Receptor crosstalk: Reprogramming B cell receptor signalling to an alternate pathway results in expression and secretion of the autoimmunity-associated cytokine, osteopontin

Journal of Internal Medicine

Volumn 265, Issue 6, 2009, Pages 632-643

  Rothstein, T L ^a   Guo, B ^a  

^a FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH   (United States)

Author keywords

Autoimmunity; B cells; Cytokines; Signal transduction

Indexed keywords

AUTOANTIBODY; B LYMPHOCYTE RECEPTOR; BRUTON TYROSINE KINASE; IMMUNOGLOBULIN; INTERLEUKIN 4; INTERLEUKIN 4 RECEPTOR; MITOGEN ACTIVATED PROTEIN KINASE; OSTEOPONTIN; PROTEIN KINASE LYN; ROTTLERIN; STAT6 PROTEIN;

AUTOIMMUNITY; CONCEPTUAL FRAMEWORK; CONFERENCE PAPER; CYTOKINE RELEASE; HUMAN; IMMUNITY; IMMUNOGLOBULIN PRODUCTION; MOLECULAR INTERACTION; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; SIGNAL TRANSDUCTION; SIGNALOSOME;

AUTOIMMUNITY; B-LYMPHOCYTES; FEMALE; HUMANS; MALE; OSTEOPONTIN; RECEPTOR CROSS-TALK; RECEPTORS, ANTIGEN, B-CELL; RECEPTORS, INTERLEUKIN-4; SIGNAL TRANSDUCTION;

EID: 66149083273     PISSN: 09546820     EISSN: 13652796     Source Type: Journal    
DOI: 10.1111/j.1365-2796.2009.02103.x     Document Type: Conference Paper

References (102)

