Genetic susceptibility to lupus: The biological basis of genetic risk found in B cell signaling pathways

Journal of Leukocyte Biology

Volumn 92, Issue 3, 2012, Pages 577-591

  Vaughn, Samuel E ^a,b   Kottyan, Leah C ^a   Munroe, Melissa E ^c   Harley, John B ^a  

^a CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER   (United States)

^b UNIVERSITY OF CINCINNATI   (United States)

^c OKLAHOMA MEDICAL RESEARCH FOUNDATION   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AUTOPHAGY PROTEIN 5; BANK1 PROTEIN; BREAKPOINT CLUSTER REGION PROTEIN; C REACTIVE PROTEIN; CD40 ANTIGEN; CD45 ANTIGEN; HERMES ANTIGEN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERFERON CONSENSUS SEQUENCE BINDING PROTEIN; INTERFERON REGULATORY FACTOR 5; INTERFERON REGULATORY FACTOR 7; INTERLEUKIN 1 RECEPTOR ASSOCIATED KINASE 1; INTERLEUKIN 10; INTERLEUKIN 2; INTERLEUKIN 21; METHYL CPG BINDING PROTEIN 2; MICRORNA 146A; NON RECEPTOR PROTEIN TYROSINE PHOSPHATASE 22; OX40 LIGAND; PROTEIN KINASE LYN; PROTEIN KINASE TYK2; PROTEIN TYROSINE KINASE; STAT4 PROTEIN; TNFAIP3 PROTEIN; TNIP1 PROTEIN; TOLL LIKE RECEPTOR 7; TRANSCRIPTION FACTOR ELF 1; TRANSCRIPTION FACTOR ETS 1; UBIQUITINATED PROTEIN; UNCLASSIFIED DRUG;

ANTIPHOSPHOLIPID SYNDROME; AUTOIMMUNE HEMOLYTIC ANEMIA; B LYMPHOCYTE; CELL SELECTION; CELL SURVIVAL; ENZYME ACTIVITY; GENE EXPRESSION; GENE FREQUENCY; GENETIC ASSOCIATION; GENETIC RISK; GENETIC SUSCEPTIBILITY; GENETIC VARIABILITY; HUMAN; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION; SINGLE NUCLEOTIDE POLYMORPHISM; SYSTEMIC LUPUS ERYTHEMATOSUS;

B-LYMPHOCYTES; GENETIC PREDISPOSITION TO DISEASE; HUMANS; LUPUS ERYTHEMATOSUS, SYSTEMIC; RECEPTORS, ANTIGEN, B-CELL; RISK FACTORS; SIGNAL TRANSDUCTION;

EID: 84865473936     PISSN: 07415400     EISSN: None     Source Type: Journal    
DOI: 10.1189/jlb.0212095     Document Type: Review

References (159)

1. Tan, E. M., Cohen, A. S., Fries, J. F., Masi, A. T., McShane, D. J., Roth-field, N. F., Schaller, J. G., Talal, N., Winchester, R.J. (1982) The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthntis Rheum. 25, 1271-1277.
2. Hochberg, M. C. (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 40, 1725.
3. Alarcon-Segovia, D., Alarcon-Riquelme, M. E., Cardiel, M. H., Caeiro, F., Massardo, L., Villa, A. R., Pons-Estel, B. A., Grupo Latinoamericano de Estudio del Lupus Eritematoso (GLADEL) (2005) Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort. Arthritis Rheum. 52, 1138-1147.
4. Deapen, D., Escalante, A., Weinrib, L., Horwitz, D., Bachman, B., Roy-Bur-man, P., Walker, A., Mack, T. M. (1992) A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum. 35, 311-318.
5. Kyogoku, C., Langefeld, C. D., Ortmann, W. A., Lee, A., Selby, S., Carlton, V. E., Chang, M., Ramos, P., Baechler, E. C., Batliwalla, F. M., et al. (2004) Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am. J. Hum. Genet. 75, 504-507.
6. Harley, J. B., Alarcon-Riquelme, M. E., Criswell, L. A., Jacob, C. O., Kimberly, R. P., Moser, K L., Tsao, B. P., Vyse, T. J., Langefeld, C. D., Nath, S. K., Guthridge, J. M., Cobb, B. L., Mirel, D. B., Marion, M. C., Williams, A. H., Divers, J., Wang, W., Frank, S. G., Namjou, B., Gabriel, S. B., Lee, A. T., Gregersen, P. k., Behrens, T. W., Taylor, K E., Fernando, M., Zi-dovetzki, R., Gaffney, P. M., Edberg, J. C., Rioux, J. D., Ojwang, J. O., James, J. A., Merrill, J. T., Gilkeson, G. S., Seldin, M. F., Yin, H., Baechler, E. C., Li, Q. Z., Wakeland, E. K., Bruner, G. R., Kaufman, K M., Kelly, J. A. (2008) Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat. Genet. 40, 204-210.
7. Gateva, V., Sandling, J. K, Hom, G., Taylor, K E., Chung, S. A., Sun, X., Ortmann, W., Kosoy, R., Ferreira, R. C., Nordmark, G., et al. (2009) A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat. Genet. 41, 1228-1233.
8. Morris, D. L., Roberts, A. L., Witherden, A. S., Tarzi, R., Barros, P., Whittaker, J. C., Cook, T. H., Aitman, T. J., Vyse, T. J. (2010) Evidence for both copy number and allelic (NA1/NA2) risk at the FCGR3B locus in systemic lupus erythematosus. Eur. J. Hum. Genet. 18, 1027-1031.
9. Karassa, F. B., Trikalinos, T. A, Ioannidis, J. P. (2002) Role of the Fc7 receptor IIa polymorphism in susceptibility to systemic lupus erythematosus and lupus nephritis: a meta-analysis. Arthritis Rheum. 46, 1563-1571.
10. Karassa, F. B., Trikalinos, T. A., Ioannidis, J. P. (2003) The Fc y RIIIA-F158 allele is a risk factor for the development of lupus nephritis: a meta-analysis. Kidney Int. 63, 1475-1482.
11. Yu, B., Chen, Y., Wu, Q., Li, P., Shao, Y., Zhang, J., Zhong, Q., Peng, X., Yang, H., Hu, X., Chen, B., Guan, M., Wan, J., Zhang, W. (2011) The association between single-nucleotide polymorphisms of NCF2 and systemic lupus erythematosus in Chinese mainland population. Clin. Rheumatol. 30, 521-527.
