Pathogenesis of Type 1 Diabetes: Comparison
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Please note this is a comparison between Version 2 by Amina Yu and Version 1 by Ana Zajec.

Type 1 diabetes (T1D) is a T-cell-mediated autoimmune disease of pancreatic β-cells, with the possible interplay of antiviral responses and other environmental factors on top of the genetic susceptibility. This ultimately leads to an aberrant β-cell stress response and the immune-mediated destruction of β-cells in the pancreata of predisposed individuals.

  • type 1 diabetes
  • genetics
  • β-cell
  • epigenetics
  • viral infections

1. Pathology of β-Cells

The early immune responses triggering insulitis are innate and include the activation of pattern recognition receptors by endogenous “danger signals” or exogenous ligands produced during viral infections on β-cells, which is a possible link between environmental risk factors and the development of T1D [11][1]. This results in type I interferon (such as IFNα) production by the β-cells and other cells present in islets, which initiates the recruitment of immune cells. Macrophages are among the first responders and the main cell type producing TNFs. This triggers NF-κB activation in β-cells, which is mostly pro-apoptotic [12][2]. In the later stages, the inflammatory microenvironment in the pancreatic islets increases the vascular permeability and facilitates the infiltration of naïve and non-islet-reactive T cells in addition to activated T cells [13][3]. The infiltrates are of predominantly CD8+ T type but also include CD20+ B cells, CD4+ T cells, and CD68+ macrophages [14,15][4][5]. TheyIt arewas found within and around pancreatic islets [14][4]. The β-cell response to cytokines, such as IL1-β and IFNγ, present in this stage is the activation of the anti-inflammatory pathways (i.for example., IL10, IL4/13) and immune checkpoint proteins (i.e.for example, PDL-1 and HLA-E) [12,16,17][2][6][7]. Furthermore, pro-inflammatory cytokines disrupt β-cells’ metabolic and electrical activity, insulin granule synthesis and content, and gap junction coupling, as well as excessive generation of reactive oxygen species (ROS) and activation of caspases [18,19][8][9]. Both types of immunity remain present throughout the course of the disease [12][2].
The evidence points to two age-related disease endotypes, namely T1DE1 and T1DE2 (type 1 diabetes endotype 1 and 2, respectively). In T1DE1, individuals are younger at the onset, more frequently carry the HLA-DR4/DQ8 allele, and initially develop anti-insulin autoantibodies (IAA). The hallmarks of this endotype are insulitis with many CD8+ T cells and CD20high B cells, few residual insulin-containing islets (ICIs), and abnormal insulin processing in the remaining β-cells. In T1DE2, individuals are older (>13 years) at the time of clinical manifestation, usually carry the HLA-DR3/DQ2 allele, and initially present with anti-GAD Abs (GADA). Insulitis with low levels of CD8+ T cells, the CD20low B-cell phenotype, and more residual ICIs and normal insulin processing are indicative of this type, with weaker evidence for a major T cell role in the pathogenesis [15,20][5][10]. Heterogeneity and possible subtypes of T1D pathophysiology were corroborated by a recent studyone of pancreas tissue slices from organ donors, which correlates anatomical and physiological insights. Alongside the islet infiltration by immune cells and evidence of β-cell mass reduction, dysfunction of β-cells was observed [21,22][11][12]. This could represent a critical early event in T1D pathogenesis as β-cell dysfunction exists years before the clinical presentation of T1D [23][13].
