TYPE 1 DIABETES MELLITUS (T1D) acco

TYPE 1 DIABETES MELLITUS (T1D) accounts for about 10-15 % of all cases of diabetes (1). T1D is a multifactorial disease where a genetic predisposition combines with environmental trigger(s) to induce the activation of a specific autoimmune destruction of pancreatic beta-cells (1-3).

Several loci, increasing the risk to develop T1D, have been identified (2-5). Among them, the human leukocyte antigen (HLA) locus is by far the most common predisposing polymorphism (2,4). Other well documented predisposing loci include the insulin locus, the cytotoxic T-lymphocyte antigen 4 (CTLA4) locus and the phosphatase non-receptor type 22 (PTPN22) locus (2,3). In addition, a recent genome wide association study of ~2000 T1D subjects suggested several new candidate loci, encoding for genes involved in immune signaling, such as the receptor tyrosine kinase ErbB3 (ERBB3), the SH2B adaptor protein 3 (SH2B3/LNK), the TRAF-type zinc finger domain containing 1 (TRAFD1) and the protein tyrosine phosphatase non-receptor type 11 (PTPN11) (4,5). Most of these genes are related to the immune system, and may predispose the individual to an exacerbated inflammatory and immune response to a given stimulus, potentially increasing the risk of autoimmunity. Others, such as the insulin locus and some tyrosine phosphatases, may affect beta-cell function and antigen presentation.

The HLA locus contains genes coding for the major histocompatibility complex (MHC) molecules (6). There are two types of MHC molecules: 1) MHC class I – which are expressed in almost every nucleated cell of the body and are involved in the presentation of intracellular antigens; 2) MHC class II – which are expressed at the surface of antigen presenting cells (APC) (i.e. dendritic cells, macrophages and lymphocytes-B) and involved in the presentation of extracellular antigens. MHC class II are present in three different forms: DR, DQ and DP which are composed of two chains (a and b) encoded by genes A and B. The genetic predisposition to T1D caused by the HLA locus is related to specific polymorphisms of the DQ and DR forms of the MHC class II molecules (1-3). Some specific combinations of alleles for the DQA1 and DQB1 genes, namely DQA1*0501-DQB1*0201, DQA1*0301-DQB1*0302 and alleles for the DRB1 gene namely DRB1*03 and DRB1*04, significantly increase the risk to develop T1D. Homozygosity for either of these risk haplotypes is identified in 30% of T1D patients but only in 3% of the general population (3). On the other hand, the haplotype DQA1*0102-DQB1*0602 is protective against T1D. The effect of the HLA locus on T1D risk is probably due to a non-optimal presentation of self-antigens to naïve lymphocytes during their maturation process in the thymus, leading to an inefficient deletion of auto-reactive lymphocytes. In line with this, transgenic expression of the MHC class II risk allele in mice sensitizes the immune system to beta-cell autoantigens, such as glutamic acid decarboxylase (GAD65) (7). The polymorphisms of the insulin locus that increase diabetes risk are characterized by variable numbers of tandem repeat (VNTR) regions ~365 bp upstream of the translational start site (3). The number of VNTRs (from 30 to 170 repeats) affects the level of expression of the insulin gene; low amounts of VNTRs (30 to 60 repeats) cause high expression in the pancreas and low expression in the thymus. Low expression of insulin in the thymus may lead to inefficient destruction of self-reactive T-cells during their maturation process (3). The other predisposition loci, PTPN22 and CTLA4, encode for negative regulators of lymphocyte activity. The PTPN22 locus encodes Lyp, a tyrosine phosphatase that inhibits antigen-specific T-cell activation by dephosphorylating key components of the T-cell receptor (TCR) signaling cascade (3). CTLA4 is a T-lymphocyte receptor which interacts with a ligand expressed at the surface of B-lymphocytes and dendritic cells, causing inhibition of T-lymphocyte activation (3). The polymorphisms for those loci associated with T1D are characterized by a loss of function leading to hyperactivity of T-lymphocytes.

