Role of distinct immune components in the radiation-induced abrogation of systemic lupus erythematosus development in mice

Abstract

The New Zealand Black × New Zealand White F1 [(NZB/NZW) F1] mouse develops an autoimmune condition resembling aspects of human systemic lupus erythematosus (SLE). We investigated the effects of a novel prophylactic thoraco-abdominal gamma irradiation protocol on the onset and evolution of lupus in these animals. Survival of irradiated mice was higher when compared with nonirradiated mice. Kidney lesions were milder and autoantibody levels were lower in irradiated mice. To identify possible mechanisms involved in the radiation-induced improvement of disease, distinct components of humoral and cellular immune responses were evaluated. Because B-1 cells are known to be involved in various autoimmune diseases, we investigated the participation of these cells in SLE progression. Unexpectedly, B-1 cells were not depleted in (NZB/NZW) F1, even after several rounds of irradiation. No alterations were found in viability and physiology of B-1 cells in SLE animals with the exception of constitutive overexpression of the anti-apoptotic molecule Bcl-2, which may account for the observed radioresistance. Thus, a role for B-1 cells in murine SLE cannot be excluded, since the irradiation protocol did not effectively eliminate these cells. Additionally, we demonstrate a marked delay in the ability of splenocytes to repopulate the spleen after irradiation in (NZB/NZW) F1, in contrast to leucocytes in other cellular compartments. The implications of these findings for the fate of SLE in this model are discussed. Lupus (2007) 16, 947—954.

Keywords

B-1 cells irradiation systemic lupus erythematosus

Get full access to this article

View all access options for this article.

References

Morahan G. , Morel L. Genetics of autoimmune diseases in humans and in animal models. Curr Opin Immunol 2002; 14: 803—811.

Carreno L. , Lopez-Longo FJ , Gonzalez CM , Monteagudo I. Treatment options for juvenile-onset systemic lupus erythematosus . Paediatr Drugs 2002; 4: 241—256.

Wakeland EK , Liu K. , Graham RR , Behrens TW Delineating the genetic basis of systemic lupus erythematosus. Immunity 2001; 15: 397—408.

Rahman ZS , Tin SK , Buenaventura PN et al. A novel susceptibility locus on chromosome 2 in the (New Zealand Black × New Zealand White)F1 hybrid mouse model of systemic lupus erythematosus . J Immunol 2002; 168: 3042—3049.

Theofilopoulos AN , Dixon FJ Murine models of systemic lupus erythematosus . Adv Immunol 1985; 37: 269—390.

Sidman CL , Shultz LD , Hardy RR , Hayakawa K. , Herzenberg LA Production of immunoglobulin isotypes by Ly-1+ B cells in viable motheaten and normal mice. Science 1986; 232: 1423—1425.

Hayakawa K. , Hardy RR , Honda M. , Herzenberg LA , Steinberg AD Ly-1 B cells: functionally distinct lymphocytes that secrete IgM autoantibodies . Proc Natl Acad Sci USA 1984; 81: 2494—2498.

Tsui HW , Siminovitch KA , de Souza L. , Tsui FW Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene. Nat Genet 1993; 4: 124—129.

Baumgarth N. , Tung JW , Herzenberg LA Inherent specificities in natural antibodies: a key to immune defense against pathogen invasion. Springer Semin Immunopathol 2005; 26: 347—362.

10.

Lam KP , Rajewsky K. B cell antigen receptor specificity and surface density together determine B-1 versus B-2 cell development. J Exp Med 1999; 190: 471—477.

11.

Martin F. , Kearney JF B-cell subsets and the mature preimmune repertoire. Marginal zone and B1 B cells as part of a `natural immune memory'. Immunol Rev 2000; 175: 70—79.

12.

Hardy RR B-1 B cell development. J Immunol 2006; 177: 2749—2754.

13.

Montecino-Rodriguez E. , Dorshkind K. New perspectives in B-1 B cell development and function. Trends Immunol 2006 ; 27: 428—433.

14.

Stoermann B. , Kretschmer K. , Duber S. , Weiss S. B-1a cells are imprinted by the microenvironment in spleen and peritoneum. Eur J Immunol 2007 ; 37: 1613—1620.

15.

Loor F. , Jachez B. , Montecino-Rodriguez E. et al. Radiation therapy of spontaneous autoimmunity: a review of mouse models. Int J Radiat Biol Relat Stud Phys Chem Med 1988; 53: 119—136.

16.

Fuks Z. , Strober S. , Bobrove AM , Sasazuki T. , McMichael A. , Kaplan HS Long term effects of radiation of T and B lymphocytes in peripheral blood of patients with Hodgkin's disease. J Clin Invest 1976; 58: 803—814.

