Molecular mimicry between human endogenous retrovirus clone 4-1 and HLA class I antigen with reference to the pathogenesis of systemic lupus erythematosus

H. Ogasawara, H. Kaneko, T. Hishikawa, I. Sekigawa1, Y. Takasaki, H. Hashimoto, S. Hirose1, Y. Kaneko2 and N. Maruyama3

Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113,
1 Department of Medicine, Juntendo University Izu-Nagaoka Hospital, 1129 Nagaoka, Izu-Nagaoka-cho, Tagata-gun, Shizuoka 410-2295,
2 Ajinomoto Co., Inc., 15-1-1, Kyobashi, Chuo-ku, Tokyo 104 and
3 Department of Molecular Pathology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173, Japan

Correspondence to: I. Sekigawa, Department of Medicine, Juntendo Izu-Nagaoka Hospital, 1129 Nagaoka, Izu-Nagaoka-cho, Tagata-gun, Shizuoka 410-2295, Japan.

SIR, Retroviruses have repeatedly been suggested as aetiological factors in systemic lupus erythematosus (SLE) [1]. Although their role in this disease remains unclear and unproven, molecular mimicry between virus and human tissue components seems to be a representative mechanism of autoimmunity mediated by retroviruses [24]. Recent reports have indicated that endogenous retroviruses exist widely not only in animal, but also in human, genomic DNA. Generally, they seem to lack the extracellular phase characteristic of retroviruses and are inherited as stable Mendelian genes. Since they make up at least 0.1–0.6% of human DNA, they contribute substantially to the architecture of the human genome [5]. Several reports have indicated that the activation of these human endogenous retrovirus (HERV) sequences, followed by the expression of HERV proteins, may play an important role in the induction of autoimmune diseases such as SLE [1, 6]. Clone 4-1 is a member of the HERV-E family and shows sequence homology with Molony murine leukaemia virus; it has ~8.8 kb of sequence including open reading frames in the gag and env regions [7]. This clone 4-1 is present in the genomic DNA of almost all Japanese individuals. We detected antibodies to clone 4-1 gag and env products in 48.3 and 10.7% of Japanese SLE patients, respectively. These antibodies were not detected in the serum of normal individuals [1, 8]. These findings indicate that transcription of HERV genes may be facilitated and virus particles or components may be produced in some SLE patients. Furthermore, a computer search of current entries in sequence libraries revealed that there are extremely high homologous sequences between the clone 4-1 gag region and the E antigen of HLA class I molecules (Fig. 1Go). Although virus-infected cells are known to be eliminated by CD8+ cytotoxic T-lymphocyte (CTL) and/or natural killer (NK) cells, recent evidence indicates that the binding signal of killer cell inhibitory receptor (KIR) on CD8+ cells and E antigen on virus-infected cells can inhibit cell lytic effects of CD8+ cells on virus-infected cells [9, 10]. The homology between clone 4-1 gag protein and E antigen may contribute to the escape of endogenous retrovirus production from the killing effects of CTL and/or NK cells. Regarding cytomegalovirus (CMV) infection, which is reported occasionally to promote the exacerbation of SLE [11], a glycoprotein homologous to HLA class I antigens encoded in CMV is known to be a ligand of KIR [12, 13]. This may be related to the escape effect of CMV from killing by CTL and/or NK cells. The precise role of HERV clone 4-1 in the induction of immune dysregulation of autoimmune diseases is still unknown. However, the cross-reaction of anti-clone 4-1 antibodies with human tissue molecules may be significant for the induction of autoimmunity. For example, our computer search revealed high homology between clone 4-1 gag and certain human tissue sequences, such as human aortas (data not shown). We are now investigating whether virus particles from clone 4-1 can promote immune abnormalities in vitro, including T-cell activation and anergy, which are observed in lymphocytes of SLE patients [1], using recombinant clone 4-1 products.



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FIG. 1.  Homologous sequences between HERV clone 4-1 and HLA class I E antigen. The percentage of homology between them is ~91%.

 

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Accepted 25 May 1999





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