Both exogenous and endogenous retroviruses display a marked variety of interactions with their host and, in a susceptible individual, may be inciting, contributory, or perpetuating factors in the pathogenesis of autoimmune conditions . Studies looking at the role of HERVs have been conducted in most organ-specific and systemic autoimmune conditions, including rheumatoid arthritis (RA), juvenile rheumatoid arthritis (JRA), psoriasis, systemic lupus erythematosus (SLE), systemic sclerosis, Sjogren syndrome (SS), multiple sclerosis (MS), alopecia areata, type I diabetes, primary biliary cirrhosis, essential thrombocythemia (ET), and Graves disease. Although disease associations have been established, there is as yet no proven definite causative association between HERVs and disease . Evidence for a relationship between HERVs and autoimmune diseases is suggested by the finding of circulating antibodies reactive with endogenous retroviral proteins and endogenous retroviral gene expression (mRNA transcripts and proteins) in autoimmune diseases, and the evidence that human endogenous retroviruses can encode superantigenic activity .
The proposed mechanisms by which expression of defective retroviruses might lead to the dysregulation of the immune response include:
• Transcriptional activation. HERVs may act as insertional mutagens or cis-regulatory elements causing activation, inhibition, or alternative splicing of cellular genes involved in immune function. A-type retrovi-ruses, for example, can function as transpositional elements, and sequences in their transcriptional control region (LTR) can activate cellular genes, including those of cytokines or oncogenes. HERVs also may encode elements like tat in HIV-1 or tax in HTLV-1, both of which are capable of transactivating cellular genes. Alternatively, an HERV-encoded protein also may act in trans to regulate gene expression.
• Superantigen (SAg) motifs that bypass the normal MHC restrictive process of T-cell stimulation. SAg are microbial proteins that sequentially bind to MHC class II proteins and the VP chain of the T-cell receptor and thereby strongly stimulate and expand T cells. EBV and perhaps other DNA viruses can induce endogenous SAg genes encoded by HERV . EBV SAg expression is regulated by type I interferons [10,11]. Recently it has been shown that negative thymic selection to HERV-K18 SAg constitutes a first checkpoint controlling peripheral tolerance compared with SAg reactivity .
• Production of neo-antigens by modification of cellular components. Virally encoded components may associate physically with or otherwise modify cellular proteins or structures, thereby rendering them autoantigenic.
• Molecular mimicry. Expression of retroviral antigens that cross-react with major histocompatibility complex (MHC) components could disrupt the idiotypic network that regulates the immune system resulting in autoimmunity. Several retroviral proteins share amino acid sequence similarities with cellular proteins, which could explain the humoral immunity reported in autoimmune disease elicited by cross-reactivity with HERV proteins. The 70K protein of U1snRNP was the first lupus autoantigen shown to contain a region of homology and immunologic cross-reactivity with a conserved p30 Gag protein of most mammalian-type C retroviruses. Query and Keene  showed that: (1) anti-p30Gag antibodies recognize a recombinant 70K-LacZ fusion protein and U1 snRNPs, and (2) autoantibodies against U1 snRNPs were elicited by immunization with p30Gag. They proposed, therefore, that autoimmunity to U1RNP may be triggered by expression of an endogenous retroviral Gag protein. Anti-Gag antibodies elicited by the HERVs could cross-react with the 70K protein and, subsequently, recognition could expand to additional 70K epitopes .
• Epitope spreading. T-cell recognition of a self epitope is followed by activation of autoreactive T cells recognizing other epitopes of the same antigen, and, with time, epitopes of other proteins .
• Activation of innate immunity through pattern recognition receptors. HERV-W Env is able to specifically activate cells of the innate immune system through CD14 and TLR4. This activation is associated with the production of major proinflammatory cytokines .
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