Supplementary Table 1 | Genes associated with lupus in murine transgenic models and validated in patients with SLE
Gene
Allele
Mouse phenotype
Human phenotype
Ptprc (CD45)
Fcgr2b
E613R KI
KO
Lymphoproliferation, ANA, GN1
Post-GC tolerance checkpoint3
Lyn
KO, Tg
Lymphoproliferation, ANA, GN7–9
Tnfsf13
(BAFF)
Ctla4
Tg
Lymphoproliferation, ANA, GN12,13
Increased presence in B cell lipid rafts2
Genetic association; down-regulation on
memory B cells4-6
Decreased expression; increased presence
in B cell lipid rafts2, 10, 11
Increased expression; synergy with IL-1714,
KO
Multi-organ infiltrates and inflammation16
Pdcd1
(Pd-1)
Lat
Cblb
KO
Arthritis, GN, background dependent19
Y136F KI
KO
Lymphoproliferation21
Multi-organ infiltrates, ANA23
Cdkn1a
(P21)
Bcl2
KO
ANA, GN23
B cell Tg
Lymphoproliferation, ANA, GN25
Il2ra
(CD25)
Il2
Cd40lg
(CD154)
KO
T cell proliferation, ANA, hyper IgG31
KO
B cell Tg
epidermis Tg
Ifng
Keratin
promoter Tg
T cell proliferation, ANA, hyper IgG33
ANA, GN
Dermatitis, lymphadenopathy, hyper IgG,
ANA, GN35, 36
ANA, GN38
Il4
Class I
promoter Tg
KO
15
Il10
ANA, GN43
Increases disease severity in MRL/lpr
mice45
AutoAb, GN; photosensitivity47
Co-stimulation blockade therapy; Decreased
Treg associated with CTLA-4 variants17, 18
Genetic association20
Elevated in CD4+ T cells22
Induces CD40L hyper-expression on CD4+
T cells24
Decreased levels; genetic association26, 27
Increased expression on B and T cells,
glomeruli, serum29, 30
Genetic association32
Decreased expression34
Increased expression on lymphocytes37
Genetic association with nephritis, arthritis;
combined effect with IL-18 variants;
Mitogen-induced over-expression39-42
Mitogen-induced over-expression; Genetic
association42, 44
Genetic association46
Autoantigen48
Trove2
(RO60)
Trim21
(RO52)
KO
KO
TH17-mediated induced autoimmunity,
dermatitis, ANA, GN49
Genetic association, autoantigen48, 50
C1qa
C4
Mfge8
KO
KO
KO
ANA, GN51
ANA, GN53
Increased GCs, ANA, GN55
Genetic association52
Genetic association54
Elevated serum level; genetic association56,
57
ANA, GN58
Genetic association59
Type-I IFN-dependent generalized
Association with Chilblain lupus and Aicardiautoimmunity60
Goutieres syndrome61, 62
Abbreviations: ANA, anti-nuclear antibodies; GC, germinal center; GN, glomerulonephritis; IFN, interferon; IL-interleukin;
KO, knockout; SLE, systemic lupus erythematosus; Tg, transgenic.
Dnase1
Trex1
KO
KO
References
1.
Majeti, R. et al. An inactivating point mutation in the inhibitory wedge of CD45 causes
lymphoproliferation and autoimmunity. Cell 103, 1059-1070 (2000).
2.
Jury, E.C., Flores-Borja, F., & Kabouridis, P.S. Lipid rafts in T cell signalling and disease. Semin. Cell Dev.
Biol. 18, 608-615 (2007).
3.
Fukuyama, H., Nimmerjahn, F., & Ravetch, J.V. The inhibitory Fc receptor modulates autoimmunity by
limiting the accumulation of immunoglobulin G+ anti-DNA plasma cells. Nat. Immunol. 6, 99-106 (2005).
4.
Mackay, M. et al. Selective dysregulation of the Fc
2157-2164 (2006).
5.
Su, K. et al.
erythematosus. J. Immunol. 178, 3272-3280 (2007).
6.
Lee, Y.H., Ji, J.D., & Song,
erythematosus and lupus nephritis: a meta-analysis. Lupus 18, 727-734 (2009).
7.
Hibbs, M.L. et al. Multiple defects in the immune-system of Lyn-deficient mice, culminating in
autoimmune-disease. Cell 83, 301-311 (1995).
8.
Hibbs, M.L. et al. Sustained activation of Lyn tyrosine kinase in vivo leads to autoimmunity. J. Exp. Med.
196, 1593-1604 (2002).
9.
Nishizumi, H. et al. Impaired proliferation of peripheral B-cells and indication of autoimmune-disease in
Lyn-deficient mice. Immunity 3, 549-560 (1995).
J Exp. Med. 203,
10. Huck, S., Le, C.R., Youinou, P., & Zouali, M. Expression of B cell receptor-associated signaling molecules in
human lupus. Autoimmunity 33, 213-224 (2001).
