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Using single-gene deletions to identify checkpoints in the progression of systemic autoimmunity
Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
2003 (English)In: Annals of the New York Academy of Sciences, ISSN 0077-8923, Vol. 987, 236-239 p.Article in journal (Refereed) Published
Abstract [en]

Systemic lupus erythematosus is a multigenic disorder of unknown etiology. To investigate the roles that specific genes play in lupus, we have examined the disease profiles in mice with single-gene deletions. In total, some 17 genes have been studied. Absence of certain genes, such as CD40L, CD28, or Igh6, abrogated induction of autoimmunity. Other genes, such as Igh5, IL-4, or ICAM-1, had little effect on the development of disease. Intermediate effects were observed in IL-6-deficient mice, while absence of β2-microglobulin resulted in loss of hypergammaglobulinemia and IgG1 autoantibodies, but produced little change in anti-chromatin antibodies or glomerular deposits. The most interesting observations were obtained with genes related to the expression or function of interferon-γ (IFN-γ). Reductions in IFN-γ levels in murine lupus are associated with reductions in both autoantibody levels and immune-complex- mediated pathology. Genes involved in up-regulation of IFN-γ expression, such as IL-12, STAT-4, or ICE, did not significantly influence autoimmunity, whereas absence of IFN-γ or IFN-γ receptor led to greatly reduced autoantibody response and immunopathology. Absence of IRF-1, a gene ex-pressed in response to IFN-γ, resulted in selective retention of anti-chromatin antibodies but little glomerular pathology. These studies suggest that the presence of a baseline level of IFN-γ, rather than increased expression, is important for autoimmunity. Furthermore, as the IRF-1 knockout demonstrates, specific defects in signaling pathways and gene expression subsequent to IFN-γ/IFN-γ receptor interaction may influence only certain disease parameters. It has not escaped our attention that IFN-γ influences the expression and function of other immunologically relevant genes, such as IL-4, IL-6, and β2-microglobulin. Thus, these genes may be part of the downstream events following IFN-γ/IFN-γ receptor interaction that promote the development of autoimmunity.

Place, publisher, year, edition, pages
2003. Vol. 987, 236-239 p.
Keyword [en]
Autoimmunity, IFN-γ, systemic lupus erythematosus, interleukin
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-26490DOI: 10.1111/j.1749-6632.2003.tb06053.xLocal ID: 11046OAI: diva2:247039
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2011-01-13

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Hultman, Per
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