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Interrogation of Childhood Onset Systemic Lupus Erythematosus Immunome

Full Title: Interrogation of Childhood Onset Systemic Lupus Erythematosus Immunome for the Elucidation of Disease Mechanisms

Major Category: Research and Disease Areas

Subcategory: Loss of Tolerance

By Yeo Joo Guan (Team Lead), Camillus Chua, Poh Su Li

The pathogenesis of Systemic Lupus Erythematosus (SLE) involves multiple derangements that perturb the fine balance between immunity and regulation. Traditional investigational approaches focusing on the pathogenic or protective role of individual cell type or molecule independently are inadequate for the study of a complex, multifactorial disease like SLE. The lack of a holistic understanding of the lupus immunome is a critical unmet need. Simultaneously, there are other important knowledge gaps pertaining to the role of B regulatory cells in SLE where there is a lack of specific cell surface and transcriptional factor markers akin to the forkhead box protein P3 (Foxp3) found in T regulatory cells.

The over-arching hypothesis is that abnormalities in multiple components of the immune system contribute to lupus pathogenesis. Specifically, we hypothesise that the immune regulatory component is dysfunctional (both quantitatively and qualitatively) during lupus flare. To address such unmet needs, we aim to use a high dimensional approach using mass cytometry to unravel the contribution of the regulatory and inflammatory immunome to lupus pathogenesis simultaneously. This will be achieved with the characterisation of 37 immune markers at the single cell level using mass cytometry, followed by an unbiased and unsupervised analysis with a machine learning custom software based on dimensional reductions followed by automated cells classification and clustering. Subsequently, hierarchical prioritisation of the cell populations based on its strength of association with disease activity for downstream mechanistic characterisation with fluorescence based flow cytometry sorting of the target cells of interest for full transcriptome analysis and in-vitro functional study will be done.

This approach has the immediate dual translational potential of identifying immune cell subsets relevant for clinical prognostication and the elucidation of disease mechanisms which will subsequently provide important information for the development of a multi-pronged immunotherapeutic strategy against SLE.