12. Graham, R. R., Cotsapas, C., Davies, L., Hackett, R., Lessard, C. J., Leon, J. M., Burtt, N. P., Guiducci, C., Parkin, M., Gates, C., Plenge, R. M., Behrens, T. W., Wither, J. E., Rioux, J. D., Fortin, P. R., Graham, D. C., Wong, A. K., Vyse, T. J., Daly, M. J., Altshuler, D., Moser, K L., Gaffney, P. M. (2008) Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat. Genet. 40, 1059-1061.
13. Jacob, C. O., Eisenstein, M., Dinauer, M. C., Ming, W., Liu, Q., John, S., Quismorio Jr., F. P., Reiff, A., Myones, B. L., Kaufman, K M., McCurdy, D., Harley, J. B., Silverman, E., Kimberly, R. P., Vyse, T. J., Gaffney, P. M., Moser, K L., Klein-Gitelman, M., Wagner-Weiner, L., Langefeld, C. D., Armstrong, D. L., Zidovetzki, R. (2012) Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase. Proc. Natl. Acad. Sci. USA 109, E59-E67.
14. Edberg, J. C., Wu, J., Langefeld, C. D., Brown, E. E., Marion, M. C., McGwin Jr., G., Petri, M., Ramsey-Goldman, R., Reveille, J. D., Frank, S. G., Kaufman, K M., Harley, J. B., Alarcon, G. S., Kimberly, R. P. (2008) Genetic variation in the CRP promoter: association with systemic lupus erythematosus. Hum. Mol. Genet. 17, 1147-1155.
15. Sanchez, E., Comeau, M. E., Freedman, B. I., Kelly, J. A., Kaufman, K. M., Langefeld, C. D., Brown, E. E., Alarcon, G. S., Kimberly, R. P., Edberg, J. C. et al. (2011) Identification of novel genetic susceptibility loci in African American lupus patients in a candidate gene association study. Arthritis Rheum. 63, 3493-3501.
16. Han, J. W., Zheng, H. F., Cui, Y., Sun, L. D., Ye, D. Q., Hu, Z., Xu, J. H., Cai, Z. M., Huang, W., Zhao, G. P., et al. (2009) Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat. Genet. 41, 1234-1237.
17. Yu, H. H., Liu, P. H., Lin, Y. C., Chen, W. J., Lee, J. H., Wang, L. C., Yang, Y. H., Chiang, B. L. (2010) Interleukin 4 and STAT6 gene polymorphisms are associated with systemic lupus erythematosus in Chinese patients. Lupus 19, 1219-1228.
18. Lin, Y. J., Wan, L., Huang, C. M., Sheu, J.J., Chen, S. Y., Lin, T. H., Chen, D. Y., Hsueh, K C., Lai, C. C., Tsai, F.J. (2010) IL-10 and TNF-α promoter polymorphisms in susceptibility to systemic lupus erythematosus in Taiwan. Clin. Exp. Rheumatol. 28, 318-324.
19. Bowness, P., Davies, K A., Norsworthy, P. J., Athanassiou, P., Taylor-Wiede-man, J., Borysiewicz, L. K., Meyer, P. A., Walport, M.J. (1994) Hereditary C1q deficiency and systemic lupus erythematosus. QJM 87, 455-464.
20. Davies, K A., Schifferli, J. A., Walport, M.J. (1994) Complement deficiency and immune complex disease. Springer Semin. Immunopathol 15, 397-416.
21. Nishino, H., Shibuya, K., Nishida, Y., Mushimoto, M. (1981) Lupus ery-thematosus-like syndrome with selective complete deficiency of C1q. Ann. Intern. Med. 95, 322-324.
22. Suzuki, Y., Ogura, Y., Otsubo, O., Akagi, K, Fujita, T. (1992) Selective deficiency of C1s associated with a systemic lupus erythematosus-like syndrome. Report of a case. Arthritis Rheum. 35, 576-579.
23. Walport, M. J., Davies, K A., Morley, B. J., Botto, M. (1997) Complement deficiency and autoimmunity. Ann. N. Y. Acad. Sci. 815, 267-281.
24. Cunninghame Graham, D. S., Morris, D. L., Bhangale, T. R., Criswell, L. A., Syvanen, A. C., Ronnblom, L., Behrens, T. W., Graham, R. R., Vyse, T.J. (2011) Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with systemic lupus erythematosus. PLoS Genet. 7, e1002341.
25. Abelson, A. K., Delgado-Vega, A. M., Kozyrev, S. V., Sanchez, E., Velazquez-Cruz, R., Eriksson, N., Wojcik, J., Linga Reddy, M. V., Lima, G., D'Alfonso, S., et al. (2009) STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk. Ann. Rheum. Dis. 68, 1746-1753.
26. Remmers, E. F., Plenge, R. M., Lee, A. T., Graham, R. R., Hom, G., Behrens, T. W., de Bakker, P. I., Le, J. M., Lee, H. S., Batliwalla, F., et al. (2007) STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N. Engl. J. Med. 357, 977-986.
27. Yuan, H., Feng, J. B., Pan, H. F., Qiu, L. X., Li, L. H., Zhang, N., Ye, D. Q. (2010) A meta-analysis of the association of STAT4 polymorphism with systemic lupus erythematosus. Mod. Rheumatol. 20, 257-262.
28. Namjou, B., Sestak, A. L., Armstrong, D. L., Zidovetzki, R., Kelly, J. A., Jacob, N., Ciobanu, V., Kaufman, K M., Ojwang, J. O., Ziegler, J., et al. (2009) High-density genotyping of STAT4 reveals multiple haplotypic associations with systemic lupus erythematosus in different racial groups. Arthritis Rheum. 60, 1085-1095.
29. Namjou, B., Kothari, P. H., Kelly, J. A., Glenn, S. B., Ojwang, J. O., Adler, A., Alarcon-Riquelme, M. E., Gallant, C. J., Boackle, S. A., Criswell, L. A., et al. (2011) Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes Immun. 12, 270-279.
30. Lee-Kirsch, M. A., Gong, M., Chowdhury, D., Senenko, L., Engel, K., Lee, Y. A., de Silva, U., Bailey, S. L., Witte, T., Vyse, T. J., et al. (2007) Mutations in the gene encoding the 3-5= DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat. Genet. 39, 1065-1067.
31. Kozyrev, S. V., Abelson, A. K., Wojcik, J., Zaghlool, A., Linga Reddy, M. V., Sanchez, E., Gunnarsson, I., Svenungsson, E., Sturfelt, G., et al. (2008) Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat. Genet. 40, 211-216.