1. Chambers SA, Isenberg D. Anti-B cell therapy (rituximab) in the treatment of autoimmune diseases. Lupus 2005 14 : 210 4. (Pubitemid 40445585)
2. Goldblatt F, Isenberg DA. Anti-CD20 monoclonal antibody in rheumatoid arthritis and systemic lupus erythematosus. Handb Exp Pharmacol 2008 181 : 163 81.
3. Tieng AT, Peeva E. B-cell-directed therapies in systemic lupus erythematosus. Semin Arthritis Rheum 2008 38 : 218 27.
4. Ma Y. The potential utility of B cell-directed biologic therapy in autoimmune diseases. Rheumatol Int 2008 28 : 205 15.
5. Mease PJ. B cell-targeted therapy in autoimmune disease: rationale, mechanisms, and clinical application. J Rheumatol 2008 35 : 1245 55.
6. Niiro H, Clark EA. Regulation of B-cell fate by antigen-receptor signals. Nat Rev Immunol 2002 2 : 945 56. (Pubitemid 37323215)
7. Kurosaki T. Regulation of B-cell signal transduction by adaptor proteins. Nat Rev Immunol 2002 2 : 354 63. (Pubitemid 37328758)
8. Gauld SB, Dal Porto JM, Cambier JC. B cell antigen receptor signaling: roles in cell development and disease. Science 2002 296 : 1641 2. (Pubitemid 34579149)
9. Fruman DA, Satterthwaite AB, Witte ON. Xid-like phenotypes: a B cell signalosome takes shape. Immunity 2000 13 : 1 3.
10. Tsukada S, Saffran DC, Rawlings DJ et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 1993 72 : 279 90. (Pubitemid 23044942)
11. Rawlings DJ, Saffran DC, Tsukada S et al. Mutation of unique region of Bruton's tyrosine kinase in immunodeficient XID mice. Science 1993 261 : 358 61. (Pubitemid 23281007)
12. Thomas JD, Sideras P, Smith CI, Vorechovsky I, Chapman V, Paul WE. Colocalization of X-linked agammaglobulinemia and X-linked immunodeficiency genes. Science 1993 261 : 355 8. (Pubitemid 23281006)
13. Sieckmann DG, Asofsky R, Mosier DE, Zitron IM, Paul WE. Activation of mouse lymphocytes by anti-immunoglobulin. I. Parameters of the proliferative response. J Exp Med 1978 147 : 814 29. (Pubitemid 8303494)
14. Parker DC, Fothergill JJ, Wadsworth DC. B lymphocyte activation by insoluble anti-immunoglobulin: induction of immunoglobulin secretion by a T cell-dependent soluble factor. J Immunol 1979 123 : 931 41. (Pubitemid 9211275)
15. Khan WN, Alt FW, Gerstein RM et al. Defective B cell development and function in Btk-deficient mice. Immunity 1995 3 : 283 99.
16. Bajpai UD, Zhang K, Teutsch M, Sen R, Wortis HH. Bruton's tyrosine kinase links the B cell receptor to nuclear factor kappaB activation. J Exp Med 2000 191 : 1735 44. (Pubitemid 30331570)
17. Petro JB, Rahman SM, Ballard DW, Khan WN. Bruton's tyrosine kinase is required for activation of IkappaB kinase and nuclear factor kappaB in response to B cell receptor engagement. J Exp Med 2000 191 : 1745 54. (Pubitemid 30331571)
18. Satterthwaite AB, Cheroutre H, Khan WN, Sideras P, Witte ON. Btk dosage determines sensitivity to B cell antigen receptor cross-linking. Proc Natl Acad Sci USA 1997 94 : 13 152 7. (Pubitemid 27518491)
19. Fruman DA, Snapper SB, Yballe CM et al. Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85alpha. Science 1999 283 : 393 7. (Pubitemid 129501102)
20. Suzuki H, Terauchi Y, Fujiwara M et al. Xid-like immunodeficiency in mice with disruption of the p85alpha subunit of phosphoinositide 3-kinase. Science 1999 283 : 390 2. (Pubitemid 129501101)
21. Jumaa H, Wollscheid B, Mitterer M, Wienands J, Reth M, Nielsen PJ. Abnormal development and function of B lymphocytes in mice deficient for the signaling adaptor protein SLP-65. Immunity 1999 11 : 547 54.
22. Pappu R, Cheng AM, Li B et al. Requirement for B cell linker protein (BLNK) in B cell development. Science 1999 286 : 1949 54. (Pubitemid 129515902)
23. Wang D, Feng J, Wen R et al. Phospholipase Cgamma2 is essential in the functions of B cell and several Fc receptors. Immunity 2000 13 : 25 35.
