Interferon-alpha treatment of female (NZW x BXSB)F(1) mice mimics some but not all features associated with the Yaa mutation.

Abstract

OBJECTIVE:

Male (NZW x BXSB)F(1) mice develop antiphospholipid syndrome (APS) and proliferative glomerulonephritis that is markedly accelerated by the Yaa locus encoding an extra copy of Tlr7. Female (NZW x BXSB)F(1) mice with only 1 active copy of Tlr7 develop late-onset glomerulonephritis but not APS. Because a major function of Toll-like receptor 7 is to induce type I interferons (IFNs), our goal was to determine whether IFNalpha can induce or accelerate the manifestations of systemic lupus erythematosus (SLE) in female (NZW x BXSB)F(1) mice.

METHODS:

Eight-week-old female (NZW x BXSB)F(1) mice were injected with a single dose of adenovirus expressing IFNalpha. Mice were monitored for the development of thrombocytopenia and proteinuria. Sera were tested for anticardiolipin and anti-Sm/RNP antibodies. Mice were killed at 17 or 22 weeks of age, and their kidneys and hearts were examined histologically and by immunohistochemistry. Spleen cells were phenotyped, and enzyme-linked immunospot assays for autoantibody-producing B cells were performed.

RESULTS:

IFNalpha markedly accelerated nephritis and death in female (NZW x BXSB)F(1) mice. A significant increase in spleen cell numbers associated with a striking increase in the number of activated B and T cells was observed. Marginal-zone B cells were retained. IFNalpha-induced increased titers of autoantibodies were observed, but thrombocytopenia was not observed. Cardiac damage was milder than that in male mice.

CONCLUSION:

IFNalpha accelerates the development of renal inflammatory disease in female (NZW x BXSB)F(1) mice but induces only mild APS and does not induce thrombocytopenia. The effect of IFNalpha on SLE disease manifestations is strain dependent. These findings are relevant to our understanding of the physiologic significance of the IFN signature.

• Authors: Meera Ramanujam, Philip Kahn, Weiqing Huang, Haiou Tao, Michael P Madaio, Stephen M Factor, Anne Davidson
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 60 Issue 4 Pg. 1096-101 (Apr 2009) ISSN: 0004-3591 [Print] United States
• PMID: 19333924 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interferon-alpha
• Membrane Glycoproteins
• Tlr7 protein, mouse
• Toll-Like Receptor 7

Topics

• Adenoviridae (genetics)
• Animals
• Antiphospholipid Syndrome (genetics, immunology, mortality)
• B-Lymphocytes (cytology)
• Disease Models, Animal
• Female
• Gene Dosage
• Interferon-alpha (genetics)
• Lupus Nephritis (genetics, immunology, mortality)
• Membrane Glycoproteins (genetics, immunology)
• Mice
• Mice, Inbred Strains
• Mice, Mutant Strains
• Phenotype
• Platelet Count
• Proteinuria (genetics, immunology, mortality)
• Severity of Illness Index
• Species Specificity
• Spleen (cytology)
• Toll-Like Receptor 7 (genetics, immunology)