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National Institute of Allergy and Infectious Diseases, NIH pp 371–376Cite as

Mind Your Xs and Ys: Genetics of the Autoimmune Disease Systemic Lupus Erythematosus

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Part of the book series: Infectious Disease ((ID))

Abstract

Systemic autoimmune diseases are disorders in which a variety of genetic and environmental factors interact to result in a loss of tolerance to self antigens and emergence of pathogenic autoantibodies. Multiple genes contribute to the development of these diseases, modulated by hormonal, environmental and infectious factors. Determining these interactions and their consequences is a fundamental step in elucidating the mechanisms that give rise to disease and will provide insights into methods for effective treatment. Systemic lupus erythematosus (SLE) is one of the most prevalent autoimmune diseases, affecting two million people in the USA. This disease has a 9:1female-to-male bias; symptoms usually arise during women’s child-bearing years [1,2]. Lupus is most common in minority populations, such as African Americans, Latinos and Native Americans. Lupus disease is associated with a wide range of symptoms. In its mildest form, this disease causes general fatigue, fevers and skin rashes. In its most severe form, lupus causes a lethal inflammatory disease that leads to kidney, heart and lung failure. A hallmark of this disease is the presence of anti-nuclear antibodies (ANA) in the serum, which is an indication of B-cell reactivity against common self antigens. Our laboratory is conducting research that aims to understand genetic and environmental causes of lupus disease. We are investigating animal models of lupus disease in order to identify novel susceptibility factors and to discover mechanisms underlying the onset of systemic autoimmune disease.

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References

  1. Castro J, Balada E, Ordi-Ros J et al (2008) The complex immunogenetic basis of systemic lupus erythematosus, Autoimmun Rev 7:345–351

    Article  PubMed  CAS  Google Scholar 

  2. Jonsen A, Bengtsson A A, Nived O et al (2007) Gene-environment interactions in the aetiology of systemic lupus erythematosus, Autoimmunity 40:613–617

    Article  PubMed  Google Scholar 

  3. Ravetch J V & Bolland S (2001) IgG Fc receptors. Annu Rev Immunol 19 275– 290

    Article  PubMed  CAS  Google Scholar 

  4. Bolland S & Ravetch J V (2000) Spontaneous autoimmune disease in FcgRII deficient mice results from strain-specific epistasis, Immunity 13:277–285

    Article  PubMed  CAS  Google Scholar 

  5. Bolland S, Yim Y S, Tus K et al (2002) Genetic modifiers of systemic lupus erythematosus in FcgammaRIIB(-/-) mice, J Exp Med 195:1167–1174

    Article  PubMed  CAS  Google Scholar 

  6. Tarasenko T, Dean J A, Bolland S (2007) FcgammaRIIB as a modulator of autoimmune disease susceptibility, Autoimmunity 40:409–417

    Article  PubMed  CAS  Google Scholar 

  7. Mackay M, Stanevsky A, Wang T et al (2006) Selective dysregulation of the FcgammaIIB receptor on memory B cells in SLE, J Exp Med 203:2157–2164

    Article  PubMed  CAS  Google Scholar 

  8. Tarasenko T, Kole H K, Bolland S (2008) A lupus-suppressor BALB/c locus restricts IgG2 autoantibodies without altering intrinsic B cell-tolerance mechanisms, J. Immunol 180:3807–3814

    PubMed  CAS  Google Scholar 

  9. Chen C, Nagy Z, Prak E L et al (1995) Immunoglobulin heavy chain gene replacement: a mechanism of receptor editing, Immunity 3:747–755

    Article  PubMed  CAS  Google Scholar 

  10. Chen C, Prak E L, Weigert M (1997) Editing disease-associated autoantibodies, Immunity 6:97–105

    Article  PubMed  Google Scholar 

  11. Li,H, Jiang Y, Prak E L et al (2001) Editors and editing of anti-DNA receptors, Immunity 15:947–957

    Article  PubMed  CAS  Google Scholar 

  12. Fukuyama H, Nimmerjahn F, Ravetch J V (2005) The inhibitory Fcgamma receptor modulates autoimmunity by limiting the accumulation of immunoglobulin G+ anti-DNA plasma cells, Nat. Immunol 6:99–106

