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.
Highlights
Anti-neutrophil Cytoplasmic Autoantibody (ANCA) disease is multifactorial in origin, as with many autoimmune diseases, involving complex interactions of genetic polymorphisms, epigenetic changes and environmental influences [1,2,3,4,5]
The gain-of-function allelic variant has a single nucleotide polymorphism (SNP) changing a cytosine to a thymine (C1858T) which converts the codon from one coding for arginine (R) to one for tryptophan (W) (R620W), and this amino acid change confers a gain-of-function phenotype
Three (21%) were in the non-relapsing group while 11(79%) were in the relapsing-disease group. This is the first report of studies on the basal activity of the protein tyrosine phosphatase non-receptor 22 (PTPN22)-gain-of-function protein in non-stimulated leukocytes, immediately following blood draw
Summary
Anti-neutrophil Cytoplasmic Autoantibody (ANCA) disease is multifactorial in origin, as with many autoimmune diseases, involving complex interactions of genetic polymorphisms, epigenetic changes and environmental influences [1,2,3,4,5]. In 2004, a single nucleotide polymorphism (SNP) in the PTPN22 gene was identified that resulted in a protein modification, which disrupted the regulatory domain of the phosphatase conferring a gain-offunction phenotype [25,26] The following year this genetic variant was linked with proteinase 3(PR3)-ANCA disease in a cohort of patients from Germany [24] and in 2009 a similar association was made in a study of a cohort from Great Britain [27]. Binding of ANCA to its antigens stimulates cellular signal transduction pathways causing changes in gene transcription, cell activation status, and neutrophil degranulation [45,46,47,48,49]. It is the aberrant release of neutrophils’ noxious constituents that causes inflammation of vessel walls and injury of highly vascularized organs such as the kidney and lung [50,51,52,53]
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