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Characterization of reciprocal MRL-Fas(lpr) and C57BL/6-Fas(lpr) congenic mice reveals significant effects from Lmb3

Academic Article
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Overview

authors

  • Santiago-Raber, M. L.
  • Haraldsson, M. K.
  • Theofilopoulos, Argyrios
  • Kono, Dwight

publication date

  • June 2007

journal

  • Journal of Immunology  Journal

abstract

  • Susceptibility to severe lupus in MRL-Fas(lpr) mice requires not only the lpr mutation but also other predisposing genes. Using (MRL-Fas(lpr) x B6-Fas(lpr))F2 (where B6 represents C57BL/6) intercrosses that utilize the highly susceptible MRL and poorly susceptible B6 backgrounds, we previously mapped CFA-enhanced systemic lupus-like autoimmunity to four loci, named Lmb1-4, on chromosomes 4, 5, 7, and 10. In the current study, we generated and analyzed reciprocal interval congenic mice for susceptibility to CFA-enhanced autoimmunity at all four Lmb loci. Although all loci had at least a slight effect on lymphoproliferation, only Lmb3 demonstrated a major effect on lymphoproliferation and anti-chromatin Ab levels. Further characterization of Lmb3, primarily by comparing MRL-Fas(lpr) with MRL.B6-Lmb3 Fas(lpr) congenic mice, revealed that it also played a significant role in spontaneous lupus, modifying lymphoproliferation, IgG and autoantibody levels, kidney disease, and survival. The less susceptible B6 Lmb3 locus was associated with a marked reduction in numbers of CD4(+) and double-negative (CD4(-)CD8(-)) T cells, particularly in lymph nodes, as well as reduced T cell proliferation and enhanced T cell apoptosis, both in vivo and in vitro. IFN-gamma-producing CD4(+) T cells were also reduced in MRL.B6-Lmb3 Fas(lpr) mice. Further mapping using subinterval congenic mice placed Lmb3 in the telomeric portion of chromosome 7. Thus, Lmb3, primarily through its effects on CD4(+) and double-negative T cells, appears to be a highly penetrant lupus-modifying locus. Identification of the underlying genetic alteration responsible for this quantitative trait locus should provide new insights into lupus-modifying genes.

subject areas

  • Animals
  • Apoptosis
  • Autoantibodies
  • Autoimmunity
  • CD4-Positive T-Lymphocytes
  • CD8-Positive T-Lymphocytes
  • Chromosomes
  • Fas Ligand Protein
  • Genetic Predisposition to Disease
  • Immunoglobulin G
  • Interferon-gamma
  • Kidney
  • Lupus Erythematosus, Systemic
  • Lymphocyte Activation
  • Mice
  • Mice, Congenic
  • Mice, Inbred MRL lpr
  • Quantitative Trait Loci
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Identity

International Standard Serial Number (ISSN)

  • 0022-1767

PubMed ID

  • 17548658
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Additional Document Info

start page

  • 8195

end page

  • 8202

volume

  • 178

issue

  • 12

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