Skip to main content

Advertisement

SpringerLink
Log in

Autoimmunity: Homeostasis of Innate Immunity Gone Awry

  • Key Review Article
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Abbreviations

aHUS:

Atypical hemolytic uremic syndrome

TMA:

Thrombotic microangiopathy

AP:

Alternative pathway

HUS:

Hemolytic uremic syndrome

HELLP:

Hemolysis elevated liver enzymes low platelets

AMD:

Age-related macular degeneration

RPE:

Retinal pigment epithelium

SNP:

Single nucleotide polymorphism

GAS:

Group A streptococcus

SLE:

Systemic lupus erythematosus

DNase1:

Deoxyribonuclease1

TREX1:

Three prime repair exonuclease 1

AGS:

Aicardi-Goutières syndrome

ISD:

Interferon stimulatory DNA

TLR:

Toll-like receptor

GWAS:

Genome wide association study

References

  1. Al-Mayouf SM, Sunker A, Abdwani R, Abrawi SA, Almurshedi F, Alhashmi N, Al Sonbul A, Sewairi W, Qari A, Abdallah E, Al-Owain M, Al Motywee S, Al-Rayes H, Hashem M, Khalak H, Al-Jebali L, Alkuraya FS. Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus. Nat Genet. 2011;43(12):1186–8.

    Article  PubMed  CAS  Google Scholar 

  2. Anderson DH, Radeke MJ, Gallo NB, Chapin EA, Johnson PT, Curletti CR, Hancox LS, Hu J, Ebright JN, Malek G, Hauser MA, Rickman CB, Bok D, Hageman GS, Johnson LV. The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res. 2010;29(2):95–112.

    Article  PubMed  CAS  Google Scholar 

  3. Atkinson JP. Complement deficiency: predisposing factor to autoimmune syndromes. Clin Exp Rheumatol. 1989;7 Suppl 3:S95–101.

    PubMed  Google Scholar 

  4. Atkinson JP, Liszewski MK, Richards A, Kavanagh D, Moulton EA. Hemolytic uremic syndrome: an example of insufficient complement regulation on self-tissue. Ann N Y Acad Sci. 2005;1056:144–52.

    Article  PubMed  CAS  Google Scholar 

  5. Botto M, Dell’agnola C, Bygrave AE, Thompson EM, Cook HT, Petry F, Loos M, Pandolfi PP, Walport MJ. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet. 1998;19(1):56–9.

    Article  PubMed  CAS  Google Scholar 

  6. Carroll MC. The lupus paradox. Nat Genet. 1998;19(1):3–4.

    Article  PubMed  CAS  Google Scholar 

  7. Chitrabamrung S, Rubin RL, Tan EM. Serum deoxyribonuclease I and clinical activity in systemic lupus erythematosus. Rheumatol Int. 1981;1(2):55–60.

    Article  PubMed  CAS  Google Scholar 

  8. Crow YJ, Hayward BE, Parmar R, Robins P, Leitch A, Ali M, Black DN, Van Bokhoven H, Brunner HG, Hamel BC, Corry PC, Cowan FM, Frints SG, Klepper J, Livingston JH, Lynch SA, Massey RF, Meritet JF, Michaud JL, Ponsot G, et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus. Nat Genet. 2006;38(8):917–20.

    Article  PubMed  CAS  Google Scholar 

  9. Edwards AO, Ritter 3rd R, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308(5720):421–4.

    Article  PubMed  CAS  Google Scholar 

  10. Elkon KB, Wiedeman A. Type I IFN system in the development and manifestations of SLE. Curr Opin Rheumatol. 2012;24(5):499–505.

    Article  PubMed  CAS  Google Scholar 

  11. Fakhouri F, Jablonski M, Lepercq J, Blouin J, Benachi A, Hourmant M, Pirson Y, Durrbach A, Grunfeld JP, Knebelmann B, Fremeaux-Bacchi V. Factor H, membrane cofactor protein, and factor I mutations in patients with hemolysis, elevated liver enzymes, and low platelet count syndrome. Blood. 2008;112(12):4542–5.

