题名：Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients.
作者：Dotta F, Censini S, Roep BO, Marchetti P
来源：Proc Natl Acad Sci U S A[IF=10.338] 2007 Mar 20 104(12):5115-20
Department of Internal Medicine, Endocrine and Metabolic Sciences, and Biochemistry, University of Siena, 53100 Siena, Italy.
Type 1 diabetes is characterized by T cell-mediated autoimmune destruction of pancreatic beta cells. Several studies have suggested an association between Coxsackie enterovirus seroconversion and onset of disease. However, a direct link between beta cell viral infection and islet inflammation has not been established. We analyzed pancreatic tissue from six type 1 diabetic and 26 control organ donors. Immunohistochemical, electron microscopy, whole-genome ex vivo nucleotide sequencing, cell culture, and immunological studies demonstrated Coxsackie B4 enterovirus in specimens from three of the six diabetic patients. Infection was specific of beta cells, which showed nondestructive islet inflammation mediated mainly by natural killer cells. Islets from enterovirus-positive samples displayed reduced insulin secretion in response to glucose and other secretagogues. In addition, virus extracted from positive islets was able to infect beta cells from human islets of nondiabetic donors, causing viral inclusions and signs of pyknosis. None of the control organ donors showed signs of viral infection. These studies provide direct evidence that enterovirus can infect beta cells in patients with type 1 diabetes and that infection is associated with inflammation and functional impairment.
Faculty Member Comments
Sir William Dunn School of Pathology, University of Oxford, United Kingdom
This paper shows that Coxsackie B4 virus infection of islet beta cells and natural killer (NK) cell-mediated non-destructive inflammation and insulitis are found in some recent-onset type 1 diabetic patients. Coxsackie enteroviruses have been increasingly associated with development of type 1 diabetes in recent years, but it was not clear which of the following mechanisms were involved: 1) destruction of beta cells by virus-induced cytolysis, or 2) an inflammatory response to the infection leading to subclinical levels of beta destruction, release of normally sequestered antigens and then pathogenic autoreactive T cell responses, and 3) sharing of antigenic determinants by viral and self-antigens and thereby induction of cross-reactive T-cell responses. These authors found that in 3 of 6 recently diagnosed type 1 diabetes (T1D) patients, but none of 26 control pancreas samples, clear evidence of Coxsackie B4 virus infection was detectable. The virus could be isolated and was able to infect pancreases from control organ donors in vitro, demonstrating clear beta cell tropism. In pancreases of the 3 T1D patients that showed viral infection, no T-cells autoreactive to beta cell determinants were seen. Instead there was mild inflammation largely dominated by NK cells. In these patients there was a clear inability of the beta cells to respond to raising glucose by secreting insulin, but insulin was still produced at normal levels. Intriguingly, these patients also did not carry any of the HLA haplotypes known to be associated with a predisposition to T1D. What this would suggest is that, in some cases at least, the onset of T1D symptoms can separated from any autoimmune reactions in that it may be largely due to Coxsackie virus infection, which somehow causes NK cell-dominated insulitis and beta cell dysfunction but not destruction. What now needs to be established, in a larger set of patients, is how often this actually occurs and whether the Coxsackie virus infection persists in these patients and subsequently leads to autoimmune beta-cell destruction or not. Whatever the outcome of these future studies, this work does suggest that some early onset T1D patients might not yet have any islet cell destruction, and that therefore some (simpler to implement and more successful?) strategy might be conceived at this stage to halt or even reverse the effects of viral infection.
Competing interests: None declared
Evaluated 3 Apr 2007