24. Hashimoto A, Takeda K, Inaba M et al. Cutting edge: essential role of phospholipase C-gamma 2 in B cell development and function. J Immunol 2000 165 : 1738 42. (Pubitemid 30643122)
25. Hayashi K, Nittono R, Okamoto N et al. The B cell-restricted adaptor BASH is required for normal development and antigen receptor-mediated activation of B cells. Proc Natl Acad Sci USA 2000 97 : 2755 60. (Pubitemid 30159244)
26. Xu S, Tan JE, Wong EP, Manickam A, Ponniah S, Lam KP. B cell development and activation defects resulting in xid-like immunodeficiency in BLNK-SLP-65-deficient mice. Int Immunol 2000 12 : 397 404. (Pubitemid 30142711)
27. Okkenhaug K, Bilancio A, Farjot G et al. Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 2002 297 : 1031 4.
28. Clayton E, Bardi G, Bell SE et al. A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation. J Exp Med 2002 196 : 753 63.
29. Jou ST, Carpino N, Takahashi Y et al. Essential, nonredundant role for the phosphoinositide 3-kinase p110delta in signaling by the B-cell receptor complex. Mol Cell Biol 2002 22 : 8580 91. (Pubitemid 35397173)
30. Saijo K, Mecklenbrauker I, Santana A, Leitger M, Schmedt C, Tarakhovsky A. Protein kinase C beta controls nuclear factor kappaB activation in B cells through selective regulation of the IkappaB kinase alpha. J Exp Med 2002 195 : 1647 52. (Pubitemid 34666078)
31. Su TT, Guo B, Kawakami Y et al. PKC-beta controls I kappa B kinase lipid raft recruitment and activation in response to BCR signaling. Nat Immunol 2002 3 : 780 6.
32. Paul WE. Interleukin 4: signalling mechanisms and control of T cell differentiation. Ciba Found Symp 1997 204 : 208 16. discussion 216-209. (Pubitemid 127781338)
33. Kaplan MH, Schindler U, Smiley ST, Grusby MJ. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 1996 4 : 313 9. (Pubitemid 26132509)
34. Shimoda K, van Deursen J, Sangster MY et al. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 1996 380 : 630 3. (Pubitemid 26119016)
35. Takeda K, Tanaka T, Shi W et al. Essential role of Stat6 in IL-4 signalling. Nature 1996 380 : 627 30. (Pubitemid 26119015)
36. Bruns HA, Schindler U, Kaplan MH. Expression of a constitutively active Stat6 in vivo alters lymphocyte homeostasis with distinct effects in T and B cells. J Immunol 2003 170 : 3478 87. (Pubitemid 36359213)
37. Erb KJ, Ruger B, von Brevern M, Ryffel B, Schimpl A, Rivett K. Constitutive expression of interleukin (IL)-4 in vivo causes autoimmune-type disorders in mice. J Exp Med 1997 185 : 329 39. (Pubitemid 27078289)
38. Foote LC, Evans JW, Cifuni JM et al. Interleukin-4 produces a breakdown of tolerance in vivo with autoantibody formation and tissue damage. Autoimmunity 2004 37 : 569 77. (Pubitemid 40378510)
39. Howard M, Farrar J, Hilfiker M et al. Identification of a T cell-derived b cell growth factor distinct from interleukin 2. J Exp Med 1982 155 : 914 23. (Pubitemid 12187863)
40. Rabin EM, Ohara J, Paul WE. B-cell stimulatory factor 1 activates resting B cells. Proc Natl Acad Sci USA 1985 82 : 2935 9. (Pubitemid 15097767)
41. Rabin EM, Mond JJ, Ohara J, Paul WE. B cell stimulatory factor 1 (BSF-1) prepares resting B cells to enter S phase in response to anti-IgM and lipopolysaccharide. J Exp Med 1986 164 : 517 31. (Pubitemid 16050698)
42. Mizuguchi J, Beaven MA, Ohara J, Paul WE. BSF-1 action on resting B cells does not require elevation of inositol phospholipid metabolism or increased [Ca2+]i. J Immunol 1986 137 : 2215 9. (Pubitemid 16020714)
43. Hodgkin PD, Go NF, Cupp JE, Howard M. Interleukin-4 enhances anti-IgM stimulation of B cells by improving cell viability and by increasing the sensitivity of B cells to the anti-IgM signal. Cell Immunol 1991 134 : 14 30.
