An interplay between genetics and environmental factors such as the virome, microbiome and metabolome is suggested to regulate immune tolerance, with the introduction of environmental, lifestyle or dietary exposures currently being investigated as either accelerating or protective
[42]. A range of potential environmental triggers has been proposed, including viruses. The hypothesised role of viral infections in the initiation of IA and the progression to T1D is supported by a large body of epidemiological and animal model-based evidence
[43][44]. Multiple viruses have been associated with IA/T1D to date, including enterovirus (EV)
[45][46][47][48][49][50][51][52][53][54], rotavirus
[55][56][57][58][59][60][61], cytomegalovirus
[62][63][64][65][66][67][68], Epstein-Barr virus
[63][69][70], parechovirus
[71][72][73], influenza
[74][75][76], parvovirus
[77][78], mumps
[79][80][81], rubella
[80][81][82][83][84][85] and human endogenous retrovirus
[86][87][88][89]. By far, the strongest supporting evidence exists for EVs. Our previous meta-analysis of 26 molecular studies and >4400 participants revealed EV infection was 10 times greater at the onset of T1D compared to healthy controls
[90]. Furthermore, T1D-specific risk alleles contained within genes involved in immune function have been shown to alter susceptibility to viral infection or affect the extent of the host antiviral response
[91]. The rs1990760 SNP within
IFIH1 has been associated with increased detection of EV RNA in blood
[92] and separately with severe EV-A71 infection
[93]. The rs2476601 SNP within
PTPN22 has been associated with lower IFN production by macrophages in response to TLR ligand stimulation (as would occur during viral infection)
[94], and additionally it has been suggested that PTPN22 could suppress the function of effector T cells, diminishing their response to viral infection and allowing the establishment of persistent infection
[91][95].
The timing of environmental triggers is likely to be critical, with environmental influences potentially commencing in utero and within the first year of life, emphasising the importance of longitudinal prospective cohort studies that follow at-risk children from pregnancy, such as the Environmental Determinants of Islet Autoimmunity (ENDIA) and Type 1 Diabetes Prediction and Prevention (DIPP)-novum studies
[96][97]. Our recent meta-analysis of observational studies revealed maternal viral infections during pregnancy resulted in offspring that were twice more likely to develop T1D (OR 2.16, 95% CI 1.22–3.80;
p = 0.008), highlighting the need to measure infections in utero as well as during early life. The adoption of large, national or international prospective birth cohort studies allows for the examination of any temporal links between infection in utero and the eventual development of IA or T1D in the offspring
[46].