Defining pathogenic B cell regulation and role in scleroderma-associated interstitial lung disease (SSc-ILD)

Lead Research Organisation: University College London
Department Name: Medicine

Abstract

Scleroderma (SSc) is a severe autoimmune disease with high risk of tissue damage leading to premature death. It has three main interlinking abnormalities: autoimmunity, inflammation and fibrosis of tissues and organs. These include blood vessels, lungs and the heart. The severity and extent to which these organs are affected vary among the patients. Notably, lung fibrosis contributes to the cause of death in approximately 50% of these patients. Involvement of the lung is strongly linked to the type of autoantibodies that are produced by autoreactive B cells. Findings from the two centres indicate that patients fail to purge these autoreactive B lymphocytes. Recent evidence suggests that targeting B lymphocytes improves patient outcome in particular those affected by lung fibrosis but it appears that this treatment only benefits a proportion of patients. There are now emerging biologic agents (tocilizumab and rituximab) and anti-fibrotic agents (nintedanib) that benefit patients with lung fibrosis at early and late stages of disease, respectively. I, therefore, propose that the disease-specific pathways that drive lung fibrosis in SSc differ for patients with different autoantibody specificities and at different stages of disease. By analogy, blocking the activation of specific B cells that express high levels of interleukin-6 as a key mediator of fibrosis appear to be beneficial in an autoimmune neurological condition (neuromyelitis optica) further supporting my proposed strategy in SSc as an antibody-driven disease.

I will review patient groups at UCL that are treated with tocilizumab/rituximab to assess clinical characteristics that distinguish responders from non-responders for lung fibrosis. This will help me identify patient subgroups with lung fibrosis from whom I will obtain blood samples to isolate B cells before and after treatment with tocilizumab/rituximab. I will then have access to new laboratory techniques at QMUL that will provide exciting tools to evaluate the different populations of B cells in the bloods. The technique I propose to use has already been applied in rheumatoid arthritis and multiple sclerosis with remarkable success. This is a major step forward because this present application with modern scientific approaches will allow B cells to be studied at single cells levels for their origin and biological signatures in response to tocilizumab/rituximab treatment. This will define the distinct types of B cells, antibody signatures and the key mediators expressed by these cells from patients with different autoantibody subtypes and stage of disease, and further understanding of their potential importance in SSc lung fibrosis. From the analysis of these B cells, I expect to identify distinct cellular and antibody signature that will distinguish clinical responders from non-responders to the biologic agents pre-treatment. The data will be used to develop a new model to predict how B cells responses impact on overall disease outcome (specifically lung function) and on other cell types like fibroblasts that are directly involved in the scarring process in the lungs.

Definition of the detailed properties and functions of B cells and their biologic signatures will have future implications in precision medicine by facilitating better targeted treatments and determine which of the emerging B cell-directed therapies for SSc will work best for lung fibrosis for an individual patient. This is vital considering the very high clinical burden of SSc and current variations in response to available drugs. As well as providing information about B cell immunology and impact on treatments, this study will also have wider implications on other common autoimmune or fibrotic diseases affecting the lungs including idiopathic pulmonary disease where B cells may interact in different ways with other cell types driving the disease, and that similar investigative or therapeutic approaches may be applicable.

Technical Summary

Systemic sclerosis-associated interstitial lung disease (SSc-ILD) has significant mortality of up to 50% and early development of lung fibrosis is associated with aggressive clinical course. SSc-ILD is strongly associated with levels and specificity of autoantibodies and mediators expressed by B cells. However, current biologic therapies targeting B cells appear to benefit only a proportion of patients. The two collaborating centres recently discovered subsets of autoreactive IL-6-producing transitional B cells likely to initiate and SSc sustain disease processes. My proposal will analyse the transcriptome and antibody repertoire of circulating B cells from patients with SSc-ILD to identify biomarkers that predict responsiveness pre-treatment with rituximab or tocilizumab.

My aims are (1) to undertake detailed retrospective clinical assessments including autoantibody profiling in SSc cohorts in relation to treatment responsiveness to rituximab and tocilizumab. This data will inform patient selection criteria for the remainder of this project. (2) to recruit patients with high risk for progressive ILD for single B cell transcriptome and antibody repertoire analyses before and after treatment. I hope to retrieve 2 patient samples per subgroup (treatment subgroups and non-progressor/progressor subgroups for scRNA-seq). (3) Using scRNA-seq, further characterisation of the repopulating B cells after treatment in relation to patient's clinical response will be undertaken. This may help to identify pathogenic B cells from other healthy B cells in responder compared with non-responder patients.

This project will use approaches already established in rheumatoid arthritis and multiple sclerosis to identify pathogenic B cells. This study will define the relevance of subsets of B cells to SSc pathogenesis and facilitate precision medicine with targeted biologic therapies in SSc-ILD.

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