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学科主题: 临床医学
题名:
High Basal Activity of the PTPN22 Gain-of-Function Variant Blunts Leukocyte Responsiveness Negatively Affecting IL-10 Production in ANCA Vasculitis
作者: Cao, Yali1; Yang, Jiajin1; Colby, Kerry1; Hogan, Susan L.1; Hu, Yichun1; Jennette, Caroline E.1; Berg, Elisabeth A.1; Zhang, Youkang3; Jennette, J. Charles1,2; Falk, Ronald J.1,2; Preston, Gloria A.1,2
刊名: PLOS ONE
发表日期: 2012-08-03
DOI: 10.1371/journal.pone.0042783
卷: 7, 期:8
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Multidisciplinary Sciences
研究领域[WOS]: Science & Technology - Other Topics
关键词[WOS]: PROTEIN-TYROSINE-PHOSPHATASE ; ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODY ; SINGLE-NUCLEOTIDE POLYMORPHISM ; SMALL-VESSEL VASCULITIS ; SYSTEMIC-LUPUS-ERYTHEMATOSUS ; SRC FAMILY KINASES ; WEGENERS-GRANULOMATOSIS ; RHEUMATOID-ARTHRITIS ; GENETIC ASSOCIATION ; HUMAN NEUTROPHILS
英文摘要:

Consequences of expression of the protein tyrosine phosphatase nonreceptor 22 (PTPN22) gain-of-function variant were evaluated in leukocytes from patients with anti-neutrophil cytoplasmic autoantibody (ANCA) disease. The frequency of the gain-of-function allele within the Caucasian patient cohort was 22% (OR 1.45), compared to general American Caucasian population (16.5%, p = 0.03). Examination of the basal phosphatase activity of PTPN22 gain-of-function protein indicated persistently elevated activity in un-stimulated peripheral leukocytes, while basal activity was undetectable in leukocytes from patients without the gain-of-function variant. To examine consequences of persistently high PTPN22 activity, the activation status of ERK and p38 MAPK were analyzed. While moderate levels of activated ERK were observed in controls, it was undetectable in leukocytes expressing PTPN22 gain-of-function protein and instead p38MAPK was up-regulated. IL-10 transcription, reliant on the ERK pathway, was negatively affected. Over the course of disease, patients expressing variant PTPN22 did not show a spike in IL-10 transcription as they entered remission in contrast to controls, implying that environmentally triggered signals were blunted. Sustained activity of PTPN22, due to the gain-of-function mutation, acts as a dominant negative regulator of ERK activity leading to blunted cellular responsiveness to environmental stimuli and expression of protective cytokines.

语种: 英语
所属项目编号: 2PO1DK 58335
项目资助者: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/National Institutes of Health (NIH) ; China Scholarship Council
WOS记录号: WOS:000307284100171
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/54213
Appears in Collections:北京大学第一临床医学院_肾脏内科_期刊论文

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作者单位: 1.Univ N Carolina, Dept Med, Div Nephrol & Hypertens, UNC Kidney Ctr, Chapel Hill, NC USA
2.Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC USA
3.Peking Univ, Dept Med, Inst Nephrol, Hosp 1, Beijing 100871, Peoples R China

Recommended Citation:
Cao, Yali,Yang, Jiajin,Colby, Kerry,et al. High Basal Activity of the PTPN22 Gain-of-Function Variant Blunts Leukocyte Responsiveness Negatively Affecting IL-10 Production in ANCA Vasculitis[J]. PLOS ONE,2012,7(8).
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