**3. Genetic factors**

recognition of multiple islet antigens. A number of investigators have addressed in the Non-Obese Diabetic (NOD) mouse (spontaneously develops type 1 diabetes) the importance of immune reactivity to insulin with the dramatic finding that eliminating immune responses to insulin blocks development of diabetes and insulitis, and importantly immune responses to downstream autoantigens such as the Islet specific molecule Glucose-6-phosphatase catalytic subunit-Related Protein( IGRP) [9]. Knocking out both insulin genes (mice in contrast to humans have two insulin genes) with introduction of a mutated insulin with alanine rather than tyrosine at position 16 of the insulin B chain prevents development of diabetes [10]. Recognition of this B-chain peptide of insulin by T lymphocytes depends upon a "nonstringent" T cell receptor with conservation of only the alpha chain sequence (Valpha and

As in other immune diseases both genetic factors as well as environmental factors contribute in the pathogenesis of the disease (Figure 2). Environmental factors exert their effects ones

**Figure 2.** A schematic figure shows how environmental factors trigger TYPE 1 DIABETES onset in genetically suscepti‐ ble persons which ends to the process of β-cell-specific autoimmunity processes which lead to the destruction of pan‐ creatic β-cell. As antigen presenting cell is triggered by auto antigens it releases intiinfalmatory cytokines eg IL-1 that signals T-helper 1 class to activate B-cell and T cell in order to release autoantibodies to attach pancreatic β-cell.

Jalpha) and not the N-region of the alpha chain, or the Beta chain [11].

genetic susceptibility factors already exist.

76 Type 1 Diabetes

A mutation of the Forkhead bOX Protein 3 (FOXP3 gene, a transcription factor that controls the development of regulatory T cells is a cause of neonatal diabetes [12]. The syndrome is termed IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome. As reflected in the name, children with disorder suffer from overwhelming autoimmunity and usually die as infants. Of note bone marrow transplantation can reverse disease. IPEX syndrome is rare, as is neonatal diabetes. In the differential diagnosis of neonatal diabetes it must be recognized that half of children developing permanent neonatal diabetes have a mutation of the Kir6.2 molecule of the sulfonylurea receptor. These children with their nonautoimmune form of diabetes can be treated with oral sulfonylurea therapy.

Though more common than IPEX syndrome, the Autoimmune Polyendocrine Syndrome Type 1 (APS-1) syndrome is also rare. It results from a mutation of the "autoimmune regulator" AIRE gene, another transcription factor [13]. Approximately 15% of patients with this syn‐ drome develop autoimmune diabetes. The leading hypothesis as to etiology (e.g. Addison's disease, mucocutaneous candidiasis, and hypoparathyroidism) is that AIRE controls expres‐ sion of autoantigens and negative selection of autoreactive T lymphocytes within the thymus. A very recent dramatic discovery is the demonstration that essentially 100% of patients with Autoimmune Polyendocrine Syndrome type 1 (APS-1) have autoantibodies reacting with interferon alpha and other interferons. Such autoantibodies are extremely rare and essentially not found in patients with type 1 diabetes or Addison's disease outside of the syndrome.

Patients with type 1 diabetes and their relatives are at risk for development of thyroid autoimmunity, celiac disease, Addison's disease, pernicious anemia and a series of other autoimmune disorders [14]. Approximately 1/20 patients with type 1 diabetes have celiac disease by biopsy though the majority have no symptoms [15]. These asymptomatic individ‐ uals are usually detected with screening for transglutaminase autoantibodies. The level of transglutaminase autoantibodies relates to the probability of a positive biopsy and it is important for clinicians to know the threshold for likely positive biopsy for the assay they employ [16]. There remains controversy as to whether asymptomatic celiac disease when detected should be treated with a gluten free diet and large clinical trials are needed to address this question.

#### **3.1. MHC genes**

Type 1 diabetes has become one of the most intensively studied polygenic disorders. There are MHC as well as non-MHC genes or loci candidate to contribute in the genetic susceptibility to type 1 diabetes pathogenesis. According to the recent version of the National Center for Biotechnology Information (NCBI) map viewer these genes are located on all human chromo‐ somes [17] (Figure 3). The strongest associations with both susceptibility and protection from type 1 diabetes are HLA DR and DQ molecules. For instance DQB1\*0602 alleles are associated with dominant protection and DR3-DQ2 molecules (DQB1\*0201) and DR4-DQ8 (DQB1\*0302) with susceptibility [18].

ibility to type 1 diabetes resides in certain non-MHC genes that have an effect only in the

Update of Type 1 Diabetes http://dx.doi.org/10.5772/55960 79

In particular, polymorphisms of a promoter of the insulin gene and an amino acid change of PTPN22 are associated with the risk of TYPE 1 DIABETES in multiple populations [4-6]. A repeat sequence in the 5' region of the insulin gene is associated with greater insulin expression in the thymus and it is hypothesized that this contributes to decreasing the development of diabetes [7]. The polymorphism of the lymphocyte-specific tyrosine phosphatase gene influences T cell receptor signaling, and the same polymorphism is a major risk factor for

A polymorphism in the cytotoxic T-lymphocyte-associated antigen-4 gene was shown to be associated with the risk of type 1 diabetes in a meta-analysis of 33 studies involving over 5000 patients [9]. Other genes are implicated in risk for type 1 diabetes (eg, CTLA-4) [10] and other genetic loci, but their influence is very small, or so small that replication has been difficult.

