Introduction
The immune system is comprised of innate and adaptive immunity, which works in the vicinity. Both immune systems act as per recognition and response strategy with the help of their respective components. When the cells of innate and adaptive immune system escape from autoreactivity through clonal deletion or negative selection, it is known as immune tolerance. The malfunctioning of this precise process of immune tolerance gives birth to autoreactive B and T cells, which proceeds towards autoimmunity [1]. During the incidences of autoimmunity bodily elements like DNA, secreted proteins, cells are targeted by antibodies that are generated by B cells during immune response, thus trigger various autoimmune diseases (AIDs). AIDs are common and serious clinical issues that are prevalent in the young population [2]. AID varies in accordance with the affected organs, with their clinical manifestations either limited to a particular tissue or disseminated. Along with these variations, AIDs are believed to proceed in consecutive phases of initiation, propagation and resolution. Like many other complex disorders, it is believed to arise from a combination of genetic and environmental factors [3, 4]. Genetic control of the immune response to polypeptide antigens is well known. Various AIDs like type 1 diabetes (T1D), rheumatoid arthritis, multiple sclerosis are polygenic in their inheritance patterns. A particular allele combination of several genes is responsible for solitary susceptibility towards certain autoimmune disease [5, 6].
T1D is an organ-specific AID featured by the destruction of pancreatic β-cells. The decreased β cell mass with infiltration of mononuclear cells into Islets of Langerhans is known as Insulitis and it is the hallmark of T1D. Fifteen to 30% of T1D patients reported other autoimmune comorbidities like thyroiditis, Addison’s disease, celiac disease [7, 8]. Plenty of evidence elicits the impact of autoimmunity and its types upon the pathogenesis of T1D. Therefore, brushing the knowledge of basic concepts and interpreting the emerging researches may enable the advancement of in-use therapies to restrict the incidence of immune driven diseases like T1D.
Innate Immunity Involvement in Pathogenesis of Type 1 Diabetes
The innate immune system implements the initial defense when triggered by a foreign pathogen. It is known for its non-specific defense mechanism and is incapable of maintaining the repertoire of antigenic encounters. Therefore, it does not have a memory of foreign pathogens [9- 11]. The innate immunity job is done by an array of skilled molecules referred to as pathogen associated molecular patterns (PAMPs) [9]. Studies have correlated the aberration in innate immunity with TID pathogenesis [10]. However, it is a major contributor to generate an inflammatory response by utilizing a variety of cells and induce cellular mechanisms for the fulfillment of immune response. The cells involved in innate immunity are macrophages, dendritic cells, natural killer cells, neutrophils, epithelial cells. Every cell functions in its respective way, from phagocytosis to direct lysis of the host cell [12, 13]. In autoimmune responses, the immune system fails to discriminate between self and non-self, thus links to the pathogenesis of AID [9].
Inflammatory Response
It is an accomplishment of innate immunity, which includes various cellular receptors known as pattern recognition receptors (PRRs), found on cellular surfaces or released in tissue fluids. These PRRs and PAMP interactions trigger the release of a variety of cytokines and chemokines accountable for inflammatory pathways [14, 15]. Inflammatory response combats the serious consequences of tissue injury from antigenic attack and restores the tissues for healing. The defective inflammatory response may have the risk for developing AID like T1D. The term Insulitis has been coined to refer to inflammation in the islets of Langerhans in the pancreas. Various studies confirm that the increment of inflammatory markers in prolonged T1D, with significant correlation, actively contributes to the progression of T1D towards nephropathy [16, 17].
Wilcox and team, in immunopathological analysis of the inflamed islet of T1D patient sample, reported the recruitment of particular immune cells at a specific stage of T1D advancement [18]. An observation has been reinforced by a research in which α-1- antitrypsin, a protease inhibitor, was injected to NOD (non-obese diabetic) mice, which protect the tissue from enzymes generated by inflammation and also reverses new-onset diabetes [19]. Macrophages and other antigen-presenting cells (APC) initiate T cells sensitization and activate regulatory mechanisms [20].
Macrophages play a major role in the development of β-cell-cytotoxic T cell complex during T1D. Along with CD8+ cytotoxic cells, macrophages are also responsible for the early loss of β-cells at a later stages of insulitis, and CD20+cells additionally play a role in β-cell destruction [18,20].
