Background/Purpose: Pathogenic immune responses can be profoundly shaped by the interplay between the periphery and the microenvironment. In this work we aimed at defining the immune mechanisms at the interface between the skin microenvironment and the periphery that are relevant for the disease pathogenesis in Systemic sclerosis (SSc), an autoimmune disorder of the connective tissue.

Methods:

Utilising an Immunomics platform that integrated in the same experimental flow: mass cytometry (CyTOF) for the identification of disease-specific immune signatures (35 T cell specific markers), next generation RNAseq to characterize molecular patterns of antigen-specific T cells both in the periphery and in the skin microenvironment, NanoString platform to decipher the molecular characteristics of the skin microenvironment and various functional assays to validate the findings. Using this approach we interrogated peripheral blood (n=59) and compared them with healthy controls (n=33). We also compared paired lesional skin and peripheral blood derived T cells (n=7). Datasets were analysed by in-house developed computational tools.

Results:

Pathogenic Th17/Treg, Th17/Tfh cells and prototype Th17 cells were enriched in SSc subjects both in the periphery and in the skin microenvironment. Whole transcriptome analysis revealed skin derived T cells had elevated expression of IL-11 receptor (IL-11RA). Pathway analysis showed SSc skin derived T cells induced a distinct set of IL-17 regulated genes in dermal fibroblasts including IL-11. Skin derived IL-11 induced secretion of Th17 polarizing cytokines such as IL-1b and IL-6 from monocytes and polarized naive T cells to a Th17 phenotype. IL-11/IL-11RA signaling was regulated along a MAP3K8, STAT3 and PIM-1 signaling axis.

Conclusion:

By combining complementary ex vivo and in vitro approaches with non-biased data-driven analysis we could show that there exists a self reverberating pathogenic loop at the interface between the systemic and the skin microenvironment. This loop centred on the IL-17, IL-11 and IL11-RA triad expands and maintains disease-specific and pathogenic Th17 T cell subsets. Our findings have a dual translational valency both for targeted therapies and for understanding immune pathogenesis of SSc. 

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pathogenic-t-cell-responses-in-systemic-sclerosis-is-shaped-by-novel-cytokine-axis-in-the-microenvironment-a-multidimensional-high-throughput-analysis/