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Rebecca J Brownlie, Rose Zamoyska, Robert J Salmond
A number of polymorphisms in immune-regulatory genes have been identified as risk factors for the development of autoimmune disease. PTPN22, that encodes a tyrosine phosphatase, has been associated with the development of several autoimmune diseases including type 1 diabetes, rheumatoid arthritis and systemic lupus erythematosus. PTPN22 regulates the activity and effector functions of multiple important immune cell types including lymphocytes, granulocytes and myeloid cells. In this review, we describe the role of PTPN22 in regulating T cell activation and effector responses...
March 7, 2018: Immunology
Robert C Sharp, Shazia A Beg, Saleh A Naser
AIM: To establish the relationship of protein tyrosine phosphatase non-receptor type 2 and 22 ( PTPN2/22 ) polymorphisms and mycobacterial infections in Crohn's disease (CD). METHODS: All 133 subjects' blood samples were genotyped for nine single nucleotide polymorphisms (SNPs) in PTPN2/22 using TaqMan™ genotyping, while the effect of the SNPs on PTPN2/22 and IFN- γ gene expression was determined using RT-PCR. Detection of Mycobacterium avium subspecies paratuberculosis (MAP) IS900 gene was done by nPCR after DNA extraction from the isolated leukocytes of each subjects' blood samples...
February 14, 2018: World Journal of Gastroenterology: WJG
Robert C Sharp, Shazia A Beg, Saleh A Naser
A shared genetic pre-disposition, chronic inflammation, and treatment with similar biologics between Rheumatoid arthritis (RA) and Crohn's disease (CD) have intrigued us to investigate whether the two disorders share trigger association or possible causation. We hypothesized earlier that Single Nucleotide Polymorphisms (SNPs) in the negative regulators Protein Tyrosine Phosphatase Non-receptor type 2 and 22 (PTPN2/22) lead to a dysregulated immune response, susceptibility to environmental triggers, and continued apoptosis as seen in chronic inflammation in RA and CD...
2018: Frontiers in Cellular and Infection Microbiology
Juliane Houcken, Christina Degenhart, Klaus Bender, Jochem König, Lara Frommer, George J Kahaly
Context: Single nucleotide polymorphisms (SNP) of various genes increase susceptibility to monoglandular autoimmunity. Scarce data are available in autoimmune polyglandular syndromes (APS). Objective: Evaluate potential associations of eight SNP with APS. Setting: Academic referral endocrine clinic. Patients: A total of 543 patients with APS, monoglandular autoimmunity and controls. Intervention: The SNP protein tyrosine phosphatase non-receptor type 22 (PTPN22) rs2476601 (+1858), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) rs3087243 (CT60) and rs231775 (AG49), Vitamin D Receptor (VDR) rs1544410 (Bsm I), rs7975232 (Apa I), rs731236 (Taq I), tumor necrosis factor alpha rs1800630 (-863) and Interleukin-2 receptor alpha rs10795791 were tested by single base extension in all subjects...
February 1, 2018: Journal of Clinical Endocrinology and Metabolism
Karine Chemin, Daniel Ramsköld, Lina-Marcela Diaz-Gallo, Jessica Herrath, Miranda Houtman, Karolina Tandre, Lars Rönnblom, Anca Catrina, Vivianne Malmström
The presence of the PTPN22 risk allele (1858T) is associated with several autoimmune diseases including rheumatoid arthritis (RA). Despite a number of studies exploring the function of PTPN22 in T cells, the exact impact of the PTPN22 risk allele on T-cell function in humans is still unclear. In this study, using RNA sequencing, we show that, upon TCR-activation, naïve human CD4+ T cells homozygous for the PTPN22 risk allele overexpress a set of genes including CFLAR and 4-1BB, which are important for cytotoxic T-cell differentiation...
January 31, 2018: European Journal of Immunology
Ghaleb Bin Huraib, Fahad Al Harthi, Misbahul Arfin, Sadaf Rizvi, Abdulrahaman Al-Asmari
Background: Psoriasis is a complex autoimmune disease caused by the interaction of genetic and environmental factors. PTPN22 gene polymorphism has been reported to affect psoriasis susceptibility; however, no data are available for Middle Eastern populations. Objective: The aim of this study was to investigate the association of PTPN22 (1858C/T) R620W polymorphism with psoriasis in a Saudi cohort. Methods: Saudi subjects (n = 306) including patients with psoriasis (n = 106) and matched controls (n = 200) were studied for PTPN22 variants using tetra-primer amplification refractory mutation system-polymerase chain reaction method...
2018: Clinical Medicine Insights. Arthritis and Musculoskeletal Disorders
Alicia M Wallis, Gail A Bishop
This brief review presents current understanding of how the signaling adapter protein TRAF3 can both induce and block inhibitory signaling pathways in B and T lymphocytes, via association with kinases and phosphatases, and subsequent regulation of their localization within the cell. In B lymphocytes, signaling through the interleukin 6 receptor (IL-6R) induces association of TRAF3 with IL-6R-associated JAK1, to which TRAF3 recruits the phosphatase PTPN22 (protein tyrosine phosphatase number 22) to dephosphorylate JAK1 and STAT3, inhibiting IL-6R signaling...
