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Genetic susceptibility to PolyI:C-induced IFNα/β-dependent accelerated disease in lupus-prone mice

Genes & Immunity volume 7, pages 555–567 (2006)Cite this article

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology. Associations between viral infections and the onset of SLE have been suggested, and recent studies have provided evidence that type I interferons (IFNα/β) might play a role in the SLE disease process. Viruses and interferons have also been implicated in mouse models of SLE. We generated a model of accelerated proteinuria, in which lupus-prone mice were injected repeatedly with polyinosinic:polycytidylic acid (polyI:C), mimicking exposure to virus-derived double stranded RNA (dsRNA), leading to the production of IFNα/β. PolyI:C-treated (B6.Nba2 × NZW)F1 and (B6 × NZW)F1 hybrid mice developed significantly increased levels of anti-dsDNA autoantibodies, characteristic of lupus. Most significantly, polyI:C-treated (B6.Nba2 × NZW)F1 mice, but not (B6 × NZW)F1 or parental strains, developed lupus-like nephritis in an accelerated fashion, which was dependent on IFNα/β and associated with elevated deposition of total IgG, IgG2a and complement factor C3 in the glomerular capillary walls. These data suggest that reagents, which increase the levels of endogenous IFNα/β (directly or indirectly), can accelerate the course of lupus-like nephritis, the development of which is dependent on the presence of both NZW- and Nba2-encoded genes.

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Abbreviations

ANA:

antinuclear autoantibody

B6:

C57BL/6

ds:

double stranded

EBV:

Epstein–Barr virus

IC:

immune complex

IFNα/β:

type I interferons

Ig:

immunoglobulin

Nba2 :

New Zealand Black Autoimmunity 2

NZB:

New Zealand Black

NZW:

New Zealand White

pI:C:

polyI:C

SLE:

systemic lupus erythematosus

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Acknowledgements

This study was funded by The Denver Autoimmunity Center of Excellence (#AI46374-07) (TNJ, PM, BLK) and a grant from the Swiss National Foundation for Scientific Research (SI).

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Author notes

  1. B L Kotzin

    Present address: Amgen, Inc., Thousand Oaks, CA, USA

Authors and Affiliations

  1. Division of Clinical Immunology, University of Colorado Health Sciences Center, Denver, CO, USA

    T N Jørgensen, M T Falta, T E Metzger, S A Flannery & B L Kotzin

  2. Division of Rheumatology, University of Colorado Health Sciences Center, Denver, CO, USA

    J Thurman

  3. Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland

    S Izui

  4. Integrated Department of Immunology, University of Colorado Health Sciences Center, Denver, CO, USA

    J Thurman, J Kappler, P Marrack & B L Kotzin

  5. Howard Hughes Medical Institute, National Jewish Medical Research Center, Denver, CO, USA

    J Kappler & P Marrack

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Correspondence to T N Jørgensen.

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Jørgensen, T., Thurman, J., Izui, S. et al. Genetic susceptibility to PolyI:C-induced IFNα/β-dependent accelerated disease in lupus-prone mice. Genes Immun 7, 555–567 (2006). https://doi.org/10.1038/sj.gene.6364329

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