Immunoproteomic Profiling of Antiviral Antibodies in New-Onset Type 1 Diabetes Using Protein Arrays

Abstract

The rapid rise in the incidence of type 1 diabetes (T1D) suggests the involvement of environmental factors including viral infections. We evaluated the association between viral infections and T1D by profiling antiviral antibodies using a high-throughput immunoproteomics approach in patients with new-onset T1D. We constructed a viral protein array comprising the complete proteomes of seven viruses associated with T1D and open reading frames from other common viruses. Antibody responses to 646 viral antigens were assessed in 42 patients with T1D and 42 age- and sex-matched healthy control subjects (mean age 12.7 years, 50% males). Prevalence of antiviral antibodies agreed with known infection rates for the corresponding virus based on epidemiological studies. Antibody responses to Epstein-Barr virus (EBV) were significantly higher in case than control subjects (odds ratio 6.6; 95% CI 2.0–25.7), whereas the other viruses showed no differences. The EBV and T1D association was significant in both sex and age subgroups (≤12 and >12 years), and there was a trend toward early EBV infections among the case subjects. These results suggest a potential role for EBV in T1D development. We believe our innovative immunoproteomics platform is useful for understanding the role of viral infections in T1D and other disorders where associations between viral infection and disease are unclear.

Dynamics of diabetes and obesity: Epidemiological perspective

“…These viruses destroy β-cells of islets of Langerhans. DM occurs in congenital rubella patients even though these patients have immune markers and Human leucocyte antigen (HLA) antigens (characteristic of T1DM) [63–66]. …”

An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes

“…An explanation relies upon its transactivation and epigenetic dysregulation by infectious agents, as it has already been demonstrated (33,60,61). In T1D, the question of such dysregulation by enterovirus is raised (12), as well as the role of EBV (62). This diagram illustrates how, in a global pathogenic cascade leading to the disease, HERV-WEnv expression is placed at a crucial position, between multiple environmental factors operating in genetically susceptible individuals and multiple clinical outcomes.…”

“…Environmental viruses can trigger the transactivation of members of the HERV-W family, as this has been demonstrated for herpes virus simplex type 1, cytomegalovirus, or EBV (33,60,61). The transactivation of HERV-W by EBV is of particular interest, owing to the recent demonstration that EBV was the only virus found to be associated with T1D in an immunoproteomic array profiling antiviral antibodies of 23 viral strains (62).…”

Multiplexed Nucleic Acid Programmable Protein Arrays

“…Compared to purified protein microarrays, cell-free protein microarrays are more likely to produce naturally-folded mammalian proteins due to the decreased sample manipulation and use of enhanced cell extracts with native chaperone proteins. Moreover, the use of nucleic acids vastly simplifies the production of custom arrays since any protein can be produced as long as the gene-of-interest is synthesized; for example, arrays can be produced that represent a specific proteome or signaling pathway [17][18][19][20].…”