Additional evidence for the role of non-MHC genes comes from studies in NOD (nonobese diabetic) mice. These mice develop spontaneous autoimmune diabetes with striking similar‐ ities to type 1 diabetes in humans [11]. Autoimmune infiltration of the islets of Langerhans (insulitis) begins at about 50 days of age and clinical diabetes appears at about 120 days.

Interferon (IFN-γ)+ T cells (Th1 cells) appear to be an important mediator of the insulitis in NOD mice, and destruction of the islet cells can be slowed by the administration of anti- IFNγ antibodies. IFN-γ -inducing factor (IGIF; also called interleukin (IL)-18) and IL-12 are potent inducers of IFN-γ, and the progression of insulitis begins in parallel with increased release of these two cytokines(kent et al 2005). IGIF gene expression is upregulated in NOD mice, and the location of the IGIF gene suggests that it is a candidate gene for susceptibility to type 1 diabetes [41].Genetically altered (knockout) mice deficient in IL-18 had hyperphagia, obesity, hyperinsulinemia, and hyperglycemia; intracerebral administration of recombinant IL-18 decreased food intake and reversed hyperglycemia (Bach 2002). A new locus associated with type 1 diabetes, has been identified near the gene encoding the p40 subunit of IL12B in NOD

It was initially thought that, in contrast to Th1 cells, Th2 cells (which produce IL-4, -5, -10, and -13) protected against the onset and progression of type 1 diabetes. However, Th2 cells also are capable of inducing islet-cell destruction, and therefore the onset and progression of type

In our extensive cytokine gene polymorphisms effect on type 1 diabetes immunogenetics ( 44-46]we have shown clearly that a single nucleotide polymorphism (SNP) in the genetic of IL-4 gene, however, would contribute to the domination of T-h-1 cell to Th2 (IL-4) [46], lack of action of IL-4, the th2 cytokine initiator. Further, a Single Nucleotide Polymorphism (SNP) in the Transforming Growth Factor (TGF)-β gene ends up to lower production of TGF- β protein level. That may contribute to the lack of immunosuppressive effect of TGF- β in the patho‐

1 diabetes are probably under the control of both Th1 and Th2 cells [1,43].

presence of the appropriate MHC alleles.

multiple autoimmune disorders [8].

mice [42].

genesis of type 1 diabetes [47].

**Figure 3.** A schematic projection of type 1 diabetes susceptible genes location according to 2012 version of NCBI map viewer. Type 1 diabetes susceptible genes were reported on all chromosome of human[17].

Type 1 diabetes is a T cell organ specific autoimmune disease [19] with approximately 40% of the familial aggregation accounted for by the MHC region [20-21]. Nevertheless, it is generally assumed that the positive predictive value of MHC alleles is relatively low given the complex genetics and potential multiple environmental factors hypothesized to contribute to diabetes risk. However, approximately 1/2 to 1/3 of U.S. children who develop type 1 diabetes prior to age 15 have the highest risk DR/DQ genotype (HLA-DRB1\*03-DQA1\*0501-DQB1\*0201/ DRB1\*04-DQA1\*0301-DQB1\*0302, DR3-DQB1\*02-01/DR4-DQB1\*0302) [22-25]. Pursuing the hypothesis that additional major determinants of Type 1 diabetes risk (in addition to DR/ DQ genes) are within or close to the MHC region, highly conserved HLA-F [24-32].

Recently, OR gene have been associated with different diseases which support the hypothesis of the importance of OR in CNS in addition to smell [33]. Increasing studies suggest significant association among SNP in OR genes that link autoimmunity, psychiatric disorders, and smell impairment [33-36].

Interestingly, a large cluster of the human OR family 14, subfamily J and member 1gene (OR14J1) were found in proximity to the HLA-F, and so they were called "MHC-linked" ORgenes [1, 37-38]. Olfactory Receptor (OR) is our Central Nervous System (CNS) external messenger which translates the information from the odorant into neural pulses, a window for our mind. In addition, the important role of CNS in the pathogenesis of type 1 diabetes any variation in the genetic make-up of the OR might lead to the destruction of its function and notably malfunction of the CNS. The OR14J1C allele of OR gene in the conserved region of HLA-F showed a significant association with type 1 diabetes, except the known diabetogenic DQ/DR genes [39].

#### **3.2. Non–MHC genes**

Although important, the MHC susceptibility genes are not sufficient to induce type 1 diabetes, suggesting polygenic inheritance in most cases [40]. An important component of the suscept‐ ibility to type 1 diabetes resides in certain non-MHC genes that have an effect only in the presence of the appropriate MHC alleles.

