C1r/C1s deficiency is insufficient to induce murine systemic lupus erythematosus


C1s deficiency is strongly associated with the development of human systemic lupus erythematosus (SLE); however, the mechanisms by which C1s deficiency contributes to the development of SLE have not yet been elucidated in detail. Using ICR-derived-glomerulonephritis (ICGN) mouse strain that develops SLE and very weakly expresses C1s in the liver, we investigated the protective roles of C1s against SLE. A genetic sequence analysis revealed complete deletion of the C1s1 gene, a mouse homolog of the human C1s gene, with partial deletion of the C1ra and C1rb genes in the ICGN strain. This deletion led to the absence of C1r/C1s and a low level of C1q in the circulation. In order to investigate whether the C1r/C1s deficiency induces SLE, we produced a congenic mouse strain by introducing the deletion region of ICGN into the C57BL/6 strain. Congenic mice exhibited no C1r/C1s and a low level of C1q in the circulation, but did not have any autoimmune defects. These results suggest that C1r/C1s deficiency is not sufficient to drive murine SLE and also that other predisposing genes exist in ICGN mice.

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  1. 1.

    Ogura A, Asano T, Matsuda J, Takano K, Nakagawa M, Fukui M. Characteristics of mutant mice (ICGN) with spontaneous renal lesion: a new model for human nephrotic syndrome. Lab Anim. 1989;23:169–74.

    CAS  Article  Google Scholar 

  2. 2.

    Cho AR, Uchio-Yamada K, Torigai T, Miyamoto T, Miyoshi I, Matsuda J. et al. Deficiency of the tensin2 gene in the ICGN mouse, an animal model for congenital nephrotic syndrome. Mamm Genome. 2006;17:407–16.

    CAS  Article  Google Scholar 

  3. 3.

    Uchio-Yamada K, Sawada K, Tamura K, Katayama S, Monobe Y, Yamamoto Y, et al. Tenc1 deficient mice develop glomerular disease in a strain-specific manner. Nephron Exp Nephrol. 2013;123:22–33.

    CAS  Article  Google Scholar 

  4. 4.

    Uchio-Yamada K, Monobe Y, Akagi K, Yamamoto Y, Ogura A, Manabe N. Tensin2-deficient mice on FVB/N background develop severe glomerular disease. J Vet Med Sci. 2016;78:811–8.

    CAS  Article  Google Scholar 

  5. 5.

    Tamura K, Uchio-Yamada K, Manabe N, Noto T, Hirota R, Unami A, et al. Gene expression analysis detected low expression level of C1s gene in ICR-derived glomerulonephritis (ICGN) Mice. Nephron Exp Nephrol. 2013;123:34–45.

    CAS  Article  Google Scholar 

  6. 6.

    Hess C, Kemper C. Complement-mediated regulation of metabolism and basic cellular processes. Immunity. 2016;45:240–54.

    CAS  Article  Google Scholar 

  7. 7.

    Garnier G, Circolo A, Xu Y, Volanakis JE. Complement C1r and C1s genes are duplicated in the mouse: differential expression generates alternative isomorphs in the liver and in the male reproductive system. Biochem J. 2003;371:631–40.

    CAS  Article  Google Scholar 

  8. 8.

    Schwaeble W, Schäfer MK, Petry F, Fink T, Knebel D, Weihe E, et al. Follicular dendritic cells, interdigitating cells, and cells of the monocyte-macrophage lineage are the C1q-producing sources in the spleen. Identification of specific cell types by in situ hybridization and immunohistochemical analysis. J Immunol. 1995;155:4971–8.

    CAS  PubMed  Google Scholar 

  9. 9.

    Chen G, Tan CS, Teh BK, Lu J. Molecular mechanisms for synchronized transcription of three complement C1q subunit genes in dendritic cells and macrophages. J Biol Chem. 2011;286:34941–50.

    CAS  Article  Google Scholar 

  10. 10.

    Lintner KE, Wu YL, Yang Y, Spencer CH, Hauptmann G, Hebert LA, et al. Early components of the complement classical activation pathway in human systemic autoimmune diseases. Front Immunol. 2016;7:36.

    Article  Google Scholar 

  11. 11.

    Macedo AC, Isaac L. Systemic lupus erythematosus and deficiencies of early components of the complement classical pathway. Front Immunol. 2016;7:55.

    Article  Google Scholar 

  12. 12.

    Amano MT, Ferriani VP, Florido MP, Reis ES, Delcolli MI, Azzolini AE, et al. Genetic analysis of complement C1s deficiency associated with systemic lupus erythematosus highlights alternative splicing of normal C1s gene. Mol Immunol. 2008;45:1693–702.

