Mar 04, 2002
Antiviral defenses expressed by pancreatic islet cells are required to prevent diabetes after infection with coxsackievirus B4 (CVB4), according to a March 4th report in the Advance Online Publication of Nature Immunology. Thus, enhancing the antiviral defenses of individuals predisposed to develop autoimmune type I diabetes may help prevent disease onset.
Enteroviral infection has been linked with progression to type 1 diabetes in susceptible individuals. However, the host factors affecting beta cell permissiveness to viral infection are not known. For this study, Dr. Nora Sarvetnick, of The Scripps Research Institute in La Jolla, California, generated transgenic nonobese diabetic mice that express a negative regulator of interferon signaling.
The islets of wild-type and nontransgenic NOD mice treated with interferon-alpha and infected with CVB4 maintained very low viral titers and retained their normal structure. "Interferons induced the rapid transition of pancreatic islet cells to an antiviral state, which was critical for a block in CVB4 replication in vitro," the investigators write.
In islets from the transgenic NOD mice, however, CVB4 replication was uninhibited, regardless of whether interferon was added or not, and extensive degenerative changes and cell death were observed.
Transgenic mice were infected with CVB4, after which 19 of 20 developed hyperglycemia by day 12, with blood glucose levels often exceeding 500 mg/dL. In contrast, only 1 of 33 nontransgenic mice became become hyperglycemic.
The authors demonstrated that diabetes development did not depend on the presence of CD8+ T cells. Furthermore, generalized activation of natural killer cells was not responsible for destruction of the beta cells. However, depletion of NK cells during infection with CVB4 resulted in far less destruction of islet cells and a milder form of insulitis.
"Our data show that by responding to interferons, the beta cell not only restrains CVB4 infection and replication, but also escapes antiviral activities raised by the host's innate immune system," they write. Defective islet cell responses to viral infection appear to increase cellular damage and the release of beta cell antigens, thus elevating the level of epitopes sufficiently to initiate autoimmunity.
"This article is interesting in showing that infection could affect the beta cell and that the innate immune response, via the natural killer cell, is the mediator of damage," Dr. Noel R. Rose, of The Johns Hopkins University School of Medicine in Baltimore, told Reuters Health.
However, he added, "The chance that this is the direct explanation for development of the disease is remote," because it would account for only relatively rare cases of diabetes following virus infection.
Dr. Rose did suggest the possibility that exposure to a toxin could affect the beta cell by preventing it from producing alpha-interferon, and thus making it directly susceptible to viral infection.
© 2002 Reuters Ltd