32. Fan, Y., Tao, J. H., Zhang, L. P., Li, L. H., Ye, D. Q. (2011) The association between BANK1 and TNFAIP3 gene polymorphisms and systemic lupus erythematosus: a meta-analysis. Int. J. Immunogenet. 38, 151-159.
33. Hughes, T., Kim-Howard, X., Kelly, J. A., Kaufman, K M., Langefeld, C. D., Ziegler, J., Sanchez, E., Kimberly, R. P., Edberg, J. C., Ramsey-Goldman, R., et al. (2011) Fine-mapping and transethnic genotyping establish IL2/IL21 genetic association with lupus and localize this genetic effect to IL21. Arthritis Rheum. 63, 1689-1697.
34. Zhong, H., Li, X. L., Li, M., Hao, L. X., Chen, R. W., Xiang, K., Qi, X. B., Ma, R. Z., Su, B. (2011) Replicated associations of TNFAIP3, TNIP1 and ETS1 with systemic lupus erythematosus in a southwestern Chinese population. Arthritis Res. Ther. 13, R186.
35. Kawasaki, A., Ito, S., Furukawa, H., Hayashi, T., Goto, D., Matsumoto, I., Kusaoi, M., Ohashi, J., Graham, R. R., Matsuta, K, et al. (2010) Association of TNFAIP3 interacting protein 1, TNIP1 with systemic lupus erythematosus in a Japanese population: a case-control association study. Arthritis Res. Ther. 12, R174.
36. He, C. F., Liu, Y. S., Cheng, Y. L., Gao, J. P., Pan, T. M., Han, J. W., Quan, C., Sun, L. D., Zheng, H. F., Zuo, X. B., et al. (2010) TNIP1, SLC15A4, ETS1, RasGRP3 and IKZF1 are associated with clinical features of systemic lupus erythematosus in a Chinese Han population. Lupus 19, 1181-1186.
37. Luo, X., Yang, W., Ye, D. Q., Cui, H., Zhang, Y., Hirankarn, N., Qian, X., Tang, Y., Lau, Y. L., de Vries, N., Tak, P. P., Tsao, B. P., Shen, N. (2011) A functional variant in microRNA-146a promoter modulates its expression and confers disease risk for systemic lupus erythematosus. PLoS Genet. 7, e1002128.
38. Lofgren, S. E., Frostegard, J., Truedsson, L., Pons-Estel, B. A., D'Alfonso, S., Witte, T., Lauwerys, B. R., Endreffy, E., Kovacs, L, Vas-concelos, C., Martins da Silva, B., Kozyrev, S. V., Alarcon-Riquelme, M. E. (2012) Genetic association of miRNA-146a with systemic lupus erythematosus in Europeans through decreased expression of the gene. Genes Immun. 13, 268-274.
39. Barcellos, L. F., May, S. L., Ramsay, P. P., Quach, H. L., Lane, J. A., Nititham, J., Noble, J. A., Taylor, K E., Quach, D. L., Chung, S. A., et al. (2009) High-density SNP screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions. PLoS Genet. 5, e1000696.
40. Zhang, Y., Yang, W., Mok, C. C., Chan, T. M., Wong, R. W., Mok, M. Y., Lee, K W., Wong, S. N., Leung, A. M., Lee, T. L., et al. (2011) Two missense variants in UHRF1BP1 are independently associated with systemic lupus erythematosus in Hong Kong Chinese. Genes Immun. 12, 231-234.
41. Adrianto, I., Wen, F., Templeton, A., Wiley, G., King, J. B., Lessard, C. J., Bates, J. S., Hu, Y., Kelly, J. A., Kaufman, K.M., et al. (2011) Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus. Nat. Genet. 43, 253-258.
42. Lodolce, J. P., Kolodziej, L. E., Rhee, L., Kariuki, S. N., Franek, B. S., McGreal, N. M., Logsdon, M. F., Bartulis, S. J., Perera, M. A., Ellis, N. A., et al. (2010) African-derived genetic polymorphisms in TNFAIP3 mediate risk for autoimmunity. J. Immunol. 184, 7001-7009.
43. Musone, S. L., Taylor, K. E., Lu, T. T., Nititham, J., Ferreira, R. C., Ort-mann, W., Shifrin, N., Petri, M. A., Kamboh, M. I., Manzi, S., et al. (2008) Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat. Genet. 40, 1062-1064.
44. Sigurdsson, S., Goring, H. H., Kristjansdottir, G., Milani, L., Nordmark, G., Sandling, J. K., Eloranta, M. L., Feng, D., Sangster-Guity, N., Gun-narsson, I., et al. (2008) Comprehensive evaluation of the genetic variants of interferon regulatory factor 5 (IRF5) reveals a novel 5 bp length polymorphism as strong risk factor for systemic lupus erythematosus. Hum. Mol. Genet. 17, 872-881.
45. Sigurdsson, S., Padyukov, L., Kurreeman, F. A., Liljedahl, U., Wiman, A. C., Alfredsson, L., Toes, R., Ronnelid, J., Klareskog, L., Huizinga, T. W., Alm, G., Syvanen, A. C., Ronnblom, L. (2007) Association of a haplotype in the promoter region of the interferon regulatory factor 5 gene with rheumatoid arthritis. Arthritis Rheum. 56, 2202-2210.
46. Sigurdsson, S., Nordmark, G., Goring, H. H., Lindroos, K, Wiman, A. C., Sturfelt, G., Jonsen, A., Rantapaa-Dahlqvist, S., Moller, B., Kere, J., et al. (2005) Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am. J. Hum. Genet. 76, 528-537.
47. Graham, R. R., Kozyrev, S. V., Baechler, E. C., Reddy, M. V., Plenge, R. M., Bauer, J. W., Ortmann, W. A., Koeuth, T., Gonzalez Escribano, M. F., Pons-Estel, B., et al. (2006) A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat. Genet. 38, 550-555.
48. Budarf, M. L., Goyette, P., Boucher, G., Lian, J., Graham, R. R., Claudio, J. O., Hudson, T., Gladman, D., Clarke, A. E., Pope, J. E., et al. (2011) A targeted association study in systemic lupus erythematosus identifies multiple susceptibility alleles. Genes Immun. 12, 51-58.
49. Lu, R., Vidal, G. S., Kelly, J. A., Delgado-Vega, A. M., Howard, X. K., Macwana, S. R., Dominguez, N., Klein, W., Burrell, C., Harley, I. T., et al. (2009) Genetic associations of LYN with systemic lupus erythematosus. Genes Immun. 10, 397-403.
