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Title: Investigating the role of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) in Fcγ receptor signalling in myeloid cells
Author: Clarke, Fiona
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
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The C1858T single nucleotide polymorphism in the human protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene encodes an R620W missense mutation in PTPN22 (PTPN22R620W) and is associated with an increased susceptibility to multiple autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus and type 1 diabetes. PTPN22 is expressed in all immune cells and is a negative regulator of Src and spleen tyrosine kinase (Syk) family kinases downstream of multiple immunoreceptors including the T cell receptor, the B cell receptor, the αLβ2 integrin LFA-1, Toll-like receptors and dectin-1. As many of the autoimmune diseases associated with the polymorphism in PTPN22 have an autoantibody component to their pathology, the aim of this thesis was to identify whether PTPN22 regulates signalling downstream of Fc receptors. Fcγ receptors (FcγRs) recognise the Fc region of IgG autoantibodies when they bind to autoantigens and form immune complexes. After immune complex binding and receptor crosslinking, FcγRs signal via Src and Syk family kinases, known targets of PTPN22, leading to effector functions including antigen uptake, antigen presentation and cytokine secretion. Bone marrow derived dendritic cells (BMDCs) from wild type (WT) and Ptpn22-/- mice were pulsed with ovalbumin:anti-ovalbumin immune complexes (ova ICs). Co-culture with WT ova specific CD4+ T cells revealed that ova IC pulsed Ptpn22-/- BMDCs have an enhanced capability to induce T cell proliferation. PTPN22 was found to be dispensable for ova IC binding, internalisation and processing, but the enhanced T cell proliferation was associated with an increased capability of Ptpn22-/- BMDCs to present immune complex derived antigens and to form ova IC dependent BMDC-T cell conjugates. These findings highlight PTPN22 as a negative regulator of FcγR mediated responses and provide a link between the association of PTPN22R620W with autoantibody associated autoimmune diseases. Despite the requirement for PTPN22 in regulating T cell responses after ova IC stimulation, PTPN22 was not required for T cell responses after BMDCs were pulsed with OVA323-339 peptide or ova protein. To investigate the role of PTPN22 in autoimmunity in more detail, a mouse model of rheumatoid arthritis was utilised. Ptpn22-/- mice were found to develop more severe disease using the K/BxN serum transfer model. Despite this, WT and Ptpn22-/- arthritic mice displayed similar joint erosion and immune cell infiltration. In addition, PTPN22 was found to be dispensable for the in vitro differentiation and function of osteoclasts, the cells which are responsible for the bone erosion observed in arthritis.
Supervisor: Cope, Andrew Paul ; Guermonprez, Pierre Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available