Professor Hill Gaston

Research

I am interested in the pathogenesis of inflammatory arthritis with particular emphasis on HLA-B27 associated spondyloarthritis (SpA) and the role of T cells. As well as the association with HLA-B27, recent genetic evidence strongly implicates the Th17/IL-23 pathway in disease.Th17 cells are increased in SpA especially in affected joints. My lab previously shown high numbers of bacteria-specific T cells in reactive arthritis joints, but the bacterial epitopes recognized are not conserved in human proteins - i.e. molecular mimicry was not demonstrated. We pursued the idea that expression of B27 alters dendritic cell function, via ER stress pathways. We have shown that ER stress greatly favours IL-23 production over IL-12 in a mechanism depending on the transcription factor CHOP. B27 expression alone does not initiate ER stress but intracellular infection with SpA-associated bacteria does. In more recent work my lab investigated how signals from pathogens through PRRs interact with stress responses to affect cytokine production, particularly IL-23, but my last PhD student worked on TSLP and the factors influencing its production in response to mannans. We have characterized T cell subsets in blood, joints (and skin in patients with psoriasis and arthritis) in terms of surface phenotype and production of cytokines such as IL-17, IL-22, GM-CSF and IFNγ.

My current roles are principally with grant -giving bodies - Versus Arthritis (previously Arthritis Research UK), the Kennedy Trust for Rheumatology Research, Evelyn Trust - and I continue to review grants for major funders and manuscripts. I have also done some consultancy in relation to patents on biological therapies.

Publications

Key publications:

Goodall JC, Wu C, Zhang Y, Ellis L, O’Brien L, Saudek V, and Gaston JSH, ER stress signals are integrated by dendritic cells to enhance IL-23 responses to Toll-like receptor. PNAS (USA) 2010 107: (41) 17698–17703.

Kaur G, Goodall JC, Jarvis LB, Gaston JSH. Characterisation of Foxp3 Splice Variants in human CD4+ and CD8+ T cells - Identification of Foxp3Δ7 in human regulatory T cells. Molecular Immunology 2010 48:321–332

Soond DR, Bjorgo E, Moltu K, Dale VQ, Patton DT, Torgersen KM, Galleway F, Twomey B, Clark J, Gaston JSH, Tasken K, Bunyard, P, and Okkenberg K. PI3Kp110d regulates T cell cytokine production during primary and secondary immune responses in mice and humans. Blood 2010 115:2203–2213

Jarvis LB, Goodall JC, Gaston JSH. Human leukocyte antigen class I-restricted immunosuppression by human CD8+ regulatory T cells requires CTLA-4 mediated interaction with dendritic cells. Human Immunology 2008 69:687–695

Robinson PC, Costello ME, Leo P, Bradbury LA, Hollis K, Cortes A, et al. ERAP2 is associated with ankylosing spondylitis in HLA-B27-positive and HLA-B27-negative patients. Ann Rheum Dis. 2015;74(8):1627-9 (2015)

Wu, C., Goodall, J.C., Busch, R., and Gaston, J.S.H. Relationship of CD146 expression to secretion of interleukin (IL)-17, IL-22 and interferon-γ by CD4+ T cells in patients with inflammatory arthritis. Clin Exp Immunol 179(3):378-91 (2015)

Elder, MJ, Webster, SJ, Williams, DL, Gaston, JSH and Goodall, JC. TSLP production by dendritic cells is modulated by IL-1ß and components of the endoplasmic reticulum stress response. Eur J Immunol 46(2):455-63. (2016)

Baraliakos X, Heldmann F, van den Bosch F, et al. Long-term efficiency of infliximab in patients with ankylosing spondylitis: real life data confirm the potential for dose reduction. RMD Open;2:e000272. doi:10.1136/rmdopen-2016-000272 (2016)

Prevosto C, Usmani MF, McDonald S, Gumienny AM, Key T, Goodman RS, et al. Allele-Independent Turnover of Human Leukocyte Antigen (HLA) Class Ia Molecules. PLoS One. 11(8):e0161011 (2016).

Webster SJ, Ellis L, O'Brien LM, Tyrrell B, Fitzmaurice TJ, Elder MJ, et al. IRE1alpha mediates PKR activation in response to Chlamydia trachomatis infection. Microbes Infect 18(7-8):472-83. (2016).

Gaston, J.S.H. Recent advances in understanding spondyloarthritis. F1000Res 6:304 (2017).

Gaston, J.S.H. and Jadon, D. R. Th17 cell responses in spondyloarthritis. Best Practice & Research Clinical Rheumatology. In press (2018).

Elder, M.J., Webster, S.J., Fitzmaurice,T.J. Aran S., Shaunak, D., Steinmetz, M., Chee, R., Mallat, Z., Cohen, E.S., Williams, D.L., Gaston, J.S.H., Goodall, J.C. Dendritic cell-derived TSLP negatively regulates HIF-1α and IL-1β during dectin-1 signalling, Frontiers in Immunology, section Molecular Innate Immunity on-line (2019).

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