17.

Singh TP , Rabah R. , Cooper LT , Walters HL Total lymphoid irradiation: new therapeutic option for refractory giant cell myocarditis. J Heart Lung Transplant 2004; 23: 492—495.

18.

Almeida SR , Aroeira LS , Frymuller E. et al. Mouse B-1 cell-derived mononuclear phagocyte, a novel cellular component of acute nonspecific inflammatory exudate. Int Immunol 2001; 13: 1193—1201.

19.

Bradford MM A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248—254.

20.

Ina Y. , Sakai K. Prolongation of life span associated with immunological modification by chronic low-dose-rate irradiation in MRL-lpr/lpr mice. Radiat Res 2004; 161: 168—173.

21.

Strober S. , Field E. , Hoppe RT et al. Treatment of intractable lupus nephritis with total lymphoid irradiation. Ann Intern Med 1985; 102: 450—458.

22.

Kotzin BL , Strober S. Reversal of nzb/nzw disease with total lymphoid irradiation. J Exp Med 1979; 150: 371—378.

23.

Schurman DJ , Hirshman HP , Strober S. Total lymphoid and local joint irradiation in the treatment of adjuvant arthritis. Arthritis Rheum 1981; 24: 38—44.

24.

Werwitzke S. , Trick D. , Kamino K. et al. Inhibition of lupus disease by anti-double-stranded DNA antibodies of the IgM isotype in the (NZB × NZW)F1 mouse. Arthritis Rheum 2005; 52: 3629—3638.

25.

Murakami M. , Tsubata T. , Okamoto M. et al. Antigen-induced apoptotic death of Ly-1 B cells responsible for autoimmune disease in transgenic mice. Nature 1992; 357: 77—80.

26.

Ishida H. , Muchamuel T. , Sakaguchi S. , Andrade S. , Menon S. , Howard M. Continuous administration of anti-interleukin 10 antibodies delays onset of autoimmunity in NZB/W F1 mice. J Exp Med 1994 ; 179: 305—310.

27.

Taurog JD , Moutsopoulos HM , Rosenberg YJ , Chused TM , Steinberg AD CBA/N X-linked B-cell defect prevents NZB B-cell hyperactivity in F1 mice . J Exp Med 1979; 150: 31—43.

28.

Xu Z. , Duan B. , Croker BP , Wakeland EK , Morel L. Genetic dissection of the murine lupus susceptibility locus Sle2: contributions to increased peritoneal B-1a cells and lupus nephritis map to different loci . J Immunol 2005; 175: 936—943.

29.

Blenman KR , Duan B. , Xu Z. et al. IL-10 regulation of lupus in the NZM2410 murine model. Lab Invest 2006; 86: 1136—1148.

30.

Murakami M. , Yoshioka H. , Shirai T. , Tsubata T. , Honjo T. Prevention of autoimmune symptoms in autoimmune-prone mice by elimination of B-1 cells. Int Immunol 1995; 7: 877—882.

31.

Reap EA , Sobel ES , Cohen PL , Eisenberg RA Conventional B cells, not B-1 cells, are responsible for producing autoantibodies in lpr mice. J Exp Med 1993 ; 177: 69—78.

32.

Wen X. , Zhang D. , Kikuchi Y. et al. Transgene-mediated hyper-expression of IL-5 inhibits autoimmune disease but increases the risk of B cell chronic lymphocytic leukemia in a model of murine lupus. Eur J Immunol 2004; 34: 2740—2749.

33.

Casali P. , Notkins AL Probing the human B-cell repertoire with EBV: polyreactive antibodies and CD5+ B lymphocytes. Annu Rev Immunol 1989 ; 7: 513—535.

34.

Reed JC Bcl-2 and the regulation of programmed cell death. J Cell Biol 1994; 124: 1—6.

35.

Zan-Bar I. , Slavin S. , Strober S. Induction and mechanism of tolerance to bovine serum albumin in mice given total lymphoid irradiation (TLI). J Immunol 1978; 121: 1400—1404.

36.

Pecaut MJ , Nelson GA , Gridley DS Dose and dose rate effects of whole-body gamma-irradiation: I. Lymphocytes and lymphoid organs. In Vivo 2001; 15: 195—208.

37.

Slavin S. , Strober S. , Fuks Z. , Kaplan HS Use of total lymphoid irradiation in tissue transplantation in mice . Transplant Proc 1977; 9: 1001—1004.

38.

Westhovens R. , Verwilghen J. , Dequeker J. Total lymphoid irradiation in rheumatoid arthritis. A ten-year followup. Arthritis Rheum 1997; 40: 426—429.