Indeed, it is becoming obvious that the pathogenesis of T1D involves both pancreatic β-cells and immune cells and that the crosstalk between them is of utmost importance in T1D development [9][14]. β-cells are not just passive targets but actively participate and possibly amplify pathogenic processes [24,25][15][16]. They employ compensatory mechanisms in response to immune stress, which become deleterious in the long-run. During increased insulin synthesis or other environmental stresses, they adapt their ER and mitochondria functions by triggering the unfolded protein response (UPR) to restore cellular homeostasis [26,27,28][17][18][19]. Increased production of proteins can lead to increased concentrations of misfolded proteins and the accumulation of defective ribosomal products, which serve as neoepitopes in the HLA-I presentation pathway. Similarly, other granule proteins, expressed with insulin during the β-cell glucose response, contribute to the HLA-I peptidome presented by β-cells [13,29,30,31,32][3][20][21][22][23]. Interestingly, at the same time, down-regulation of the pathways involved in the integration of energy metabolism and the regulation of gene expression in β-cells occurs [26][17]. The genes involved in those pathways are critical for insulin release and the maintenance of the β-cell phenotype and function [17][7]. Furthermore, proinflammatory signalling (following viral infection) induces the dedifferentiation of β-cells, characterized by a decreased expression of the key β-cell genes involved in maintaining β-cell identity and function, leading to the loss of insulin production [33,34][24][25].
Recent findings also reveal the possible involvement of hybrid and chimeric neoepitopes, formed in the transpeptidation reaction in stressed β-cells, in diabetogenic CD4+ T-cell activation [35,36,37,38,39][26][27][28][29][30]. In connection to this, HLA-I hyperexpression has been described in recently diagnosed and long-term individuals with T1D, as well as in AAb+ donors before the clinical presentation of the disease. Interestingly, HLA-I was mostly expressed by α-cells regardless of disease status [40][31]. They were also found to be functionally impaired, expressed proinflammatory signals, and had altered gene expression [41,42,43][32][33][34]. Still, β-cells are more affected by this process, suggesting the immune attack of β-cells is related to the presence or presentation of insulin [40][31]. Increased expression of HLA-II and the components in the HLA-II antigen processing and presentation pathway was observed in the β-cells of individuals with T1D as well, and it appears to be unique to T1D. This suggests a direct role for β-cells in T1D pathology, acting as professional APCs (antigen-presenting cells) in the autoimmune response [44][35]. The exposure of human β-cells to pro-inflammatory cytokines IFNα, IL1-β, and IFNγ results in chromatin remodelling, alternative splicing, and first exon usage, leading to the differential expression of genes, most notably increased expression of HLA-I, which, together with ER stress and β-cell apoptosis, may lead to an increased presentation of neoantigens, thus contributing to the recruitment of auto-reactive CD8+ T cells that selectively attack β-cells [16,45][6][36]. Neoantigens can also be generated via differential mRNA splicing and posttranslational modifications, both part of the β-cell stress response [13,30][3][21].
β-cells, as part of the endocrine system, are capable of long-distance communication by the secretion of insulin and other granule proteins, as well as exosome-derived proteins (GAD56 and IA-2) directly into the bloodstream. Under stress, they also secrete high amounts of (pre)proinsulin and insulin peptides [13][3]. Furthermore, stress, such as elevated cytokine levels, impairs cell–cell communication, which is necessary for normal insulin secretion [18][8]. Endocrine secretion of autoantigens facilitates their uptake by APCs outside of the pancreas, again emphasising the active role of β-cells in potentiating immune responses against themselves [13][3].

