Abstract
Genetic and environmental factors contribute in the pathogenesis of systemic lupus erythematosus (SLE). Lupus nephritis, the most common and severe manifestation of SLE, involves inflammation in the kidney leading to loss of renal function. However, it is not clear what controls the progression of lupus nephritis; this is an important research question, considering its implications in clinical treatment of lupus nephritis. Finding genes that underlie the development and progression of lupus nephritis will shed light on this question. NZM2328 is a spontaneous mouse model for SLE. Most NZM2328 female mice develop autoantibodies (e.g., antinuclear antibody and anti-dsDNA antibody), glomerulonephritis (GN), and severe proteinuria between 5 and 12 months of age. In contrast, C57L/J mice fail to exhibit similar signs of autoimmune disease. We used classical genetics to map and identify SLE genes in offspring generated by backcrossing C57L/J to NZM2328. Quantitative trait loci (QTL) controlling acute (Agnz1 and Agnz2) and chronic (Cgnz1) GN features were uncovered by the analysis. To verify the Cgnz1 and Agnz1 on distal mouse chromosome 1, we produced the NZM23238.C57Lc1 (Lc1) congenic strain, which replaced NZM2328 Cgnz1 and Agnz1 alleles with those derived from C57L/J. The development of acute GN and chronic GN was markedly reduced in Lc1 mice, confirming the linkage findings. Further map** by the generation of intrachromosomal recombinants of NZM2328.Lc1 support the thesis that acute GN and chronic GN are under separate genetic control.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Cameron JS (1999) Lupus nephritis. J Am Soc Nephrol 10(2):413–424
Houssiau FA, Vasconcelos C, D’Cruz D, Sebastiani GD, de Ramon GE et al (2004) Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: lessons from long-term followup of patients in the euro-lupus nephritis trial. Arthritis Rheum 50(12):3934–3940
Deapen D, Escalante A, Weinrib L, Horwitz D, Bachman B et al (1992) A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum 35(3):311–318
Alarcon-Segovia D, Alarcon-Riquelme ME, Cardiel MH, Caeiro F, Massardo L et al (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(4): 1138–1147
Deng Y, Tsao BP (2010) Genetic susceptibility to systemic lupus erythematosus in the genomic era. Nat Rev Rheumatol 6(12):683–692
Gualtierotti R, Biggioggero M, Penatti AE, Meroni PL (2010) Updating on the pathogenesis of systemic lupus erythematosus. Autoimmun Rev 10(1):3–7
Delgado-Vega A, Sanchez E, Lofgren S, Castillejo-Lopez C, Alarcon-Riquelme ME (2010) Recent findings on genetics of systemic autoimmune diseases. Curr Opin Immunol 22(6):698–705
Kaiser R, Criswell LA (2010) Genetics research in systemic lupus erythematosus for clinicians: methodology, progress, and controversies. Curr Opin Rheumatol 22(2):119–125
Borchers AT, Naguwa SM, Shoenfeld Y, Gershwin ME (2010) The geoepidemiology of systemic lupus erythematosus. Autoimmun Rev 9(5):A277–A287
Jorgensen TN, Gubbels MR, Kotzin BL (2004) New insights into disease pathogenesis from mouse lupus genetics. Curr Opin Immunol 16(6):787–793
Morel L (2010) Genetics of SLE: evidence from mouse models. Nat Rev Rheumatol 6(6): 348–357
Theofilopoulos AN, Dixon FJ (1985) Murine models of systemic lupus erythematosus. Adv Immunol 37:269–390
Borchers A, Ansari AA, Hsu T, Kono DH, Gershwin ME (2000) The pathogenesis of autoimmunity in New Zealand mice. Semin Arthritis Rheum 29(6):385–399
Andrews BS, Eisenberg RA, Theofilopoulos AN, Izui S, Wilson CB et al (1978) Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med 148(5):1198–1215
Rudofsky UH, Evans BD, Balaban SL, Mottironi VD, Gabrielsen AE (1993) Differences in expression of lupus nephritis in New Zealand mixed H-2z homozygous inbred strains of mice derived from New Zealand black and New Zealand white mice. Origins and initial characterization. Lab Invest 68(4):419–426
Rudofsky UH, Lawrence DA (1999) New zealand mixed mice: a genetic systemic lupus erythematosus model for assessing environmental effects. Environ Health Perspect 107(Suppl 5): 713–721
Kono DH, Theofilopoulos AN (2006) Genetics of SLE in mice. Springer Semin Immunopathol 28(2):83–96
Theofilopoulos AN, Kono DH (2001) Genetics of systemic autoimmunity and glomerulonephritis in mouse models of lupus. Nephrol Dial Transplant 16(Suppl 6):65–67
Fairhurst AM, Wandstrat AE, Wakeland EK (2006) Systemic lupus erythematosus: multiple immunological phenotypes in a complex genetic disease. Adv Immunol 92:1–69
Waters ST, Fu SM, Gaskin F, Deshmukh US, Sung SS et al (2001) NZM2328: a new mouse model of systemic lupus erythematosus with unique genetic susceptibility loci. Clin Immunol 100(3):372–383
Waters ST, McDuffie M, Bagavant H, Deshmukh US, Gaskin F et al (2004) Breaking tolerance to double stranded DNA, nucleosome, and other nuclear antigens is not required for the pathogenesis of lupus glomerulonephritis. J Exp Med 199(2):255–264
Ge Y, Fu SM. MS in preparation. In press.
