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. 1998 Mar 15;101(6):1362–1372. doi: 10.1172/JCI728

Genetic dissection of SLE pathogenesis. Sle1 on murine chromosome 1 leads to a selective loss of tolerance to H2A/H2B/DNA subnucleosomes.

C Mohan 1, E Alas 1, L Morel 1, P Yang 1, E K Wakeland 1
PMCID: PMC508691  PMID: 9502778

Abstract

One of the hallmarks of SLE is the loss of tolerance to chromatin. The genes and mechanisms that trigger this loss of tolerance remain unknown. Our genetic studies in the NZM2410 lupus strain have implicated genomic intervals on chromosomes 1 (Sle1), 4 (Sle2), and 7 (Sle3) as conferring strong lupus susceptibility. Interestingly, B6 mice that are congenic for Sle1 (B6.NZMc1) have elevated IgG antichromatin Abs. This study explores the antinuclear antibody fine specificities and underlying cellular defects in these mice. On the B6 background, Sle1 by itself is sufficient to generate a robust, spontaneous antichromatin Ab response, staining Hep-2 nuclei homogeneously, and reacting primarily with H2A/H2B/DNA subnucleosomes. This targeted immune response peaks at 7-9 mo of age, affects both sexes with equally high penetrance (> 75%), and interestingly, does not "spread" to other subnucleosomal chromatin components. Sle1 also leads to an expanded pool of histone-reactive T cells, which may have a role in driving the anti-H2A/H2B/DNA B cells. However, these mice do not exhibit any generalized immunological defects or quantitative aberrations in lymphocyte apoptosis. We hypothesize that Sle1 may lead to the presentation of chromatin in an immunogenic fashion, or directly impact tolerance of chromatin-specific B cells.