Pattern Recognition Receptors
Toll-like receptors (TLR) are a type of PRR which recognizes foreign molecules and induces innate immune system by initiating the consecutive signaling pathways such as production of cytokines, activation of adaptive immune cascades, and manifests directly in the pathogenesis of T1D [21]. Previous studies reported the profound effect of TLRs in the development of AID, thus the expression of TLRs was assessed in T1D showing the increased expression of TLR2 and TLR4 along with nuclear factor (NF-κ) and interferon-β (IFN-β) on monocytes [22]. A cohort study reported elevated ligands of TLR2 and TLR4 in T1D patients with significantly noticed consequences of disease progression [23].
Various studies demonstrated the role of TLR in the pathogenesis of T1D with the help of animal models. In non-diabetic mice models, researchers revealed that TLR3 is not required for the onset of autoimmune diabetes while TLR9 deficient mice showed a significantly decreased incidence of diabetes [21, 24].
Diverse results appear in TLR signaling, as in a recent study, TLR3 induces β cell apoptotic pathway, TLR2 recognizes lipopolysaccharide receptors of microorganisms and avoids initiation of T1D and, on the other hand, it also corroborates in worsening the disease [25]. Thus, numerous studies revealed varied TLR signaling outcomes in relation to insulitis and T1D.
Virus Components
It is well known that viruses in viral infections trigger TLR signaling by identifying the molecular structures associated with the respective viruses. Although, viral infections imply the induction of T1D, the exact mechanism is still elusive. Numerous viruses like rotavirus, rubella, mumps serve their components as TLR ligands, thus it is possible to gain an obvious understanding of the functioning of the innate immune system through TLR signaling [26].
Numerous studies reported the association between virus and T1D pathogenesis. As in an autopsy sample of the pancreas of newly diagnosed patients with T1D, enterovirus was detected, whereas in another study, enteroviral capsid protein vp1 was seen in the islets of 44 newly diagnosed T1D patients [27]. As mentioned above, TLR9-deficient mice showed a reduction in the incidence of diabetes, but in a study focusing only on TLR9 over bio breeding diabetes-resistant (BBDR) rats infected with Kilham rat virus (KRV), 25-40% of rats constantly developed T1D [28, 29]. The theory behind these results enlightens that KRV infection induces a transcription factor (STAT-1) through TLR9 signaling pathways. Therefore, viral infections can efficiently develop autoreactivity. In these reports, the componential mechanism of the innate immune system sheds light on the association with insulitis progression and T1D [28, 29].
Adaptive Immunity in Type 1 Diabetes
The adaptive immune system is highly specific, utilizes T cells, and APC for recognition of antigens. Adaptive immunity creates immunological memory that induces T cell facsimile which further coordinates with B cells to generate antigen-specific antibodies. Both T cell types, CD4+ and CD8+, are required for the initiation of T1D. By distributing B cells antigens over APCs, T cells differentiate into effector cells; CD4+ as insulin reactive and CD8+ mainly kill β-cells. CD4+ T cells assist CD8+ T cells for antibody production by B cells and activate native macrophages [30].
Humoral Immunity
Autoantibodies are contemplated as ill-fated byproducts of the immune system and responsible for causing harm to an individual. The presence of autoantibodies is the signal of emerging β-cell immunity, for the prognosis of T1D. Detection of five autoantibodies has been proposed for the prognosis of T1D [31]. Autoimmune etiology of T1D revealed the presence of Islet specific antibodies in the serum of patients than healthy individuals. Islet specific autoantibodies were the first to be observed and because of their specificity, they are viewed as diagnostic markers for T1D [32]. Various other autoantibodies for specific antigen were identified, such as insulin autoantibody (IAA), glutamic acid decarboxylase autoantibody (GADA), islet antigen-2 autoantibody (IA-2), and zinc transporter autoantibody (ZnT8-A). According to various surveys, the frequency of detected autoantibodies is clearly associated with the risk of bringing the disease into an overt condition, and the constant presence of at least one of them by the age of 5 years confirms the risk of disease progression. Thus, the circulation of autoantibodies to the respective islet cells antigen can initiate destruction of β-cells [32, 33]. Extension of humoral autoimmune response takes place in a short span of time; if such broadening does not happen after the appearance of the initial presence of antibodies, it rarely appears after [34].
Insulin has been declared as the primary autoantigen. The A chain of insulin requires post-translational modification which allows it to be recognized by T cells. IAA is the first seen autoantibody in young children during the preclinical phase and has shown firm genetic susceptibility with T1D. IAA is a diagnostic marker for TID, resulting from autoreactive B cells and CD4+ T cell interactions [35, 36].