    Article  PubMed  CAS  Google Scholar 

  12. Fang CJ, Fremeaux-Bacchi V, Liszewski MK, Pianetti G, Noris M, Goodship TH, Atkinson JP. Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome. Blood. 2008;111(2):624–32.

    Article  PubMed  CAS  Google Scholar 

  13. Fda. (2011) Eculizumab. Available online at: http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm273089.htm).

  14. Gall A, Treuting P, Elkon KB, Loo YM, Gale Jr M, Barber GN, Stetson DB. Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease. Immunity. 2012;36(1):120–31.

    Article  PubMed  CAS  Google Scholar 

  15. Gold B, Merriam JE, Zernant J, Hancox LS, Taiber AJ, Gehrs K, Cramer K, Neel J, Bergeron J, Barile GR, Smith RT, Hageman GS, Dean M, Allikmets R. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet. 2006;38(4):458–62.

    Article  PubMed  CAS  Google Scholar 

  16. Haapasalo K, Jarva H, Siljander T, Tewodros W, Vuopio-Varkila J, Jokiranta TS. Complement factor H allotype 402H is associated with increased C3b opsonization and phagocytosis of Streptococcus pyogenes. Mol Microbiol. 2008;70(3):583–94.

    Article  PubMed  CAS  Google Scholar 

  17. Hageman G, Gehrs K, Johnson L, Anderson D. Age-Related Macular Degeneration (AMD). In: Kolb H, Fernandez NR, editors. Webvision: The Organization of the Retina and Visual System. Salt Lake City: University of Utah Health Sciences Center; 2008.

    Google Scholar 

  18. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, Hageman JL, Stockman HA, Borchardt JD, Gehrs KM, Smith RJ, Silvestri G, Russell SR, Klaver CC, Barbazetto I, Chang S, Yannuzzi LA, Barile GR, Merriam JC, Smith RT, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. 2005;102(20):7227–32.

    Article  PubMed  CAS  Google Scholar 

  19. Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P, Spencer KL, Kwan SY, Noureddine M, Gilbert JR, Schnetz-Boutaud N, Agarwal A, Postel EA, Pericak-Vance MA. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308(5720):419–21.

    Article  PubMed  CAS  Google Scholar 

  20. Harley IT, Kaufman KM, Langefeld CD, Harley JB, Kelly JA. Genetic susceptibility to SLE: new insights from fine mapping and genome-wide association studies. Nat Rev Genet. 2009;10(5):285–90.

    Article  PubMed  CAS  Google Scholar 

  21. Johnson LV, Leitner WP, Staples MK, Anderson DH. Complement activation and inflammatory processes in Drusen formation and age related macular degeneration. Exp Eye Res. 2001;73(6):887–96.

    Article  PubMed  CAS  Google Scholar 

  22. Karayel E, Burckstummer T, Bilban M, Durnberger G, Weitzer S, Martinez J, Superti-Furga G. The TLR-independent DNA recognition pathway in murine macrophages: Ligand features and molecular signature. Eur J Immunol. 2009;39(7):1929–36.

    Article  PubMed  CAS  Google Scholar 

  23. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning AK, Sangiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308(5720):385–9.

    Article  PubMed  CAS  Google Scholar 

  24. Koffler D, Agnello V, Carr RI, Kunkel HG. Anti-DNA antibodies and renal lesions of patients with systemic lupus erythematosus. Transplant Proc. 1969;1(4):933–8.

    PubMed  CAS  Google Scholar 

  25. Koffler D, Agnello V, Carr RI, Kunkel HG. Variable patterns of immunoglobulin and complement deposition in the kidneys of patients with systemic lupus erythematosus. Am J Pathol. 1969;56(3):305–16.

    PubMed  CAS  Google Scholar 

  26. Koffler D, Agnello V, Thoburn R, Kunkel HG. Systemic lupus erythematosus: prototype of immune complex nephritis in man. J Exp Med. 1971;134(3):169–79.