    Article  PubMed  CAS  Google Scholar 

  13. Murphy E D & Roths J B (1979) A Y chromosome associated factor in strain BXSB producing accelerated autoimmunity and lymphoproliferation, Arthritis Rheum 22:1188–1194

    Article  PubMed  CAS  Google Scholar 

  14. Izui S, Iwamoto M, Fossati L et al (1995) The Yaa gene model of systemic lupus erythematosus, Immunol Rev 144: 137–156

    Article  PubMed  CAS  Google Scholar 

  15. Amano H, Amano E, Moll T et al (2003) The Yaa mutation promoting murine lupus causes defective development of marginal zone B cells, J Immuno 170:2293–2301

    CAS  Google Scholar 

  16. Amano H, Amano E, Santiago-Raber M L et al (2005) Selective expansion of a monocyte subset expressing the CD11c dendritic cell marker in the Yaa model of systemic lupus erythematosus, Arthritis Rheum 52:2790–2798

    Article  PubMed  CAS  Google Scholar 

  17. Anolik J H, Barnard J, Owen T et al (2007) Delayed memory B cell recovery in peripheral blood and lymphoid tissue in systemic lupus erythematosus after B cell depletion therapy, Arthritis Rheum 56: 3044–3056

    Article  PubMed  CAS  Google Scholar 

  18. Pisitkun P, Deane J A, Difilippantonio M J et al (2006) Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication, Science 312:1669–1672

    Article  PubMed  CAS  Google Scholar 

  19. Diebold S S, Kaisho T, Hemmi H et al (2004) Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA, Science 303:1529–1531

    Article  PubMed  CAS  Google Scholar 

  20. Lund J M, Alexopoulou L, Sato A et al (2004) Recognition of single-stranded RNA viruses by Toll-like receptor 7, Proc Natl Acad Sci USA 101:5598–5603

    Article  PubMed  CAS  Google Scholar 

  21. Takeda K, Kaisho T, Akira S (2003) Toll-like receptors, Annu Rev Immunol 21:335–376

    Article  PubMed  CAS  Google Scholar 

  22. Leadbetter E A, Rifkin I R, Hohlbaum A M et al (2002) Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors, Nature 416:603–607

    Article  PubMed  CAS  Google Scholar 

  23. Marshak-Rothstein A & Rifkin I R (2007) Immunologically active autoantigens: the role of toll-like receptors in the development of chronic inflammatory disease, Annu Rev Immunol 25:419–441

    Article  PubMed  CAS  Google Scholar 

  24. Deane J A, Pisitkun P, Barrett R S et al (2007) Control of toll-like receptor 7 expression is essential to restrict autoimmunity and dendritic cell proliferation, Immunity 27:801– 810

    Article  PubMed  CAS  Google Scholar 

  25. Fairhurst A M, Hwang S H, Wang A et al (2008) Yaa autoimmune phenotypes are conferred by overexpression of TLR7, Eur J Immunol 38:1971–1978

    Article  PubMed  CAS  Google Scholar 

  26. Viglianti G A, Lau C M, Hanley T M et al (2003) Activation of autoreactive B cells by CpG dsDNA, Immunity 19:837–847

    Article  PubMed  CAS  Google Scholar 

  27. Chaturvedi A, Dorward D, Pierce S K (2008) The B cell receptor governs the subcellular location of Toll-like receptor 9 leading to hyperresponses to DNA-containing antigens, Immunity 28:799–809

    Article  PubMed  CAS  Google Scholar 

  28. Lau C M, Broughton C, Tabor A S et al (2005) RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement, J Exp Med 202:1171–1177

    Article  PubMed  CAS  Google Scholar 

  29. Cella M, Jarrossay D, Facchetti F et al (1999) Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon, Nat Med 5:919–923

    Article  PubMed  CAS  Google Scholar 

  30. Colonna M, Krug A, Cella M (2002) Interferon-producing cells: on the front line in immune responses against pathogens, Curr Opin Immunol 14:373–379

    Article  PubMed  CAS  Google Scholar 

  31. Means T K, Latz E, Hayashi F et al (2005) Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9, J Clin Invest 115:407–417