2. Genetic Predisposition

The overall risk of T1D in the general population is moderately low (with the exception of some populations, such as Sardinian and Finnish, with over 35% incidence), and most studiweres found significant differences in the genetic, immunologic, metabolic, and clinical characteristics of T1D in people with different ethnic backgrounds. This risk is 15-fold higher among the relatives of individuals with T1D [46][37]. Interestingly, children in T1D families have different risks depending on the sex of a person with T1D [47,48][38][39]. Another proof for the genetic contribution to T1D is an association between disease-causing variants in the genes connected with immune function and the occurrence of T1D. SItudie was largely employed two different approaches for studylearning T1D genetics, namely candidate gene association studiones and genome-wide linkage analysis studies (GWAS) [46,49][37][40].
A genetic link between T1D and T2D is of special interest as the associated loci for them were thought to be almost completely separated despite the partially shared phenotype. Newer studies, however, found several shared risk genes or genetic polymorphisms [59,61,62,63,64][41][42][43][44][45]. Some of the genes located in shared risk loci interact to mutually regulate important islet functions that are disturbed by disease-associated variants, leading to β-cell dysfunction [61][42]. The regulatory impacts on shared genes and pathways generate overlapping biological mechanisms, which mediate pleiotropic effects on T1D and T2D. Interestingly, a high-risk genetic profile for T1D modifies the biological pathways that increase the risk of developing both T1D and T2D but not vice versa [65][46].
The DR3-DQ2 and DR4-DQ8 haplotypes of HLA class II genes are well established as major risk factors of T1D [66,67[47][48][49],68], and at least one is present in 90% of individuals with T1D and both in 40% (for apparently healthy controls, these numbers are 30% and 3%, respectively). However, they only partly explain the increased risk for T1D development as they influence seroconversion but not the age of the onset, clinical progression, or C-peptide loss [15][5]. HLA-I alleles HLA-A*24 and HLA-B*39 and non-HLA genes, such as INS, CTLA4, PTPN22, and IL-2RA, are also widely accepted as having an impact in T1D and could improve the understanding of disease heterogeneity [49,69][40][50]. In this domain, at least a part of the missing genetic component can be attributed to undetected rare and low frequency variants in at least 40 different loci, which have larger effect sizes and play more significant roles in susceptibility to common diseases, including T1D [70,71][51][52].
Protective alleles have also been described, which are present more frequently in the general population as opposed to individuals with T1D [46,72][37][53]. For example, the DR1501-DQ6 protective haplotype has been linked to higher frequencies of islet Ag-specific CD4+ effector T (Teff) and regulatory T (Treg) cells. Interestingly, Teffs, although still capable of expressing IFN-γ and IL-4, were more likely to express IL-10 when compared to Teffs from people with susceptible haplotypes, and Tregs successfully suppressed Teffs in an Ag-specific manner, indicating a possible mechanism of action for a haplotype-dependent effect on T1D pathology [73][54]. Since T1D and coeliac disease share their main susceptibility alleles, HLA-DQ2 and HLA-DQ8, which contribute to the coexistence of both diseases, it is plausible that some other genes also have an influence. Research on the Slovenian population revealed a dual role of PTPN22 rs2476601 polymorphism in increased risk for T1D and protection against coeliac disease [74][55].
The genetic pathways involved in different stages of the disease are highly divergent, and genetics is currently the only tool capable of detecting those at risk before the development of islet autoimmunity [75][56]. More and more genetic-based evidence points to the predisposition at the β-cell level, with risk variants affecting the susceptibility to pro-apoptotic stimuli and influencing β-cell phenotypes [50,57,76][57][58][59]. New in-depth analyses of the potential role of genetic variants in the progression from islet autoimmunity to clinical T1D at the genome-wide level using next-generation sequencing identified several novel risk genes associated with T1D. They are associated with the progression from islet autoimmunity to overt T1D and are particularly involved in the pathways critical to the response to viral infections and interferon signalling in β-cells and autoimmunity development in T cells [55,66][47][60]. In fact, more than 80% of the identified candidate genes in T1D are expressed in β-cells [17,77][7][61]. Therefore, the identification of new classes of genetic variants involved in T1D is important for better risk prediction, understanding of the pathology, and possible intervention [24,63,75,78][15][44][56][62].

