Human endogenous retroviruses and other autoimmune conditions

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Alopecia areata

In this autoimmune condition characterized by an aberrant T-cell response against hair follicle self-antigens, serum antibodies reacting with human intracisternal A-type retrovirus proteins have been found [53].

Rheumatoid arthritis

Evidence implicating retroviruses in rheumatoid arthritis can be drawn from the parallels between human and animal retroviral infections. Animal retroviral pathogens, such as caprine arthritis encephalitis virus and maedi visna virus, cause chronic arthritis in sheep and goats with similarities to human RA. An association of HRV-5 and RA has been claimed based on the detection by nested PCR of proviral DNA in approximately 50% of synovial samples from patients who have RA (12/25) [54]. A recent study evaluated by real time PCR synovial tissue from 75 patients who had RA, the same number of patients who had osteoarthritis (OA), and 50 controls. All tissue specimens tested negative for HRV-5 proviral DNA. The authors emphasize the importance of using strict and reproducible methods for the study of HERV [55]. An elevated multi-epitope-specific antibody response toward HERV-K proteins also has been documented in patients who have RA [56].

Increased levels of HERV-K10 expression were shown in PBMCs from patients who had RA compared with those from OA and healthy controls [57]. Another study evaluated the synovial expression of HERV-K (HML-2) by reverse transcription PCR and immunofluorescence in RA, OA, and healthy controls. HERV-K env gene-derived mRNA and the Rec protein were found to be expressed in normal and rheumatoid synovial cells with differences in the transcription levels of certain transcripts (apparent lower expression levels in arthritic synovia) [58].

Juvenile rheumatoid arthritis

The expression levels of HERV-K18 by semiquantitative reverse transcription PCR were evaluated in JRA. HERV-18 superantigen transcripts were found to be elevated in the peripheral blood and in the synovial fluid mononuclear cells in JRA, and its expression was strongly induced by IFN-a. The levels of HERV-K18 in peripheral blood were independent of serum IFN-a levels, seropositivity for EBV, or the percentage of circulating B cells [59]. A concern about this report is the small sample size and the use of semiquantitative reverse transcription PCR.

Sjogren syndrome

The fact that Sjogren-like syndromes occur in a proportion of HIV and HTLV-1 infections lead to the search for other retroviruses in idiopathic disease. In fact, 33% of the sera from patients who have SS react against the p24 group specific antigen of HIV-1, whereas 47% of the salivary gland biopsies contain an epithelial cytoplasmic protein reactive with a monoclonal antibody to p24 of HIV [60]. The discovery of a human intracisternal A-type retroviral particle that was antigenically related to HIV but distinguishable from this virus by ultrastructural, physical, and enzymatic criteria in lym-phoblastoid cells exposed to homogenates of salivary tissue from patients who had SS was the first evidence of an HERV in SS [61].

Subsequently it was shown that 88% of patients who have SS have seror-eactivity to HIAP, and that there is a strong correlation between HIAP-1 reactivity and the presence of anti-SS-A and SS-B antibodies [21].

Other viruses have been linked to SS. An increased prevalence of HTLV-reactive antibodies in 36% of Japanese patients who had SS was shown by ELISA, particle agglutination assay, and Western blot [62]. A different study, from an HTLV-1 endemic area, showed that 23% of SS versus 3% of the general population was seropositive for HTLV. In this study, salivary IgA antibodies to HTLV-1 were common among seropositive patients who had SS (5/7), which was interpreted as suggestive of increased viral activity in the salivary glands [63]. In contrast, in the United States and Europe there is no increased reactivity among similar patients to HTLV proteins [16].

Only higher frequency of provirus of HERV-K113 in patients who had SS was found in a study that evaluated the geographic distribution of HERV-K113 and HERV-K115 and their prevalence in different autoimmune diseases. In this study the geographic distribution for both HERVs was similar [64].

Essential thrombocytopenia

By electron microscopy immunostaining, HERV-K10 gag protein was detected in two patients who had ET. In these patients, HERV-K10 formed clusters in the cytoplasm and it was also found in intracellular vacuoles from megakaryocytes [65].


Recent progress in the genetics of psoriasis showed that within the major locus of susceptibility (6p21.3, PSORS1) an endogenous retroviral sequence was mutated and that this mutation segregated with the disease [66]. By im-munofluorescence confocal microscopy, a differential expression and a characteristic dust-like cytoplasmic staining of HERV-E Env protein was reported in psoriatic lesions in contrast to normal skin or atopic dermatitis samples. The intensity of HERV-E Env expression in psoriatic skin was decreased in nonlesional samples compared with lesional or perilesional samples. Furthermore, HERV-E Env expression also could be downregulated by UVB [67]. More recently the expression of three HERV families, namely

HERV-W, -K, and -E, was confirmed in normal and psoriatic skin, the level of expression being higher in psoriatic skin samples. Two types of sequences were mainly represented, which shared homology with the HERV-K and the ERV-9/HERV-W families. Only resident cutaneous cells expressed these sequences in contrast to blood and sera samples that were negative. Trans-complementation or trans-activation (ie, human papillomavirus, HIV-1) are the postulated mechanisms to explain the endogenous retroviral reactivation [68]. Another study found a high frequency of IgG antibodies against gag and env genes of the murine leukemia virus-like group of HERVs. Moreover, these antibodies reacted with an epidermal epitope in protein extracts from normal and psoriatic skin cultures [69].

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