    PubMed  CAS  Google Scholar 

  27. Lachmann PJ. Inherited complement deficiencies. Philos Trans R Soc Lond B Biol Sci. 1984;306(1129):419–30.

    Article  PubMed  CAS  Google Scholar 

  28. Lee-Kirsch MA, Gong M, Chowdhury D, Senenko L, Engel K, Lee YA, De Silva U, Bailey SL, Witte T, Vyse TJ, Kere J, Pfeiffer C, Harvey S, Wong A, Koskenmies S, Hummel O, Rohde K, Schmidt RE, Dominiczak AF, Gahr M, et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet. 2007;39(9):1065–7.

    Article  PubMed  CAS  Google Scholar 

  29. Liu Z, Davidson A. Taming lupus-a new understanding of pathogenesis is leading to clinical advances. Nat Med. 2012;18(6):871–82.

    Article  PubMed  Google Scholar 

  30. Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60.

    Article  PubMed  Google Scholar 

  31. Macanovic M, Lachmann PJ. Measurement of deoxyribonuclease I (DNase) in the serum and urine of systemic lupus erythematosus (SLE)-prone NZB/NZW mice by a new radial enzyme diffusion assay. Clin Exp Immunol. 1997;108(2):220–6.

    Article  PubMed  CAS  Google Scholar 

  32. Manuelian T, Hellwage J, Meri S, Caprioli J, Noris M, Heinen S, Jozsi M, Neumann HP, Remuzzi G, Zipfel PF. Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome. J Clin Invest. 2003;111(8):1181–90.

    PubMed  CAS  Google Scholar 

  33. Menne J, Nitschke M, Stingele R, Abu-Tair M, Beneke J, Bramstedt J, Bremer JP, Brunkhorst R, Busch V, Dengler R, Deuschl G, Fellermann K, Fickenscher H, Gerigk C, Goettsche A, Greeve J, Hafer C, Hagenmuller F, Haller H, Herget-Rosenthal S, et al. Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case–control study. BMJ. 2012;345:e4565.

    Article  PubMed  Google Scholar 

  34. Morita M, Stamp G, Robins P, Dulic A, Rosewell I, Hrivnak G, Daly G, Lindahl T, Barnes DE. Gene-targeted mice lacking the Trex1 (DNase III) 3′– > 5′ DNA exonuclease develop inflammatory myocarditis. Mol Cell Biol. 2004;24(15):6719–27.

    Article  PubMed  CAS  Google Scholar 

  35. Namjou B, Kothari PH, Kelly JA, Glenn SB, Ojwang JO, Adler A, Alarcon-Riquelme ME, Gallant CJ, Boackle SA, Criswell LA, Kimberly RP, Brown E, Edberg J, Stevens AM, Jacob CO, Tsao BP, Gilkeson GS, Kamen DL, Merrill JT, Petri M, et al. Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes Immun. 2011;12(4):270–9.

    Article  PubMed  CAS  Google Scholar 

  36. Napirei M, Karsunky H, Zevnik B, Stephan H, Mannherz HG, Moroy T. Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat Genet. 2000;25(2):177–81.

    Article  PubMed  CAS  Google Scholar 

  37. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361(17):1676–87.

    Article  PubMed  CAS  Google Scholar 

  38. Orebaugh CD, Fye JM, Harvey S, Hollis T, Perrino FW. The TREX1 exonuclease R114H mutation in Aicardi-Goutieres syndrome and lupus reveals dimeric structure requirements for DNA degradation activity. J Biol Chem. 2011;286(46):40246–54.

    Article  PubMed  CAS  Google Scholar 

  39. Pickering MC, Botto M, Taylor PR, Lachmann PJ, Walport MJ. Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv Immunol. 2000;76:227–324.

    Article  PubMed  CAS  Google Scholar 

  40. Raychaudhuri S, Iartchouk O, Chin K, Tan PL, Tai AK, Ripke S, Gowrisankar S, Vemuri S, Montgomery K, Yu Y, Reynolds R, Zack DJ, Campochiaro B, Campochiaro P, Katsanis N, Daly MJ, Seddon JM. A rare penetrant mutation in CFH confers high risk of age-related macular degeneration. Nat Genet. 2011;43(12):1232–6.

