PATHOGENESIS OF AUTOIMMUNITY IN NEW ZEALAND MICE

Project: Research project

Project Details

Description

Molecular and genetic tools have been utilized that shed light on the genes
that contribute to the susceptibility to murine lupus and the cellular and
subcellular mechanisms that lead to immunopathology. The MHC genes and
their products are amongst those that have been consistently shown to
contribute towards development of disease. To understand the contribution
of MHC genes, notably MHC class II, our laboratory has developed two new
inbred strains, NZB.H-2b mice, like NZB.H-2d mice. The study of 10th
generation animals is striding because NZB.H-2bm12 mice develop
autoantibodies to dsDNA. In contrast, NZB.H-2b mice, like NZB.H-2d mice,
develop low titer antibodies to ssDNA but have no evidence for production
of antibodies to dsDNA. Furthermore, NZB.H-2bm12 mice manifest and IgM to
IgG switch in the production of antibodies to dsDNA, demonstrate
proteinuria, have reduced survival and glomerulonephritis at autopsy.
Thus, the gene conversion at amino acid glomerulonephritis at autopsy.
Thus, the gene conversion at amino acid residues 68, 71 and 72 of I-Ebetab
that resulted in the I-Abm12 mutation has led to accelerated autoimmunity
on the NZB background. this data is particularly interesting because the
contribution of NZW to accelerated autoimmunity in the NZB x NZW Fl hybrid
has recently been mapped to a single amino acid change at residue 72 of I-
Ebeta. We believe that amino acid 72 is a hotspot for disorders of immune
regulation. The use of our newly developed congenic NZB line expressing
the I-Abm12 mutation will allow us to address the role of thymic education
for anti-dsDNA responses and to determine whether abnormal autoantibodies
to dsDNA are due to a selective defect at the T cell level or due to global
abnormalities of B cells and/or macrophages. Similarly, we will be able to
determine whether the induction of anti-dsDNA responses are MHC restricted
and/or a result of abnormalities in the cytokine network. Finally, we will
develop innovative techniques to clone T cells specific for dsDNA,
permitting the study of T cell repertoire. We believe that NZB.H-2bm12
mice will allow specific dissection of the cellular requirements for
autoantibody production uncomplicated by the issue of heterozygosity.
StatusFinished
Effective start/end date6/30/764/30/95

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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