3. Environmental Risk Factors in Connection to Genetic Predisposition

3.1. Viral Infections

As more epidemiological and pathological evidence builds up, infections, particularly by viruses, and their possible involvement in T1D pathology, are being investigated [93][63]. There is plenty of circumstantial evidence for the involvement of enteroviral infections in pancreatic and other tissues [94,95,96][64][65][66]. For example, individuals with T1D have detectable anti-enteroviral antibodies and Coxsackievirus B (CVB) RNA in the blood and stool 6 to 12 months before AAb development, and recently diagnosed individuals with T1D have detectable enterovirus infections within their pancreata and islets [95,97][65][67]. Moreover, in the pancreatic cellular infiltrates of individuals with T1D, there is a high expression of TLR3/4, indicative of a proinflammatory innate immune response to an infection [98][68]. Enterovirus capsid protein VP1 was found in the islets of individuals with T1D both close to the time of onset [80][69] and several years after [53][70], although many attempts in the past have failed to demonstrate viral existence in the pancreas because of very low viral RNA concentrations [80][69]. The persistence of CVB4 in pancreatic β cells disturbs insulin maturation with the release of antigenic proinsulin by β cells and causes abnormalities in cellular functions and DNA methylation, as well as a steep decline in glucose-induced insulin secretion [99][71]. Enteroviral β-cell tropism stems from several factors, with the most prominent being the presence of enteroviral receptors on β-cells (for example, Coxsackie and Adenovirus Receptor—CAR) [77,100][61][72]. CAR-SIV, a specific isoform of CAR, is selectively and highly expressed in β-cells [77][61], and CAR expression in the pancreata of individuals with T1D is increased compared to healthy controls [97,98][67][68]. Moreover, children who carried the minor SNP allele rs6517774 in the CAR gene region were more likely to develop islet autoimmunity [97][67]. Another important discovery favouring enteroviral β-cell tropism was specific β-cell intracellular factors that the virus can hijack for successful infection and replication in β-cells [77][61]. At the same time, β-cells are thought to upregulate a range of anti-viral proteins in response to an interferon encounter [77,101][61][73]. Furthermore, risk-associated genetic variants found in susceptible individuals are associated either with altered interferon responses [77,98,100,102][61][68][72][74], impairment of the virus clearance, or inducement of the cytokine storm and destruction of β-cells, substantiating the possible role of viruses in initiating the diabetogenic process [58][75]. It was also demonstrated that viral particles spread to neighbouring sites via extracellular vesicles, thus evading immune responses from the host [103][76]. This suggests that a prolonged low-grade infection of β-cells, owing to defective antiviral resistance, triggers the presentation of both β-cell and viral antigens at the cell surface, a potentiated inflammatory response, β-cell damage, and autoantigen release [77,100,101][61][72][73]. The theory is supported by observations of incomplete antibody responses to enteroviruses in children with T1D and interferon and HLA-I hyperexpression, indirect evidence for (entero)viral infection [53,80][69][70]. β-cells also display a very low expression of antioxidants and high expression of cytokine and Toll-like receptors. All this, together with the fact that β-cells are terminally differentiated, rarely proliferate, and are sensitive to the interferon response, might explain why they are so susceptible to viral infections [77][61].
New methods in the detection of viral RNA (for example, single-molecule in situ hybridization, smFISH) can confirm the presence of viral mRNA throughout the whole pancreas with high sensitivity, specificity, and accuracy and at lower viral loads than by classical immunostaining and even PCR [95][65]. In association with this is the fact that individuals with T1D are more susceptible to future infections by bacteria, viruses, fungi, and parasites, which is connected to defects of the innate and adaptive immune responses [53,104][70][77]. Another virus that is commonly associated with T1D pathology is rotavirus, although it is better documented in animal models than in humans, and the potential effects of rotavirus vaccination on T1D development remain unclear [105,106][78][79]. The world epidemic of COVID-19 indicated the possible involvement of SARS-CoV-2 in T1D pathogenesis, and there are several clionical case reportes describing the new onset of T1D in COVID-19 patients [107,108,109][80][81][82]. Indeed, SARS-CoV-2 has been shown to infect and replicate in the cells of the human endocrine and exocrine pancreas and elicit β-cell impairment in glucose-dependent insulin secretion and β-cell apoptosis [110,111][83][84]. Whether COVID-19-induced β-cell damage is transient or permanent and whether SARS-CoV-2 can linger in the β-cell, causing chronic infection, and induce T1D on its own will require further investigations [112][85].
An interesting phenomenon of T1D is its seasonality, but the role of geographical location is still debatable because of sparse epidemiological data from equatorial regions, although there are reports of such seasonality disappearing close to the equator [80,81][69][86]. Seasonal patterns appear to be connected to environmental exposure to seasonal respiratory infections [81][86] and enteroviral infections [80][69] in colder months. Nevertheless, autoimmunity is probably not caused solely by a virus infection but is rather a consequence of simultaneous disadvantageous factors, for example, change in diet and sun exposure. Defects in the circadian clock regulators lead to stress in immune cells, which, in turn, exacerbate the proinflammatory response from β-cells. Again, environmental factors only play a substantial role in connection with a genetic predisposition, as is evident in children with a high-risk HLA allele, which acquired autoantibodies against islet cells during enteroviral infection more often than those without HLA risk [80][69].

