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Biomarkers of Diabetes
Published in Awanish Kumar, Ashwini Kumar, Diabetes, 2020
Before moving on to the serum biomarkers for T1DM, we must mention briefly the genetic markers. Mutation and variation in HLA genotypes are widely associated with the risk of progression of T1DM. This high risk is attributed due to the fact that the HLA genes are highly responsible for T-cell selection, antigen presentation and T-cell activation. Among the HLA alleles, HLA DR and HLA DQ class II loci are most responsible for the T1DM risk. Among these, specifically, HLA DRB1*03, HLA DRB1*04 and HLA DQB1*0302 (HLA DR3/4 DQ8) impart the highest risk in the development and progression of T1DM. Apart from the HLA genotypes, two other genes, INS (the pro-insulin gene) and PTPN22 (protein tyrosine phosphatase N22), also significantly increase the risk of development of T1DM. A VNTR variant of INS, INS VNTR I, is shown to be responsible for increased T1DM risk while an increase in phosphatase activity of PTP is seen in T1DM patients [4].
Precision medicine in diabetes mellitus
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Sandhiya Selvarajan, Akila Srinivasan, Nishanthi Anandabaskar, Sadishkumar Kamalanathan, Melvin George
Apart from HLA, polymorphisms of insulin genes in chromosome 11 have also been found to confer genetic susceptibility to the development of type 1 diabetes mellitus (Ramos-Lopez et al., 2008). It is also found that polymorphisms in the CTLA4 (cytotoxic T-lymphocyte antigen-4) gene located in chromosome 2q33 are associated with increased risk of type 1 diabetes mellitus (Ueda et al., 2003). Another gene associated with increased risk of type 1 diabetes mellitus is the protein tyrosine phosphatase, a nonreceptor type 22 (PTPN22) gene on chromosome 1p13 that encodes for lymphoid-specific phosphatase (LYP), which prevents spontaneous T cell activation. Similarly polymorphism in the PTPN22 gene leads to development of type 1 diabetes mellitus (Steck et al., 2006). In addition, polymorphisms in IL2RA (CD25), which encodes for the subunit IL-2Rα of the interleukin-2 (IL-2) receptor complex is also implicated in the occurrence of type 1 diabetes mellitus (Vella et al., 2005). Knowledge of these genes and polymorphisms in the occurrence of type 1 diabetes mellitus would pave the way for the early identification of individuals with an increased risk of developing type 1 diabetes mellitus (i.e., even before metabolic derangement occurs). This may help in establishing measures to prevent the occurrence of type 1 diabetes mellitus.
The Use of Placenta-Derived Cells in Autoimmune Disorders
Published in Ornella Parolini, Antonietta Silini, Placenta, 2016
Antonietta R. Silini, Ornella Parolini, Mario Delgado
Most autoimmune diseases are multigenic, whereby multiple susceptibility genes work together to produce an abnormal phenotype. In 2000, the type I diabetes locus was mapped in the major histocompatibility complex (MHC) to a 570-kilobase region (Herr et al. 2000), and other groups identified sequence variants in the NOD2 (CARD15) gene (Hugot et al. 2001) or variations in the 5q31 cytokine gene cluster (Rioux et al. 2001), which are associated with increased susceptibility to Crohn’s disease. Other larger studies have identified the IDDM12/CTLA4 locus in Graves’ disease (Hampe et al. 2001; Ogura et al. 2001); the PTPN22 gene in type I diabetes, rheumatoid arthritis, and SLE (Begovich et al. 2004; Kyogoku et al. 2004; Onengut-Gumuscu et al. 2004; Smyth et al. 2004); and the PDCD1 gene in SLE and rheumatoid arthritis (RA) (Lin et al. 2004; Prokunina et al. 2002). The observation that genes such as PTPN22 are common to different autoimmune diseases supports the hypothesis that some immunological pathways are common to multiple disorders, whereas other pathophysiological mechanisms are disease-specific.
PTPN22: structure, function, and developments in inhibitor discovery with applications for immunotherapy
Published in Expert Opinion on Drug Discovery, 2022
Brenson A. Jassim, Jianping Lin, Zhong-Yin Zhang
PTPN22 is a key desensitization node in T cell signaling and immune response with multiple validated substrates and several putative ones. While there is still debate concerning the exact role of the R620W variant in autoimmunity, numerous studies have shown this mutation is beneficial in an oncology context. Global PTPN22 deletion enhances anti-tumor immunity and the response of effector T cells to antigens. PTPN22 deficiency/R620W variant enhances efficacy of both adoptive cell transfer and immune checkpoint inhibition therapies. PTPN22 targeting offers a systemic and validated approach for novel immunotherapies and combination strategies. Furthermore, correlation of the autoimmune-associated variant with diminished risk of cancer and more efficacious CPI response suggests PTPN22 may offer a valuable biomarker for immunotherapy response and precision oncology. Several small molecule PTPN22 inhibitors exist, with varying degrees of biological characterization for each. Strategies for their discovery include fragment and structure-based design, ligand-based design, virtual screening via docking and/or pharmacophore modeling, and high-throughput screening.
The Relationship between PTPN22 R620W Polymorphisms and the Susceptibility to Autoimmune Thyroid Diseases: An Updated Meta-analysis
Published in Immunological Investigations, 2022
Huaiyong Wu, Siyuan Wan, Mengying Qu, Bingxuan Ren, Lixiang Liu, Hongmei Shen
It has been demonstrated that iodine is an environmental factor for AITD (Shen 2005), and the associated genetic interactions are highly complex, of which PTPN22 may be associated with AITD. PTPN22 has been shown to play an important role in the negative regulation of T lymphocyte activation and development. PTPN22 primarily encodes lymphoid protein tyrosine phosphatase (LYP) and participates in the dephosphorylation and activation of T cell receptor (TCR)-related kinases and their substrates (Ghorban et al. 2019). A large amount of genetic and immunological evidence has demonstrated that PTPN22 is associated with a variety of autoimmune diseases, among which the R620W (rs2476601) polymorphism in PTPN22 has strong consistency with autoimmune diseases (Cambier 2013; Fousteri et al. 2013).
Single Nucleotide Polymorphisms of PTPN22 Gene in Iranian Patients with Ulcerative Colitis
Published in Fetal and Pediatric Pathology, 2019
Maryam Sadr, Bobak Moazzami, Narjes Soleimanifar, Nazanin Elhamian, Arezoo Rezaei, Nasser Ebrahimi Daryani, Nima Rezaei
PTPN22 gene also known as lymphocyte tyrosine phosphatase and PTPN8, encodes a member of the non-receptor class 4 subfamily of the protein-tyrosine phosphatase family [8]. The encoded protein is a lymphoid-specific intracellular phosphatase that is associated with the molecular adapter protein Casitas B-lineage Lymphoma (CBL) and may be involved in regulating CBL function in the T-cell receptor signaling pathway [9]. Recently, variants of the PTPN22 gene have been associated with several autoimmune diseases such as Type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, and Graves' disease [10,11]. Given the suspected autoimmune nature of IBD, in the present study we examined five polymorphisms of PTPN22 gene that may play important roles in the signaling pathways of T cells.