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Selected References

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  1. Agnello V., Arbetter A., Ibanez de Kasep G., Powell R., Tan E. M., Joslin F. Evidence for a subset of rheumatoid factors that cross-react with DNA-histone and have a distinct cross-idiotype. J Exp Med. 1980 Jun 1;151(6):1514–1527. doi: 10.1084/jem.151.6.1514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Amoura Z., Chabre H., Koutouzov S., Lotton C., Cabrespines A., Bach J. F., Jacob L. Nucleosome-restricted antibodies are detected before anti-dsDNA and/or antihistone antibodies in serum of MRL-Mp lpr/lpr and +/+ mice, and are present in kidney eluates of lupus mice with proteinuria. Arthritis Rheum. 1994 Nov;37(11):1684–1688. doi: 10.1002/art.1780371118. [DOI] [PubMed] [Google Scholar]
  3. Arents G., Burlingame R. W., Wang B. C., Love W. E., Moudrianakis E. N. The nucleosomal core histone octamer at 3.1 A resolution: a tripartite protein assembly and a left-handed superhelix. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10148–10152. doi: 10.1073/pnas.88.22.10148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Beaudette N. V., Fulmer A. W., Okabayashi H., Fasman G. D. Study of conformational states and reversibility of histone complexes. Biochemistry. 1981 Nov 10;20(23):6526–6535. doi: 10.1021/bi00526a003. [DOI] [PubMed] [Google Scholar]
  5. Bernstein K. A., Valerio R. D., Lefkowith J. B. Glomerular binding activity in MRL lpr serum consists of antibodies that bind to a DNA/histone/type IV collagen complex. J Immunol. 1995 Mar 1;154(5):2424–2433. [PubMed] [Google Scholar]
  6. Burlingame R. W., Boey M. L., Starkebaum G., Rubin R. L. The central role of chromatin in autoimmune responses to histones and DNA in systemic lupus erythematosus. J Clin Invest. 1994 Jul;94(1):184–192. doi: 10.1172/JCI117305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Burlingame R. W., Rubin R. L., Balderas R. S., Theofilopoulos A. N. Genesis and evolution of antichromatin autoantibodies in murine lupus implicates T-dependent immunization with self antigen. J Clin Invest. 1993 Apr;91(4):1687–1696. doi: 10.1172/JCI116378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Burlingame R. W., Rubin R. L. Subnucleosome structures as substrates in enzyme-linked immunosorbent assays. J Immunol Methods. 1990 Dec 5;134(2):187–199. doi: 10.1016/0022-1759(90)90380-e. [DOI] [PubMed] [Google Scholar]
  9. Casciola-Rosen L. A., Anhalt G., Rosen A. Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J Exp Med. 1994 Apr 1;179(4):1317–1330. doi: 10.1084/jem.179.4.1317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chabre H., Amoura Z., Piette J. C., Godeau P., Bach J. F., Koutouzov S. Presence of nucleosome-restricted antibodies in patients with systemic lupus erythematosus. Arthritis Rheum. 1995 Oct;38(10):1485–1491. doi: 10.1002/art.1780381015. [DOI] [PubMed] [Google Scholar]
  11. Desai-Mehta A., Mao C., Rajagopalan S., Robinson T., Datta S. K. Structure and specificity of T cell receptors expressed by potentially pathogenic anti-DNA autoantibody-inducing T cells in human lupus. J Clin Invest. 1995 Feb;95(2):531–541. doi: 10.1172/JCI117695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Emlen W., Niebur J., Kadera R. Accelerated in vitro apoptosis of lymphocytes from patients with systemic lupus erythematosus. J Immunol. 1994 Apr 1;152(7):3685–3692. [PubMed] [Google Scholar]
  13. Filaci G., Grasso I., Contini P., Imro M. A., Lanza L., Scudeletti M., Rossi E., Puppo F., Damasio E., Indiveri F. dsDNA-, nucleohistone- and DNASE I-reactive T lymphocytes in patients affected by systemic lupus erythematosus: correlation with clinical disease activity. Clin Exp Rheumatol. 1996 Sep-Oct;14(5):543–550. [PubMed] [Google Scholar]
  14. Fisher C. L., Shores E. W., Eisenberg R. A., Cohen P. L. Cellular interactions for the in vitro production of anti-chromatin autoantibodies in MRL/Mp-lpr/lpr mice. Clin Immunol Immunopathol. 1989 Feb;50(2):231–240. doi: 10.1016/0090-1229(89)90131-1. [DOI] [PubMed] [Google Scholar]
  15. HARGRAVES M. M., RICHMOND H., MORTON R. Presentation of two bone marrow elements; the tart cell and the L.E. cell. Proc Staff Meet Mayo Clin. 1948 Jan 21;23(2):25–28. [PubMed] [Google Scholar]
  16. HOLMAN H. R., DEICHER H. R., KUNKEL H. G. The L. E. cell and the L. E. serum factors. Bull N Y Acad Med. 1959 Jul;35(7):409–418. [PMC free article] [PubMed] [Google Scholar]
  17. HOLMAN H. R., KUNKEL H. G. Affinity between the lupus erythematosus serum factor and cell nuclei and nucleoprotein. Science. 1957 Jul 26;126(3265):162–163. doi: 10.1126/science.126.3265.162. [DOI] [PubMed] [Google Scholar]
