Viral persistence may be due to a successful evasion from the host immune system leading to viral pathogenesis. species involved in human diseases (ACD and ACC) and over 250 serologically distinct viruses [9,10]. These ubiquitous pathogens across the world are transmitted mainly by the fecalCoral and respiratory routes and can infect a wide range of tissues [11,12]. Even though most enteroviral infections remain asymptomatic, they have been associated with a wide spectrum of clinical signs ranging from relatively GNG12 mild symptoms such as fever, gastro-enteritis, skin lesions and headache to severe acute forms such as meningitis, hepatitis, encephalitis, myocarditis, pancreatitis and hand, foot and mouth disease [10,12,13,14,15]. In addition to these severe acute clinical features, enteroviral infections, especially infections with coxsackievirus B (CV-B) (B), are the most suspected environmental factors involved in the development of chronic diseases such as T1D [4,5,6,16]; however, the precise etiology and the mechanisms that trigger virus-induced autoimmunity against islet antigens are not fully understood. Indeed, after initial replication in the gastrointestinal Isoalantolactone mucosa, CV-B spreads into the bloodstream through the lymphatic system and reach target organs [17]. The frequent detection of enteroviral components (protein and RNA) in the serum, monocytes, gut mucosa and pancreas as well as anti-CV-B antibodies in saliva of diabetic patients supports the role of persistent infection in the pathogenesis of T1D [18,19,20,21,22,23,24,25,26,27,28,29]. CV-Bs are able to establish a persistent infection in beta cells for up to several years with low levels of viral replication [30,31]. This chronic infection promotes inflammation and innate immunity resulting in insulitis and progressive destruction of insulin-producing cells by preexisting cytotoxic T cells [32]. T1D Isoalantolactone is believed to be a chronic T cell-mediated autoimmune disease against pancreatic beta cells but other immune cells such as B cells, macrophages, dendritic cells and Natural killer (NK) cells may also be involved in its pathogenesis. Chronic CV-B4 infection of human pancreatic islets can activate Isoalantolactone the production of interferon (IFN)- and IFN- (by the double-stranded RNA generated during viral replication) and can trigger insulitis with a predominant NK cells infiltration in the early phase of T1D [29,30,33,34]. Viral persistence may be due to a successful evasion from the host immune system leading to viral pathogenesis. Virus-infected cells can escape recognition and destruction by cytotoxic T cells by developing various strategies including the inhibition of the expression and/or function of HLA class I antigens [35]. In contrast, cells with abnormal cell surface expression of HLA class I antigen can nevertheless be recognized and killed by NK cells. NK cells are innate effector lymphocytes which contribute to the hosts first line of defense against viruses based on their cytolytic activity towards infected cells and their interactions with the innate and adaptive immune system through their capacity to produce a variety of cytokines such as IFN- following their activation [36,37,38]. The cytolytic activity of NK cells is modulated by a balance between activating and inhibitory signals transduced via interactions between target cells and NK cell surface receptors [35,39]. The altered numbers, phenotypes and functions of NK cells have been frequently reported in type 1 diabetic patients [40,41,42,43,44,45,46,47]. Moreover, cell-mediated cytotoxicity of NK cells towards various cells infected with CV-B including pancreatic beta cells have been described in animal and human studies which suggest that the defective clearance of pancreatic beta cells infected with CV-B could influence the viral persistence and the susceptibility to virus-induced islet autoimmunity in T1D [31,36,48,49,50]. In this review, the issue of the role.
