Dissection of the role of MHC class II A and E genes in autoimmune susceptibility in murine lupus models with intragenic recombination

Proc Natl Acad Sci U S A. 2004 Sep 21;101(38):13838-43. doi: 10.1073/pnas.0405807101. Epub 2004 Sep 10.

Abstract

Systemic lupus erythematosus (SLE) is a multigenic autoimmune disease, and the major histocompatibility complex (MHC) class II polymorphism serves as a key genetic element. In SLE-prone (NZB x NZW)F(1) mice, the MHC H-2(d/z) heterozygosity (H-2(d) of NZB and H-2(z) of NZW) has a strong impact on disease; thus, congenic H-2(d/d) homozygous F(1) mice do not develop severe disease. In this study, we used Ea-deficient intra-H-2 recombination to establish A(d/d)-congenic (NZB x NZW)F(1) mice, with or without E molecule expression, and dissected the role of class II A and E molecules. Here we found that A(d/d) homozygous F(1) mice lacking E molecules developed severe SLE similar to that seen in wild-type F1 mice, including lupus nephritis, autoantibody production, and spontaneously occurring T cell activation. Additional evidence revealed that E molecules prevent the disease in a dose-dependent manner; however, the effect is greatly influenced by the haplotype of A molecules, because wild-type H-2(d/z) F(1) mice develop SLE, despite E molecule expression. Studies on the potential of dendritic cells to present a self-antigen chromatin indicated that dendritic cells from wild-type F(1) mice induced a greater response of chromatin-specific T cells than did those from A(d/d) F(1) mice, irrespective of the presence or absence of E molecules, suggesting that the self-antigen presentation is mediated by A, but not by E, molecules. Our mouse models are useful for analyzing the molecular mechanisms by which MHC class II regions regulate the process of autoimmune responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Antinuclear / blood
  • Autoantibodies / blood
  • Base Sequence
  • Chromatin / immunology
  • DNA Primers
  • DNA, Satellite / genetics
  • Disease Models, Animal
  • Flow Cytometry
  • HLA Antigens / genetics
  • HLA Antigens / immunology*
  • HLA-A Antigens / immunology*
  • HLA-E Antigens
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / immunology*
  • Histocompatibility Antigens Class II / immunology*
  • Lupus Erythematosus, Systemic / genetics
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / urine
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred Strains
  • Polymorphism, Genetic / genetics
  • Promoter Regions, Genetic
  • Proteinuria
  • T-Lymphocytes / immunology
  • Tumor Necrosis Factor-alpha / genetics

Substances

  • Antibodies, Antinuclear
  • Autoantibodies
  • Chromatin
  • DNA Primers
  • DNA, Satellite
  • HLA Antigens
  • HLA-A Antigens
  • Histocompatibility Antigens Class I
  • Histocompatibility Antigens Class II
  • Tumor Necrosis Factor-alpha