Transgenic models of tolerance and autoimmunity: with special reference to systemic lupus erythematosus

Abstract

Transgenic and knockout mouse carrying rearranged antigen-receptor genes have been invaluable for the elucidation of basic mechanisms in autoimmunity and have contributed new models of human autoimmune diseases. Several examples of transgenic models expressing rearranged immunoglobulin genes have been described. These models have provided a window into the events involved in this process, allowing the development and fate of self-reactive lymphocytes to be followed in vivo. In the B cell lineage, as in T cells, self-reactive cells have been found to undergo several distinct fates in vivo: they can be physically eliminated, functionally inactivated, or they can persist unchanged or become activated. Nevertheless the precise understanding of the molecular events leading to lymphocyte deletion, anergy or activation remains a challenge.

Keywords

autoimmunity anti-DNA antibodies transgenic models tolerance pathogenicity

Get full access to this article

View all access options for this article.

References

Owen RD . Immunogenetic consequences of vascular anastomoses between bovine twins . Science 1945; 102: 400–410 .

Billingham RE , Brent L , Medawar PB . Activity acquired tolerance of foreign cells . Nature 1953; 172: 603–606 .

Burnet FM . The Clonal Selection Theory of Acquired Immunity. Vanderbilt University Press: Nashville, TN , 1959.

Burnet FM , Fenner F . The Production of Antibodies. Macmillian: Melbourne , 1949.

Lederberg J . Genes and antibodies . Science 1959; 129: 1649–1653 .

Bretscher P , Colin M . A theory of self-nonself discrimination: paralysis and induction involve the recognition of one and two determinations on antigen, respectively . Science 1970; 163: 1042–1049 .

Muller DL , Jenkins MK , Schwartz RH . Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy . A Rev Immunol 1989; 7: 445–480 .

Goodnow CC . B-cell tolerance . Curr Opin Immunol 1992; 4: 703–710 .

Fulcher DA , Basten A . B-cell activation versus tolerance-the central role of immunoglobulin receptor engagement and T-cell help . Int Rev Immunol 1997;15: 33–52 .

10.

Isenberg DA , Garton M , Reichlin MW , Reichlin M . Long-term follow-up of autoantibody profiles in black female lupus patients and clinical comparison with Caucasian and Asian patients . Br J Rheumatol 1997; 36: 229–233 .

11.

Theofilopoulous AN , Dixon FJ . Murine models of systemic lupus erythematosus . Adv Immunol 1985; 37: 269–278 .

12.

Veniant M , Menard J , Bruneval P , Morley S , Gonzales MF , Mullins J . Vascular damage without hypertension in transgenic rats expressing prorenin exclusively in the liver . J Clin Invest 1996; 98: 1966–1970 .

13.

Ohashi PS , Oehen S , Buerki K , Pircher H , Ohashi CT , Odermatt B et al. Ablation of ‘tolerance’ and induction of diabetes by virus infection in viral antigen transgenic mice . Cell 1991; 65: 305–317 .

14.

Goodnow CC , Crosbie J , Jorgensen H , Brink RA , Basten A . Induction of self-tolerance in mature peripheral B lymphocytes . Nature 1989; 342: 385–391 .

15.

Healy JI , Dolmetsch RE , Timmerman LA , Cyster JG , Thomas ML , Crabtree GR , Lewis RS , Goodnow CC . Different nuclear signals are activated by the B cell receptor during positive versus negative signalling . Immunity 1997; 6: 419–428 .

16.

Goodnow CC . Transgenic mice and analysis of B-cell tolerance . A Rev Immunol 1992; 10: 489–518 .

17.

Cooke MP , Heath AW , Shokat KM , Zeng Y , Finkelman FD , Linsley PS , Howard M , Goodnow CC . Immunoglobulin signal transduction guides the specificity of B cell-T cell interactions and is blocked in tolerant self-reactive Bcells . J Exp Med 1994; 179: 425–438 .

18.

Rthmell JC , Fournier S , Weintraub BC , Allison JP , Goodnow CC . Repression of B7.2 on self-reactive B cells is essential to prevent proliferation and allow Fas-mediated deletion by CD4(+) T cells . J Exp Med 1998; 188: 651–659 .

19.

Foote LC , Marshak-Rothstein A , Rothstein TL . Tolerant B lymphocytes acquire resistance to Fas-mediated apoptosis after treatment with interleukin 4 but not after treatment with specific antigen unless a surface immunoglobulin threshold is exceeded . J Exp Med 1998; 187: 847–853 .

20.

