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NCKIR6: Ultra-high throughput analysis of immunoglobulin repertoires in health and autoimmune disease.


   Kennedy Institute of Rheumatology

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  Prof L Dustin, Prof John Frater  No more applications being accepted  Funded PhD Project (Students Worldwide)

Oxford United Kingdom Bioinformatics Immunology

About the Project

Rheumatic autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, and Sjögren’s syndrome are associated production of specific autoantibodies. The reasons for failure of immune tolerance to a finite number of autoantigens are poorly understood. Using a bespoke microfluidics platform, the supervisors have developed a workflow to sequence paired immunoglobulin heavy and light chain genes for hundreds of thousands to millions of B cells in a single blood sample. The student will use this platform to characterise the full immunoglobulin repertoire of naïve, activated, and antibody-secreting B cell subsets in the peripheral blood in samples from patients with autoimmune disease, compared to the same B cell subsets in healthy donors. This work will lead to a valuable atlas of immunoglobulin repertoire breadth at different stages of the B cell lifespan and will help to identify the points at which self-tolerance may fail in autoimmune disease.

TRAINING OPPORTUNITIES:

microfluidics, flow cytometry, fluorescence-activated cell sorting, bioinformatics, molecular biology


References

KEY PUBLICATIONS (5 maximum):
1. Martin GE…. Frater J. Epigenetic Features of HIV-Induced T-Cell Exhaustion Persist Despite Early Antiretroviral Therapy. Front Immunol. 2021 Jun 4;12:647688. doi: 10.3389/fimmu.2021.647688. PMID: 34149690; PMCID: PMC8213372.
2. Frater J, …. Oxford COVID Vaccine Trial Group. Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 in HIV infection: a single-arm substudy of a phase 2/3 clinical trial. Lancet HIV. 2021 Jun 18:S2352-3018(21)00103-X. doi: 10.1016/S2352-3018(21)00103-X. Epub ahead of print. PMID: 34153264; PMCID: PMC8213361.
3. Jones M… Frater J. Low copy target detection by Droplet Digital PCR through application of a novel open access bioinformatic pipeline, 'definetherain'. J Virol Methods. 2014 Jun;202(100):46-53. doi: 10.1016/j.jviromet.2014.02.020. Epub 2014 Mar 2. PMID: 24598230; PMCID: PMC4003534.
4. Charles ED, Brunetti C, Marukian S, Ritola KD, Talal AH, Marks K, Jacobson IM, Rice CM, Dustin LB. Clonal B cells in patients with hepatitis C virus-associated mixed cryoglobulinemia contain an expanded anergic CD21low B-cell subset. Blood. 2011 May 19;117(20):5425-37. doi: 10.1182/blood-2010-10-312942. Epub 2011 Mar 18. PMID: 21421840; PMCID: PMC3109715.
5. Charles ED… Dustin LB. Somatic hypermutations confer rheumatoid factor activity in hepatitis C virus-associated mixed cryoglobulinemia. Arthritis Rheum. 2013 Sep;65(9):2430-40. doi: 10.1002/art.38041. PMID: 23754128; PMCID: PMC4026862.
KEYWORDS: Immunology, Immune repertoire, autoimmune disease, bioinformatics, microfluidics
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