Project ID CM-HD2024_67


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Basic & Medical Biosciences, Department of Medical & Molecular GeneticsWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Basic & Medical Biosciences, Department of Medical & Molecular GeneticsWebsite

Additional Supervisor Prof J Kennedy Cruickshank, Andrew Webb

Autoimmune Biomarkers: linking pathological mechanism for OX40-OX40L to cellular targeting for therapy

Scientific basis
Systemic Lupus Erythematosus is a chronic, multi-system autoimmune disease, with increased disease severity in non-European ancestries and more females than males with lupus. The relapsing-remitting disease course makes it challenging to treat successfully.

We have a long-standing interest in two TNF superfamily genes, (OX40 and OX40L), as independent risk factors for SLE, as membrane-bound (mOX40) and serum (sOX40) proteins. The mechanism of production for sOX40 is unknown, but may involve alternative-splicing or cleavage by metalloproteinases (MMP). A co-stimulatory immune signal produced when OX40 binds to its unique receptor, OX40L, is an important regulatory factor for SLE (a disease of increased immune activity). We have both genetic associations and functional data to drive our interest in OX40.

1) Investigate how genetic variation at OX40 impacts production of sOX40
2) Infer the cellular source of sOX40
3) Ascertain whether levels of sOX40 in human T-cells are correlated with increased expression of specific OX40 transcript isoforms or MMP transcripts
4) Establish whether increased sOX40 is correlated with specific OX40 transcript isoforms or whether production of sOX40 is prevented by MMP-blocking agents in cultured T-cells.

Techniques and skills
Multi-omic analysis of GWAS and scRNA-Seq datasets; multi-analyte immunoassay (MSD), multi-parameter flow cytometry (Cytek Aurora), cell culture, bioinformatics

Objectives for each year
Year 1: Measure sOX40 by multi-analyte immunoassays, in SLE patients and healthy controls selected on the basis of OX40 genotype. In accompanying scRNA-Seq data discover whether specific OX40 transcript isoforms or MMP transcripts are correlated with high levels of sOX40.

Year 2: Determine the OX40+ cell-type correlated with the highest serum level of OX40 using flow cytometry in SLE T-cells and healthy controls.

Year 3: Establish whether activation of Jurkat T-cells changes the proportion of OX40 transcript isoforms or whether production of OX40 is reduced using MMP-blocking agents.

Representative Publications

Roberts AL, Morea A, Amar A, Zito A, El-Sayed Moustafa JS, Tomlinson M, Bowyer RCE, Zhang X, Christiansen C, Costeira R, Steves CJ, Mangino M, Bell JT, Wong CCY, Vyse TJ, Small KS. Age acquired skewed X chromosome inactivation is associated with adverse health outcomes in humans (2022). Elife 11: e78263. Gajdasik DW, Gaspal F, Halford EE, Fiancette R, Dutton EE, Willis C, Rückert T, Romagnani C, Gerard A, Bevington SL, MacDonald AS, Botto M, Vyse T & Withers DR. Th1 responses in vivo require cell-specific provision of OX40L dictated by environmental cues (2020). Nat. Commun. 11(1): 3421 Manku H, Langefeld CD, Guerra SG, Malik TH, Alarcon-Riquelme M, Anaya JM, Bae SC, Boackle SA, Brown EE, Criswell LA, Freedman BI, Gaffney PM, Gregersen PA, Guthridge JM, Han SH, Harley JB, Jacob CO, James JA, Kamen DL, Kaufman KM, Kelly JA, Martin J, Merrill JT, Moser KL, Niewold TB, Park SY, Pons-Estel BA, Sawalha AH, Scofield RH, Shen N, Stevens AM, Sun C, Gilkeson GS, Edberg JC, Kimberly RP, Nath SK, Tsao BP, Vyse TJ. Trans-ancestral studies fine map the SLE-susceptibility locus TNFSF4. (2013). PLoS Genet. 9(7): e1003554.
Cunninghame Graham DS, Graham RR, Manku H, Wong AK, Whittaker JC, Gaffney PM, Moser KL, Rioux JD, Altshuler D, Behrens TW and Vyse TJ. Polymorphism at the TNF Superfamily Gene OX40L Confers Susceptibility Lupus Erythematosus. (2008). Nat. Genet. 40(1) 83-89. Cortini A, Ellinghaus U, Malik T, Cunninghame Graham DS, Botto M, Vyse, TJ B-cell OX40L supports T Follicular Helper Cell Development and Contributes to SLE Pathogenesis. (2017). Anal. Rheum Dis. 76(12): 2095-2103. Odhams CA, Cortini A, Chen L, Roberts AL, Vinuela A, Buil A, Small KS, Dermitzakis ET, Morris DL, Vyse TJ. and Cunninghame Graham DS. Mapping eQTLs with RNA-seq reveals novel susceptibility genes, non-coding RNAs and alternative-splicing events in systemic lupus erythematosus. (2017). Hum Mol Genet 26, 1003-1017.