50. Yang, W., Shen, N., Ye, D. Q., Liu, Q., Zhang, Y., Qian, X. X., Hiran-karn, N., Ying, D., Pan, H. F., Mok, C. C., et al. (2010) Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genet. 6, e1000841.
51. Ramos, P. S., Criswell, L. A., Moser, K. L., Comeau, M. E., Williams, A. H., Pajewski, N. M., Chung, S. A., Graham, R. R., Zidovetzki, R., Kelly, J. A., et al. (2011) A comprehensive analysis of shared loci between systemic lupus erythematosus (SLE) and sixteen autoimmune diseases reveals limited genetic overlap. PLoS Genet. 7, e1002406.
52. Lessard, C. J., Adrianto, I., Kelly, J. A., Kaufman, K M., Grundahl, K M., Adler, A., Williams, A. H., Gallant, C.J., Anaya, J. M., Bae, S. C., et al. (2011) Identification of a systemic lupus erythematosus susceptibility locus at 11p13 between PDHX and CD44 in a multiethnic study. Am. J. Hum. Genet. 88, 83-91.
53. Yang, J., Yang, W., Hirankarn, N., Ye, D. Q., Zhang, Y., Pan, H. F., Mok, C. C., Chan, T. M., Wong, R. W., et al. (2011) ELF1 is associated with systemic lupus erythematosus in Asian populations. Hum. Mol. Genet. 20, 601-607.
54. Hom, G., Graham, R. R., Modrek, B., Taylor, K E., Ortmann, W., Gar-nier, S., Lee, A. T., Chung, S. A., Ferreira, R. C., et al. (2008) Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N. Engl. J. Med. 358, 900-909.
55. Molineros, J. E., Kim-Howard, X., Deshmukh, H., Jacob, C. O., Harley, J. B., Nath, S. K (2009) Admixture in Hispanic Americans: its impact on ITGAM association and implications for admixture mapping in SLE. Genes Immun. 10, 539-545.
56. Sheng, Y.J., Gao, J. P., Li, J., Han, J. W., Xu, Q., Hu, W. L., Pan, T. M., Cheng, Y. L., Yu, Z. Y., Ni, C., Yao, S., He, C. F., Liu, Y. S., Li, Y., Ge, H. M., Xiao, F. L., Sun, L. D., Yang, S., Zhang, X. J. (2011) Follow-up study identifies two novel susceptibility loci PRKCB and 8p11.21 for systemic lupus erythematosus. Rheumatology (Oxford) 50, 682-688.
57. Suarez-Gestal, M., Calaza, M., Endreffy, E., Pullmann, R., Ordi-Ros, J., Sebastiani, G. D., Ruzickova, S., Jose Santos, M., Papasteriades, C., Marchini, M., Skopouli, F. N., Suarez, A., Blanco, F. J., D'Alfonso, S., Bijl, M., Carreira, P., Witte, T., Migliaresi, S., Gomez-Reino, J. J., Gonzalez, A. (2009) Replication of recently identified systemic lupus erythematosus genetic associations: a case-control study. Arthritis Res. Ther. 11, R69.
58. Vazgiourakis, V. M., Zervou, M. I., Choulaki, C., Bertsias, G., Melissour-gaki, M., Yilmaz, N., Sidiropoulos, P., Plant, D., Trouw, L. A., Toes, R. E., Kardassis, D., Yavuz, S., Boumpas, D. T., Goulielmos, G. N. (2011) A common SNP in the CD40 region is associated with systemic lupus erythematosus and correlates with altered CD40 expression: implications for the pathogenesis. Ann. Rheum. Dis. 70, 2184-2190.
59. Shen, N., Fu, Q., Deng, Y., Qian, X., Zhao, J., Kaufman, K M., Wu, Y. L., Yu, C. Y., Tang, Y., Chen, J. Y., et al. (2010) Sex-specific association of X-linked Toll-like receptor 7 (TLR7) with male systemic lupus erythematosus. Proc. Natl. Acad. Sci. USA 107, 15838-15843.
60. Sawalha, A. H., Webb, R., Han, S., Kelly, J. A., Kaufman, K M., Kimberly, R. P., Alarcon-Riquelme, M. E., James, J. A., Vyse, T. J., Gilkeson, G. S., Choi, C. B., Scofield, R. H., Bae, S. C., Nath, S. K., Harley, J. B. (2008) Common variants within MECP2 confer risk of systemic lupus erythematosus. PLoS One 3, e1727.
61. Webb, R., Wren, J. D., Jeffries, M., Kelly, J. A., Kaufman, K M., Tang, Y., Frank, M. B., Merrill, J., Kimberly, R. P., Edberg, J. C., et al. (2009) Variants within MECP2, a key transcription regulator, are associated with increased susceptibility to lupus and differential gene expression in patients with systemic lupus erythematosus. Arthritis Rheum. 60, 1076-1084.
62. Moser, K L., Kelly, J. A., Lessard, C. J., Harley, J. B. (2009) Recent insights into the genetic basis of systemic lupus erythematosus. Genes Im-mun. 10, 373-379.
63. Deng, Y., Tsao, B. P. (2010) Genetic susceptibility to systemic lupus erythematosus in the genomic era. Nat. Rev. Rheumatol. 6, 683-692.
64. Siontis, K C., Patsopoulos, N. A., Ioannidis, J. P. (2010) Replication of past candidate loci for common diseases and phenotypes in 100 genome-wide association studies. Eur. J. Hum. Genet. 18, 832-837.
65. Pe'er, I., Yelensky, R., Altshuler, D., Daly, M. J. (2008) Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet. Epidemiol. 32, 381-385.
66. Harley, J. B. (2007) IL-7Ra and multiple sclerosis risk. Nat. Genet. 39, 1053-1054.
67. Trynka, G., Hunt, K A., Bockett, N. A., Romanos, J., Mistry, V., Szperl, A., Bakker, S. F., Bardella, M. T., Bhaw-Rosun, L., Castillejo, G., et al. (2011) Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat. Genet. 43, 1193-1201.
68. Nath, S. K, Han, S., Kim-Howard, X., Kelly, J. A., Viswanathan, P., Gil-keson, G. S., Chen, W., Zhu, C., Mcever, R. P., Kimberly, R. P., Alarcon-Riquelme, M. E., Vyse, T. J., Li Q-Z, Wakeland, E. K, Merrill, J. T., James, J. A., Kaufman, K M., Guthridge, J. M., Harley, J. B. (2008) A nonsynonymous functional variant in integrin-a(M) (encoded by ITGAM) is associated with systemic lupus erythematosus. Nat. Genet. 40, 152-154.
