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AB0118 The lymphatic system: a gatekeeper for migration of pathogenic t-cells towards synovial joints and entheses in psoriasis
  1. R Bisoendial1,
  2. E Prens2,
  3. A Mus3,
  4. P Asmawidjaja3,
  5. N Davelaar3,
  6. A Hofman4,
  7. J-B Jaquet4,
  8. J Hazes3,
  9. M Kok5,
  10. E Lubberts3
  1. 1Department of Rheumatology, Maasstad hospital and Erasmus Medical Center
  2. 2Department of Dermatology
  3. 3Department of Rheumatology, Erasmus University Medical Center
  4. 4Department of Plastic surgery
  5. 5Department of Rheumatology, Maasstad hospital, Rotterdam, Netherlands

Abstract

Background The factors underlying the transition of psoriasis (PsO) to psoriatic arthritis (PsA) are poorly understood. The lymphatic system may control the homing of disease-associated T-cells to skin and extra-cutaneous sites like synovial joints and entheses.

Objectives To study the capacity of lymphatic endothelial cells (LEC) to regulate T-cell homing capabilities in PsA.

Methods Human dermal LEC (0.5x104), and fibroblast-like synoviocytes of a patient with PsA (PsA-FLS; 1.0x104) were pre-incubated for 3 days with PsA synovial fluid (PsA-SF; 0/10/20% v/v) and co-cultured with 2.5x104 allogeneic CD4+CD45RO+CD25- T-cells that were sorted from peripheral blood mononuclear cells of 3 donors (with or without stimulation with αCD3/αCD28). After 72 h, T-cells were analyzed by flow cytometry. The CCR6+ T-helper (Th) subsets Th17.1 (CCR4-/CXCR3+), Th17/Th22 (CCR4+/CXCR3-), Th17 (CCR4+/CXCR3-/CCR10-) and Th22 (CCR4+/CXCR3-/CCR10+), and CCR6- subsets Th1 (CCR4-/CXCR3+), and Th2 (CCR4+/CXCR3-) were identified. We also looked at cutaneous lymphocyte- associated antigen (CLA). IL-17A, IL-22, and TNF protein levels were determined by ELISA. Statistical analysis included unpaired t-test (two-sided) for two-group comparison or one-way ANOVA with the Tukey-Kramer post hoc test for multi-group comparisons.

Results Stimulation of CD4+CD45RO+ T-cells in co-culture with PsA-FLS skewed towards the CCR6+ subset Th17/Th22, which were predominantly Th17 cells. Th17 differentiation upon stimulation was suppressed in co-culture with LEC, even when LEC were pre-incubated with PsA-SF. T-cell stimulation in co-culture with LEC, as compared to PsA-FLS, promoted the generation of the Th22 subset. Upon co-culture with untreated LEC, stimulated T-cells showed higher expression of the skin homing receptor CLA than those that were co-cultured with PsA-FLS. The proportional reduction in CLA expression on T-cells in the co-cultures with LEC pre-incubated with PsA-SF 20% was comparable to PsA-FLS, however LEC conserved CLA expression on CD4+CD45RO T-cells at a higher level than PsA-FLS; this phenomenon particularly affected the CCR6+ T-cells. In line, a trend towards lower IL-17A and higher IL-22 levels were observed in the co-cultures with LEC that were pretreated with PsA-SF 20%, as compared to the co-culture with PsA-FLS. No differences were seen for TNF protein levels.

Conclusions LECs are directly involved in T-cell differentiation and homing capabilities, as shown by suppression of Th17 differentiation upon stimulation, as compared to PsA-FLS. Also, LEC promoted Th22 generation, and conserved CLA expression in CCR6+ T-cells, even when LEC were preincubated with PsA-SF. Studies are underway to confirm that LECs from relevant biological tissues (e.g. synovium and lymph nodes) are critical for tissue-restricted T-cell migration to skin and synovial membranes in PsA.

Disclosure of Interest None declared

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