It is generally accepted that certain viral infections can trigger the development of autoimmune diseases. However, the exact mechanisms by which these viruses induce autoimmunity are still not understood. In this review, we first describe hypothetical mechanisms by which viruses induce some representative autoimmune diseases. Then, we focus on Epstein–Barr virus (EBV) and discuss its role in the pathogenesis of rheumatoid arthritis (RA). The discussion is mainly based on our own previous findings that (A) EBV DNA and its products EBV-encoded small RNA (EBER) and latent membrane protein 1 (LMP1) are present in the synovial lesions of RA, (B) mRNA expression of the signaling lymphocytic activation molecule-associated protein (SAP)/SH2D1A gene that plays a critical role in cellular immune responses to EBV is reduced in the peripheral T cells of patients with RA, and (C) EBV infection of mice reconstituted with human immune system components (humanized mice) induced erosive arthritis that is pathologically similar to RA. Additionally, environmental factors may contribute to EBV reactivation as follows: Porphyromonas gingivalis peptidylarginine deiminase (PAD), an enzyme required for citrullination, engenders antigens leading to the production of citrullinated peptides both in the gingiva and synovium. Anti-citrullinated peptides autoantibody is an important marker for diagnosis and disease activity of RA. These findings, as well as various results obtained by other researchers, strongly suggest that EBV is directly involved in the pathogenesis of RA, a typical autoimmune disease.
It is well known that an excess or deficiency, as well as a metabolic disorder in trace elements, causes various disturbances in the body; and further that there are many met alloenzymes or metal-enzyme-complexes which contain these trace elements. In recent years with the advance in research methods, active attempts have been made to clarify the correlation between trace elements and those enzymes which require them as a co factor.Regarding zinc and zinc metabolism, a review by Vallee (1) is well known among many reports from various workers. As to the correlation between zinc and carbonic anhydrase, Vallee et al. (2,3) and Wolff (4) reported that in red blood cells, the zinc level is directly related to carbonic anhydrase activity and its content. In order to find a simi lar relation between 65Zn metabolism and carbonic anhydrase activity in the liver, the authors have made several researches both in tumor-bearing animals (5-7) and animals with abnormal endocrine milieu (8-10), but failed to obtain any definitive conclusion. Many studies have been made on zinc metabolism under various diseases, especially in hepatic disorders (4,11,12). Baxter and Smith (13) reported that administration of carbon tetrachloride into rats made no change in 65Zn uptake in their livers but decreased 54Mn uptake; and Smith et al . (14) reported that "Mg uptake increased in similarly treated animals.Further, there have been many reports on change in iron metabolism and hepatic catalase activity in tumor-bearing animals. Also, the authors previously reported on the relation between "Fe metabolism and catalase activity in liver of Ehrlich ascites cancer bearing mice (15). Similar reports were made on liver-damaged animals (16)(17)(18)(19)(20)(21)(22)(23)(24).Concerning the other metal metabolism, Thiers and Vallee (25), Thiers et al. (26) and Reynolds et al. (27) reported that the administration of carbon tetrachloride results in striking increase of calcium and decrease of potassium content of the mitochondria of rat liver as compared with normal mitochondria, and that the sodium concentration is
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