  18. HOLMAN H., DEICHER H. R. The reaction of the lupus erythematosus (L.E.) cell factor with deoxyribonucleoprotein of the cell nucleus. J Clin Invest. 1959 Nov;38:2059–2072. doi: 10.1172/JCI103984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kaliyaperumal A., Mohan C., Wu W., Datta S. K. Nucleosomal peptide epitopes for nephritis-inducing T helper cells of murine lupus. J Exp Med. 1996 Jun 1;183(6):2459–2469. doi: 10.1084/jem.183.6.2459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kono D. H., Theofilopoulos A. N. Genetic contributions to SLE. J Autoimmun. 1996 Aug;9(4):437–452. doi: 10.1006/jaut.1996.0061. [DOI] [PubMed] [Google Scholar]
  21. Kozono Y., Kotzin B. L., Holers V. M. Resting B cells from New Zealand Black mice demonstrate a defect in apoptosis induction following surface IgM ligation. J Immunol. 1996 Jun 1;156(11):4498–4503. [PubMed] [Google Scholar]
  22. Kramers C., Hylkema M. N., van Bruggen M. C., van de Lagemaat R., Dijkman H. B., Assmann K. J., Smeenk R. J., Berden J. H. Anti-nucleosome antibodies complexed to nucleosomal antigens show anti-DNA reactivity and bind to rat glomerular basement membrane in vivo. J Clin Invest. 1994 Aug;94(2):568–577. doi: 10.1172/JCI117371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. LACHMANN P. J., KUNKEL H. G. Correlation of antinuclear antibodies and nuclear staining patterns. Lancet. 1961 Aug 19;2(7199):436–437. doi: 10.1016/s0140-6736(61)92523-5. [DOI] [PubMed] [Google Scholar]
  24. Lambert P. H., Dixon F. J. Pathogenesis of the glomerulonephritis of NZB/W mice. J Exp Med. 1968 Mar 1;127(3):507–522. doi: 10.1084/jem.127.3.507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lefkowith J. B., Gilkeson G. S. Nephritogenic autoantibodies in lupus: current concepts and continuing controversies. Arthritis Rheum. 1996 Jun;39(6):894–903. doi: 10.1002/art.1780390605. [DOI] [PubMed] [Google Scholar]
  26. Losman M. J., Fasy T. M., Novick K. E., Monestier M. Monoclonal autoantibodies to subnucleosomes from a MRL/Mp(-)+/+ mouse. Oligoclonality of the antibody response and recognition of a determinant composed of histones H2A, H2B, and DNA. J Immunol. 1992 Mar 1;148(5):1561–1569. [PubMed] [Google Scholar]
  27. McCoubrey-Hoyer A., Okarma T. B., Holman H. R. Partial purification and characterization of plasma DNA and its relation to disease activity in systemic lupus erythematosus. Am J Med. 1984 Jul;77(1):23–34. doi: 10.1016/0002-9343(84)90431-5. [DOI] [PubMed] [Google Scholar]
  28. McGhee J. D., Felsenfeld G. Nucleosome structure. Annu Rev Biochem. 1980;49:1115–1156. doi: 10.1146/annurev.bi.49.070180.005343. [DOI] [PubMed] [Google Scholar]
  29. Mohan C., Adams S., Stanik V., Datta S. K. Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus. J Exp Med. 1993 May 1;177(5):1367–1381. doi: 10.1084/jem.177.5.1367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Mohan C., Datta S. K. Lupus: key pathogenic mechanisms and contributing factors. Clin Immunol Immunopathol. 1995 Dec;77(3):209–220. doi: 10.1006/clin.1995.1146. [DOI] [PubMed] [Google Scholar]
  31. Mohan C., Morel L., Yang P., Wakeland E. K. Genetic dissection of systemic lupus erythematosus pathogenesis: Sle2 on murine chromosome 4 leads to B cell hyperactivity. J Immunol. 1997 Jul 1;159(1):454–465. [PubMed] [Google Scholar]
  32. Mohan C., Shi Y., Laman J. D., Datta S. K. Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis. J Immunol. 1995 Feb 1;154(3):1470–1480. [PubMed] [Google Scholar]
  33. Mohan T. C., Nadarajah M., Sng E. H. Relation of antinuclear fluorescence patterns and titres to autoantibody prevalence. Ann Acad Med Singapore. 1989 Jul;18(4):339–344. [PubMed] [Google Scholar]
  34. Morel L., Mohan C., Yu Y., Croker B. P., Tian N., Deng A., Wakeland E. K. Functional dissection of systemic lupus erythematosus using congenic mouse strains. J Immunol. 1997 Jun 15;158(12):6019–6028. [PubMed] [Google Scholar]
  35. Morel L., Rudofsky U. H., Longmate J. A., Schiffenbauer J., Wakeland E. K. Polygenic control of susceptibility to murine systemic lupus erythematosus. Immunity. 1994 Jun;1(3):219–229. doi: 10.1016/1074-7613(94)90100-7. [DOI] [PubMed] [Google Scholar]
  36. Morel L., Yu Y., Blenman K. R., Caldwell R. A., Wakeland E. K. Production of congenic mouse strains carrying genomic intervals containing SLE-susceptibility genes derived from the SLE-prone NZM2410 strain. Mamm Genome. 1996 May;7(5):335–339. doi: 10.1007/s003359900098. [DOI] [PubMed] [Google Scholar]
  37. Nelson D. A., Mencke A. J., Chambers S. A., Oosterhof D. K., Rill R. L. Subnucleosomes and their relationships to the arrangement of histone binding sites along nucleosome deoxyribonucleic acid. Biochemistry. 1982 Aug 31;21(18):4350–4362. doi: 10.1021/bi00261a026. [DOI] [PubMed] [Google Scholar]
  38. Nicoletti I., Migliorati G., Pagliacci M. C., Grignani F., Riccardi C. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods. 1991 Jun 3;139(2):271–279. doi: 10.1016/0022-1759(91)90198-o. [DOI] [PubMed] [Google Scholar]