January 17, 2018: Journal of Leukocyte Biology
Sanjeev Kumar Shukla, Govind Singh, Shahzad Ahmad, Prabhat Pant
In Autoimmune disease a combination of infection, genetic and environmental factors causes an autoimmune response to the thyroid gland (characterized by lymphocytic infiltrations), thyroid stimulating hormone receptor (TSHR) and different thyroid antigens. Graves' and Hashimoto disease are autoimmune disorders with genetic predisposition. CD40 that stimulates the proliferation and differentiation of lymphocytes is an essential immunomodulatory component for follicular cells in the thyroid and the cell that present the antigen...
January 8, 2018: Microbial Pathogenesis
Ashok Sharma, Xiang Liu, David Hadley, William Hagopian, Wei-Min Chen, Suna Onengut-Gumuscu, Carina Törn, Andrea K Steck, Brigitte I Frohnert, Marian Rewers, Anette-G Ziegler, Åke Lernmark, Jorma Toppari, Jeffrey P Krischer, Beena Akolkar, Stephen S Rich, Jin-Xiong She
Traditional linkage analysis and genome-wide association studies have identified HLA and a number of non-HLA genes as genetic factors for islet autoimmunity (IA) and type 1 diabetes (T1D). However, the relative risk associated with previously identified non-HLA genes is usually very small as measured in cases/controls from mixed populations. Genetic associations for IA and T1D may be more accurately assessed in prospective cohorts. In this study, 5806 subjects from the TEDDY (The Environmental Determinants of Diabetes in the Young) study, an international prospective cohort study, were genotyped for 176,586 SNPs on the ImmunoChip...
January 5, 2018: Journal of Autoimmunity
Bahadır Batar, Sezen Özman, Kenan Barut, Özgür Kasapçopur, Mehmet Güven
Background/aim: Juvenile idiopathic arthritis (JIA) is a chronic complex autoimmune disease. Genetic and environmental factors increase the risk of JIA. It is accepted that alterations in immune system pathways play an important role in the pathogenesis of JIA. The aim of the study was to investigate the possible association between immune system regulatory gene polymorphisms and JIA in Turkish patients. Materials and methods: We analyzed eight polymorphisms, TNF-alpha-863 C > A, TNFRII 196 T > G, IL2-631 G > A, IL13-1112 C > T, CCR2 190 G > A, CCR5delta32, CTLA4-1661 A > G, and PTPN22 1858 C > T, in 76 patients with JIA and in 80 healthy controls, who were of a similar age and same sex...
December 19, 2017: Turkish Journal of Medical Sciences
Amy G Clark, Elizabeth S Buckley, Mary H Foster
Systemic lupus erythematosus is a debilitating autoimmune disease in which autoantibodies and autoreactive T cells destroy kidneys and other organs. Disease is clinically and genetically heterogeneous, suggesting that underlying mechanisms vary between patients. We previously used an autoantibody transgenic mouse reporter system to examine the effect of different autoimmune backgrounds on B-cell tolerance, failure of which is a fundamental defect in lupus. We identified a defect consistent with reversible anergy induced by endotoxin stimulation of B cells from Ig transgenic New Zealand Black (NZB) mice...
December 18, 2017: European Journal of Immunology
Manoj B Parmar, Daniel Nisakar Meenakshi Sundaram, Remant Bahadur K C, Robert Maranchuk, Hamidreza Montazeri Aliabadi, Judith C Hugh, Raimar Löbenberg, Hasan Uludağ
Triple-negative breast cancer is an aggressive form of breast cancer with few therapeutic options if it recurs after adjuvant chemotherapy. RNA interference could be an alternative therapy for metastatic breast cancer, where small interfering RNA (siRNA) can silence the expression of aberrant genes critical for growth and migration of malignant cells. Here, we formulated a siRNA delivery system using lipid-substituted polyethylenimine (PEI) and hyaluronic acid (HA), and characterized the size, ζ-potential and cellular uptake of the nanoparticulate delivery system...
January 15, 2018: Acta Biomaterialia
Yasser A Soliman, Nashwa I Hashaad, Sherin M Emam, Rehab R Mohamed
Juvenile idiopathic arthritis (JIA) the most common chronic arthropathy of childhood is a diverse group of chronic arthritis diseases. The protein tyrosine phosphatase N22 (PTPN22) gene exhibits regulatory activities for both T and B cells. This study aimed to study PTPN gene polymorphism in JIA. The study included 60 children with JIA and 40 age and sex matched healthy children as controls. Patients and control groups were subjected to PTPN gene polymorphism analysis. Our findings indicated a significant difference in PTPN22 polymorphism between JIA patients and the control group (P = 0...