44. Hashimoto A, Okada H, Jiang A et al. Involvement of guanosine triphosphatases and phospholipase C-gamma2 in extracellular signal-regulated kinase, c-Jun NH2-terminal kinase, and p38 mitogen-activated protein kinase activation by the B cell antigen receptor. J Exp Med 1998 188 : 1287 95. (Pubitemid 28478017)
45. Sakata N, Kawasome H, Terada N, Gerwins P, Johnson GL, Gelfand EW. Differential activation and regulation of mitogen-activated protein kinases through the antigen receptor and CD40 in human B cells. Eur J Immunol 1999 29 : 2999 3008. (Pubitemid 30099024)
46. Jacob A, Cooney D, Pradhan M, Coggeshall KM. Convergence of signaling pathways on the activation of ERK in B cells. J Biol Chem 2002 277 : 23420 6.
47. Moriyama M, Yamochi T, Semba K, Akiyama T, Mori S. BCL-6 is phosphorylated at multiple sites in its serine- and proline-clustered region by mitogen-activated protein kinase (MAPK) in vivo. Oncogene 1997 14 : 2465 74. (Pubitemid 27268165)
48. Fukuda T, Yoshida T, Okada S et al. Disruption of the Bcl6 gene results in an impaired germinal center formation. J Exp Med 1997 186 : 439 48. (Pubitemid 27332902)
49. Niu H, Ye BH, Dalla-Favera R. Antigen receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription factor. Genes Dev 1998 12 : 1953 61. (Pubitemid 28323870)
50. Richards JD, Dave SH, Chou CH, Mamchak AA, DeFranco AL. Inhibition of the MEK-ERK signaling pathway blocks a subset of B cell responses to antigen. J Immunol 2001 166 : 3855 64. (Pubitemid 32224911)
51. Piatelli MJ, Doughty C, Chiles TC. Requirement for a hsp90 chaperone-dependent MEK1-2-ERK pathway for B cell antigen receptor-induced cyclin D2 expression in mature B lymphocytes. J Biol Chem 2002 277 : 12144 50.
52. Tunyaplin C, Shaffer AL, Angelin-Duclos CD, Yu X, Staudt LM, Calame KL. Direct repression of prdm1 by Bcl-6 inhibits plasmacytic differentiation. J Immunol 2004 173 : 1158 65. (Pubitemid 38924291)
53. Guo B, Rothstein TL. B cell receptor (BCR) cross-talk: IL-4 creates an alternate pathway for BCR-induced ERK activation that is phosphatidylinositol 3-kinase independent. J Immunol 2005 174 : 5375 81. (Pubitemid 40593176)
54. Guo B, Blair D, Chiles TC, Lowell CA, Rothstein TL. Cutting Edge: B cell receptor (BCR) cross-talk: the IL-4-induced alternate pathway for BCR signaling operates in parallel with the classical pathway, is sensitive to Rottlerin, and depends on Lyn. J Immunol 2007 178 : 4726 30. (Pubitemid 46595252)
55. Niiro H, Clark EA. Branches of the B cell antigen receptor pathway are directed by protein conduits Bam32 and Carma1. Immunity 2003 19 : 637 40. (Pubitemid 37490788)
56. Gschwendt M, Muller HJ, Kielbassa K et al. Rottlerin, a novel protein kinase inhibitor. Biochem Biophys Res Commun 1994 199 : 93 8. (Pubitemid 24179919)
57. Gauld SB, Cambier JC. Src-family kinases in B-cell development and signaling. Oncogene 2004 23 : 8001 6. (Pubitemid 39468857)
58. Xu Y, Harder KW, Huntington ND, Hibbs ML, Tarlinton DM. Lyn tyrosine kinase: accentuating the positive and the negative. Immunity 2005 22 : 9 18. (Pubitemid 40143447)
59. Wang J, Koizumi T, Watanabe T. Altered antigen receptor signaling and impaired Fas-mediated apoptosis of B cells in Lyn-deficient mice. J Exp Med 1996 184 : 831 8. (Pubitemid 26313541)
60. Chan VW, Meng F, Soriano P, DeFranco AL, Lowell CA. Characterization of the B lymphocyte populations in Lyn-deficient mice and the role of Lyn in signal initiation and down-regulation. Immunity 1997 7 : 69 81. (Pubitemid 27357266)
61. Chan VW, Lowell CA, DeFranco AL. Defective negative regulation of antigen receptor signaling in Lyn-deficient B lymphocytes. Curr Biol 1998 8 : 545 53. (Pubitemid 28222888)
62. Guo B, Tumang JR, Rothstein TL. B cell receptor crosstalk: B cells express osteopontin through the combined action of the alternate and classical BCR signaling pathways. Mol Immunol 2009 46 : 587 91.