    CAS  Article  Google Scholar 

  13. 13.

    Dragon-Durey MA, Quartier P, Frémeaux-Bacchi V, Blouin J, de Barace C, Prieur AM, et al. Molecular basis of a selective C1s deficiency associated with early onset multiple autoimmune diseases. J Immunol. 2001;166:7612–6.

    CAS  Article  Google Scholar 

  14. 14.

    Abe K, Endo Y, Nakazawa N, Kanno K, Okubo M, Hoshino T, et al. Unique phenotypes of C1s deficiency and abnormality caused by two compound heterozygosities in a Japanese family. J Immunol. 2009;182:1681–8.

    CAS  Article  Google Scholar 

  15. 15.

    Inoue N, Saito T, Masuda R, Suzuki Y, Ohtomi M, Sakiyama H. Selective complement C1s deficiency caused by homozygous four-base deletion in the C1s gene. Hum Genet. 1998;103:415–8.

    CAS  Article  Google Scholar 

  16. 16.

    Wu YL, Brookshire BP, Verani RR, Arnett FC, Yu CY. Clinical presentations and molecular basis of complement C1r deficiency in a male African-American patient with systemic lupus erythematosus. Lupus. 2011;20:1126–34.

    CAS  Article  Google Scholar 

  17. 17.

    Demirkaya E, Zhou Q, Smith CK, Ombrello MJ, Deuitch N, Tsai WL, et al. Deficiency of complement 1r subcomponent in early-onset systemic lupus erythematosus: the role of disease-modifying alleles in a monogenic disease. Arthritis Rheumatol. 2017;69:1832–9.

    CAS  Article  Google Scholar 

  18. 18.

    de Bracco MM, Windhorst D, Stroud RM, Moncada B. The autosomal recessive mode of inheritance of C1r deficiency in a large Puerto Rican family. Clin Exp Immunol. 1974;16:183–8.

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Lee SL, Wallace SL, Barone R, Blum L, Chase PH. Familial deficiency of two subunits of the first component of complement. C1r and C1s associated with a lupus erythematosus-like disease. Arthritis Rheum. 1978;21:958–67.

    CAS  Article  Google Scholar 

  20. 20.

    Chevailler A, Drouet C, Ponard D, Alibeu C, Suraniti S, Carrère F, et al. Non-coordinated biosynthesis of early complement components in a deficiency of complement proteins C1r and C1s. Scand J Immunol. 1994;40:383–8.

    CAS  Article  Google Scholar 

  21. 21.

    Slingsby JH, Norsworthy P, Pearce G, Vaishnaw AK, Issler H, Morley BJ, et al. Homozygous hereditary C1q deficiency and systemic lupus erythematosus. A new family and the molecular basis of C1q deficiency in three families. Arthritis Rheum. 1996;39:663–70.

    CAS  Article  Google Scholar 

  22. 22.

    Aggarwal R, Sestak AL, D’Souza A, Dillon SP, Namjou B, Scofield RH. Complete complement deficiency in a large cohort of familial systemic lupus erythematosus. Lupus. 2010;19:52–7.

    CAS  Article  Google Scholar 

  23. 23.

    Hannema AJ, Kluin-Nelemans JC, Hack CE, Eerenberg-Belmer AJ, Mallée C, van Helden HP. SLE like syndrome and functional deficiency of C1q in members of a large family. Clin Exp Immunol. 1984;55:106–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Thanei S, Trendelenburg M. Anti-C1q autoantibodies from systemic lupus erythematosus patients induce a proinflammatory phenotype in macrophages. J Immunol. 2016;196:2063–74.

    CAS  Article  Google Scholar 

  25. 25.

    Schaller M, Bigler C, Danner D, Ditzel HJ, Trendelenburg M. Autoantibodies against C1q in systemic lupus erythematosus are antigen-driven. J Immunol. 2009;183:8225–31.

    CAS  Article  Google Scholar 

  26. 26.

    Trouw LA, Groeneveld TW, Seelen MA, Duijs JM, Bajema IM, Prins FA, et al. Anti-C1q autoantibodies deposit in glomeruli but are only pathogenic in combination with glomerular C1q-containing immune complexes. J Clin Invest. 2004;114:679–88.

    CAS  Article  Google Scholar 

  27. 27.

    Trouw LA, Seelen MA, Visseren R, Duijs JM, Benediktsson H, de Heer E, et al. Anti-C1q autoantibodies in murine lupus nephritis. Clin Exp Immunol. 2004;135:41–8.

