Enterovirus markers and serum CXCL10 in children with type 1 diabetes

Abstract

Most patients with type 1 diabetes are considered to have a T-cell mediated autoimmune disease. The chemokine CXCL10 promotes the migration of activated T-cells. Virus infections might contribute to the pathogenesis of type 1 diabetes and enterovirus protein and/or genome have been detected in b-cells from a majority of tested newly diagnosed children with type 1 diabetes. The chemokine CXCL10 is induced in human islet cells by enterovirus infections in vivo and in vitro, but is not expressed in islets from normal organ donors. Since CXCL10 is a chemokine known to be induced by virus infections and/or cellular damage, our aim was to study if levels of CXCL10 are elevated in serum from children with type 1 diabetes and whether it correlates to the presence of enterovirus markers. CXCL10, neutralizing antibody titer rises against certain enterovirus, and antibodies against GAD65 were measured in serum, and enterovirus PCR was performed on whole blood from 83 type 1 diabetes patients at onset, 48 siblings and 69 controls. CXCL10 was also measured in serum from 46 patients with proven enterovirus infection and in serum from 46 patients with other proven virus infections. The CXCL10 serum levels were not elevated in children at onset of type 1 diabetes and there was a considerable overlap between the groups with 99 (8-498) pg/ml in serum from children with type 1 diabetes, 120 (17-538) pg/ml in serum from controls, and 117 (7-448) pg/ml in siblings of the children with type 1 diabetes. The CXCL10 serum levels in patients with proven enterovirus infection were slightly increased compared to the levels in the other groups, 172 (0-585) pg/ml but there was no statistically significant difference. In contrast, CXCL10 serum levels in patients with other proven virus infections were clearly elevated 418 (34-611) pg/ml. Despite that elevated CXCL10 levels have been demonstrated in some groups of patients with type 1 diabetes, in this study the mean CXCL10 serum levels were not elevated in patients with type 1 diabetes neither in patients with proven enterovirus infection. In contrast, in patients with other virus infections the CXCL10 levels were elevated, presumably reflecting the severity or the site of infection. This suggests that local production of CXCL10 in the affected organ cannot be measured reproducible in serum and that its potential use in clinical practice is limited.

Immunology in the clinic review series; focus on type 1 diabetes and viruses: how viral infections modulate beta cell function

“…Viruses may cause beta cell destruction either by cytopathic effects on the target cells or indirectly by triggering or potentiating the autoimmune response. In this regard, it is of interest that recent studies showed IFN‐γ‐induced protein 10 (IP‐10) expression, a chemokine that promotes the migration of activated T cells, in the islets of recent‐onset type 1 diabetic patients [36] and in the sera of newly diagnosed children with type 1 diabetes [37].…”

“…Viruses may cause beta cell destruction either by cytopathic effects on the target cells or indirectly by triggering or potentiating the autoimmune response. In this regard, it is of interest that recent studies showed IFN-g-induced protein 10 (IP-10) expression, a chemokine that promotes the migration of activated T cells, in the islets of recent-onset type 1 diabetic patients [36] and in the sera of newly diagnosed children with type 1 diabetes [37]. The established role of inflammation in the different stages of the insulitic process [38] and increasing evidence in support of the contribution of viral infections to a proinflammatory islet scenario are strongly suggestive that viruses may indeed contribute to beta cell damage both directly (e.g.…”

Synergistic Expression of the CXCL10 Gene in Response to IL-1β and IFN-γ Involves NF-κB, Phosphorylation of STAT1 at Tyr701, and Acetylation of Histones H3 and H4

“…Additionally, CXCL10 circulates at higher levels in diabetic patients than in nondiseased individuals (8,14,15). Transgenic expression of CXCL10 driven by pancreatic b cell-specific promoters revealed islets enriched with specific leukocytes (10,16).…”

Viral Infections and Diabetes

“…Notable is the fact that both lytic and non lytic Coxsackievirus B4 strains are able to upregulate CXCL I0 secretion from human islets during infections, contributing to islet inflammation and immune-mediated B-celI destruction in Tl OM. 95 Molecular m im icry has also been proposed as inductive or accelerating mechanism of TI OM . It has been demonstrated that a short peptide sequence (PEVKEK) of the P2-C CVB4 protein share an homologous sequence with GA065 and that can induce a cross reaction between antibodies, T celIs, viral peptides and islet celI antigens."…”