69. Wen, F., Ellingson, S. M., Kyogoku, C., Peterson, E. J., Gaffney, P. M. (2011) Exon 6 variants carried on systemic lupus erythematosus (SLE) risk haplotypes modulate IRF5 function. Autoimmunity 44, 82-89.
70. Lofgren, S. E., Yin, H., Delgado-Vega, A. M., Sanchez, E., Lewen, S., Pons-Estel, B. A., Witte, T., D'Alfonso, S., Ortego-Centeno, N., Martin, J., Alarcon-Riquelme, M. E., Kozyrev, S. V. (2010) Promoter insertion/ deletion in the IRF5 gene is highly associated with susceptibility to systemic lupus erythematosus in distinct populations, but exerts a modest effect on gene expression in peripheral blood mononuclear cells. J. Rheumatol. 37, 574-578.
71. Hu, X., Kim, H., Stahl, E., Plenge, R., Daly, M., Raychaudhuri, S. (2011) Integrating autoimmune risk loci with gene-expression data identifies specific pathogenic immune cell subsets. Am. J. Hum. Genet. 89, 496-506.
72. Harley, I. T. W., Kaufman, K. M., Langefeld, C. D., Harley, J. B., Kelly, J. A. (2009) Genetic susceptibility to SLE: new insights from fine mapping and genome-wide association studies. Nat. Rev. Genetics10, 285-290.
73. Zuk, O., Hechter, E., Sunyaev, S. R., Lander, E. S. (2012) The mystery of missing heritability: genetic interactions create phantom heritability. Proc. Natl. Acad. Sci. USA 109, 1193-1198.
74. Sherer, Y., Gorstein, A., Fritzler, M. J., Shoenfeld, Y. (2004) Autoantibody explosion in systemic lupus erythematosus: more than 100 different antibodies found in SLE patients. Semin. Arthritis Rheum. 34, 501-537.
75. Arbuckle, M. R., McClain, M. T., Rubertone, M. V., Scofield, R. H., Dennis, G. J., James, J. A., Harley, J. B. (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N. Engl. J. Med. 349, 1526-1533.
76. Tsokos, G. C. (2011) Systemic lupus erythematosus. N. Engl. J. Med. 365, 2110-2121.
77. Cervera, R., Piette, J. C., Font, J., Khamashta, M. A., Shoenfeld, Y., Camps, M. T., Jacobsen, S., Lakos, G., Tincani, A., Kontopoulou-Griva, et al. (2002) Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 46, 1019-1027.
78. Dal Porto, J. M., Gauld, S. B., Merrell, K. T., Mills, D., Pugh-Bernard, A. E., Cambier, J. (2004) B cell antigen receptor signaling 101. Mol. Immunol. 41, 599-613.
79. Kurosaki, T., Shinohara, H., Baba, Y. (2010) B cell signaling and fate decision. Ann. Rev. Immunol. 28, 21-55.
80. Hou, P., Araujo, E., Zhao, T., Zhang, M., Massenburg, D., Veselits, M., Doyle, C., Dinner, A. R., Clark, M. R. (2006) B cell antigen receptor signaling and internalization are mutually exclusive events. PLoS Biol. 4, e200.
81. Pillai, S., Mattoo, H., Cariappa, A. (2011) B cells and autoimmunity. Curr. Opin. Immunol. 23, 721-731.
82. Harley, J. B., Alarcon-Riquelme, M. E., Criswell, L. A., Jacob, C. O., Kimberly, R. P., Moser, K L., Tsao, B. P., Vyse, T. J., Langefeld, C. D. (2008) Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat. Genet. 40, 204-210.
83. Flores-Borja, F., Kabouridis, P. S., Jury, E. C., Isenberg, D. A., Mageed, R. A. (2005) Decreased Lyn expression and translocation to lipid raft signaling domains in B lymphocytes from patients with systemic lupus erythematosus. Arthritis Rheum. 52, 3955-3965.
84. Flores-Borja, F., Kabouridis, P. S., Jury, E. C., Isenberg, D. A., Mageed, R. A. (2006) Altered lipid raft-associated proximal signaling and translocation of CD45 tyrosine phosphatase in B lymphocytes from patients with systemic lupus erythematosus. Arthritis Rheum. 56, 291-302.
85. Nishizumi, H., Taniuchi, I., Yamanashi, Y., Kitamura, D., Ilic, D., Mori, Watanabe, T., Yamamoto, T. (1995) Impaired proliferation of peripheral B cells and indication of autoimmune disease in Lyn-deficient mice. Immunity 3, 549-560.
86. Hibbs, M. L., Tarlinton, D. M., Armes, J., Grail, D., Hodgson, G., Maglitto, R., Stacker, S. A., Dunn, A. R. (1995) Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease. Cell 83, 301-311.
87. Saijo, K, Schmedt, C., Su I-h, Karasuyama, H., Lowell, C. A., Reth, M., Adachi, T., Patke, A., Santana, A., Tarakhovsky, A. (2003) Essential role of Src-family protein tyrosine kinases in NF-kB activation during B cell development. Nat. Immunol. 4, 274-279.
88. Chan, V. W., Meng, F., Soriano, P., Defranco, A. L., Lowell, C. A. (1997) Characterization of the B lymphocyte populations in Lyn-defi-cient mice and the role of Lyn in signal initiation and down-regulation. Immunity 7, 69-81.
89. Wang, J., Koizumi, T., Watanabe, T. (1996) Altered antigen receptor signaling and impaired Fas-mediated apoptosis of B cells in Lyn-defi-cient mice. J. Exp. Med. 184, 831-838.
90. Gross, A. J., Proekt, I., DeFranco, A. L. (2011) Elevated BCR signaling and decreased survival of Lyn-deficient transitional and follicular B cells. Eur. J. Immunol. 41, 3645-3655.
91. Gross, A. J., Lyandres, J. R., Panigrahi, A. K., Prak, E. T. L., Defranco, A. L. (2009) Developmental acquisition of the Lyn-CD22-SHP-1 inhibitory pathway promotes B cell tolerance. J. Immunol. 182, 5382-5392.
92. Cornall, R. J., Cyster, J. G., Hibbs, M. L., Dunn, A. R., Otipoby, K. L., Clark, E. A., Goodnow, C. C. (1998) Polygenic autoimmune traits: Lyn, CD22, and SHP-1 are limiting elements of a biochemical pathway regulating BCR signaling and selection. Immunity 8, 497-508.