11. Flores-Borja, F., Kabouridis, P.S., Jury, E.C., Isenberg, D.A., & Mageed, R.A. Decreased Lyn expression and
translocation to lipid raft signaling domains in B lymphocytes from patients with systemic lupus
erythematosus. Arthritis Rheum. 52, 3955-3965 (2005).
12. Khare, S.D. et al. Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice. Proc. Natl.
Acad. Sci. USA 97, 3370-3375 (2000).
13. Mackay, F. et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune
manifestations. J. Exp. Med. 190, 1697-1710 (1999).
14. Cheema, G.S., Roschke, V., Hilbert, D.M., & Stohl, W. Elevated serum B lymphocyte stimulator levels in
patients with systemic immune-based rheumatic diseases. Arthritis Rheum. 44, 1313-1319 (2001).
15. Doreau, A. et al. Interleukin 17 acts in synergy with B cell-activating factor to influence B cell biology and
the pathophysiology of systemic lupus erythematosus. Nat. Immunol. 10, 778-785 (2009).
16. Tivol, E.A. et al. Loss of Ctla-4 leads to massive lymphoproliferation and fatal multiorgan tissue
destruction, revealing a critical negative regulatory role of Ctla-4. Immunity 3, 541-547 (1995).
17. Davidson, A., Diamond, B., Wofsy, D., & Daikh, D. Block and tackle: CTLA4Ig takes on lupus. Lupus 14, 197203 (2005).
18. Barreto, M. et al. Low frequency of CD4+CD25+ Treg in SLE patients: a heritable trait associated with
CTLA4 and TGFbeta gene variants. BMC Immunology 10, 5 (2009).
19. Nishimura, H., Nose, M., Hiai, H., Minato, N., & Honjo, T. Development of lupus-like autoimmune diseases
by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11, 141-151
(1999).
20. Prokunina, L. et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus
erythematosus in humans. Nat. Genet. 32, 666-669 (2002).
21. Sommers, C.L. et al. A LAT mutation that inhibits T cell development yet induces lymphoproliferation.
Science 296, 2040-2043 (2002).
22. Januchowski, R., Wudarski, M., Chwalinska-Sadowska, H., & Jagodzinski, P.P. Prevalence of ZAP-70, LAT,
SLP-76, and DNA methyltransferase 1 expression in CD4+ T cells of patients with systemic lupus
erythematosus. Clin. Rheumatol. 27, 21-27 (2008).
23. Bachmaier, K. et al. Negative regulation of lymphocyte activation and autoimmunity by the molecular
adaptor Cbl-b. Nature 403, 211-216 (2000).
24. Yi, Y., McNerney, M., & Datta, S.K. Regulatory defects in Cbl and mitogen-activated protein kinase
(extracellular signal-related kinase) pathways cause persistent hyperexpression of CD40 ligand in human
lupus T cells. J. Immunol. 165, 6627-6634 (2000).
25. Balomenos, D. et al. The cell cycle inhibitor p21 controls T-cell proliferation and sex-linked lupus
development. Nat. Med. 6, 171-176 (2000).
26. Ho, C.Y., Wong, C.K., Li, E.K., Tam, L.S., & Lam, C.W. Expression of cyclin B1 and cyclin dependent kinase
inhibitor p21 in lymphocytes in patients with systemic lupus erythematosus. J. Rheumatol. 29, 2537-2544
(2002).
27. Kim, K. et al. A regulatory SNP at position -899 in CDKN1A is associated with systemic lupus
erythematosus and lupus nephritis. Genes Immun. 10, 482-486 (2009).
28. Strasser,A. et al. Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits
autoimmune disease. Proc. Natl. Acad. Sci. U. S. A 88, 8661-8665 (1991).
29. Liphaus, B.L., Kiss, M.H., Carrasco, S., & Goldenstein-Schainberg, C. Increased Fas and Bcl-2 expression on
peripheral blood T and B lymphocytes from juvenile-onset systemic lupus erythematosus, but not from
juvenile rheumatoid arthritis and juvenile dermatomyositis. Clin. Dev. Immunol. 13, 283-287 (2006).
30. Fathi, N.A. et al. Glomerular expression and elevated serum Bcl-2 and Fas proteins in lupus nephritis:
preliminary findings. Clin. Exp. Immunol. 146, 339-343 (2006).
31. Willerford, D.M. et al. Interleukin-2 receptor alpha chain regulates the size and content of the peripheral
lymphoid compartment. Immunity 3, 521-530 (1995).
32. Carr, E. et al. Contrasting genetic association of IL2RA with SLE and ANCA - associated vasculitis. BMC
Medical Genetics 10, 22 (2009).
33. Sadlack, B. et al. Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an
uncontrolled activation and proliferation of CD4+ T cells. Eur. J. Immunol. 25, 3053-3059 (1995).
34. Crispin, J.C. & Tsokos, G.C. Transcriptional regulation of IL-2 in health and autoimmunity. Autoimmun. Rev.
8, 190-195 (2009).