63. Patarca R, Freeman GJ, Singh RP et al. Structural and functional studies of the early T lymphocyte activation 1 (Eta-1) gene. Definition of a novel T cell-dependent response associated with genetic resistance to bacterial infection. J Exp Med 1989 170 : 145 61. (Pubitemid 19179701)
64. O'Regan A, Berman JS. Osteopontin: a key cytokine in cell-mediated and granulomatous inflammation. Int J Exp Pathol 2000 81 : 373 90. (Pubitemid 32291179)
65. O'Regan AW, Nau GJ, Chupp GL, Berman JS. Osteopontin (Eta-1) in cell-mediated immunity: teaching an old dog new tricks. Immunol Today 2000 21 : 475 8.
66. Denhardt DT, Giachelli CM, Rittling SR. Role of osteopontin in cellular signaling and toxicant injury. Annu Rev Pharmacol Toxicol 2001 41 : 723 49. (Pubitemid 32385904)
67. Senger DR, Wirth DF, Hynes RO. Transformation-specific secreted phosophoproteins. Nature 1980 286 : 619 21.
68. Oldberg A, Franzen A, Heinegard D. Cloning and sequence analysis of rat bone sialoprotein (osteopontin) cDNA reveals an Arg-Gly-Asp cell-binding sequence. Proc Natl Acad Sci USA 1986 83 : 8819 23. (Pubitemid 17223492)
69. Brown LF, Papadopoulos-Sergiou A, Berse B et al. Osteopontin expression and distribution in human carcinomas. Am J Pathol 1994 145 : 610 23. (Pubitemid 24285968)
70. Liaw L, Birk DE, Ballas CB, Whitsitt JS, Davidson JM, Hogan BL. Altered wound healing in mice lacking a functional osteopontin gene (spp1). J Clin Invest 1998 101 : 1468 78. (Pubitemid 28166845)
71. Ashkar S, Weber GF, Panoutsakopoulou V et al. Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science 2000 287 : 860 4. (Pubitemid 30084330)
72. O'Regan AW, Hayden JM, Berman JS. Osteopontin augments CD3-mediated interferon-gamma and CD40 ligand expression by T cells, which results in IL-12 production from peripheral blood mononuclear cells. J Leukoc Biol 2000 68 : 495 502.
73. Shinohara ML, Jansson M, Hwang ES, Werneck MB, Glimcher LH, Cantor H. T-bet-dependent expression of osteopontin contributes to T cell polarization. Proc Natl Acad Sci USA 2005 102 : 17101 6. (Pubitemid 41692690)
74. Lampe MA, Patarca R, Iregui MV, Cantor H. Polyclonal B cell activation by the Eta-1 cytokine and the development of systemic autoimmune disease. J Immunol 1991 147 : 2902 6.
75. Iizuka J, Katagiri Y, Tada N et al. Introduction of an osteopontin gene confers the increase in B1 cell population and the production of anti-DNA autoantibodies. Lab Invest 1998 78 : 1523 33. (Pubitemid 29022228)
76. Nau GJ, Liaw L, Chupp GL, Berman JS, Hogan BL, Young RA. Attenuated host resistance against Mycobacterium bovis BCG infection in mice lacking osteopontin. Infect Immun 1999 67 : 4223 30. (Pubitemid 29357049)
77. Abel B, Freigang S, Bachmann MF, Boschert U, Kopf M. Osteopontin is not required for the development of Th1 responses and viral immunity. J Immunol 2005 175 : 6006 13. (Pubitemid 41508086)
78. Patarca R, Saavedra RA, Cantor H. Molecular and cellular basis of genetic resistance to bacterial infection: the role of the early T-lymphocyte activation-1-osteopontin gene. Crit Rev Immunol 1993 13 : 225 46. (Pubitemid 2030713)
79. Patarca R, Wei FY, Singh P, Morasso MI, Cantor H. Dysregulated expression of the T cell cytokine Eta-1 in CD4-8- lymphocytes during the development of murine autoimmune disease. J Exp Med 1990 172 : 1177 83. (Pubitemid 20343218)
80. Katagiri Y, Mori K, Hara T, Tanaka K, Murakami M, Uede T. Functional analysis of the osteopontin molecule. Ann N Y Acad Sci 1995 760 : 371 4.
81. Hudkins KL, Giachelli CM, Eitner F, Couser WG, Johnson RJ, Alpers CE. Osteopontin expression in human crescentic glomerulonephritis. Kidney Int 2000 57 : 105 16. (Pubitemid 30227758)