93. Scapini, P., Hu, Y., Chu C-L, Migone T-S, Defranco, A. L., Cassatella, M. A., Lowell, C. A. (2010) Myeloid cells, BAFF, and IFN-y establish an inflammatory loop that exacerbates autoimmunity in Lyn-deficient mice. J. Exp. Med. 207, 1757-1773.
94. Silver, K L., Crockford, T. L., Bouriez-Jones, T., Milling, S., Lambe, T., Cornall, R. J. (2007) MyD88-dependent autoimmune disease in Lyn-deficient mice. Eur. J. Immunol. 37, 2734-2743.
95. Dymecki, S. M., Niederhuber, J. E., Desiderio, S. V. (1990) Specific expression of a tyrosine kinase gene, Blk, in B lymphoid cells. Science 247, 332-336.
96. Ito, I., Kawasaki, A., Ito, S., Hayashi, T., Goto, D., Matsumoto, I., Tsut-sumi, A., Hom, G., Graham, R. R., Takasaki, Y., Hashimoto, H., Ohashi, J., Behrens, T. W., Sumida, T., Tsuchiya, N. (2009) Replication of the association between the C8orf13-BLK region and systemic lupus erythematosus in a Japanese population. Arthritis Rheum. 60, 553-558.
97. Castillejo-Lopez, C., Delgado-Vega, A. M., Wojcik, J., Kozyrev, S. V., Thavathiru, E., Wu, Y. Y., Sanchez, E., Pollmann, D., Lopez-Egido, J. R., Fineschi, S., et al. (2011) Genetic and physical interaction of the B-cell systemic lupus erythematosus-associated genes BANK1 and BLK. Ann. Rheum. Dis. 71, 136-142.
98. Texido, G., Su, I. H., Mecklenbrauker, I., Saijo, K, Malek, S. N., Desid-erio, S., Rajewsky, K, Tarakhovsky, A. (2000) The B-cell-specific Src-family kinase Blk is dispensable for B-cell development and activation. Mol. Cell. Biol. 20, 1227-1233.
99. Maas, A., Hendriks, R. W. (2001) Role of Bruton's tyrosine kinase in B cell development. Dev. Immunol. 8, 171-181.
100. Yokoyama, K, Su Ih I. H., Tezuka, T., Yasuda, T., Mikoshiba, K., Tarakhovsky, A., Yamamoto, T. (2002) BANK regulates BCR-induced calcium mobilization by promoting tyrosine phosphorylation of IP(3) receptor. EMBO J. 21, 83-92.
101. Aiba, Y., Yamazaki, T., Okada, T., Gotoh, K, Sanjo, H., Ogata, M., Ku-rosaki, T. (2006) BANK negatively regulates Akt activation and subsequent B cell responses. Immunity 24, 259-268.
102. Guo, L., Deshmukh, H., Lu, R., Vidal, G. S., Kelly, J. A., Kaufman, K M., Dominguez, N., Klein, W., Kim-Howard, X., Bruner, G. R., et al. (2009) Replication of the BANK1 genetic association with systemic lupus erythematosus in a European-derived population. Genes Immun. 10, 531-538.
103. Kozyrev, S. V., Bernal-Quiros, M., Alarcon-Riquelme, M. E., Castillejo-Lopez, C. (2012) The dual effect of the lupus-associated polymorphism rs10516487 on BANK1 gene expression and protein localization. Genes Immun.13, 129-138.
104. Cohen, S., Dadi, H., Shaoul, E., Sharfe, N., Roifman, C. M. (1999) Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp. Blood 93, 2013-2024.
105. Begovich, A. B., Carlton, V. E. H., Honigberg, L. A., Schrodi, S. J., Chokkalingam, A. P., Alexander, H. C., Ardlie, K G., Huang, Q., Smith, A. M., Spoerke, J. M., et al. (2004) A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am. J. Hum. Genet. 75, 330-337.
106. Bottini, N., Musumeci, L., Alonso, A., Rahmouni, S., Nika, K, Rostam-khani, M., MacMurray, J., Meloni, G. F., Lucarelli, P., Pellecchia, M., Eisenbarth, G. S., Comings, D., Mustelin, T. (2004) A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nature 36, 337-338.
107. Smyth, D., Cooper, J. D., Collins, J. E., Heward, J. M., Franklyn, J. A., Howson, J. M., Vella, A., Nutland, S., Rance, H. E., Maier, L., et al. (2004) Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes 53, 3020-3023.
108. Vandiedonck, C., Capdevielle, C., Giraud, M., Krumeich, S., Jais, J. P., Eymard, B., Tranchant, C., Gajdos, P., Garchon, H. J. (2006) Association of the PTPN22*R620W polymorphism with autoimmune myasthenia gravis. Ann. Neurol. 59, 404-407.
109. Lea, W., Lee, Y. (2011) The association between the PTPN22 C1858T polymorphism and systemic lupus erythematosus: a meta-analysis update. Lupus 20, 51-57.
110. Vang, T., Congia, M., Macis, M. D., Musumeci, L., Orrú, V., Zavattari, P., Nika, K., Tautz, L., Tasken, K, Cucca, F., Mustelin, T., Bottini, N. (2005) Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nature 37, 1317-1319.
111. Fiorillo, E., Orru, V., Stanford, S. M., Liu, Y., Salek, M., Rapini, N., Schenone, A. D., Saccucci, P., Delogu, L. G., Angelini, F., Manca Bitti, M. L., Schmedt, C., Chan, A. C., Acuto, O., Bottini, N. (2010) Autoimmune-associated PTPN22 R620W variation reduces phosphorylation of lymphoid phosphatase on an inhibitory tyrosine residue. J. Biol. Chem. 285, 26506-26518.
112. Rieck, M., Arechiga, A., Onengut-Gumuscu, S., Greenbaum, C., Con-cannon, P., Buckner, J. H. (2007) Genetic variation in PTPN22 corresponds to altered function of T and B lymphocytes. J. Immunol. 179, 4704-4710.
113. Lefvert, A. K, Zhao, Y., Ramanujam, R., Yu, S., Pirskanen, R., Ham-marstrom, L. (2008) PTPN22 R620W promotes production of anti-AChR autoantibodies and IL-2 in myasthenia gravis. J. Neuroimmunol. 197, 110-113.
114. Zikherman, J., Hermiston, M., Steiner, D., Hasegawa, K, Chan, A., Weiss, A. (2009) PTPN22 deficiency cooperates with the CD45 E613R allele to break tolerance on a non-autoimmune background. J. Immunol. 182, 4093-4106.