35. Higuchi, T. et al. Cutting edge: ectopic expression of CD40 ligand on B cells induces lupus-like autoimmune
disease. J. Immunol. 168, 9-12 (2002).
36. Mehling, A. et al. Overexpression of CD40 ligand in murine epidermis results in chronic skin inflammation
and systemic autoimmunity. J. Exp. Med. 194, 615-628 (2001).
37. Manea,M.E. et al. Increased expression of CD154 and FAS in SLE patients' lymphocytes. Rheumatol. Int.
30, 181-185 (2009).
38. Seery, J.P., Carroll, J.M., Cattell, V., & Watt, F.M. Antinuclear autoantibodies and lupus nephritis in
transgenic mice expressing interferon gamma in the epidermis. J. Exp. Med. 186, 1451-1459 (1997).
39. Miyake, K. et al. Genetically determined interferon
lupus nephritis. Rheumatol. 41, 518-524 (2002).
40. Tangwattanachuleeporn, M. et al. Association of interferon-gamma gene polymorphism (+874A) with
arthritis manifestation in SLE. Clin. Rheumatol. 26, 1921-1924 (2007).
41. Hirankarn, N., Tangwattanachuleeporn, M., Wongpiyabovorn, J., Wongchinsri, J., & Avihingsanon,Y.
Association of ILIFN gamma gene polymorphism (+874A). Clin. Rheumatol. 28, 219-223 (2009).
42. Lit, L.C.-W. et al. Elevated gene expression of Th1/Th2 associated transcription factors is correlated with
disease activity in patients with systemic lupus erythematosus. J. Rheumatol. 34, 89-96 (2007).
43. Erb, K.J. et al. Constitutive expression of interleukin (IL)-4 in vivo causes autoimmune-type disorders in
mice. J. Exp. Med. 185, 329-340 (1997).
44. Wu,M.C., Huang, C.M., Tsai, J.J., Chen, H.Y., & Tsai, F.J. Polymorphisms of the interleukin-4 gene in chinese
patients with systemic lupus erythematosus in Taiwan. Lupus 12, 21-25 (2003).
45. Yin, Z.N. et al. IL-10 regulates murine lupus. J. Immunol. 169, 2148-2155 (2002).
46. Gateva V. et al. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk
loci for systemic lupus erythematosus. Nat. Genet. 41, 1228-1233 (2009).
47. Xue, D. et al. A lupus-like syndrome develops in mice lacking the Ro 60-kDa protein, a major lupus
autoantigen. Proc. Natl Acad. Sci. U. S. A 100, 7503-7508 (2003).
48. Schulte-Pelkum, J., Fritzler, M., & Mahler, M. Latest update on the Ro/SS-A autoantibody system.
Autoimmun. Rev. 8, 632-637 (2009).
49. Espinosa, A. et al. Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic
autoimmunity by disregulating the IL-23-Th17 pathway. J. Exp. Med. 206, 1661-1671 (2009).
50. Frank, M.B. et al. The mapping of the human 52-kD Ro/SSA autoantigen gene to human chromosome 11,
and its polymorphisms. Am. J. Hum. Genet. 52, 183-191 (1993).
51. Botto, M. et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic
bodies. Nat. Genet. 19, 56-59 (1998).
52. Martens, H.A. et al. Analysis of C1q polymorphisms suggests association with systemic lupus
erythematosus, serum C1q and CH50 levels and disease severity. Ann. Rheum. Dis. 68, 715-720 (2009).
53. Chen, Z., Koralov, S.B., & Kelsoe, G. Complement C4 inhibits systemic autoimmunity through a mechanism
independent of complement receptors CR1 and CR2. J. Exp. Med. 192, 1339-1352 (2000).
54. Yang, Y. et al. The intricate role of complement component C4 in human systemic lupus erythematosus.
Curr. Dir. Autoimm. 7, 98-132 (2004).
55. Hanayama, R. et al. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient
mice. Science 304, 1147-1150 (2004).
56. Yamaguchi, H. et al. Milk fat globule EGF factor 8 in the serum of human patients of systemic lupus
erythematosus. J. Leukoc. Biol. 83, 1300-1307 (2008).
57. Hu, C.Y. et al. Genetic polymorphism in milk fat globule-EGF factor 8 (MFG-E8) is associated with systemic
lupus erythematosus in human. Lupus 18, 676-681 (2009).
58. Napirei, M. et al. Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat. Genet. 25, 177181 (2000).
59. Yasutomo,K. et al. Mutation of DNASE1 in people with systemic lupus erythematosus. Nat. Genet. 28, 313314 (2001).
60. Stetson, D.B., Ko, J.S., Heidmann, T., & Medzhitov, R. Trex1 prevents cell-intrinsic initiation of
autoimmunity. Cell 134, 587-598 (2008).
61. Rice, G. et al. Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant AicardiGoutieres syndrome. Am. J Hum. Genet. 80, 811-815 (2007).
62. Lee-Kirsch, M.A. et al. Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 are associated
with systemic lupus erythematosus. Nat. Genet. 39, 1065-1067 (2007).