cells: development, selection, natural autoantibody and leukemia. Curr Opin Immunol 2006;18:547–55

    PubMed  CAS  Google Scholar 

  102. Maini RN, Zyberk CP. The significance of CD5+ B-cells in rheumatic diseases. Scand J Rheumatol Suppl 1988;76:237–42

    PubMed  CAS  Google Scholar 

  103. Mantovani L, Wilder RL, Casali P. Human rheumatoid B-1a (CD5+ B) cells make somatically hypermutated high affinity IgM rheumatoid factors. J Immunol 1993;151:473–88

    PubMed  CAS  Google Scholar 

  104. Iciek LA, Waldschmidt TJ, Griffiths MM, Brooks KH. B-1 cells in systemic autoimmune responses: IgM+, Fc epsilon Rdull B-cells are lost during chronic graft-versus-host disease but not in murine AIDS or collagen-induced arthritis. Immunol Invest 1994;23:293–311

    PubMed  CAS  Google Scholar 

  105. Kruetzmann S, Rosado MM, Weber H, et al. Human immunoglobulin M memory B-cells controlling Streptococcus pneumoniae infections are generated in the spleen. J Exp Med 2003;197:939–45

    PubMed  CAS  Google Scholar 

  106. Mizoguchi A, Bhan AK. A case for regulatory B-cells. J Immunol 2006;176:705–10

    PubMed  CAS  Google Scholar 

  107. Harle P, Mobius D, Carr DJ, Scholmerich J, Straub RH. An opposing time-dependent immune-modulating effect of the sympathetic nervous system conferred by altering the cytokine profile in the local lymph nodes and spleen of mice with type II collagen-induced arthritis. Arthritis Rheum 2005;52:1305–13

    PubMed  Google Scholar 

  108. Miller LE, Justen HP, Scholmerich J, Straub RH. The loss of sympathetic nerve fibers in the synovial tissue of patients with rheumatoid arthritis is accompanied by increased norepinephrine release from synovial macrophages. FASEB J 2000;14:2097–107

    PubMed  CAS  Google Scholar 

  109. Dekkers JC, Geenen R, Godaert GL, Bijlsma JW, van Doornen LJ. Elevated sympathetic nervous system activity in patients with recently diagnosed rheumatoid arthritis with active disease. Clin Exp Rheumatol 2004;22:63–70

    PubMed  CAS  Google Scholar 

  110. Kuis W, de Jong-de Vos van Steenwijk, Sinnema G, et al. The autonomic nervous system and the immune system in juvenile rheumatoid arthritis. Brain Behav Immun 1996;10:387–98

  111. Tanaka H, Ueta Y, Yamashita U, Kannan H, Yamashita H. Biphasic changes in behavioral, endocrine, and sympathetic systems in adjuvant arthritis in Lewis rats. Brain Res Bull 1996;39:33–7

    PubMed  CAS  Google Scholar 

  112. Miller LE, Grifka J, Scholmerich J, Straub RH. Norepinephrine from synovial tyrosine hydroxylase positive cells is a strong indicator of synovial inflammation in rheumatoid arthritis. J Rheumatol 2002;29:427–35

    PubMed  CAS  Google Scholar 

  113. Kin NW, Sanders VM. It takes nerve to tell T and B-cells what to do. J Leukoc Biol 2006;79:1093–104

    PubMed  CAS  Google Scholar 

  114. Kohm AP, Sanders VM. Norepinephrine: a messenger from the brain to the immune system. Immunol Today 2000;21:539–42

    PubMed  CAS  Google Scholar 

  115. Pochet R, Delespesse G, Gausset PW, Collet H. Distribution of beta-adrenergic receptors on human lymphocyte subpopulations. Clin Exp Immunol 1979;38:578–84

    PubMed  CAS  Google Scholar 

  116. Griese M, Korholz U, Korholz D, Seeger K, Wahn V, Reinhardt D. Density and agonist-promoted high and low affinity states of the beta-adrenoceptor on human B- and T-cells. Eur J Clin Invest 1988;18:213–7

    PubMed  CAS  Google Scholar 

  117. Korholz D, Seeger K, Griese M, Wahn V, Reifenhauser A, Reinhardt D. Beta-adrenoceptor density and resolution of high and low affinity state on B- and T-cells in asthmatic and non-asthmatic children. Eur J Pediatr 1988;147:116–20

    PubMed  CAS  Google Scholar 

  118. Kohm AP, Sanders VM. Suppression of antigen-specific Th2 cell-dependent IgM and IgG1 production following norepinephrine depletion in vivo. J Immunol 1999;162:5299–308

    PubMed  CAS  Google Scholar 

  119. Podojil JR, Sanders VM. Selective regulation of mature IgG1 transcription by CD86 and beta 2-adrenergic receptor stimulation. J Immunol 1904;170:5143–51

    Google Scholar 

  120. Pongratz G, McAlees JW, Conrad DH, Erbe RS, Haas KM, Sanders VM. The level of IgE produced by a B-cell is regulated by norepinephrine in a p38. J Immunol 2006;177:2926–38

    PubMed  CAS  Google Scholar 

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Pongratz, G., Straub, R.H. B-cell involvement in the pathogenesis of RA–is there a contribution of the sympathetic nervous system?. Immunol Res 40, 148–163 (2008). https://doi.org/10.1007/s12026-007-8002-0

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