ผลลัพธ์ (อังกฤษ) 2:

TYPE 1 DIABETES MELLITUS (T1D) accounts for about 10-15% of all cases of diabetes (1). T1D is a multifactorial disease where a Genetic predisposition combines with Environmental Trigger (s) to induce the Activation of a specific autoimmune Destruction of pancreatic beta-cells (1-3). Several loci, increasing the risk to Develop T1D, have been identified (. 2-5). Among them, the human leukocyte antigen (HLA) locus is by far the most common predisposing polymorphism (2,4). Other well documented predisposing loci include the insulin locus, the cytotoxic T-lymphocyte antigen 4 (CTLA4) locus and the phosphatase non-receptor type 22 (PTPN22) locus (2,3). In addition, a recent genome wide association study of ~ 2000 T1D subjects suggested several new candidate loci, encoding for genes involved in immune signaling, such as the receptor tyrosine kinase ErbB3 (ERBB3), the SH2B adaptor protein 3 (SH2B3 / LNK),. the TRAF-type zinc finger domain containing 1 (TRAFD1) and the protein tyrosine phosphatase non-receptor type 11 (PTPN11) (4,5). Most of these genes are related to the immune system, and may predispose the individual to an exacerbated inflammatory and immune response to a given stimulus, potentially increasing the risk of autoimmunity. Others, such as the insulin and Locus tyrosine phosphatases Some, May affect beta-Cell Antigen Presentation and function. The genes coding for HLA Locus contains the Major histocompatibility Complex (MHC) molecules (6). There are two types of MHC molecules: 1) MHC class I - which are expressed in almost every nucleated cell of the body and are involved in the presentation of intracellular antigens; 2) MHC class II - which are expressed at the surface of antigen presenting cells (APC) (ie dendritic cells, macrophages and lymphocytes-B) and involved in the presentation of extracellular antigens. MHC class II are present in three different forms: DR, DQ and DP which are composed of two chains (a and b) encoded by genes A and B. The genetic predisposition to T1D caused by the HLA locus is related to specific polymorphisms of the. DQ and DR forms of the MHC class II molecules (1-3). Some specific combinations of alleles for the DQA1 and DQB1 genes, namely DQA1 * 0501-DQB1 * 0201, DQA1 * 0301-DQB1 * 0302 and alleles for the DRB1 gene namely DRB1 * 03 and DRB1 * 04, significantly increase the risk to develop T1D. . Homozygosity for either of these risk haplotypes is identified in 30% of T1D patients but only in 3% of the general population (3). On the other hand, the haplotype DQA1 * 0102-DQB1 * 0602 is protective against T1D. The effect of the HLA locus on T1D risk is probably due to a non-optimal presentation of self-antigens to naïve lymphocytes during their maturation process in the thymus, leading to an inefficient deletion of auto-reactive lymphocytes. In line with this, transgenic expression of the MHC class II risk allele in mice sensitizes the immune system to beta-cell autoantigens, such as glutamic acid decarboxylase (GAD65) (7). The polymorphisms of the insulin locus that increase diabetes risk are characterized by variable numbers of tandem repeat (VNTR) regions ~ 365 bp upstream of the translational start site (3). The number of VNTRs (from 30 to 170 repeats) affects the level of expression of the insulin gene; low amounts of VNTRs (30 to 60 repeats) cause high expression in the pancreas and low expression in the thymus. Low expression of insulin in the thymus may lead to inefficient destruction of self-reactive T-cells during their maturation process (3). The other predisposition loci, PTPN22 and CTLA4, encode for negative regulators of lymphocyte activity. The PTPN22 locus encodes Lyp, a tyrosine phosphatase that inhibits antigen-specific T-cell activation by dephosphorylating key components of the T-cell receptor (TCR) signaling cascade (3). CTLA4 is a T-lymphocyte receptor which interacts with a ligand expressed at the surface of B-lymphocytes and dendritic cells, causing inhibition of T-lymphocyte activation (3). The polymorphisms for those loci associated with T1D are characterized by a loss of function leading to hyperactivity of T-lymphocytes.