82. Chabas D, Baranzini SE, Mitchell D et al. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 2001 294 : 1731 5. (Pubitemid 33104847)
83. Yumoto K, Ishijima M, Rittling SR et al. Osteopontin deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice. Proc Natl Acad Sci USA 2002 99 : 4556 61. (Pubitemid 34286023)
84. Ohshima S, Yamaguchi N, Nishioka K et al. Enhanced local production of osteopontin in rheumatoid joints. J Rheumatol 2002 29 : 2061 7.
85. Comabella M, Pericot I, Goertsches R et al. Plasma osteopontin levels in multiple sclerosis. J Neuroimmunol 2005 158 : 231 9. (Pubitemid 39626091)
86. Xu G, Nie H, Li N et al. Role of osteopontin in amplification and perpetuation of rheumatoid synovitis. J Clin Invest 2005 115 : 1060 7. (Pubitemid 40489411)
87. Weber GF, Cantor H. Differential roles of osteopontin-Eta-1 in early and late lpr disease. Clin Exp Immunol 2001 126 : 578 83. (Pubitemid 34008735)
88. Jansson M, Panoutsakopoulou V, Baker J, Klein L, Cantor H. Cutting edge: attenuated experimental autoimmune encephalomyelitis in eta-1-osteopontin- deficient mice. J Immunol 2002 168 : 2096 9. (Pubitemid 34171807)
89. Forton AC, Petri MA, Goldman D, Sullivan KE. An osteopontin (SPP1) polymorphism is associated with systemic lupus erythematosus. Hum Mutat 2002 19 : 459.
90. DiPiro JT, Howdieshell TR, Goddard JK, Callaway DB, Hamilton RG, Mansberger AR Jr. Association of interleukin-4 plasma levels with traumatic injury and clinical course. Arch Surg 1995 130 : 1159 62. discussion 1162-1153.
91. Schmidt E, Bastian B, Dummer R, Tony HP, Brocker EB, Zillikens D. Detection of elevated levels of IL-4, IL-6, and IL-10 in blister fluid of bullous pemphigoid. Arch Dermatol Res 1996 288 : 353 7. (Pubitemid 26232085)
92. Inoue N, Inoue M, Kuriki K et al. Interleukin 4 is a crucial cytokine in controlling Trypanosoma brucei gambiense infection in mice. Vet Parasitol 1999 86 : 173 84. (Pubitemid 29425802)
93. Song GY, Chung CS, Chaudry IH, Ayala A. IL-4-induced activation of the Stat6 pathway contributes to the suppression of cell-mediated immunity and death in sepsis. Surgery 2000 128 : 133 8. (Pubitemid 30622474)
94. Chen D, Copeman DB, Burnell J, Hutchinson GW. Helper T cell and antibody responses to infection of CBA mice with Babesia microti. Parasite Immunol 2000 22 : 81 8. (Pubitemid 30098808)
95. Wise GJ, Marella VK, Talluri G, Shirazian D. Cytokine variations in patients with hormone treated prostate cancer. J Urol 2000 164 : 722 5. (Pubitemid 30637610)
96. Uchio E, Ono SY, Ikezawa Z, Ohno S. Tear levels of interferon-gamma, interleukin (IL) -2, IL-4 and IL-5 in patients with vernal keratoconjunctivitis, atopic keratoconjunctivitis and allergic conjunctivitis. Clin Exp Allergy 2000 30 : 103 9. (Pubitemid 30093887)
97. Akpolat N, Yahsi S, Godekmerdan A, Demirbag K, Yalniz M. Relationship between serum cytokine levels and histopathological changes of liver in patients with hepatitis B. World J Gastroenterol 2005 11 : 3260 3. (Pubitemid 40973896)
98. Burstein HJ, Tepper RI, Leder P, Abbas AK. Humoral immune functions in IL-4 transgenic mice. J Immunol 1991 147 : 2950 6.
99. Foote LC, Howard RG, Marshak-Rothstein A, Rothstein TL. IL-4 induces Fas resistance in B cells. J Immunol 1996 157 : 2749 53. (Pubitemid 126450025)
100. Deng C, Kaplan MJ, Yang J et al. Decreased Ras-mitogen-activated protein kinase signaling may cause DNA hypomethylation in T lymphocytes from lupus patients. Arthritis Rheum 2001 44 : 397 407. (Pubitemid 32207034)
101. Molad Y, Amit-Vazina M, Bloch O, Yona E, Rapoport MJ. Increased ERK and JNK activities correlate with disease activity in Systemic Lupus Erythematosus patients. Ann Rheum Dis 2009. [Epub ahead of print].
102. Gorelik G, Richardson B. Aberrant T cell ERK pathway signaling and chromatin structure in lupus. Autoimmun Rev 2009 8 : 196 8.