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Autoimmunity Volume 41, 2008 - Issue 4
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Original

Molecular mimicry and immunomodulation by the HRES-1 endogenous retrovirus in SLE

Andras Perl Division of Rheumatology, Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY13210, USA; Division of Rheumatology, Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY13210, USA
,
Gyorgy Nagy Division of Rheumatology, Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY13210, USA; Division of Rheumatology, Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY13210, USA
,
Agnes Koncz Division of Rheumatology, Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY13210, USA; Division of Rheumatology, Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY13210, USA
,
Peter Gergely Division of Rheumatology, Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY13210, USA; Division of Rheumatology, Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY13210, USA
,
David Fernandez Division of Rheumatology, Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY13210, USA; Division of Rheumatology, Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY13210, USA
,
Edward Doherty Division of Rheumatology, Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY13210, USA; Division of Rheumatology, Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY13210, USA
,
Tiffany Telarico Division of Rheumatology, Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY13210, USA; Division of Rheumatology, Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY13210, USA
,
Eduardo Bonilla Division of Rheumatology, Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY13210, USA; Division of Rheumatology, Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY13210, USA
&
Paul E. Phillips Division of Rheumatology, Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY13210, USA; Division of Rheumatology, Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY13210, USA
 show all
Pages 287-297 | Received 11 Sep 2007, Accepted 07 Dec 2007, Published online: 07 Jul 2009
 
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Abstract

Genetic and environmental factors are believed to influence development of systemic lupus erythematosus (SLE). Endogenous retroviruses (ERV) correspond to the integrated proviral form of infectious retroviruses, which are trapped within the genome due to mutations. ERV represent a key molecular link between the host genome and infectious viral particles. ERV-encoded proteins are recognized by antiviral immune responses and become targets of autoreactivity. Alternatively, ERV protein may influence cellular processes and the life cycle of infectious viruses. As examples, the HRES-1 human ERV encodes a 28-kDa nuclear autoantigen and a 24-kDa small GTP-ase, termed HRES-1/Rab4. HRES-1/p28 is a nuclear autoantigen recognized by cross-reactive antiviral antibodies, while HRES-1/Rab4 regulates surface expression of CD4 and the transferrin receptor (TFR) through endosome recycling. Expression of HRES-1/Rab4 is induced by the tat gene of HIV-1, which in turn down-regulates expression of CD4 and susceptibility to re-infection by HIV-1. CD4 and the TFR play essential roles in formation of the immunological synapse (IS) during normal T-cell activation by a cognate MHC class II peptide complex. The key intracellular transducer of T-cell activation, Lck, is brought to the IS via binding to CD4. T-cell receptorζ (TCRζ) chain binds to the TFR. Abnormal T-cell responses in SLE have been associated with reduced lck and TCRζ chain levels. HRES-1 is centrally located on chromosome 1 at q42 relative to lupus-linked microsatellite markers and polymorphic HRES-1 alleles have been linked to the development of SLE. 1q42 is one of the three most common fragile sites in the human genome, and is inducible by DNA demethylation, a known mechanism of retroviral gene activation. Molecular mimicry and immunomodulation by a ERV, such as HRES-1, may contribute to self-reactivity and abnormal T and B-cell functions in SLE.

Acknowledgements

This work was supported by grant RO1 AI 48079 from the National Institutes of Health and the Central New York Community Foundation.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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