    CAS  Article  Google Scholar 

  28. 28.

    Mitchell DA, Pickering MC, Warren J, Fossati-Jimack L, Cortes-Hernandez J, Cook HT, et al. C1q deficiency and autoimmunity: the effects of genetic background on disease expression. J Immunol. 2002;168:2538–43.

    CAS  Article  Google Scholar 

  29. 29.

    Botto M, Dell’Agnola C, Bygrave AE, Thompson EM, Cook HT, Petry F, et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet. 1998;19:56–9.

    CAS  Article  Google Scholar 

  30. 30.

    Circolo A, Garnier G, Volanakis JE. A novel murine complement-related gene encoding a C1r-like serum protein. Mol Immunol. 2003;39:899–906.

    CAS  Article  Google Scholar 

  31. 31.

    Kusumoto H, Hirosawa S, Salier JP, Hagen FS, Kurachi K. Human genes for complement components C1r and C1s in a close tail-to-tail arrangement. Proc Natl Acad Sci USA. 1988;85:7307–11.

    CAS  Article  Google Scholar 

  32. 32.

    Mahajan A, Herrmann M, Muñoz LE. Clearance deficiency and cell death pathways: a model for the pathogenesis of SLE. Front Immunol. 2016;7:35.

    Article  Google Scholar 

  33. 33.

    Benoit ME, Clarke EV, Morgado P, Fraser DA, Tenner AJ. Complement protein C1q directs macrophage polarization and limits inflammasome activity during the uptake of apoptotic cells. J Immunol. 2012;188:5682–93.

    CAS  Article  Google Scholar 

  34. 34.

    Fraser DA, Laust AK, Nelson EL, Tenner AJ. C1q differentially modulates phagocytosis and cytokine responses during ingestion of apoptotic cells by human monocytes, macrophages, and dendritic cells. J Immunol. 2009;183:6175–85.

    CAS  Article  Google Scholar 

  35. 35.

    Colonna L, Parry GC, Panicker S, Elkon KB. Uncoupling complement C1s activation from C1q binding in apoptotic cell phagocytosis and immunosuppressive capacity. Clin Immunol. 2016;163:84–90.

    CAS  Article  Google Scholar 

  36. 36.

    Cai Y, Teo BH, Yeo JG, Lu J. C1q protein binds to the apoptotic nucleolus and causes C1 protease degradation of nucleolar proteins. J Biol Chem. 2015;290:22570–80.

    CAS  Article  Google Scholar 

  37. 37.

    Yeo JG, Leong J, Arkachaisri T, Cai Y, Teo BH, Tan JH, et al. Proteolytic inactivation of nuclear alarmin high-mobility group box 1 by complement protease C1s during apoptosis. Cell Death Discov. 2016;2:16069.

    CAS  Article  Google Scholar 

  38. 38.

    Nguyen C, Limaye N, Wakeland EK. Susceptibility genes in the pathogenesis of murine lupus. Arthritis Res. 2002;4(Suppl 3):S255–63.

    Article  Google Scholar 

  39. 39.

    Izui S, Kelley VE, Masuda K, Yoshida H, Roths JB, Murphy ED. Induction of various autoantibodies by mutant gene lpr in several strains of mice. J Immunol. 1984;133:227–33.

    CAS  PubMed  Google Scholar 

  40. 40.

    Izui S, Higaki M, Morrow D, Merino R. The Y chromosome from autoimmune BXSB/MpJ mice induces a lupus-like syndrome in (NZW x C57BL/6)F1 male mice, but not in C57BL/6 male mice. Eur J Immunol. 1988;18:911–5.

    CAS  Article  Google Scholar 

  41. 41.

    Barker TT, Lee PY, Kelly-Scumpia KM, Weinstein JS, Nacionales DC, Kumagai Y, et al. Pathogenic role of B cells in the development of diffuse alveolar hemorrhage induced by pristane. Lab Invest. 2011;91:1540–50.

    CAS  Article  Google Scholar 

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This study was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science. We thank Ms. Kyoko Sawada for her excellent technical assistance. We are also grateful to the late Dr. Yoshie Yamamoto for her helpful discussions.

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Correspondence to Kozue Uchio-Yamada.

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Uchio-Yamada, K., Tanaka, M. & Manabe, N. C1r/C1s deficiency is insufficient to induce murine systemic lupus erythematosus. Genes Immun 20, 121–130 (2019). https://doi.org/10.1038/s41435-018-0020-5

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