Altered leukocyte signalling thresholds in rheumatoid arthritis through changes in the function of the protein tyrosine phosphatase PTPN22/LYP

Bayley, Rachel (2014). Altered leukocyte signalling thresholds in rheumatoid arthritis through changes in the function of the protein tyrosine phosphatase PTPN22/LYP. University of Birmingham. Ph.D.

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Abstract

Rheumatoid arthritis (RA) results from complex interactions between genetic and environmental risk factors. Two examples of these are the genetic variant PTPN22 R620W, a disease-associated form of the protein tyrosine phosphatase (PTP) Lyp and cigarette smoking (CS). Epidemiological studies have identified interactions between R620W and CS, but the biological mechanisms behind these interactions are unclear. Lyp is expressed by all leukocytes and changes in leukocyte function are implicated in the pathogenesis of RA. Thus the aim of this study was to characterise the effects of R620W and CS on leukocyte signalling, to determine possible mechanisms by which these factors could interact to promote the development of RA.

An assay to measure the specific activity of the Lyp phosphatase was developed. Healthy controls and RA patients were recruited and genotyped for the PTPN22 R620W variant. Following determination of genotype, neutrophils and CD4+ T cells were isolated and cell function assessed following cigarette smoke extract (CSE) treatment.

R620W in T lymphocytes increased Lyp phosphatase activity, decreased Lyp substrate phosphorylation and increased production of the pro-inflammatory cytokines IFN-γ and TNF-α. CSE treatment decreased T cell receptor signalling which was characterised by decreased PTP activity, decreased calcium (Ca2+) flux and decreased cytokine production. R620W in neutrophils was associated with increased neutrophil activation and functions including Ca2+ flux, reactive oxygen species production and migration.

Overall these data suggest that R620W may facilitate RA development and persistence by promoting the generation of inflammatory T cells and by enhancing neutrophil activation and migration. CS may promote further signalling dysfunction by oxidising the proteins controlling leukocyte signalling. These separate pathways leading to altered Lyp function may act additively or synergistically to promote the immune disturbances which underpin the development of RA.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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