Bagavant H, Fu SM (2005) New insights from murine lupus: disassociation of autoimmunity and end organ damage and the role of T cells. Curr Opin Rheumatol 17(5):523–528
Ge Y, Jiang C, Gaskin F, Sung SJ, Bagavant H et al (2009) Pathogenesis of proliferative lupus nephritis: different genetic control for acute and chronic glomerulonephritis and new insight into the mechanism of immune complex mediated nephritis. Arthritis Rheum 60:2019
Darvasi A (1998) Experimental strategies for the genetic dissection of complex traits in animal models. Nat Genet 18(1):19–24
Rodriguez MR, Lundgren A, Sabastian P, Li Q, Churchill G et al (2009) A Cmv2 QTL on chromosome X affects MCMV resistance in New Zealand male mice. Mamm Genome 20(7):414–423
Asif M, Rahman M, Mirza JI, Zafar Y (2008) High resolution metaphor agarose gel elecctrophoresis for genoty** with microsatellite markers. Pak J Agric Sci 45(1):75–79
Manly KF, Olson JM (1999) Overview of QTL map** software and introduction to map manager QT. Mamm Genome 10(4):327–334
Broman KW, Wu H, Sen S, Churchill GA (2003) R/qtl: QTL map** in experimental crosses. Bioinformatics 19(7):889–890
Lander E, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11(3):241–247
Morel L, Rudofsky UH, Longmate JA, Schiffenbauer J, Wakeland EK (1994) Polygenic control of susceptibility to murine systemic lupus erythematosus. Immunity 1(3):219–229
Drake CG, Rozzo SJ, Hirschfeld HF, Smarnworawong NP, Palmer E et al (1995) Analysis of the new zealand black contribution to lupus-like renal disease. Multiple genes that operate in a threshold manner. J Immunol 154(5):2441–2447
Mohan C, Alas E, Morel L, Yang P, Wakeland EK (1998) Genetic dissection of SLE pathogenesis. Sle1 on murine chromosome 1 leads to a selective loss of tolerance to H2A/H2B/DNA subnucleosomes. J Clin Invest 101(6):1 362–1372
Rozzo SJ, Allard JD, Choubey D, Vyse TJ, Izui S et al (2001) Evidence for an interferon-inducible gene, Ifi202, in the susceptibility to systemic lupus. Immunity 15(3):435–443
Morel L, Blenman KR, Croker BP, Wakeland EK (2001) The major murine systemic lupus erythematosus susceptibility locus, Sle1, is a cluster of functionally related genes. Proc Natl Acad Sci U S A 98(4):1787–1792
Heidari Y, Fossati-Jimack L, Carlucci F, Walport MJ, Cook HT et al (2009) A lupus-susceptibility C57BL/6 locus on chromosome 3 (Sle18) contributes to autoantibody production in 129 mice. Genes Immun 10(1):47–55
Wakeland E, Morel L, Achey K, Yui M, Longmate J (1997) Speed congenics: a classic technique in the fast lane (relatively speaking). Immunol Today 18(10):472–477
Scalzo AA, Brown MG, Chu DT, Heusel JW, Yokoyama WM et al (1999) Development of intra-natural killer complex (NKC) recombinant and congenic mouse strains for map** and functional analysis of NK cell regulatory loci. Immunogenetics 49(3):238–241
Scalzo AA, Wheat R, Dubbelde C, Stone L, Clark P et al (2003) Molecular genetic characterization of the distal NKC recombination hotspot and putative murine CMV resistance control locus. Immunogenetics 55(6):370–378
Brown MG, Zhang J, Du Y, Stoll J, Yokoyama WM et al (1999) Localization on a physical map of the NKC-linked Cmv1 locus between Ly49b and the prp gene cluster on mouse chromosome 6. J Immunol 163(4):1991–1999
Brown MG, Dokun AO, Heusel JW, Smith HR, Beckman DL et al (2001) Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science 292(5518): 934–937
**e X, Stadnisky MD, Brown MG (2009) MHC class I dk locus and Ly49G2+ NK cells confer H-2k resistance to murine cytomegalovirus. J Immunol 182(11):7163–7171
**e X, Stadnisky MD, Coats ER, Ahmed Rahim MM, Lundgren A et al (2010) MHC class I D(k) expression in hematopoietic and nonhematopoietic cells confers natural killer cell resistance to murine cytomegalovirus. Proc Natl Acad Sci U S A 107(19): 8754–8759
Rodriguez M, Sabastian P, Clark P, Brown MG (2004) Cmv1-independent antiviral role of NK cells revealed in murine cytomegalovirus-infected New Zealand white mice. J Immunol 173(10):6312–6318
Acknowledgments
This work was supported in part by NIH grants AI050072 (M.G.B.), P50-AR04522, R01-AR047988, R01-AR049449 and R01-AI079621 (S.M.F.) and a grant from Alliance for Lupus Research (S.M.F.).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2012 Springer Science+Business Media New York
About this protocol
Cite this protocol
Ge, Y., Brown, M.G., Wang, H., Fu, S.M. (2012). Genetic Approach to Study Lupus Glomerulonephritis. In: Perl, A. (eds) Autoimmunity. Methods in Molecular Biology, vol 900. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-720-4_13
Download citation
DOI: https://doi.org/10.1007/978-1-60761-720-4_13
Published:
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-60761-719-8
Online ISBN: 978-1-60761-720-4
eBook Packages: Springer Protocols