Eris JM , Basten A , Brink R , Doherty K , Kehry MR , Hodgkin PD . Anergic self-reactive B cells present self-antigen and respond normally to CD40-dependent T-cell signals but are defective in antigen-receptor-mediated functions . Proc Natl Acad Sci. USA 1994; 91: 4392–4396 .

21.

Goodnow CC , Crosbie J , Adelstein S , Lavoie TB , Smith-Gill SJ , Brink RA , Pritchard-Briscoe H , Wotherspoon JS , Loblay RH , Raphael K et al. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice . Nature 1988; 334: 676–682 .

22.

Mason DY , Jones M , Goodnow CC . Development and follicular localization of tolerant B lymphocytes in lysozyme/anti-lysozyme IgM/IgD transgenic mice . Int Immunol 1992; 4: 163–175 .

23.

Rathmell JC , Cooke MP , Ho WY , Grein J , Townsend SE , Davis MM , Fournie S , Goodnow CC . CD95 (Fas)-dependent elimination of self-reactive B cells upon interaction with CD40+ T cells . Nature 1995; 376: 181–184 .

24.

Cyster JG , Goodnow CC . Antigen induced exclusion from follicles and anergy are separate and complementary processes that influence peripheral B cell fate . Immunity 1995; 3: 691–701 .

25.

Cooke MC , Basten B , Fazekas de St Groth . Rescue of self-reactive B cells by provision of T cell help in vivo . Eur J Immunol 1998; 28: 2549–2558 .

26.

Goodnow CC , Brink R , Adams E . Breakdown of self-tolerance in anergic B lymphocytes . Nature 1991; 352: 532–536 .

27.

Staudt LM , Lenardo MJ . Immunoglobulin gene transcription . A Rev Immunol 1991; 9: 373–398 .

28.

Weaver D , Costantini F , Imanishi Kari T , Baltimore D . A transgenic immunoglobulin Mu gene prevents rearrangements of endogenous genes . Cell 1985; 42: 117–127 .

29.

Manz J , Denis K , Witte O , Brinster R , Storb U . Feedback inhibition of immunoglobulin gene rearrangement by membrane u, but not by secreted m heavy chains . J Exp Med 1988; 168: 1363–1381 .

30.

von Boehmer H , Kisielow P . Self-nonself discrimination by T cells . Science 1990; 248: 1369–1373 .

31.

Spatz L , Saenko V , Iliev A , Jones L , Geskin L , Diamond B . Light chain usage in anti-double-stranded DNA B cell subsets: role in cell fate determination . J Exp Med 1997; 185: 1317–1326 .

32.

Roark JH , Bui A , Nguyen KA , Mandik L , Erikson J . Persistence of functionally compromised anti-double-stranded DNA B cells in the periphery of non-autoimmune mice . Int Immunol 1997; 9: 1615–1626 .

33.

Erikson J , Mandik L , Bui A , Eaton A , Noorchashm H , Nguyen KA , Roark JH . Self-reactive B cells in nonautoimmune and autoimmune mice . Immunol Res 1998; 17: 49–61 .

34.

Nguyen KA , Mandik L , Bui A , Kavaler J , Norvell A , Monroe JG , Roark JH , Erikson J . Characterization of anti-single-stranded DNA B cells in a non-autoimmune background . J Immunol 1997; 159: 2633–2634 .

35.

Brarda F , Shannona M , Luning Prakb E , Litwinc S , Weigerta M . Somatic mutation and light chain rearrangement generate autoimmunity in anti-single-stranded DNA transgenic MRL/lpr mice . J Exp Med 1999; 190: 691–704 .

36.

Wellmann U , Werner A , Winkler TH . Altered selection processes of B lymphocytes in autoimmune NZB/W mice, despite intact central tolerance against DNA . Eur J Immunol 2001; 31: 2800–2810 .

37.

Li H , Jiang Y , Prak EL , Radic M , Weigert M . Editors and editing of anti-DNA receptors . Immunity 2001; 15: 947–957 .

38.

Xu H , Li H , Suri-Payer E , Hardy RR , Weigert M . Regulation of anti-DNA B cells in recombination-activating gene-deficient mice . J Exp Med 1998; 188: 1247–1254 .

39.

Chen C , Nagy Z , Prak EL , Weigert M . Immunoglobulin heavy chain gene replacement: a mechanism of receptor editing . Immunity 1995; 3: 747–755 .

40.

Ibrahim SM , Weigert M , Basu C , Erikson J , Radic MZ . Light chain contribution to specificity in anti-DNA antibodies . J Immunol 1995; 155: 3223–3233 .

41.

