Antibody reactivity to an Epstein–Barr virus BERF4-encoded epitope occurring also in Asp-57 region of HLA-DQ8 β chain

Abstract

SUMMARYA five amino acids-long sequence (GPPAA) in Iho region of Ihc 57th amino acid of HI..A-DOS /( chain, vt'hich seems to be imporlant in delining the risk for type I diabetes, occurs LUSO in the BERF4-cncoded EBNA.IC protein of Epstein-Barr virus {EBV) in six successive repeats. The antigenicity of this region was analysed using synthetic peplidcs containing different modifications of ihe GPPAA sequence. Tvt'OoCthc seven individuals who had acute EBV infeclion produced antibodies against an EBV-derivcd peplide (GPPAAGPPAAGPPA A) paralleling the EBNA: antibodies. These two cases also conlracled type I diabetes immediately after ihe infection. High antibody levels against this peptide were Ibund in a total of 12' V-;, of EBV ' individuals, and in most cases antibodies remained at high levels for several years. Human sera as well as aHinily-purificd aniibodies specific for the CiPPAAGPPAAGPPAA peptide reacted also with shorter peptide analogues (GPPAAGPPAA and GPPAA). as vi-ell as with peptides containing the surrounding niotits from DQH ji chains. However, none of these antibodies bound to denatured DQ8 fi chains in immunoblotting. The charge of the 57th amino acid modulated the antigenicily of this epitope. as peptides from Asp-57-negative DQ molecules were reaciive, while peptides from Asp-57-positive DQ molecules were not. The responsiveness was seen in both HLA-DQS-positive and -negative subjects as well as in type I diabetic individuals. The results suggest that some individuals who carry the GPPAA sequence in their HLA-DQ molecule recognize ihis epitope in EBV. This phenomenon may have potential importance in EBV-induced immune abnormalities, although cross-rcactiviiy against DQ molecules could no! be demonstrated in the present study.

Anti‐infectious Antibodies and Autoimmune‐associated Autoantibodies in Patients with Type I Diabetes Mellitus and their Close Family Members

“…Very few case reports pointed to a possible temporal relation between the onset of T1DM and acute or recent EBV infection. 26,27 Yet, low levels of anti-EBV Abs were also observed in newly-diagnosed diabetics, similar to the findings of our study. 28 Finally, the relation of toxoplasma to autoimmune diabetes has not yet been studied.…”

“…As for EBV and diabetes, there is very limited data, with conflicting findings. Very few case reports pointed to a possible temporal relation between the onset of T1DM and acute or recent EBV infection 26,27 . Yet, low levels of anti‐EBV Abs were also observed in newly‐diagnosed diabetics, similar to the findings of our study 28 .…”

Association of cytomegalovirus and other pathogens with frailty and diabetes mellitus, but not with cardiovascular disease and mortality in psycho-geriatric patients; a prospective cohort study

“…However, DM type 2 was related to the presence of high EBV IgG titers and high HHV6 response. Two case reports have described the development of a type 1 DM with HHV6 reactivation [24,25] and two other case reports during an acute EBV infection [26,27]. Reactivations of both viruses could play a role in DM and in the chronic systemic inflammation in DM [3,6,24,25], since high EBV IgG titers and a high HHV6 response suggests reactivation [28,29].…”

Hereditary Transmission of Diabetes Mellitus

“…The other five individuals who were infected but did not produce antibodies directed against these five amino-acid sequences did not develop T1D (50). The GPPAA in the region of aspartic acid-57 of HLA-DQ8 on the β chain also occurs in six successive repeats in the BERF4-encoded EBNA3C protein of the EBV.…”