Glutamic acid decarboxylase (GAD) is an effective autoantigen of T1D which exists in two isoforms: GAD65 and GAD 67 [36]. It recognizes mainly middle and C terminal epitopes of an autoantigen. Knip reported that in siblings of T1D affected children, the initial response was limited to the middle region, spreading fast towards C terminal and only in few cases to N terminal [36]. Elevated GADA levels were detected in patients suffering from T1D and autoimmune thyroid disease than in patients with T1D alone. It is supposed to be explained by the fact that GADA are expressed in β-cells and in the thyroid gland as well [7, 37].
After GAD, IA-2 is another important autoantigen. It is a transmembrane protein-tyrosine phosphatase-like protein and recognizes the cytoplasmic domain of the IA-2 molecule for activity. About 65% of patients with early-onset T1D showed autoantibodies to IA-2 and 35-50% had autoantibodies to IA-2β [38-40].
Antigen ZnT8 is composed of 6 transmembrane domains [41, 42]. In 60-80% of newl-onset T1Ds, ZnT8 was attacked by autoantibodies [43]. Eiji Kawasaki reported that 90% of early childhood cases had autoantibodies to GAD and IA-2, while 5-8% of adult patients had autoantibodies for ZnT8, therefore the estimation of ZnT8 autoantibody is limited over GADA and IA-2A in case of childhood T1D diagnosis [7]. Moreover, the frequency of ZnT8 and IA-2A is inversely proportional to the onset age [44].
β-cell-antigen specific autoantibodies do not straightly cause pathogenicity or cytotoxic effect on islet cells, yet they help to present the antigens to T cells and promote the development of T1D.
Cell-mediated Immunity
It is believed that the credit of β-cell destruction in T1D goes mainly to a cellular immune response with the help of T cells. Proofs behind this theory are the presence of T cells in insulitis and drugs used to slow down disease progression directly target T cells [45]. Pancreatic section analysis of T1D individuals showed fulminant immune infiltrate in patients Islet cognating the activity of CD4+ and CD8+ T cells in β-cell killing [46]. On contrary, the pancreas section in T2D does not show T-cell infiltration like T1D, although they have remarkably high levels of inflammatory molecules [47].
T cells get activated by autoantigenic determinants presented by MHC II molecules, and this is done with the help of APC, which eventually develops MHC II molecules. The activated T cells attack the islets and subsequently confront the associated β- cell autoantigen thereafter causing insulitis [48, 49].
Various studies on the NOD mouse model indicated the vulnerability of autoimmune diabetes on MHC II allele, CD4+, CD8+ T cells and B cells [50-53].
CD4+T cells act as a stimulant. They activate CD8+T cells, B cells to produce antibodies, and Islet inhabitant macrophages [54]. Recent studies recognized CD4+T cells in the NOD mouse model and human T1D patient as pro-inflammatory cells which secrete interferon-gamma (IFN-γ) and interleukins (IL) [55-58]. CD4+Tcells have subtypes Th1, Th2, Th17, and Tregs with varied immune effects [59]. Th1 cells mediate phagocytosis by releasing cytokines like IFN-γ and IL-2 which kill β-cells and exaggerate the condition [30, 59].
Th2 cells, on the other hand, suppress the activity of phagocytic cells. They produce cytokines IL-4 and IL-10, which promote antibody production and eosinophil activation [60, 61]. A study showed in a transgenic mouse model, that IL-4 secretion in islet cells safeguard the development of T1D [62]. Likewise, IL-10 also showed the protective effect, and evidence through research suggests that IL-10 establishes immune tolerance in NOD mice [20]. Immunotherapeutic strategies which promote the viability of Th2 cells and secretion of IL-4 can successfully combat the initiation of T1D. Despite the distinguished activity of Th2 cell-derived interleukins, many studies revealed the cooperated participation of Th1 and Th2 interleukins in the destruction of β-cells, and ultimately, initiate the pathogenesis of T1D [63].