115. Zhang, Z., Cheng, Y., Zhou, X., Li, Y., Gao, J., Han, J., Quan, C., He, S., Lv, Y., Hu, D., Zhu, K, Sun, L., Yang, S., Zhang, X. (2011) Polymorphisms at 16p13 are associated with systemic lupus erythematosus in the Chinese population. J. Med. Genet. 48, 69-72.
116. Habib, T., Funk, A., Rieck, M., Brahmandam, A., Dai, X., Panigrahi, A. K, Luning Prak, E. T., Meyer-Bahlburg, A., Sanda, S., Greenbaum, C., Rawlings, D. J., Buckner, J. H. (2011) Altered B cell homeostasis is associated with type I diabetes and carriers of the PTPN22 allelic variant. J. Immunol. 188, 487-496.
117. Menard, L., Saadoun, D., Isnardi, I., Ng, Y-S., Meyers, G., Massad, C., Price, C., Abraham, C., Motaghedi, R., Buckner, J. H., Gregersen, P. K., Meffre, E. (2011) The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans. J. Clin. Invest. 121, 3635-3644.
118. Arechiga, A. F., Habib, T., He, Y., Zhang, X., Zhang, Z. Y., Funk, A, Buckner, J. H. (2009) Cutting edge: the PTPN22 allelic variant associated with autoimmunity impairs B cell signaling. J. Immunol. 182, 3343-3347.
119. Salloum, R., Niewold, T. B. (2011) Interferon regulatory factors in human lupus pathogenesis. Transl. Res. 157, 326-331.
120. Plenge, R. M., Cotsapas, C., Davies, L., Price, A. L., de Bakker, P. I., Maller, J., Pe'er, I., Burtt, N. P., Blumenstiel, B., DeFelice, M., et al. (2007) Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat. Genet. 39, 1477-1482.
121. Thomson, W., Barton, A., Ke, X., Eyre, S., Hinks, A., Bowes, J., Donn, R., Symmons, D., Hider, S., Bruce, I. N., et al. (2007) Rheumatoid arthritis association at 6q23. Nat. Genet. 39, 1431-1433.
122. Trynka, G., Zhernakova, A., Romanos, J., Franke, L., Hunt, K A., Turner, G., Bruinenberg, M., Heap, G. A., Platteel, M., Ryan, A. W., et al. (2009) Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kB signalling. Gut 58, 1078-1083.
123. Wang, K., Baldassano, R., Zhang, H., Qu, H. Q., Imielinski, M., Kugath-asan, S., Annese, V., Dubinsky, M., Rotter, J. I., Russell, R. K., et al. (2010) Comparative genetic analysis of inflammatory bowel disease and type 1 diabetes implicates multiple loci with opposite effects. Hum. Mol. Genet. 19, 2059-2067.
124. Fung, E. Y., Smyth, D. J., Howson, J. M., Cooper, J. D., Walker, N. M., Stevens, H., Wicker, L. S., Todd, J. A. (2009) Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/ TNFAIP3 as a susceptibility locus. Genes Immun. 10, 188-191.
125. Duffin, K C., Woodcock, J., Krueger, G. G. (2010) Genetic variations associated with psoriasis and psoriatic arthritis found by genome-wide association. Dermatol. Ther. 23, 101-113.
126. Sarma, V., Lin, Z., Clark, L., Rust, B. M., Tewari, M., Noelle, R. J., Dixit, V. M. (1995) Activation of the B-cell surface receptor CD40 induces A20, a novel zinc finger protein that inhibits apoptosis. J. Biol. Chem. 270, 12343-12346.
127. Hymowitz, S. G., Wertz, I. E. (2010) A20: from ubiquitin editing to tumour suppression. Nat. Rev. Cancer 10, 332-341.
128. Skaug, B., Chen, J., Du, F., He, J., Ma, A., Chen, Z.J. (2011) Direct, noncatalytic mechanism of IKK inhibition by A20. Mol. Cell 44, 559-571.
129. Lee, E. G. (2000) Failure to regulate TNF-induced NF-k B and cell death responses in A20-deficient mice. Science 289, 2350-2354.
130. Turer, E. E., Tavares, R. M., Mortier, E., Hitotsumatsu, O., Advincula, R., Lee, B., Shifrin, N., Malynn, B. A., Ma, A. (2008) Homeostatic MyD88-dependent signals cause lethal inflammation in the absence of A20. J. Exp. Med. 205, 451-464.
131. Harhaj, E. W., Dixit, V. M. (2012) Regulation of NF-kB by deubiquiti-nases. Immunol. Rev. 246, 107-124.
132. Chu, Y., Vahl, J. C., Kumar, D., Heger, K, Bertossi, A., Wojtowicz, E., Soberon, V., Schenten, D., Mack, B., Reutelshofer, M., Beyaert, R., Amann, K, van Loo, G., Schmidt-Supprian, M. (2011) B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice. Blood 117, 2227-2236.
133. Tavares, R. M., Turer, E. E., Liu, C. L., Advincula, R., Scapini, P., Rhee, L., Barrera, J., Lowell, C. A., Utz, P. J., Malynn, B. A., Ma, A. (2010) The ubiquitin modifying enzyme A20 restricts B cell survival and prevents autoimmunity. Immunity 33, 181-191.
134. Witte, T. (2007) IgM antibodies against dsDNA in SLE. Clin. Rev. Allergy Immunol. 34, 345-347.
135. Hao, Z., Duncan, G. S., Seagal, J., Su Y-W, Hong, C., Haight, J., Chen N-J, Elia, A., Wakeham, A., Li, W. Y., Liepa, J., Wood, G. A., Casola, S., Rajewsky, K, Mak, T. W. (2008) Fas receptor expression in germinal-center B cells is essential for T and B lymphocyte homeostasis. Immunity 29, 615-627.
136. Shiote, Y., Ouchida, M., Jitsumori, Y., Ogama, Y., Matsuo, Y., Ishimaru, F., Tanimoto, M., Shimizu, K (2006) Multiple splicing variants of Naf1/ABIN-1 transcripts and their alterations in hematopoietic tumors. Int. J. Mol. Med. 18, 917-923.
137. Heyninck, K., Kreike, M. M., Beyaert, R. (2003) Structure-function analysis of the A20-binding inhibitor of NF-K B activation, ABIN-1. FEBS Lett. 536, 135-140.
