Human endogenous retroviruses and systemic lupus erythematosus

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A role of retroviruses in SLE pathogenesis is supported by an increasing body of evidence. A possible retroviral link with SLE was suspected initially because of the similarity of autoimmune manifestations and immune dysregulation between patients who have SLE and those infected with known human retroviruses, such as HIV-1. It has been shown that one third of patients who have SLE produce high-titer antibodies to various retroviral proteins, including Gag, Env, and Nef, and the p24 capsid antigen of HIV-1 and HTLV, in the absence of overt retroviral infection [16-18]. This phenomenon was attributed to molecular mimicry between retroviral antigens and host proteins. Actually, patients who have SLE also produce antibodies to HERV proteins and the striking amino acid similarities between certain Gag proteins and human autoantigens, such as a component of U1 sn-ribonucleoprotein (70K protein), topoisomerase I, and SS-B/La, have suggested that the natural targets of some antibodies in SLE may be HERV proteins. Detection of antibodies reactive with peptides present in the envelope genes of HERV-H [19], HTLV-related endogenous sequence (HRES) [20], ERV-1, human intracisternal A-type retroviral particles (HIAP) [21], ERV3, and HERV-K also have been described in patients who have SLE. Particularly in the case of HRES, there is amino acid sequence homology between HRES-1 and the gag-related region of the 70 kDa U1sn-RNP protein [22], and this has been proposed as one of the critical events in the etiopathogenesis of SLE [23]. Interestingly, the presence of anti-HRES-1 antibodies, which was documented in 50% of patients who had SLE by Western blot analysis, has been linked to clinically active disease [20]. A strong linkage between HIAP and SLE has been established. In various reports, 60% to 95% of patients who have SLE react with HIAP preparations. Interestingly, patients who have discoid or cutaneous forms of lupus display reduced seroreactivity with HIAP proteins [21].

Animal models also support a role of HERV in SLE pathogenesis. The expression of 8.4-kb MCF endogenous retroviral transcripts is a primary feature of murine lupus [24]. In the MRL/lpr mouse model for SLE, the integration of HRES-1 into the murine fas apoptosis-promoting gene results in a lowered expression of Fas protein and a consequent failure of apoptosis in autoreactive lymphocytes [25]. It seems that defective activation-induced cell death in peripheral autoreactive lymphocytes is the primary mechanism by which these mice develop systemic autoimmunity. Furthermore, the insertion of a retrotransposon into the second intron of the fas gene of MRL-lpr/lpr mice, leads to reduced apoptosis, survival of autoreactive lymphocytes, and earlier mortality [26].

HERV clone 4-1, a member of the HERV-E family, is distributed widely in the DNA of Japanese individuals. Studies from Juntendo University reported that HERV clone 4-1 sequences show increased transcription and translation in patients who have SLE compared with normal controls and that the increased transcription of HERV clone 4-1 in patients who have SLE is partially regulated by epigenetic mechanisms. The presence of the gag region antigen and messenger RNA for the clone 4-1 gag region also was described in peripheral blood mononuclear cells (PBMCs) from patients who had SLE, but not in normal controls [27]. Finally, serum antibodies to recombinant clone 4-1 gag products were detected in approximately 50% of patients who had SLE [28]. Synthetic peptides derived from HERV clone 4-1 can induce immune abnormalities observed in patients who have SLE: T-cell activation, cytokine production (increase IL-16 and IL-6 production and inhibit mitogen-mediated IL-2 production), and polyclonal B cell activation [29,30].

Although no correlation with disease activity has been proved yet, treatment with steroids reduced the amount of clone 4-1-like mRNA in patients who had SLE [31]. Furthermore, a possible correlation between plasma concentrations of anti-U1 RNP and anti-Sm antibodies and the presence of HERV-E clone 4-1 gGag mRNA in PBMC of patients who have SLE and a correlation between the level of PBMC HERV-E clone 4-1 Gag transcript and blood plasma content of antiSm antibody have been suggested. Because the U1 70-kDa protein and Sm polypeptide antigens are located on the same molecule of the spliceosome complex, the correlations described may suggest a cross-reactivity between an unknown viral antigen and anti-Sm antibody [32].

The use of a demethylating agent (5-aza-deoxycytidine) causes a quantitative increase of the clone 4-1 mRNA [33] and decreases the mRNA for DNA methyltransferase-1 (DNMT-1; methylation-regulating enzyme) in PBMCs from normal individuals. Transcription of DNMT-1 mRNA in PBMC from patients who have SLE is lower than in cells from normal controls [34]. The transcription of endogenous autoantigens, such as HERV, seems to be promoted by DNA hypomethylation, which is implied by low DNMT activity. Interestingly, estrogens may increase the expression of HERVs by reducing DNA methylation through the inhibition of DNMT activity [29].

Finally, in primary epidermal keratinocytes and in the skin of patients who have SLE, UBV radiation has been shown to activate the transcription of various endogenous retroviral pol sequences closely related to pol sequences of human endogenous retroviruses [35].

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