Th-17 cells are IL-17 producing T cells, which contributes to various infectious diseases and autoimmune disease development [64]. It is known as inflammation-causing agent which further speeds up the process of diabetes complication, and is especially detected in children [65]. Studies have shown that IL-17 is directly targeted by therapeutic agents or that the activity of IL-17-producing cells has been stopped to control autoimmune diabetes. This therapeutic strategy suggests the involvement of IL-17 in T1D pathogenesis [66]. Another type of T cells working upon the pathogenesis of T1D is CD8+. Activation of CD8+T cells happens when antigenic peptides are presented by MHC II and through this interaction, β-cells are destroyed. The requirement for MHC I in T1D pathogenesis is ambiguous. Studies reported interactions of CD8+T cells with MHC I in the early development of the disease, while others have concluded that it occurs late in diabetes pathogenesis [67-69].
Both CD4+ and CD8+ types are responsible for β-cell destruction by producing various cytokines. But CD8+T cells perform direct cytotoxicity to pancreatic β-cells because it expresses antigen presenting MHC I molecules not MHC II [68]. In a study over the NOD mice model, it was shown that mice, which lack class I MHC do not suffer from insulitis and it initiates T1D pathogenesis representing the necessity of MHC I for T1D initiation and progression [67]. CD8+ lymphocytes secrete perforins, TNF-α, IFN-γ, IL-1β, and produce nitric oxide for the demolition of β-cells thus, take part in T1D pathogenesis [70].
Conclusion
In this review, we concisely mention the role of both innate and adaptive immunity along with their cellular lineage into the pathogenesis of T1D. T1D is an outcome of an autoimmune process associated with dysregulated signaling of the immune system. Even though the researchers have enlightened the role of individual cell type in the disease progression and have generated immunosuppressive therapies respectively, the pathway commanding the launch of the autoimmune process is still unclear. Even after this understanding, incidence of the disease continues to rise. Thus, there is a need to find answers to inhibit the initiation of an autoimmune response to avoid not only T1D, but also other autoimmune diseases. We perceive the role of immune cells with recent researches for further advancement of understanding and treatment.
Acknowledgement
Authors are grateful to King Khalid University for the support.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Rosenblum, M D, Remedios K A, Abbas AK. Mechanisms of human autoimmunity. J Clin Invest. 2015; 125(6): 2228-33.
2. Incorvaia E, Sicouri L, Petersen-Mahrt SK, Schmitz KM. Hormones and AID: Balancing immunity and autoimmunity. Autoimmunity. 2013; 46: 128-37.
3. Zenewicz LA, Abraham C, Flavell RA, Cho JH. Unraveling the genetics of autoimmunity. Cell. 2010; 140(6): 791-7.
4. Hafler D, Housley W, Marson A. Genetics of autoimmunity. J Clin Invest. 2015; 125(6): 2234-41.
5. Goris A, Liston A. The immunogenetic architecture of autoimmune disease. Cold Spring Harb Perspect. Biol. 2012; 4(3): 1-14.
6. Ueda H, Howson JMM, Esposito L, Heward J, Snook H, Chamberlain G. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature. 2003; 423(6939): 506-11.
7. Eiji K. Type 1 Diabetes and Autoimmunity. Clin Pedia Endocrinol. 2014; 23(4): 99-105.
8. Hugh OD. Characteristics of Autoimmunity in Type 1 Diabetes and Type 1.5 Overlap with Type 2 Diabetes. Diabetes. 2005; 54(2): 4-10.
9. Pino SC, Kruger AJ, Bortell R. The Role of Innate Immune Pathways in Type 1 Diabetes Pathogenesis. Curr Opin Endocrinol Diab Obes. 2010; 17(2): 126-30.
10. Delves PJ, Roitt IM. The immune system. First of two parts. N Engl J Med. 2000; 343: 37-49.
11. Beyan H, Buckley LR, Yousaf N, Londei M, Leslie RD. A role for innate immunity in type 1 diabetes? Diabetes Metab Res Rev. 2003; 19(2): 89-100.
12. Han G, Wang R, Chen G, Wang J, Xu R, Wang L, et al. Interleukin17-producing gamma delta plus T cells protect NOD mice from type 1 diabetes through a mechanism involving transforming growth factor-beta. Immunol. 2010; 129(2): 197-206.
13. Simoni Y, Diana J, Ghazarian L, Beaudoin L, Lehuen A. Therapeutic manipulation of natural killer (NK) T cells in autoimmunity: are we close to reality? Clin Exp Immunol. 2013; 171(1): 8-19.
14. Medzhitov R, Janeway CA Jr. Innate immunity: impact on the adaptive immune response. Curr Opin Immunol. 1997; 9(1): 4-9.
