PREVENT-SLE: Towards PREdiction and preVENTion of Systemic Lupus Erythematosus
Lead Research Organisation:
University of Leeds
Department Name: School of Medicine
Abstract
Systemic Lupus Erythematosus (SLE) is a multisystem autoimmune disease with devastating impact; once diagnosed it is permanent. Immunosuppressive therapy leads to improvement, but lifelong medication is needed, with cumulative toxicity and damage. Insights from my work suggests a radically new paradigm based on prediction of imminent disease before it is irreversible and novel therapeutic targets for that phase.
Insight 1: SLE arises from asymptomatic autoimmunity (auto-antibody positive) in a stepwise fashion. By prospectively studying a unique "At-Risk" cohort, I found profound immune dysfunction in a dynamic equilibrium in which most patients remain healthy. However, type I interferon pathway activation (IFN-I) predicted progression to SLE, and data suggest there are other potential clinical, genetic and immunophenotypic predictors.
Insight 2:. Circulating sources of IFN-I become defective before inflammation or therapy with sustained production of IFN-I by keratinocytes; this is a reversal of the standard paradigm that SLE is caused by leucocytes attacking normal tissues. Therefore, tissues previously regarded as "target organs" may actually play an active role in initiation and maintenance of SLE. This may explain the resistance of SLE and offer new drug targets.
I will build on this strategic vision to extend these At-Risk cohorts to leverage a series of cutting edge methods to (i) accurately identify with biomarkers and a clinical risk model which At-Risk individuals will develop SLE (ii) use state of the art methods and a focus on Langerhans cells to understand why immune processes may remain confined to the skin or progress to systemic autoimmunity,; (iii) in parallel analyse circulating immune cells with single-cell RNAseq focussing on B cells and myeloid cells.
This work will lead to improved understanding of pathogenesis and trials of preventative therapies in high risk individuals: a step change in the longstanding ambition to prevent autoimmunity.
Insight 1: SLE arises from asymptomatic autoimmunity (auto-antibody positive) in a stepwise fashion. By prospectively studying a unique "At-Risk" cohort, I found profound immune dysfunction in a dynamic equilibrium in which most patients remain healthy. However, type I interferon pathway activation (IFN-I) predicted progression to SLE, and data suggest there are other potential clinical, genetic and immunophenotypic predictors.
Insight 2:. Circulating sources of IFN-I become defective before inflammation or therapy with sustained production of IFN-I by keratinocytes; this is a reversal of the standard paradigm that SLE is caused by leucocytes attacking normal tissues. Therefore, tissues previously regarded as "target organs" may actually play an active role in initiation and maintenance of SLE. This may explain the resistance of SLE and offer new drug targets.
I will build on this strategic vision to extend these At-Risk cohorts to leverage a series of cutting edge methods to (i) accurately identify with biomarkers and a clinical risk model which At-Risk individuals will develop SLE (ii) use state of the art methods and a focus on Langerhans cells to understand why immune processes may remain confined to the skin or progress to systemic autoimmunity,; (iii) in parallel analyse circulating immune cells with single-cell RNAseq focussing on B cells and myeloid cells.
This work will lead to improved understanding of pathogenesis and trials of preventative therapies in high risk individuals: a step change in the longstanding ambition to prevent autoimmunity.
Organisations
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ORCID iD |
| Edward Vital (Principal Investigator) |