Type 1 Diabetes and Viral Infections: Similarities Between Human Glutamic Acid Decarboxylase-65 (Gad65), Human Insulin and H1n1 Influenza a Virus

Abstract

Background: Exposure to viral antigens that share amino acid (AA) sequence similar with self-antigens might trigger autoimmune diseases in genetically predisposed individuals, and the molecular mimicry theory suggests that epitope mimicry between the virus and human proteins can activate autoimmune diseases like type 1 diabetes (T1DM). Objective: The purpose of this study is to explore the possible similarity between the AA sequences of human glutamic acid decarboxylase - 65 kDa isoform (GAD65) human insulin, and proteins of H1N1 influenza (strain (A/California/7/2009(H1N1)), using databanks of proteins and immunogenic peptides to explain the development of T1DM. Methods: AA sequences of the A/California/7/2009(H1N1) strain, GAD65 and human insulin, available in the NCBI (National Center for Biotechnology Information) database were compared using the Basic Local Alignment Search Tool (BLAST) software. Results: Similarities were found among the A/California/7/2009(H1N1) strain, GAD and the human insulin. The similarities between Influenza A virus (A/California/7/2009(H1N1)) and the GAD65 ranged from 15.0 % to 56.0%, with statistical significance (P 0.006 and P 0.017). The similarities between the Influenza A virus (A/California/7/2009(H1N1)) and insulin ranged from 38.0 % to 45.0%, but without statistical significance. Conclusion: Bioinformatics data suggest a possible pathogenic link between A/California/7/2009(H1N1) and T1DM. Through molecular mimicry is has been observed that sequences similarity between viral Polyprotein and self-proteins could induce a crossover immune response to self-antigens, with a breakdown of self-tolerance, resulting in autoimmune disease.

From infection to autoimmunity: ZnT8-mediated molecular mimicry in the triggering of post-COVID 19 type 1 diabetes mellitus

“…Several hypotheses have been proposed to explain this phenomenon, including the possibility of viral-triggered autoimmunity or an indirect effect on pancreatic β-cells. 14 Studies suggest that COVID-19 may induce an in ammatory response and immune dysregulation, leading to the destruction of pancreatic β-cells in genetically predisposed individuals. 15,16 The electrochemiluminescence assay showed a strong correlation between the presence of ZnT8 autoantibody and the increased risk of developing DM1, indicating a high level of a nity and predictive value.…”

Potential clinical implications of molecular mimicry‐induced autoimmunity

“…For example, coxsackievirus infection has been linked epidemiologically to the subsequent development of T1DM 35 . At the molecular level, coxsackievirus P2‐C protein shares sequence homology with GAD65, a major autoantigen in T1DM 36 . This epitope similarity may stimulate cross‐reactive T cells that recognize both viral and GAD65 peptides, initiating anti‐islet autoimmunity in genetically predisposed individuals.…”

“… 35 At the molecular level, coxsackievirus P2‐C protein shares sequence homology with GAD65, a major autoantigen in T1DM. 36 This epitope similarity may stimulate cross‐reactive T cells that recognize both viral and GAD65 peptides, initiating anti‐islet autoimmunity in genetically predisposed individuals. Homologies with GAD65 have also been found in rotavirus VP7 protein, further implicating molecular mimicry with pancreatic antigens.…”

The association between stressful life events and respiratory infections during the first 4 years of life: The Environmental Determinants of Diabetes in the Young study

“…Evidence from epidemiological studies; biomedical studies detecting enteroviruses from the blood, pancreas, and gut of T1D patients; and animal studies suggests that enterovirus infections may accelerate the pathogenesis of T1D in susceptible individuals (Beyan, Wen, & Leslie, ; Beyerlein, Wehweck, Ziegler, & Pflueger, ; Christen, Bender, & von Herrath, ; Christen & von Herrath, ; Davis‐Richardson & Triplett, ; de Beeck & Eizirik, ; Dotta & Sebastiani, ; Hober et al, ; Laitinen et al, ; Peng & Hagopian, ; Salvatoni et al, ; Yeung, Rawlinson, & Craig, ). The molecular mimicry theory suggests that epitope mimicry between a virus and human proteins can activate autoimmune diseases like T1D (de Oliveira Andrade et al, ). Respiratory infections were reported to increase the risk for T1D autoimmunity in the BABYDIET (Beyerlein et al, ; de Beeck & Eizirik, ), MIDIA (Rasmussen, Witso, Tapia, Stene, & Ronningen, ), ABIS (Wahlberg, Vaarala, Ludvigsson, & for the ABIS Study Group, ), and The Environmental Determinants of Diabetes in the Young (TEDDY; Lönnrot et al, ) studies.…”

“…Evidence from epidemiological studies; biomedical studies detecting enteroviruses from the blood, pancreas, and gut of T1D patients; and animal studies suggests that enterovirus infections may accelerate the pathogenesis of T1D in susceptible individuals (Beyan, Wen, & Leslie, 2012;Beyerlein, Wehweck, Ziegler, & Pflueger, 2013;Christen, Bender, & von Herrath, 2012;Christen & von Herrath, 2005;Davis-Richardson & Triplett, 2015;de Beeck & Eizirik, 2016;Dotta & Sebastiani, 2014;Hober et al, 2012;Laitinen et al, 2014;Peng & Hagopian, 2006;Salvatoni et al, 2013;Yeung, Rawlinson, & Craig, 2011). The molecular mimicry theory suggests that epitope mimicry between a virus and human proteins can activate autoimmune diseases like T1D (de Oliveira Andrade et al, 2016).…”