    Article  PubMed  CAS  Google Scholar 

  41. Resnikoff S, Pascolini D, Etya’ale D, Kocur I, Pararajasegaram R, Pokharel GP, Mariotti SP. Global data on visual impairment in the year 2002. Bull World Health Organ. 2004;82(11):844–51.

    PubMed  Google Scholar 

  42. Rice G, Patrick T, Parmar R, Taylor CF, Aeby A, Aicardi J, Artuch R, Montalto SA, Bacino CA, Barroso B, Baxter P, Benko WS, Bergmann C, Bertini E, Biancheri R, Blair EM, Blau N, Bonthron DT, Briggs T, Brueton LA, et al. Clinical and molecular phenotype of Aicardi-Goutieres syndrome. Am J Hum Genet. 2007;81(4):713–25.

    Article  PubMed  CAS  Google Scholar 

  43. Richards A, Kavanagh D, Atkinson JP. Inherited complement regulatory protein deficiency predisposes to human disease in acute injury and chronic inflammatory statesthe examples of vascular damage in atypical hemolytic uremic syndrome and debris accumulation in age-related macular degeneration. Adv Immunol. 2007;96:141–77.

    Article  PubMed  CAS  Google Scholar 

  44. Rodriguez De Cordoba S. aHUS: a disorder with many risk factors. Blood. 2010;115(2):158–60.

    Article  PubMed  CAS  Google Scholar 

  45. Salmon JE, Heuser C, Triebwasser M, Liszewski MK, Kavanagh D, Roumenina L, Branch DW, Goodship T, Fremeaux-Bacchi V, Atkinson JP. Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. PLoS Med. 2011;8(3):e1001013.

    Article  PubMed  CAS  Google Scholar 

  46. Seddon JM, Reynolds R, Maller J, Fagerness JA, Daly MJ, Rosner B. Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci. 2009;50(5):2044–53.

    Article  PubMed  Google Scholar 

  47. Shaw PX, Zhang L, Zhang M, Du H, Zhao L, Lee C, Grob S, Lim SL, Hughes G, Lee J, Bedell M, Nelson MH, Lu F, Krupa M, Luo J, Ouyang H, Tu Z, Su Z, Zhu J, Wei X, et al. Complement factor H genotypes impact risk of age-related macular degeneration by interaction with oxidized phospholipids. Proc Natl Acad Sci U S A. 2012;109(34):13757–62.

    Article  PubMed  CAS  Google Scholar 

  48. Stetson DB, Ko JS, Heidmann T, Medzhitov R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell. 2008;134(4):587–98.

    Article  PubMed  CAS  Google Scholar 

  49. Walport MJ. Lupus, DNase and defective disposal of cellular debris. Nat Genet. 2000;25(2):135–6.

    Article  PubMed  CAS  Google Scholar 

  50. Walport MJ. Complement. Second of two parts. N Engl J Med. 2001;344(15):1140–4.

    Article  PubMed  CAS  Google Scholar 

  51. Westra D, Wetzels JF, Volokhina EB, Van Den Heuvel LP, Van De Kar NC. A new era in the diagnosis and treatment of atypical haemolytic uraemic syndrome. Neth J Med. 2012;70(3):121–9.

    PubMed  CAS  Google Scholar 

  52. Yasutomo K, Horiuchi T, Kagami S, Tsukamoto H, Hashimura C, Urushihara M, Kuroda Y. Mutation of DNASE1 in people with systemic lupus erythematosus. Nat Genet. 2001;28(4):313–4.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Rheumatology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8045, St. Louis, MO, 63110, USA

    Hyon Ju Park & John P. Atkinson

  2. Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Hyon Ju Park & John P. Atkinson

Authors
  1. Hyon Ju Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John P. Atkinson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John P. Atkinson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Park, H.J., Atkinson, J.P. Autoimmunity: Homeostasis of Innate Immunity Gone Awry. J Clin Immunol 32, 1148–1152 (2012). https://doi.org/10.1007/s10875-012-9815-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-012-9815-8

Keywords

Search

Navigation