15. Si-Tahar M, Touqui, L, Chignard M. Innate immunity and inflammation-two facets of the same anti infectious reaction. Clin Exp Immunol. 2009; 156(2): 194-8.
16. Devaraj S, Cheung AT, Jialal I, Griffen SC, Nguyen D, Glaser N, et al. Evidence of increased inflammation and microcirculatory abnormalities in patients with type 1 diabetes and their role in microvascular complications. Diabetes. 2007; 56: 2790-96.
17. Tresz, A, Szereday L, Doria A, King GL, Orban T. Elevated C-reactive protein levels do not correspond to autoimmunity in type 1 diabetes. Diab Care. 2004; 27: 2769-70.
18. Willcox A, Richardson SJ, Bone AJ, Foulis AK, Morgan NG. Analysis of islet inflammation in human type 1 diabetes. Clin Exp Immunol. 2009; 155(2): 173-81.
19. Koulmanda M, Bhasin M, Hoffman L, Fan Z, Qipo A, Shi H, et al. Curative and beta cell regenerative effects of alpha1antitrypsin treatment in autoimmune diabetic NOD mice. Proc Natl Acad Sci. 2008; 105(42): 16242-47.
20. Tai NW, Yasuda H, Xiang YF, Zhang L, Rodriguez-Pinto D, Yokono K, et al. IL-10 conditioned dendritic cells prevent autoimmune diabetes in NOD and humanized HLA-DQ8 RIP-B7 mice. Clin Immunol. 2011; 139: 336-49.
21. Bortell R, Pino SC, Greiner DL, Zipris D, Rossini AA. Closing the circle between the bedside and the bench: Toll- like receptors in models of virally induced diabetes. Ann N Y Acad Sci. 2008: 1150: 112-22.
22. Lien E, Zipris D. The role of Toll-like receptor pathways in the mechanism of type 1 diabetes. Curr Mol Med. 2009; 9(1): 52-68.
23. Rasschaert J, Ladriere L, Urbain M, Dogusan Z, Katabua B, Sato S, et al. Toll-like receptor 3 and STAT-1 contribute to double-stranded RNA+ interferon gamma-induced apoptosis in primary pancreatic beta-cells. J Biol Chem. 2005; 280: 33984-91.
24. Wong FS, Hu C, Zhang L, Du W, Alexopoulou, L, Flavel RA, et al. The role of Toll-like receptors 3 and 9 in the development of autoimmune diabetes in NOD mice. Ann NY Acad Sci. 2008; 1150:146-8.
25. Dogusan Z, Garcia M, Flamez D, Alexopoulou L, Goldman, M, Gysemans, C, et al. Double-stranded RNA induces pancreatic beta-cell apoptosis by activation of the toll-like receptor 3 and interferon regulatory factor 3 pathways. Diabetes. 2008; 57(5): 1236-45.
26. Lang KS, Recher M, Junt, Navarini AA, Harris NL, Freigang S, et al. Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease. Nat Med. 2005; 11(2): 138-45.
27. Richardson SJ, Willcox A, Bone AJ, Foulis AK, Morgan NG. The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes. Diabetologia. 2009; 52(6): 1143-51.
28. Nair A, Wolter TR, Meyers AJ, Zipris D. Innate immune pathways in virus-induced autoimmune diabetes. Ann NY Acad Sci. 2009; 1150(1): 139-42.
29. Zipris D, Lien E, Xie JX, Greiner DL, Mordes JP, Rossini AA. TLR activation synergizes with Kilham rat virus infection to induce diabetes in BBDR rats. J Immunol. 2005; 174(1): 131-42.
30. Min L, Lu-Jun S, Xin-Yu Q. Advances in the cellular immunological pathogenesis of type 1 diabetes. J Cell Mol Med. 2014; 18(5): 749-58.
31. Mikael K, Heli S. Autoimmune mechanisms in type 1 diabetes. Autoimmune Rev. 2008; 7(7): 550-7.
32. Mannering SI, Pathiraja V, Kay WH. The case for an autoimmune aetiology of type 1 diabetes. Clin Exp Immunol. 2016; 183(1): 8-15.
33. Bingley PJ, Christie MR, Bonifacio E, Bonfanti R, Shattock M, Fonte MT, et al. Combined analysis of autoantibodies improves prediction of IDDM in islet cell antibody-positive relatives. Diabetes. 1994; 43(11): 1304-10.