  39. Oohara I., Wada A. Spectroscopic studies on histone-DNA interactions. I. The interaction of histone (H2A, H2B) dimer with DNA: DNA sequence dependence. J Mol Biol. 1987 Jul 20;196(2):389–397. doi: 10.1016/0022-2836(87)90699-1. [DOI] [PubMed] [Google Scholar]
  40. Raptis L., Menard H. A. Quantitation and characterization of plasma DNA in normals and patients with systemic lupus erythematosus. J Clin Invest. 1980 Dec;66(6):1391–1399. doi: 10.1172/JCI109992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Reap E. A., Leslie D., Abrahams M., Eisenberg R. A., Cohen P. L. Apoptosis abnormalities of splenic lymphocytes in autoimmune lpr and gld mice. J Immunol. 1995 Jan 15;154(2):936–943. [PubMed] [Google Scholar]
  42. Reeves W. H., Satoh M., Wang J., Chou C. H., Ajmani A. K. Systemic lupus erythematosus. Antibodies to DNA, DNA-binding proteins, and histones. Rheum Dis Clin North Am. 1994 Feb;20(1):1–28. [PubMed] [Google Scholar]
  43. Reininger L., Winkler T. H., Kalberer C. P., Jourdan M., Melchers F., Rolink A. G. Intrinsic B cell defects in NZB and NZW mice contribute to systemic lupus erythematosus in (NZB x NZW)F1 mice. J Exp Med. 1996 Sep 1;184(3):853–861. doi: 10.1084/jem.184.3.853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Rekvig O. P., Hannestad K. Human autoantibodies that react with both cell nuclei and plasma membranes display specificity for the octamer of histones H2A, H2B, H3, and H4 in high salt. J Exp Med. 1980 Dec 1;152(6):1720–1733. doi: 10.1084/jem.152.6.1720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Roark J. H., Kuntz C. L., Nguyen K. A., Caton A. J., Erikson J. Breakdown of B cell tolerance in a mouse model of systemic lupus erythematosus. J Exp Med. 1995 Mar 1;181(3):1157–1167. doi: 10.1084/jem.181.3.1157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Rubin R. L., Bell S. A., Burlingame R. W. Autoantibodies associated with lupus induced by diverse drugs target a similar epitope in the (H2A-H2B)-DNA complex. J Clin Invest. 1992 Jul;90(1):165–173. doi: 10.1172/JCI115832. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Rubin R. L., McNally E. M., Nusinow S. R., Robinson C. A., Tan E. M. IgG antibodies to the histone complex H2A-H2B characterize procainamide-induced lupus. Clin Immunol Immunopathol. 1985 Jul;36(1):49–59. doi: 10.1016/0090-1229(85)90038-8. [DOI] [PubMed] [Google Scholar]
  48. Rudofsky U. H., Evans B. D., Balaban S. L., Mottironi V. D., Gabrielsen A. E. Differences in expression of lupus nephritis in New Zealand mixed H-2z homozygous inbred strains of mice derived from New Zealand black and New Zealand white mice. Origins and initial characterization. Lab Invest. 1993 Apr;68(4):419–426. [PubMed] [Google Scholar]
  49. Sobel E. S., Katagiri T., Katagiri K., Morris S. C., Cohen P. L., Eisenberg R. A. An intrinsic B cell defect is required for the production of autoantibodies in the lpr model of murine systemic autoimmunity. J Exp Med. 1991 Jun 1;173(6):1441–1449. doi: 10.1084/jem.173.6.1441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Steinman C. R. Circulating DNA in systemic lupus erythematosus. Isolation and characterization. J Clin Invest. 1984 Mar;73(3):832–841. doi: 10.1172/JCI111278. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Stollar B. D. Reactions of systemic lupus erythematosus sera with histone fractions and histone-DNA complexes. Arthritis Rheum. 1971 Jul-Aug;14(4):485–492. doi: 10.1002/art.1780140408. [DOI] [PubMed] [Google Scholar]
  52. Tan E. M. Relationship of nuclear staining patterns with precipitating antibodies in systemic lupus erythematosus. J Lab Clin Med. 1967 Nov;70(5):800–812. [PubMed] [Google Scholar]
  53. Tatchell K., Van Holde K. E. Reconstitution of chromatin core particles. Biochemistry. 1977 Nov 29;16(24):5295–5303. doi: 10.1021/bi00643a021. [DOI] [PubMed] [Google Scholar]
  54. Theofilopoulos A. N. The basis of autoimmunity: Part I. Mechanisms of aberrant self-recognition. Immunol Today. 1995 Feb;16(2):90–98. doi: 10.1016/0167-5699(95)80095-6. [DOI] [PubMed] [Google Scholar]
  55. Totoritis M. C., Tan E. M., McNally E. M., Rubin R. L. Association of antibody to histone complex H2A-H2B with symptomatic procainamide-induced lupus. N Engl J Med. 1988 Jun 2;318(22):1431–1436. doi: 10.1056/NEJM198806023182204. [DOI] [PubMed] [Google Scholar]
  56. Tsao B. P., Cantor R. M., Kalunian K. C., Chen C. J., Badsha H., Singh R., Wallace D. J., Kitridou R. C., Chen S. L., Shen N. Evidence for linkage of a candidate chromosome 1 region to human systemic lupus erythematosus. J Clin Invest. 1997 Feb 15;99(4):725–731. doi: 10.1172/JCI119217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Van Houten N., Budd R. C. Accelerated programmed cell death of MRL-lpr/lpr T lymphocytes. J Immunol. 1992 Oct 1;149(7):2513–2517. [PubMed] [Google Scholar]
  58. Vyse T. J., Todd J. A. Genetic analysis of autoimmune disease. Cell. 1996 May 3;85(3):311–318. doi: 10.1016/s0092-8674(00)81110-1. [DOI] [PubMed] [Google Scholar]

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