Chen C , Nagy Z , Radic MZ , Hardy RR , Huszar D , Camper SA , Weigert M . The site and stage of anti-DNA B-cell deletion . Nature 1995; 373: 252–255 .

42.

Erikson J , Radic MZ , Camper SA , Hardy RR , Carmack C , Weigert M . Expression of anti-DNA immunoglobulin transgenes in non-autoimmune mice . Nature 1991; 349: 331–334 .

43.

Chen C , Radic MZ , Erikson J , Camper SA , Litwin S , Hardy RR , Weigert M . Deletion and editing of B cells that express antibodies to DNA . J Immunol 1994; 152: 1970–1982 .

44.

Radic MZ , Ibrahim SM , Rauch J , Camper SA , Weigert M . Constitutive secretion of transgene-encoded IgG2b autoantibodies leads to symptoms of autoimmune disease . J Immunol 1995; 155: 3213–3222 .

45.

Pewzner-Jung Y , Friedmann D , Sonoda E , Jung S , Rajewsky K , Eilat D . B cell deletion, anergy, and receptor editing in ‘knock in’ mice targeted with a germline-encoded or somatically mutated anti-DNA heavy chain . J Immunol 1998; 161: 4634–4645 .

46.

Friedmann D , Yachimovich N , Mostoslavsky G , Pewzner-Jung Y , Ben-Yehuda A , Rajewsky K , Eilat D . Production of highaffinity autoantibodies in autoimmune New Zealand Black/New Zealand white F1 mice targeted with an anti-DNA heavy chain . J Immunol 1999; 162: 4406–4416 .

47.

Bynoe MS , Spatz L , Diamond B . Characterization of anti-DNA B cells that escape negative selection . Eur J Immunol 1999; 29: 1304–1313 .

48.

Tsao BP , Ohnishi K , Cheroutre H , Mitchell B , Teitell M , Mixter P , Kronenberg M , Hahn BH . Failed self-tolerance andautoimmunity in IgG anti-DNA transgenic mice . J Immunol 1992; 149: 350–358 .

49.

Seery JP , Carroll JM , Cattell V , Watt FM . Antinuclear autoantibodies and lupus nephritis in transgenic mice expressing interferon gamma in the epidermis . J Exp Med 1997; 186: 1451–1459 .

50.

Seery JP , Wang EC , Cattell V , Carroll JM , Owen MJ , Watt FM . A central role for alpha beta T cells in the pathogenesis of murine lupus . J Immunol 1999; 162: 7241–7248 .

51.

Ehrenstein MR , Katz DR , Griffiths MH , Papadaki L , Winkler TH , Kalden JR , Isenberg DA . Human IgG anti-DNA antibodies deposit in kidneys and induce proteinuria in SCID mice . Kidney Int 1995; 48: 705–711 .

52.

Ravirajan CT , Rahman MA , Papadaki L , Griffiths MH , Kalsi J , Martin ACR , Ehrenstein MR , Latchman DS , Isenberg DA . Genetic structural and functional properties of an IgG DNA-binding monoclonal antibody from a lupus patients with nephritis . EurJ Immunol 1998; 28: 339–350 .

53.

Ravirajan CT , Smith H , Kumar S , Pearl L , Latchman DA , Isenberg DA . Human pathogenic anti-DNA light chain failed to induce nephritis without an appropriate heavy chain: demonstration using human light chain only transgenic animals(in preparation).

54.

Ibnou-Zekri N , Iwamoto M , Fossati L , McConahey PJ , Izui S . Role of the major histocompatibility complex class II Ea gene in lupus susceptibility in mice . Proc Natl Acad Sci USA 1997; 94: 14654–14659 .

55.

Ibnou-Zekri N , Iwamoto M , Gershwin ME , Izui S . Protection of murine lupus by the Ead transgene is MHC haplotype-dependent . J Immunol 2000; 164: 505–511 .

56.

Iwamoto M , Ibnou-Zekri N , Kobayakawa T , Izui S . Effect of genetic background on Ea (d) transgene-mediated protection from murine lupus . J Autoimmun 1998; 11: 241–248 .

57.

Prodeus AP , Goerg S , Shen LM , Pozdnyakova OO , Chu L , Alicot EM , Goodnow CC , Carroll MC . A critical role for complement in maintenance of self-tolerance . Immunity 1998; 9: 721–731 .

58.

Robson MG , Cook HT , Botto M , Taylor PR , Busso N , Salvi R et al. Accelerated nephrotoxic nephritis is exacerbated in C1q-deficient mice . J Immunol 2001; 166: 5820–5828 .