34. Kukko M, Kimpimäki T, Korhonen S, Kupila A, Simell S, Veijola R, et al. Dynamics of diabetes-associated autoantibodies in young children with HLA-conferred risk of type 1 diabetes recruited from the general population. J Clin Endocrinol Metab. 2005; 90: 2712-17.
35. Kimpimäki T, Kupila A, Hämäläinen AM, Kukko M, Kulmala P, Savola K, et al. The first signs of β-cell autoimmunity appear in infancy in genetically susceptible children from the general population: the Finnish Type 1 Diabetes Prediction and Prevention Study. J Clin Endocrinol Metab. 2001; 86(10): 4782-8.
36. Knip M, Kukko M, Kulmala P, Veijola R, Simell O, Åkerblom HK, et al. Humoral beta-cell autoimmunity in relation to HLA-defined disease susceptibility in preclinical and clinical type 1 diabetes. Am J Med Genet. 2001; 115(1): 48-54.
37. Kawasaki E, Takino H, Yano M, Uotani S, Matsumoto K, Takao Y, et al. Autoantibodies to glutamic acid decarboxylase in patients with IDDM and autoimmune thyroid disease. Diabetes. 1994; 43(1): 80-6.
38. Lampasona V, Bearzatto M, Genovese S, Bosi E, Ferrari M, Bonifacio E. Autoantibodies in insulin-dependent diabetes recognize distinct cytoplasmic domains of the protein tyrosine phosphatase-like IA-2 autoantigen. J Immunol. 1996; 157(6): 2707-11.
39. Achenbach P, Warncke K, Reiter J, Naserke HE, Williams AJ, Bingley PJ, et al. Stratification of type 1 diabetes risk on the basis of islet autoantibody characteristics. Diabetes. 2004; 53(2): 384-92.
40. Hoppu S, Härkönen T, Ronkainen, Åkerblom HK, Knip M. The Childhood Diabetes in Finland Study GroupIA-2 antibody epitopes and isotypes during the prediabetic process in siblings of children with type 1 diabetes. J Autoimmun. 2004; 23: 361-70.
41. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008; 133(5): 775-87.
42. Petzold C, Riewaldt J, Watts D, Sparwasser T, Sonja S, Karsten K. Foxp3 (+) regulatory T cells in mouse models of type 1 diabetes. J Diabetes Res. 2013; 2013: 940-71.
43. Wenzlau JM, Juhl K, Yu L, Moua O, Sarkar SA, Gottlieb P, et al. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci USA. 2007; 104(43): 17040-5.
44. Vaziri-Sani F, Delli AJ, Elding-Larsson H, Lindblad B, Carlsson A, Forsander G, et al. A novel triple mix radiobinding assay for the three ZnT8 (ZnT8-RWQ) autoantibody variants in children with newly diagnosed diabetes. J Immunol Methods. 2011; 371(1-2): 25-37.
45. Roep BO. The role of T cells in pathogenesis of type 1 diabetes: from cause to cure. Diabetologia. 2003; 46(3): 305-21.
46. Coppieters KT, Dotta F, Amirian N, Campbell PD, Kay TW, Atkinson MA, et al. Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients. J Exp Med. 2012; 209(1): 51-60.
47. Sarikonda G, Pettus J, Phatak S, Sachithanantham S, Miller JF, Wesley JD, et al. CD8 T-cell reactivity to islet antigens is unique to type 1 while CD4 T-cell reactivity exists in both type 1 and type 2 diabetes. J Autoimmun. 2014; 50: 77-82.
48. Pujoll BR, Todd I, Doshi M, Bottazzo GF, Sutton R, Gray D, et al. HLA class II induction in human islet cells by interferon gamma plus tumor necrosis factor or lymphotoxin. Nature. 1987; 326: 304-6.
49. Di Lorenzo TP, Peakman M, Roep BO. Translational mini review series on type 1 diabetes: systematic analysis of T cell epitopes in autoimmune diabetes. Clin Exp Immunol. 2007; 148(1): 1-16.
50. Mora C, Wong FS, Chang CH, Flavell RA. Pancreatic infiltration but not diabetes occurs in the relative absence of MHC class II-restricted CD4 T cells: studies using NOD/CIITA-deficient mice. J Immunol. 1999; 162(8): 4576-88.
51. Serreze DV, Leiter EH, Christianson GJ, Greiner D, Roopenian DC. Major histocompatibility complex class I-deficient NOD-B2mnull mice are diabetes and insulitis resistant. Diabetes. 1994; 43(3): 505-9.