138. Ashida, H., Kim, M., Schmidt-Supprian, M., Ma, A., Ogawa, M., Sa-sakawa, C. (2009) A bacterial E3 ubiquitin ligase IpaH9.8 targets NEMO/IKKy to dampen the host NF-KB-mediated inflammatory response. Nature 12, 66-73.
139. Zhang, S., Fukushi, M., Hashimoto, S., Gao, C., Huang, L., Fukuyo, Y., Nakajima, T., Amagasa, T., Enomoto, S., Koike, K, Miura, O., Yamamoto, N., Tsuchida, N. (2002) A new ERK2 binding protein, Naf1, attenuates the EGF/ERK2 nuclear signaling. Biochem. Biophys. Res. Commun. 297, 17-23.
140. Gao, L., Coope, H., Grant, S., Ma, A., Ley, S. C., Harhaj, E. W. (2011) ABIN1 protein cooperates with TAX1BP1 and A20 proteins to inhibit antiviral signaling. J. Biol. Chem. 286, 36592-36602.
141. Chen, F., Bhatia, D., Chang, Q., Castranova, V. (2006) Finding NEMO by K63-linked polyubiquitin chain. Cell Death Differ. 13, 1835-1838.
142. Zhou, X-J., Lu, X-L., Nath, S. K., Lv, J-C., Zhu, S-N., Yang, H-Z., Qin, L-X., Zhao, M-H., Su, Y., Shen, N., Li, Z-G., Zhang, H., International Consortium on the Genetics of Systemic Lupus Erythematosus (2011) Gene-gene interaction of BLK, TNFSF4, TRAF1, TNFAIP3, and REL in systemic lupus erythematosus. Arthritis Rheum. 64, 222-231.
143. Nanda, S. K, Venigalla, R. K C., Ordureau, A., Patterson-Kane, J. C., Powell, D. W., Toth, R. C. A. rthur, J. S., Cohen, P. (2011) Polyubiqui-tin binding to ABIN1 is required to prevent autoimmunity. J. Exp. Med. 208, 1215-1228.
144. Namjou, B., Choi, C. B., Harley, I. T., Alarcon-Riquelme, M. E., Kelly, J. A., Glenn, S. B., Ojwang, J. O., Adler, A., Kim, K., Gallant, C. J., et al. (2012) Evaluation of TRAF6 in a large multi-ancestral lupus cohort. Arthritis Rheum. 64, 1960-1969.
145. Hildebrand, J. M., Luo, Z., Manske, M. K., Price-Troska, T., Ziesmer, S. C., Lin, W., Hostager, B. S., Slager, S. L., Witzig, T. E., Ansell, S. M., Cerhan, J. R., Bishop, G. A., Novak, A. J. (2010) A BAFF-R mutation associated with non-Hodgkin lymphoma alters TRAF recruitment and reveals new insights into BAFF-Rsignaling. J. Exp. Med. 207, 2569-2579.
146. Inoue, J., Ishida, T., Tsukamoto, N., Kobayashi, N., Naito, A., Azuma, S., Yamamoto, T. (2000) Tumor necrosis factor receptor-associated factor (TRAF) family: adapter proteins that mediate cytokine signaling. Exp. Cell. Res. 254, 14-24.
147. Anolik, J. H., Barnard, J., Cappione, A., Pugh-Bernard, A. E., Felgar, R. E., Looney, R. J., Sanz, I. A. (2004) Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus. Arthritis Rheum. 50, 3580-3590.
148. Leandro, M. J., Edwards, J. C., Cambridge, G., Ehrenstein, M. R., Isen-berg, D. A. (2002) An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum. 46, 2673-2677.
149. Looney, R. J., Anolik, J. H., Campbell, D., Felgar, R. E., Young, F., Ar-end, L. J., Sloand, J. A., Rosenblatt, J., Sanz, I. A. (2004) B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab. Arthritis Rheum. 50, 2580-2589.
150. Merrill, J. T., Neuwelt, C. M., Wallace, D. J., Shanahan, J. C., Latinis, K M., Oates, J. C., Utset, T. O., Gordon, C., Isenberg, D. A., Hsieh H-J., Zhang, D., Brunetta, P. G. (2010) 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. 62, 222-233.
151. Rovin, B. H., Furie, R., Latinis, K, Looney, R. J., Fervenza, F. C., San-chez-Guerrero, J., Maciuca, R., Zhang, D., Garg, J. P., Brunetta, P., Appel, G., LUNAR Investigator Group (2012) Efficacy and safety of ritux-imab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab (LUNAR) Study. Arthritis Rheum. 64, 1215-1226.
152. Furie, R., Petri, M., Zamani, O., Cervera, R., Wallace, D. J., Tegzova, D., Sanchez-Guerrero, J., Schwarting, A., Merrill, J. T., Chatham, W. W., Stohl, W., Ginzler, E. M., Hough, D. R., Zhong, Z. J., Freimuth, W., van Vollenhoven, R. F. (2011) A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 63, 3918-3930.
153. McClain, M. T., Heinlen, L. D., Dennis, G. J., Roebuck, J., Harley, J. B., James, J. A. (2004) Early events in lupus humoral autoimmunity suggest initiation through molecular mimicry. Nat. Med. 11, 85-89.
154. James, J. A., Neas, B. R., Moser, K L., Hall, T., Bruner, G. R., Sestak, A. L., Harley, J. B. (2001) Systemic lupus erythematosus in adults is associated with previous Epstein-Barr virus exposure. Arthritis Rheum. 44, 1122-1126.
155. Moon, U. Y., Park, S. J., Oh, S. T., Kim, W-U., Park, S-H., Lee, S-H., Cho, C-S., Kim, H-Y., Lee, W-K., Lee, S. K (2004) Patients with systemic lupus erythematosus have abnormally elevated Epstein-Barr virus load in blood. Arthritis Res. Ther. 6, R295-R302.
156. Dykstra, M. L., Longnecker, R., Pierce, S. K (2001) Epstein-Barr virus coopts lipid rafts to block the signaling and antigen transport functions of the BCR. Immunity 14, 57-67.
157. Ning, S., Pagano, J. S. (2010) The A20 deubiquitinase activity negatively regulates LMP1 activation of IRF7. J. Virol. 84, 6130-6138.
158. Clark, M. R., Tanaka, A., Powers, S. E., Veselits, M. (2011) Receptors, subcellular compartments and the regulation of peripheral B cell responses: the illuminating state of anergy. Mol. Immunol. 48, 1281-1286.
159. Lander, E. S. (2011) Initial impact of the sequencing of the human genome. Nature 470, 187-197.