In particular, polymorphisms of a promoter of the insulin gene and an amino acid change of PTPN22 are associated with the risk of TYPE 1 DIABETES in multiple populations [4-6]. A repeat sequence in the 5' region of the insulin gene is associated with greater insulin expression in the thymus and it is hypothesized that this contributes to decreasing the development of diabetes [7]. The polymorphism of the lymphocyte-specific tyrosine phosphatase gene influences T cell receptor signaling, and the same polymorphism is a major risk factor for multiple autoimmune disorders [8].

A polymorphism in the cytotoxic T-lymphocyte-associated antigen-4 gene was shown to be associated with the risk of type 1 diabetes in a meta-analysis of 33 studies involving over 5000 patients [9]. Other genes are implicated in risk for type 1 diabetes (eg, CTLA-4) [10] and other genetic loci, but their influence is very small, or so small that replication has been difficult.

**Figure 3.** A schematic projection of type 1 diabetes susceptible genes location according to 2012 version of NCBI map

Type 1 diabetes is a T cell organ specific autoimmune disease [19] with approximately 40% of the familial aggregation accounted for by the MHC region [20-21]. Nevertheless, it is generally assumed that the positive predictive value of MHC alleles is relatively low given the complex genetics and potential multiple environmental factors hypothesized to contribute to diabetes risk. However, approximately 1/2 to 1/3 of U.S. children who develop type 1 diabetes prior to age 15 have the highest risk DR/DQ genotype (HLA-DRB1\*03-DQA1\*0501-DQB1\*0201/ DRB1\*04-DQA1\*0301-DQB1\*0302, DR3-DQB1\*02-01/DR4-DQB1\*0302) [22-25]. Pursuing the hypothesis that additional major determinants of Type 1 diabetes risk (in addition to DR/ DQ

Recently, OR gene have been associated with different diseases which support the hypothesis of the importance of OR in CNS in addition to smell [33]. Increasing studies suggest significant association among SNP in OR genes that link autoimmunity, psychiatric disorders, and smell

Interestingly, a large cluster of the human OR family 14, subfamily J and member 1gene (OR14J1) were found in proximity to the HLA-F, and so they were called "MHC-linked" ORgenes [1, 37-38]. Olfactory Receptor (OR) is our Central Nervous System (CNS) external messenger which translates the information from the odorant into neural pulses, a window for our mind. In addition, the important role of CNS in the pathogenesis of type 1 diabetes any variation in the genetic make-up of the OR might lead to the destruction of its function and notably malfunction of the CNS. The OR14J1C allele of OR gene in the conserved region of HLA-F showed a significant association with type 1 diabetes, except the known diabetogenic

Although important, the MHC susceptibility genes are not sufficient to induce type 1 diabetes, suggesting polygenic inheritance in most cases [40]. An important component of the suscept‐

viewer. Type 1 diabetes susceptible genes were reported on all chromosome of human[17].

genes) are within or close to the MHC region, highly conserved HLA-F [24-32].

impairment [33-36].

78 Type 1 Diabetes

DQ/DR genes [39].

**3.2. Non–MHC genes**

Additional evidence for the role of non-MHC genes comes from studies in NOD (nonobese diabetic) mice. These mice develop spontaneous autoimmune diabetes with striking similar‐ ities to type 1 diabetes in humans [11]. Autoimmune infiltration of the islets of Langerhans (insulitis) begins at about 50 days of age and clinical diabetes appears at about 120 days.

Interferon (IFN-γ)+ T cells (Th1 cells) appear to be an important mediator of the insulitis in NOD mice, and destruction of the islet cells can be slowed by the administration of anti- IFNγ antibodies. IFN-γ -inducing factor (IGIF; also called interleukin (IL)-18) and IL-12 are potent inducers of IFN-γ, and the progression of insulitis begins in parallel with increased release of these two cytokines(kent et al 2005). IGIF gene expression is upregulated in NOD mice, and the location of the IGIF gene suggests that it is a candidate gene for susceptibility to type 1 diabetes [41].Genetically altered (knockout) mice deficient in IL-18 had hyperphagia, obesity, hyperinsulinemia, and hyperglycemia; intracerebral administration of recombinant IL-18 decreased food intake and reversed hyperglycemia (Bach 2002). A new locus associated with type 1 diabetes, has been identified near the gene encoding the p40 subunit of IL12B in NOD mice [42].

It was initially thought that, in contrast to Th1 cells, Th2 cells (which produce IL-4, -5, -10, and -13) protected against the onset and progression of type 1 diabetes. However, Th2 cells also are capable of inducing islet-cell destruction, and therefore the onset and progression of type 1 diabetes are probably under the control of both Th1 and Th2 cells [1,43].

In our extensive cytokine gene polymorphisms effect on type 1 diabetes immunogenetics ( 44-46]we have shown clearly that a single nucleotide polymorphism (SNP) in the genetic of IL-4 gene, however, would contribute to the domination of T-h-1 cell to Th2 (IL-4) [46], lack of action of IL-4, the th2 cytokine initiator. Further, a Single Nucleotide Polymorphism (SNP) in the Transforming Growth Factor (TGF)-β gene ends up to lower production of TGF- β protein level. That may contribute to the lack of immunosuppressive effect of TGF- β in the patho‐ genesis of type 1 diabetes [47].
