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Autoreactive B cells in Sjögren’s syndrome #202014


About This PhD Project

Project Description

Primary Supervisor: Lynn B Dustin, PhD
Secondary Supervisor: Christopher D Buckley DPhil, FRCP

Sjögren’s syndrome (SS) is the second most common rheumatic disease after rheumatoid arthritis and can also arise as a complication of other autoimmune diseases. SS is characterised by lymphocytic infiltration of the salivary and lacrimal glands, and by the presence of high affinity, class switched self-reactive autoantibodies to extractable nuclear antigens (ENAs). Up to 10% of SS patients may develop non-Hodgkin B cell lymphoma (NHL); NHL risk is associated with particular autoantibody specificities (rheumatoid factor and Ro/La specific autoantibodies), monoclonal gammopathy, cryoglobulinaemia, and vasculitis. Because the pathogenesis of SS is not well understood, no specific treatments are available to prevent the long-term complications of this disease. An understanding of how autoreactive B cells escape regulation is essential to improving the lives of SS patients and to preventing B cell malignancies in this patient group. Additionally, the pathogenic roles of ENA-specific autoantibodies are poorly understood.

Therefore, we propose to identify B cells that produce ENA-specific autoantibodies in blood and in the inflamed salivary gland; to determine what makes these antibodies autoreactive; and to define how these B lymphocytes and their antibody products contribute to disease pathogenesis. Our specific goals are to:

1. Define the repertoire of autoreactive B cells by isolating antigen-binding B cells from matched
peripheral blood and salivary gland biopsies of patients with SS, cloning their expressed
immunoglobulin genes, and characterizing their clonal diversity.

2. Using serial samples from selected patients, determine whether autoreactive B cell clones
persist long-term, or are continuously replaced as suggested by a recent study of serum
autoantibodies.

3. Define the gene expression pattern of autoreactive B cells in matched samples from matched
blood and salivary gland biopsies. We will test the hypothesis that autoreactive B cells
represent a form of memory inflation, previously described in T cells.

4. Define the antigen specificity and cross-reactivity of selected cloned autoantibodies. Cloned
antibodies will be produced in vitro with authentic heavy chain isotypes, as we have previously
described. Using tools such as epitope arrays (such as the PEPperCHIP® human epitome
microarray), ELISAs, immunostaining, and immunoblotting, we will identify potential target
epitopes. This will enable us to test the hypothesis that the pathogenesis of autoimmune
disease involves selection of cross-reactive B cells that recognize both ENAs and a
pathogen.

KEYWORDS: Autoimmune disease, immunoglobulins, single-cell transcriptomics, Sjögren’s syndrome, antibody engineering.

TRAINING OPPORTUNITIES: Flow cytometry, cell sorting, human antigen-specific B cells, RNAseq, bioinformatics, single-cell analysis, translational research.

THEMES: Autoimmunity and Inflammation, Cell Dynamics; Informatics and Computational Biology

CONTACT INFORMATION: ;

References

Charles ED, Orloff MIM, Nishiuchi E, Marukian S, Rice CM, Dustin LB. Somatic hypermutations confer rheumatoid factor activity in hepatitis C virus-associated mixed cryoglobulinemia. Arthritis and Rheumatism 2013;65(9):2430-40. PMCID: PMC23754128.

Charles ED, Orloff MIM, Dustin LB. A flow cytometry-based strategy to identify and express IgM from VH1-69+ clonal peripheral B cells. J Immunol Meth 2011;363:210-20. PMCID: PMC3003765.

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;117:5425-37. PMCID: PMC3109715.

Croft AP, Campos J, Jansen K, Turner JD, Marshall J, Attar M, Savary L, Wehmeyer C, Naylor AJ, Kemble S, Begum J, Dürholz K, Perlman H, Barone F, McGettrick HM, Fearon DT, Wei K, Raychaudhuri S, Korsunsky I, Brenner MB, Coles M, Sansom SN, Filer A, Buckley CD. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 2019;570:246-251. PMCID: PMC6690841.

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