Background/Purpose:

Psoriatic arthritis (PsA) occurs in a third of patients with psoriasis (Ps) and up to 30% of patients with PsA do not have an adequate response to any treatment. The precise pathogenesis of PsA/Ps remains unknown and its understanding is crucial for the development of new therapies. We hypothesize that the microenvironment plays a crucial role in shaping the pathogenic immune response. To address this, we utilize a dual approach to decipher the transcriptome of the skin microenvironment and the immunomes of PsA patients with active disease. This multi-dimensional strategy will enable the distillation of immune cell subsets in the periphery that can potentiate pathogenic responses in the microenvironment.

Methods:

Skin punch biopsies of psoriatic and morphologically normal sites and paired whole blood were obtained from patients (n=3) with active PsA requiring intensification of treatment. Total RNA extracted from the skin punch biopsies and gene expression analysis was performed with Nanostring. Peripheral Blood Mononuclear Cells (PBMCs) from PsA patients (n=3) and sex-matched healthy donors (n=3) were stimulated with PMA-Ionomycin, stained with 37 phenotypic T cells markers and interrogated with the CyTOF platform. Dimensional reduction and unsupervised clustering analyses were performed with Multi-dimensional Automated Reduction and Visualization (MARVis), an in-house customised machine learning software.

Results:

Nanostring results revealed that gene signatures enriched in psoriatic skin (like GZMA, GZMB, ARG1, NOS2) are suggestive of inflammation mediated by subsets of immune cells such as neutrophils, CD8+ T cells and macrophages. Moreover, several immunoattractant chemokines like CCL20, CXCL13 and CXCL2 were expressed at higher levels in psoriatic skin compared to morphologically-normal skin. Given the enrichment of chemokines in the microenvironment, we next examined the immune cell subsets in the peripheral blood which may be responding to these chemical signals. We studied the systemic immune profiles of these patients with CyTOF and noticed significant differences in the immunomes of PsA patients compared to healthy donors. Specifically, in PsA patients, we observed a decline in the Mucosal Associated Invariant T (MAIT) population displaying an immune-modulatory phenotype (TCRVa7.2+CD8+CD161+CCR6+IFNγ+) and an enrichment in activated CD8+ T effector cells (CD8+CCR6+CXCR3+Tbet+GranB+). The expression of CCR6 is indicative of the migratory potential of these pro-inflammatory T cells in response to CCL20 to sites such as the skin and joints.

Conclusion:

Our approach of analysing the psoriatic skin transcriptome and immunome exemplifies the role of microenvironment in shaping the systemic immune response. We observed at the skin level, that the microenvironment secretes a cocktail of chemokines that may serve to shape the composition of the peripheral immunome and affect the relative proportion of cells infiltrating the lesions. These preliminary findings warrant further analysis on a larger PsA patient cohort and will improve the understanding of the pathogenesis of Ps and PsA and facilitate the identification of novel immune therapeutic targets.

« Back to 2017 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/deciphering-the-role-of-the-tissue-microenvironment-in-shaping-the-immune-landscape-in-psoriatic-arthritis/