Molecular Genetics of Murine Lupus Models

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The chapter that addresses the Ig germ line gene organization in lupus-prone strains of mice suggested that the disease can develop in different Ig heavy and light chain haplotypes, and that the Ig germ line genes in lupus mice are probably normal. Analyses of the Ig gene segments expressed in monoclonal autoantibodies from autoimmune mice revealed that similar, moreover, in some instances even identical, gene segments are expressed in autoantibodies and in antibodies to exogenous antigens, and that antiself and antiforeign responses are encoded by the same, or at least an overlapping, germ line gene repertoire. Evidence has been obtained that, in an individual lupus mouse, the number of autoantibody-secreting clonotypes decreases after class switch, while that of productive mutations increases, suggesting that antiself responses might be (auto) antigen-driven responses, but this conclusion should be considered tentative. Finally, based on the investigations of I-E and Mls tolerance-related Vβ clonal deletions, the chapter proposes that the abnormally proliferating, autoimmunity-inducing/enhancing double-negative TcR α:β+ lpr and gld cells are not related to immature CD4-8- thymocytes, but instead are derived from CD4 + 8 + precursors through a process resulting in down-regulation of both accessory molecules.

References (151)

  • C. Schiff et al.

    The Ig germline gene repertoire: Economy or wastage?

    Immunol. Today

    (1988)
  • J.L. Urban et al.

    Restricted use of T cell receptor V genes in murine autoimmune encephalomyelitis raises possibilities for antibody therapy.

    Cell

    (1988)
  • A.N. Theofilopoulos
  • M. Bielschowsky et al.

    Spontaneous anemia in mice of the NZB/B1 strain.

    Proc. Unit. Ontago Med. School

    (1959)
  • F.J. Helyer et al.

    The immunology and pathology of NZB mice.

    Adv. Immunol.

    (1968)
  • E.D. Murphy et al.
  • E.D. Murphy
  • B.S. Andrews et al.

    Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains.

    J. Exp. Med.

    (1978)
  • S. Izui et al.

    Induction of various autoantibodies by mutant gene lpr in several strains of mice.

    J. Immunol.

    (1984)
  • L.M. Hang et al.

    Induction of severe autoimmune disease in normal mice by simultaneous action of multiple immunostimulators.

    J. Exp. Med.

    (1985)
  • J.B. Roths et al.

    A new mutation, gld, that produces lymphoproliferation and autoimmunity in C3H/HeJ mice.

    J. Exp. Med.

    (1984)
  • M.F. Seldin et al.

    Genetic analysis of autoimmune gld mice. I. Identification of a restriction fragment length polymorphism closely linked to the mutation within a conserved linkage group.

    J. Exp. Med.

    (1988)
  • W.F. Davidson et al.

    Phenotypic, functional, and molecular genetic comparisons of the abnormal lymphoid cells of C3H-lpr/lpr and C3H-gld/gld mice.

    J. Immunol.

    (1986)
  • J.I. Morton et al.

    Transplantation of autoimmune potential. I. Development of antinuclear antibodies in H-2 histocompatible recipients of bone marrow from New Zealand Black mice.

    Proc. Natl. Acad. Sci. U.S.A.

    (1974)
  • R.A. Eisenberg et al.

    Male determined accelerated autoimmune disease in BXSB mice: Transfer by bone marrow and spleen cells.

    J. Immunol.

    (1980)
  • A.N. Theofilopoulos et al.

    Association of the lpr gene with a graft-versus-host-like disease.

    J. Exp. Med.

    (1985)
  • A.N. Theofilopoulos et al.

    The influence of thymic genotype on the SLE-like disease and T cell proliferation of MRL/Mp-lpr/lpr mice.

    J. Exp. Med.

    (1981)
  • A.D. Steinberg et al.

    Effects of thymectomy or androgen administration upon the autoimmune disease of MRL/Mp-lpr/lpr mice.

    J. Immunol.

    (1980)
  • M. Mihara et al.

