title: High basal activity of the PTPN22 gain-of-function variant blunts leukocyte responsiveness negatively affecting IL-10 production in ANCA vasculitis.
abstract: 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.
authors.affiliation: Division of Nephrology and Hypertension, UNC Kidney Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Yali
authors.initials: Y
authors.lastname: Cao
authors.forename: Jiajin
authors.initials: J
authors.lastname: Yang
authors.forename: Kerry
authors.initials: K
authors.lastname: Colby
authors.forename: Susan L
authors.initials: SL
authors.lastname: Hogan
authors.forename: Yichun
authors.initials: Y
authors.lastname: Hu
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Jennette
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Berg
authors.forename: Youkang
authors.initials: Y
authors.lastname: Zhang
authors.forename: J Charles
authors.initials: JC
authors.lastname: Jennette
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Falk
authors.forename: Gloria A
authors.initials: GA
authors.lastname: Preston
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology*; D019295:Computational Biology; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D007962:Leukocytes / Q000201:enzymology*; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D050505:Mutant Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics; D014657:Vasculitis / Q000201:enzymology* / Q000276:immunology*; D044465:White People / Q000235:genetics
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D050505:Mutant Proteins; D012333:RNA, Messenger; D016753:Interleukin-10; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22