52. Yang M, Charlton B, Gautam AM. Development of insulitis and diabetes in B cell-deficient NOD mice. J Autoimmun. 1997; 10(3): 257-60.
53. Noorchashm H, Noorchashm N, Kern J, Rostami SY, Barker CF, Naji A. B-cells are required for the initiation of insulitis and sialitis in nonobese diabetic mice. Diabetes. 1997; 46(6): 941-6.
54. Wang Y, Hao L, Gill RG, Lafferty KJ. Autoimmune diabetes in NOD mouse is L3T4 T-lymphocyte dependent. Diabetes. 1987; 36(4): 535-8.
55. Arif S, Tree TI, Astill TP, Tremble JM, Bishop AJ, Dayan CM, et al. Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. J Clin Invest. 2004; 113(3): 451-63.
56. Michels AW, Landry LG, McDaniel KA, Yu L, Campbell-Thompson M, Kwok WW, et al. Islet-derived CD4 T cells targeting proinsulin in human autoimmune diabetes. Diabetes. 2017; 66(3): 722-34.
57. Gomez TI, Simon VR, Alonso LJ, Arif S, Calvino SC, Gonzalez FA, et al. Characterization of the autoimmune response against the nerve tissue S100beta in patients with type 1 diabetes. Clin Exp Immunol. 2015; 180 (2): 207-17.
58. Bellemore SM, Nikoopour E, Schwartz JA, Krougly O, Lee-Chan E, Singh B. Preventative role of interleukin-17 producing regulatory T helper type 17 (Treg 17) cells in type 1 diabetes in non-obese diabetic mice. Clin Exp Immunol. 2015; 182 (3): 261-9.
59. Santamaria P. The long and winding road to understanding and conquering type 1 diabetes. Immunity. 2010; 32(4): 437-45.
60. Romagnani S. Th1/Th2 cells. Inflamm Bowel Dis. 1999; 5(4): 285-94.
61. Lin MS, Tse HM, Delmastro MM, Bertera S, Wong CT, Lakomy R, et al. A multivalent vaccine for type 1 diabetes skews T cell subsets to Th2 phenotype in NOD mice. Immunol Res. 2011; 50(2-3): 213-20.
62. Ruffner MA, Robbins PD. Dendritic cells transduced to express interleukin 4 reduce diabetes onset in both normoglycemic and prediabetic nonobese diabetic mice. PLoS One. 2010;5(7): e11848. DOI: 10.1371/journal.pone.0011848
63. Azar ST, Tamim H, Beyhum HN, Habbal MZ, Almawi WY. Type I (insulin-dependent) diabetes is a Th1- and Th2-mediated autoimmune disease. Clin Diagn Lab Immun. 1999; 6(3): 306-10.
64. Marwaha AK, Crome SQ, Panagiotopoulos C, Berg KB, Qin H, Ouyang Q, et al. Cutting edge increased IL-17- secreting T cells in children with new-onset type 1 diabetes. J Immunol. 2010; 185(7): 3814–8.
65. Crome SQ, Wang AY, Levings MK. Translational Mini-Review Series on Th17 Cells: function and regulation of human T helper 17 cells in health and disease. Clin Exp Immunol. 2010; 159(2): 109-19.
66. Lee IF, Wang XJ, Hao JQ, Akhoundsadegh N, Chen L, Liu L, et al. B7-H4. Ig inhibits the development of Type 1 diabetes by regulating Th17 cells in NOD mice. Cell Immunol. 2013; 282: 1-8.
67. Rasche S, Busick RY, Quinn A. GAD65-Specific Cytotoxic T lymphocytes mediate beta-cell death and loss of function. Rev Diabet Stud. 2009; 6(1): 43-53.
68. Katz J, Benoist C, Mathis D. Major histocompatibility complex class-i molecules are required for the development of insulitis in nonobese diabetic mice. Eur J Immunol. 1993; 23(12): 3358-60.
69. Bulek AM, Cole DK, Skowera A, Dolton G, Gras S, Madura F, et al. Structural basis for the killing of human beta cells by CD8(+) T cells in type 1 diabetes. Nat Immunol. 2012; 13(3): 283-9.
70. Barral AM, Thomas HE, Ling EM, Darwish R, Rodrigo E, Christen U, et al. SOCS-1 protects from virally-induced CD8 T cell mediated type 1 diabetes. J Autoimmun. 2006; 27: 166-73.