Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.679782
Title: Studies of the protein tyrosine phosphatase PTPN22/Lyp in Ptpn22 deficient mice
Author: Sanchez-Blanco, Cristina
ISNI:       0000 0004 5372 0984
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2015
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Abstract:
An R620W polymorphism in the haematopoietic protein tyrosine phosphatase PTPN22 increases susceptibility to a number of autoimmune diseases, including rheumatoid arthritis. PTPN22 is a negative regulator of immune cell signalling and its role has been best characterised in T cell receptor (TCR) signal transduction. Functional studies in the mouse are needed to clarify the role of Ptpn22 function. In this PhD project, the Ptpn22 deficient mouse was investigated in the context of chronic inflammatory disease, by investigating its role in T cell activation and downstream effector pathways. Ptpn22-/- mice revealed a modest increase in severity of joint inflammation compared to Ptpn22+/+ and Ptpn22+/- mice in a collagen-induced arthritis (CIA) study. Increased proportions of IFN-γ+ CD4+ T cells, CD4+ effector/memory T cells (CD4+ CD44hi CD62Llo) and regulatory CD4+ T cells (CD4+ CD25+ Foxp3+) were observed in Ptpn22-/- mice compared to Ptpn22+/+ littermates in response to immunisation with type II chicken collagen in complete Freund’s adjuvant. This was accompanied by a decrease in the levels of chicken type II collagen specific IgG1:IgG2c, suggesting an enhanced polarisation to the Th1 lineage in the absence of Ptpn22. Ptpn22+/+ and Ptpn22-/- naïve CD4+ T cells polarise to a Th1 phenotype to a similar extent in vitro in the absence of antigen presentation. However, Ptpn22-/- bone marrow derived dendritic cells were found to polarise CD4+ T cells to a Th1 phenotype in in vitro DC: T cell co-culture experiments utilising transgenic OT-II CD4+ T cells. Ptpn22-/- mice developed more severe inflammatory arthritis than Ptpn22+/+ mice in the K/BxN serum transfer arthritis model. The data presented in this thesis describe a negative regulatory role for Ptpn22 in Th1 differentiation in the CIA model resulting in exacerbated inflammatory arthritis in the Ptpn22 deficient mouse. Evidence suggests a T cell extrinsic influence of Ptpn22 deficiency on the antigen presenting cell in promoting pathways of Th1 differentiation. Furthermore, preliminary findings suggest a role for Ptpn22 in the regulation of IgG1 mediated downstream effector pathways. These results highlight a role for Ptpn22 in negatively regulating multiple pathways in the innate and adaptive immune response, alterations in which could ultimately result in autoimmunity.
Supervisor: Cope, Andrew Paul Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.679782  DOI: Not available
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