January 2017: Egyptian Journal of Immunology
Rebecca J Brownlie, Celine Garcia, Mate Ravasz, Dietmar Zehn, Robert J Salmond, Rose Zamoyska
Transforming growth factor β (TGFβ) is important in maintaining self-tolerance and inhibits T cell reactivity. We show that CD8+ T cells that lack the tyrosine phosphatase Ptpn22, a major predisposing gene for autoimmune disease, are resistant to the suppressive effects of TGFβ. Resistance to TGFβ suppression, while disadvantageous in autoimmunity, helps Ptpn22-/- T cells to be intrinsically superior at clearing established tumors that secrete TGFβ. Mechanistically, loss of Ptpn22 increases the capacity of T cells to produce IL-2, which overcomes TGFβ-mediated suppression...
November 7, 2017: Nature Communications
R Engelmann, A Biemelt, A Johl, D Kuthning, B Müller-Hilke
Attenuated T cell receptor (TCR) signalling contributes to the susceptibility for autoimmunity as shown via mutants of PTPN22 and Zap70 genes. We here set out to investigate the effect of an attenuated TCR signal on the composition of the thymic epithelial cell (TEC) compartment. To that extent, we combined flow cytometry and histology and compared the TEC subpopulations of Zap70 wild type with SKG mutant mice. We found an increased cortical TEC compartment in SKG thymi at the expense of reduced numbers of mature medullary TECs and a 4...
January 2018: Scandinavian Journal of Immunology
G Ahmadov
The PTPN22 gene was studied in 160 children with type 1 diabetes mellitus under the age of 18 years and in 271 healthy children. Of the 160 patients, 50.6% (n=81) were boys, 49.4% (n=79) were girls. The average age of diabetic children was 9.1 years. The survey was conducted on the basis of the Children's Clinical Hospital No. 6 in Baku city. For all patients, a special questionnaire was filled out. Only children of Azerbaijani nationality were included in the study. As a comparison group, 271 students of the Medical College No...
October 2017: Georgian Medical News
Fiona Clarke, Christine K Jordan, Enrique Gutiérrez-Martinez, Jack A Bibby, Cristina Sanchez-Blanco, Georgina H Cornish, Xuezhi Dai, David J Rawlings, Rose Zamoyska, Pierre Guermonprez, Andrew P Cope, Harriet A Purvis
The PTPN22R620W single nucleotide polymorphism increases the risk of developing multiple autoimmune diseases including type 1 diabetes, rheumatoid arthritis and lupus. PTPN22 is highly expressed in antigen presenting cells (APCs) where the expression of the murine disease associated variant orthologue (Ptpn22R619W) is reported to dysregulate pattern recognition receptor signalling in dendritic cells (DCs) and promote T-cell proliferation. Because T-cell activation is dependent on DC antigen uptake, degradation and presentation, we analysed the efficiency of these functions in splenic and GM-CSF bone marrow derived DC from wild type (WT), Ptpn22-/- or Ptpn22R619W mutant mice...
2017: PloS One
Xian-Hua Wang, Ai-Guo Ma, Xiu-Xia Han, Lei Chen, Hui Liang, Aishan-Litifu, Abudumijit-Ablez, Feng Xue
AIMS: To investigate the association of several single nucleotide polymorphisms (SNPs) within Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene and additional gene- gene and gene- type 2 diabetes mellitus (T2DM) interaction with pulmonary tuberculosis (PTB) risk in Chinese Uygur population. METHODS: A total of 722 participants (186 males, 536 females) were selected, including 360 PTB patients and 362 control participants. Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combination among SNPs and T2DM...
September 12, 2017: Oncotarget
Suelen Cristina de Lima, José Eduardo Adelino, Sergio Crovella, Jaqueline de Azevedo Silva, Paula Sandrin-Garcia
Studies performed in the past years showed PTNP22 1858 C > T (rs2476601) polymorphism as associated with systemic lupus erythematosus susceptibility, although conflicting findings are still found. In this context, a powerful statistical study, such as meta-analysis, is necessary to establish a consensus. The aim of this study was to evaluate association studies between the PTPN22 1858 C > T polymorphism and SLE by a meta-analysis update, including three recently published studies in the last three years...
October 8, 2017: Autoimmunity
Baoyu Duan, Dan Ye, Songcheng Zhu, Wenwen Jia, Chenqi Lu, Guiying Wang, Xudong Guo, Yangyang Yu, Chuanyue Wu, Jiuhong Kang
Angiogenesis is crucially involved in many physiological and pathological processes including tumor growth, but the molecular mechanisms regulating angiogenesis are incompletely understood. In this study, we investigated the functions and mechanism of histone deacetylase 10 (HDAC10), a member of the HDAC II family, in regulation of angiogenesis. HDAC10 overexpression in human umbilical vein endothelial cells (HUVECs) promoted tube formation, whereas depletion of HDAC10 from HUVECs inhibited tube formation in vitro and in vivo...
September 22, 2017: Oncotarget
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