3.2. Endogenized Viral Elements in the Genome

Another important group of viral entities connected to T1D pathology is human endogenized retroviruses (HERVs). They represent a potential link between genetic and environmental factors and can be transactivated by environmental viruses, such as enteroviruses, and by inflammatory stimuli [119,120][87][88]. Of note, CVB4, the enterovirus most frequently mentioned in connection to T1D pathology, was recently found to induce the transcription of a HERV-W-Env (the envelope protein of HERV-W) in primary cell cultures, such as monocytes, macrophages, and pancreatic cells [120][88]. Its role in T1D pathology is further supported by its detection in individuals with T1D, particularly in pancreatic acinar cells near the pancreatic lesions. Furthermore, anti-HERV-W-Env Abs have been detected in the sera of individuals with T1D and of those at risk for developing T1D, their presence overlapped with or preceded AAbs, and the extent of HERV-W-Env expression seems to be correlated with disease progression. In β-cells, HERV-W-Env inhibits insulin secretion, possibly through its interaction with TLR4, which could also lead to decreased β-cell functionality and viability. In favour of this is the fact that TLR4 signalling downstream elements, such as NF-κB, MyD88, and TRIF, are upregulated in individuals with T1D. HERV-W-Env also affects immune cells. It promotes macrophage recruitment within the pancreas, induces expression of proinflammatory cytokines in monocytes, and incites T cell responses with superantigen characteristics [119][87]. HERVs have also been associated with the activation of autoreactive T cells and the generation of IFN-γ [98][68].

3.3. Gut Biome

The role of the microbiome in T1D is also the subject of much interest as the presence of the specific and varied intestinal microbiota is critical in the development of the innate immune system, most importantly Th17 and Treg lymphocytes, for maintaining the mucosal barrier and producing different metabolites and vitamins [121][89]. Specifically, short-chain fatty acids (SCFAs) produced through the bacterial intestinal fermentation of dietary complex carbohydrates act as major mediators of crosstalk between the microbiome and human host. They also participate in the regulation of glucose, lipid, and energy metabolism, and modulation of gene expression, cell proliferation, and inflammation [122][90]. Their role in T1D is not completely understood and can be positively or negatively correlated with the risk of T1D, which depends on the microbial species and the type of SCFA produced [121,122,123][89][90][91]. Individuals with T1D are reported to have reduced diversity (dysbiosis) of their microbiota [53,88][70][92]. The microbiome shifts towards Gram-negative bacteria and results in increased release of LPS, thus stimulating a proinflammatory response, although most studiweres excluded the small intestine microbiome, which is better linked to the pancreas [53][70]. At the same time, intestinal permeability increases due to an SCFA-mediated impaired intestinal integrity. Accordingly, exogenous antigens and the microbial components can translocate into the circulation and promote systemic inflammation and autoimmune progression [123,124][91][93]. Consequently, alteration of the microbiome composition could lead to the loss of immune tolerance, which precedes the onset of T1D [125][94].
Alterations in the gut virome in children have been linked to autoimmune conditions, including T1D, although the results are inconclusive as of yet [126,127][95][96]. Studies of iIntestinal proteomes and metabolomes corroborated the role of microbiota in mucosal barrier function and modulating the immune response, respectively [88][92]. Although the mycobiome represents only 0.1% of the intestinal microbiome, its role in maintaining the homeostasis of the body seems to be significant, and the analysis of the mycobiome composition in the adults with T1D and T2D compared to the control group demonstrated differences in the profile of the gut mycobiota of individuals with T1D [128][97]. StudBies of birth mode and breastfeeding influences on the microbiome in connection with T1D development and intestinal viromes are offering an interesting view on the matter; however, the evidence is scarce and inconclusive [88][92]. On the other hand, the use of broad-spectrum antibiotics early in life had a positive association with an increased risk for developing T1D [88,129][92][98]. If the intestinal microbiota influences islet autoimmunity, this should also be detectable outside the intestinal mucosa. Indeed, one group [130][99] examined the systemic anti-commensal Ab response against intestinal bacteria and linked high-risk HLA haplotypes with these Abs in serum and future T1D diagnosis. Diet is an important factor in intestinal microbiome composition and it, in turn, exerts its influence, not only directly stimulating an appropriate immune response but also through the epigenetic regulation of immune cells with metabolites, such as butyrate, acetate, polyphenols, and vitamins. In dysbiosis, the metabolome balance is disturbed, consequently influencing aberrant crosstalk between bacteria and the host’s immune system [131,132][100][101].

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