    Immunologic abnormality in NZB/NZW F1 mice. Thymus-independent of B cell abnormality and requirement for T cells in the development of autoimmune disease, as evidenced by an analysis of the athymic nude individuals.

    J. Immunol.

    (1988)
  • D. Wofsy et al.

    Successful treatment of autoimmunity in NZB/NZW F1 mice with monoclonal antibody to L3T4.

    J. Exp. Med.

    (1985)
  • T.J. Santoro et al.

    The contribution of L3T4+ T cells to lymphoproliferation and autoantibody production in MRL-lpr/lpr mice.

    J. Exp. Med.

    (1988)
  • G.J. Prud'homme et al.

    B cell dependence on and response to accessory signals in murine lupus strains.

    J. Exp. Med.

    (1983)
  • S.K. Datta et al.

    Induction of a cationic shift in IgG anti-DNA autoantibodies. Role of T helper cells with classical and novel phenotypes in three murine models of lupus nephritis.

    J. Exp. Med.

    (1987)
  • F.W. Alt et al.

    Regulation of genome rearrangement events during lymphocyte differentiation.

    Immunol. Rev.

    (1986)
  • P.H. Brodeur et al.

    The immunoglobulin heavy chain variable region (Igh-V) locus in the mouse. I. One hundred Igh-V genes comprise seven families of homologous genes.

    Eur. J. Immunol.

    (1984)
  • E. Winter et al.

    Members of novel VH gene families are found in VDJ regions of polyclonally activated B-lymphocytes.

    EMBO J.

    (1985)
  • R. Kofler

    A new murine Ig VH gene family (VH10).

    J. Immunol.

    (1988)
  • R. Kofler et al.

    Ig heavy chain variable region gene complex of lupus mice exhibits normal restriction fragment length polymorphism.

    J. Exp. Med.

    (1985)
  • R. Kofler et al.

    Immunoglobulin k light chain variable region gene complex organization and immunoglobulin genes encoding anti-DNA autoantibodies in lupus mice.

    J. Clin. Invest.

    (1988)
  • Kofler, R.(1987). Unpublished...
  • W. Trepicchio et al.

    The Igh-V locus of MRL mice: Restriction fragment length polymorphism in eleven strains of mice as determined with VH and D gene probes.

    J. Immunol.

    (1985)
  • C. Painter et al.

    Functional and molecular studies of V genes expressed in autoantibodies.

    Immunol. Rev.

    (1986)
  • A.N. Theofilopoulos et al.

    Molecular aspects of murine systemic lupus erythematosus.

    Springer Semin. Immunopathol.

    (1986)
  • G.J. Prud'homme et al.

    Identification of a B cell differentiation factor(s) spontaneously produced by proliferating T cells in murine lupus strains of the lpr/lpr genotype.

    J. Exp. Med.

    (1983)
  • P. Augereau et al.

    The mouse immunoglobulin heavy-chain enhancer: Effect on transcription in vitro and binding of proteins present in HeLa and lymphoid B cell extract.

    EMBO J.

    (1986)
  • E.A. Kabat et al.

    “Sequences of Proteins of Immunological Interest”

    (1983)
  • R. Kofler et al.

    Molecular analysis of the murine lupus-associated anti-self response: Involvement of a large number of heavy and light chain variable region genes.

    Eur. J. Immunol.

    (1987)
  • L.A. D'Hoostelaere et al.

    The Igk L chain allelic groups among the Igk haplotypes and Igk crossover populations suggest a gene order.

    J. Immunol.

    (1988)
  • S. Cory et al.

    Sets of immunoglobulin Vk genes homologous to ten cloned Vk sequences: Implications for the number of germline Vk genes.

    J. Mol. Appl. Genet.

    (1981)
  • E.P. Zeelon et al.

    An experimental approach to enumerate the genes coding for immunoglobulin variable-regions.

    Nucleic Acids Res.

    (1981)
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