Table 1.

General mechanisms of virus-induced autoimmunity.

Mechanism	Description	References
Molecular mimicry	Viral antigens with structural similarity with self-antigens can be presented to and activate autoreactive T-lymphocytes.	[8,9,14,15,16,17,18]
Epitope-spreading	Over time, persistent viral infection elicits autoantibodies directed not only towards initial antigens but also multiple epitopes of the same antigens or even different antigens, increasing breadth of immune response.	[8,9,14,19]
Superantigen production	Superantigens lack antigenic specificity and bind to T-cell receptor (TCR) and major histocompatibility complex (MHC) class II molecules, activating T-lymphocytes with a wide range of specificities.	[8,9,14]
Bystander activation	Release of cytokine by antigen-presenting cells (APCs) or virus-specific T- lymphocytes activates neighboring preprimed autoreactive T-lymphocytes.	[8,9,14,20]
Altered apoptosis and clearance deficit	Viral infections can increase cell apoptosis, with activation of T-helper 17 (Th17) and release of nondigested nuclear material; if a clearance deficit is present, this process may stimulate autoreactive B-lymphocytes survival.	[8,9,14,22]
Epigenetic factors	DNA methylation, histone modifications and RNA-based mechanisms are the three main epigenetic modalities which allow viruses to modulate expression of genes involved in immune response.	[8,9,14,23,24,25,26]
Persistent or recurrent viral infection	Persistent infection by lymphotropic viruses can stimulate expansion of polyclonal lymphocytes, leading to autoantibody production Recurrent infections can trigger “facilitating antibodies” which enhance inflammation and antigen exposure in subsequent infective episodes, leading to autoimmunity (e.g.,T1D)	[8,9,14,27,28,29,30]
Innate immunity activation	Viral DNA/RNA bind to different PRRs which initiate pathways leading to type I IFN response	[31,32,33]
Direct cytotoxicity	Viruses can infect and directly kill target cells, causing AIDs	[29,34]