Role of PTPN2 in rheumatoid arthritis

PTPN2在类风湿性关节炎中的作用

• 批准号: 10852548
• 负责人: Nunzio Bottini
• 金额: $ 55.64万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10852548
• 关键词: Affect; Applications Grants; Arthritis; Arthritogenic; Autoimmune Diseases; Autoimmunity; CD4 Positive T Lymphocytes; Cells; Chronic Childhood Arthritis; Colon; Complex; Cytokine Receptors; Data; Development; Disease; Environmental Risk Factor; Equilibrium; FOXP3 gene; Funding; Genes; Genetic; Genetic Risk; Goals; Grant; Heterozygote; Homozygote; Human; IL17 gene; Immune; Immunologic Deficiency Syndromes; Immunology; In Vitro; Inflammation; Inflammatory Bowel Diseases; Interleukin-6; Intestines; Investigation; Janus kinase; Joints; Knock-out; Knowledge; Knowledge acquisition; Maps; Modeling; Morbidity - disease rate; Mus; Myeloid Cells; Orphan; Pathogenesis; Pathogenicity; Patients; Peripheral; Phase; Phenotype; Phosphorylation; Physiology; Population; Predisposition; Process; Protein Dephosphorylation; Receptor Signaling; Regulatory T-Lymphocyte; Research; Rheumatoid Arthritis; Risk; Role; STAT protein; STAT3 gene; Severities; Signal Pathway; Signal Transduction; Sorting; Source; T-Cell Receptor; T-Lymphocyte; T-cell protein tyrosine phosphatase; Testing; Tissues; Variant; arthritis therapy; autoimmune arthritis; genetic manipulation; genetic variant; human disease; in vivo; loss of function; mouse model; novel; overexpression; personalized medicine; receptor; risk variant; src-Family Kinases

ABSTRACT The objective of this grant application is to understand how loss-of-function genetic variants of the PTPN2 gene -encoding the T cell-protein tyrosine phosphatase (TC-PTP)- enhance risk of rheumatoid arthritis (RA). PTPN2 is ubiquitous, and very highly expressed in immune cells and is a critical negative regulator of Janus kinases and signal transducers and activators of transcription downstream multiple cytokine receptors. In order to model the mechanism of action of PTPN2 autoimmunity-associated variants in RA, we assessed mice carrying Ptpn2 haploinsufficiency (Ptpn2+/- mice), which causes a loss of expression of PTPN2 comparable to the human PTPN2 RA-risk variants. We found that in the SKG RA model- characterized by CD4 T cell-driven disease- partial loss of function of PTPN2 caused significant enhancement of arthritis severity. By leveraging conditional Ptpn2 haploinsufficiency and fate-mapping mice, we showed that the phenotype of SKG.Ptpn2+/- mice is due to enhanced inflammation-induced FoxP3+ regulatory T cell (Treg) instability, a process known to lead to conversion of peripheral FoxP3+ Treg into pathogenic FoxP3- “exTreg” expressing interleukin-17 (IL-17). We have evidence that the enhanced conversion of Ptpn2+/- Tregs into IL-17-producing “exTreg” is due to increased STAT3 phosphorylation after stimulation with IL-6 and potentially other inflammation-induced factors. Here we apply for funding to further understand the mechanism of action of PTPN2 in Treg instability and the pathogenesis of RA via mouse immunology and cell signaling studies. In Aim 1 and 2 we will elucidate the mechanism and topology of enhanced inflammation-induced instability and pathogenicity of SKG.Ptpn2+/- Treg. In Aim 3 we will assess whether overexpression of PTPN2 in Treg can reverse the Treg and arthritis phenotype induced by Ptpn2+/- in SKG mice. Our long-term goal is to acquire knowledge of PTPN2 functional genetics to enable the discovery of personalized and non-immunosuppressive therapies for RA patients carrying genetic PTPN2 risk variants.

摘要

项目成果

T-helper cell regulation of CD45 phosphatase activity by galectin-1 and CD43 governs chronic lymphocytic leukaemia proliferation.

• DOI: 10.1111/bjh.18285
• 发表时间: 2022-08
• 期刊: BRITISH JOURNAL OF HAEMATOLOGY
• 影响因子: 6.5
• 作者: Imbery, John F.;Heinzelbecker, Julia;Jebsen, Jenny K.;McGowan, Marc;Myklebust, Camilla;Bottini, Nunzio;Stanford, Stephanie M.;Skanland, Sigrid S.;Tveita, Anders;Tjonnfjord, Geir E.;Munthe, Ludvig A.;Szodoray, Peter;Nakken, Britt
• 通讯作者: Nakken, Britt