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Deciphering the link between PTPN22 and autoimmunity

Gautam, Pratigya 2011. Deciphering the link between PTPN22 and autoimmunity. PhD Thesis, Cardiff University.

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Abstract

Recent genetic studies have linked a C to T single nucleotide polymorphism (SNP) in the protein tyrosine phosphatase (PTP) non-receptor type 22 (PTPN22) to several autoimmune diseases (ADs). This changes amino acid at position 620 from an Arginine (R) to a Tryptophan (W) in the protein, Lyp. Lyp is thought to be a negatively regulator of TCR signalling by dephosphorylating Src family kinases Lck and Fyn, and Zap70. However, the cellular and molecular mechanisms of predisposition to ADs by the R620W polymorphism are not yet understood. Several studies have reported the R620W polymorphism as a “gain of function” change resulting in an increase in the PTP activity of Lyp. It has been further hypothesised that the W620 isoform suppresses TCR signalling more potently than the R620 isoform, resulting in the survival of auto-reactive cells that would normally be deleted by negative selection in the thymus. Alternatively, the impact of Lyp W620 on TCR signalling may have an effect on the development and functioning of T regulatory cells. To investigate the effect of the R620W polymorphism in T cells, lentivirus plasmids expressing the R and W isoforms of Lyp were generated and used to introduce the Lyp and wLyp isoforms in leukaemic T cells thereby generating H9 and E6.1 cell lines over- R W expressing the Lyp and Lyp isoforms. Investigation of activation marker expression and cytokine production by these T cell lines post activation showed no differences in CD69 activation marker expression between the RLyp and wLyp expressing T cells or between the R/wLyp expressing and control cells (not expressing exogenous Lyp). However, there was a trend towards a reduction in IL-2 production observed by R/WLyp expressing H9 T cells compared to control cells. In addition, a significant reduction in IL-10 production by R/wLyp expressing H9 T cells compared to control cells was observed. This effect of Lyp on IL-10 production suggests a potential mechanism by which wLyp, if indeed a more active PTP, may predispose to ADs.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
ISBN: 9781303196607
Date of First Compliant Deposit: 30 March 2016
Last Modified: 19 Mar 2016 23:30
URI: http://orca.cardiff.ac.uk/id/eprint/54471

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