    PubMed  CAS  Google Scholar 

  32. Lee H K, Lund J M, Ramanathan B et al. (2007) Autophagy-dependent viral recognition by plasmacytoid dendritic cells, Science 315:1398–1401

    Article  PubMed  CAS  Google Scholar 

  33. Ono M, Bolland S, Tempst P et al (1996), Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor Fc(gamma)RIIB, Nature 383:263–266

    Article  PubMed  CAS  Google Scholar 

  34. Rohrschneider L R, Fuller J F, Wolf I et al (2000) Structure, function, and biology of SHIP proteins, Genes Dev 14:505–520

    PubMed  CAS  Google Scholar 

  35. Bolland S, Pearse R N, Kurosaki T et al (1998) SHIP modulates immune receptor responses by regulating membrane association of Btk, Immunity 8: 509–516

    Article  PubMed  CAS  Google Scholar 

  36. Ono M, Okada H, Bolland S et al (1997), Deletion of SHIP or SHP-1 reveals two distinct pathways for inhibitory signaling, Cell 90:293–301

    Article  PubMed  CAS  Google Scholar 

  37. Kalesnikoff J, Sly L M, Hughes M R et al (2003), The role of SHIP in cytokine-induced signaling, Rev. Physiol Biochem Pharmacol 149:87–103

    Article  PubMed  CAS  Google Scholar 

  38. Helgason C D, Damen J E, Rosten P et al (1998) Targeted disruption of SHIP leads to hemopoietic perturbations, lung pathology, and a shortened life span Genes Dev 12:1610–1620

    Article  PubMed  CAS  Google Scholar 

  39. Aman M J, Lamkin T D, Okada H et al (1998) The inositol phosphatase SHIP inhibits Akt/PKB activation in B cells, J Biol Chem 273:33922–33928

    Article  PubMed  CAS  Google Scholar 

  40. Liu Q, Sasaki T, Kozieradzki I et al (1999) SHIP is a negative regulator of growth factor receptor-mediated PKB/Akt activation and myeloid cell survival, Genes Dev., 13, 786–791.

    Article  PubMed  CAS  Google Scholar 

  41. Tarasenko T, Kole H K, Chi A W et al (2007) T cell-specific deletion of the inositol phosphatase SHIP reveals its role in regulating Th1/Th2 and cytotoxic responses. Proc Natl Acad Sci USA 104:11382–11387

    Article  PubMed  CAS  Google Scholar 

  42. Aranami T & Yamamura T (2008) Th17 Cells and autoimmune encephalomyelitis (EAE/MS), Allergol Int 57:115–120

    Article  PubMed  CAS  Google Scholar 

  43. Furuzawa-Carballed, J, Vargas-Rojas M I, Cabral A R (2007) Autoimmune inflammation from the Th17 perspective, Autoimmun Rev 6:169–175

    Article  Google Scholar 

  44. Adelman M K & Marchalonis J J (2002) Endogenous retroviruses in systemic lupus erythematosus: candidate lupus viruses, Clin Immunol 102:107–116

    Article  PubMed  CAS  Google Scholar 

  45. Hill N J, King C, &Flodstrom-Tullberg M (2008) Recent acquisitions on the genetic basis of autoimmune disease, Front Biosci 13:4838–4851

    Article  PubMed  CAS  Google Scholar 

  46. Zandman-Goddard G & Shoenfeld Y (2005) Infections and SLE. Autoimmunity 38:473–485

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Laboratory of Immunogenetics, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD, USA

    Steve P. Crampton & Silvia Bolland

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  1. Steve P. Crampton
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  2. Silvia Bolland
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Editors and Affiliations

  1. Dept. Health & Human Services, National Institute of Health, Rockledge Drive 6610, Bethesda, 20892, Maryland, USA

    Vassil St. Georgiev

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Crampton, S.P., Bolland, S. (2010). Mind Your Xs and Ys: Genetics of the Autoimmune Disease Systemic Lupus Erythematosus. In: Georgiev, V. (eds) National Institute of Allergy and Infectious Diseases, NIH. Infectious Disease. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-512-5_37

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  • DOI: https://doi.org/10.1007/978-1-60761-512-5_37

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  • Publisher Name: Humana Press, Totowa, NJ

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