Coxsackie–adenovirus receptor expression is enhanced in pancreas from patients with type 1 diabetes

Abstract

ObjectivesOne of the theories connecting enterovirus (EV) infection of human islets with type 1 diabetes (T1D) is the development of a fertile field in the islets. This implies induction of appropriate proteins for the viral replication such as the coxsackie–adenovirus receptor (CAR). The aim of this study was to investigate to what extent CAR is expressed in human islets of Langerhans, and what conditions that would change the expression.DesignImmunohistochemistry for CAR was performed on paraffin-embedded pancreatic tissue from patients with T1D (n=9 recent onset T1D, n=4 long-standing T1D), islet autoantibody-positive individuals (n=14) and non-diabetic controls (n=24) individuals. The expression of CAR was also examined by reverse transcription PCR on microdissected islets (n=5), exocrine tissue (n=5) and on explanted islets infected with EV or exposed to chemokines produced by EV-infected islet cells.ResultsAn increased frequency of patients with T1D and autoantibody-positive individuals expressed CAR in the pancreas (p<0.039). CAR staining was detected more frequently in pancreatic islets from patients with T1D and autoantibody-positive subjects (15/27) compared with (6/24) non-diabetic controls (p<0.033). Also in explanted islets cultured in UV-treated culture medium from coxsackievirus B (CBV)-1-infected islets, the expression of the CAR gene was increased compared with controls. Laser microdissection of pancreatic tissue revealed that CAR expression was 10-fold higher in endocrine compared with exocrine cells of the pancreas. CAR was also expressed in explanted islets and the expression level decreased with time in culture. CBV-1 infection of explanted islets clearly decreased the expression of CAR (p<0.05). In contrast, infection with echovirus 6 did not affect the expression of CAR.ConclusionsCAR is expressed in pancreatic islets of patients with T1D and the expression level of CAR is increased in explanted islets exposed to proinflammatory cytokines/chemokines produced by infected islets. T1D is associated with increased levels of certain chemokines/cytokines in the islets and this might be the mechanism behind the increased expression of CAR in TID islets.

Proteomic and Transcriptional Profiles of Human Stem Cell-Derived β Cells Following Enteroviral Challenge

“…Finally, infection resulted in a nearly 10-fold decrease in expression of CXADR, which encodes CAR, the receptor for the coxsackie virus. This finding is congruent with reported data for explanted human islets following CVB infection [7]. Table S2.…”

“…Coxsackie viral antigens can be detected in pancreatic tissues from subjects with T1D [3], and serum viral RNA is more frequently reported in T1D cases even before the detection of autoantibody [5,6], indicating that viral infection may participate early in T1D pathogenesis. Human pancreatic islet cells express the coxsackie and adenovirus receptor (CAR), and significant β-cell stress and damage may occur following viral infection, as evidenced in samples from T1D and autoantibody-positive subjects [2,7]. In addition, human islet autoimmunity is associated with prolonged coxsackievirus infection [8].…”

Coxsackievirus B1 infections are associated with the initiation of insulin-driven autoimmunity that progresses to type 1 diabetes

“…This feature could then be modulated by other viral characteristics and/or beta cell sensitivity to these viruses. In vitro studies have suggested that EVs infect mainly beta cells in cultured human islets [15,16], and that CAR expression is upregulated in islets of individuals with type 1 diabetes compared with controls [17]. In fact, in vivo tropism of CVB to human pancreatic islets has also been documented in post mortem examination of children with a fatal CVB infection [18,19].…”

Unexpected subcellular distribution of a specific isoform of the Coxsackie and adenovirus receptor, CAR-SIV, in human pancreatic beta cells

“…Ylipaasto et al [ 3 ] confirmed a role for CAR by demonstrating that pre-treatment of isolated human islets with a blocking antibody (clone RmcB) protected the cells from CVB infection [ 3 ]. More recently, CAR expression was confirmed in human pancreas, albeit using an antiserum that does not discriminate between the various isoforms [ 20 ]. We have thus characterised and mapped the expression and distribution of CAR isoforms in human pancreas.…”