Background/Purpose: Psoriasis (PsO) is a common inflammatory skin disease that is characterized by acanthosis, impaired immune cell migration, and remodeling of the vascular and lymphatic system. Up to ~30% of PsO patients develop psoriatic arthritis (PsA). The factors that determine the transition from PsO to PsA or vice versa are poorly understood. The lymphatic system may regulate the homing capabilities of disease-associated T-cells and control their migration to skin and extra-cutaneous sites like synovial joints and entheses.

Methods: Primary human dermal lymphatic endothelial cells (LECs) were preincubated for 3 days with TNF (10 ng/mL), IL-17A (100 ng/mL), rheumatoid arthritis synovial fluid (SF-RA; 20% v/v) or psoriatic arthritis synovial fluid (SF-PsA; 20% v/v). After removing the media, LECs were cocultured with allogeneic (CD3-enriched) skin-derived T-cells (SDTC) or peripheral blood mononuclear cells (PBMCs) for 48 hours (each from 3 separate donors) in the presence of 0.3 μg/ml αCD3 and 0.4 μg/ml αCD28. T-cells were then immunophenotyped by flow cytometry on a 4-laser LSRII analyzer using antibodies directed to CD45, CD3, CD4, CXCR3, CCR4, and CCR6. Based on the latter three, the most relevant T-helper (Th) subsets were characterized, including the CCR6+ subpopulations Th17.1 (CXCR3+/CCR4-), Th17/Th22 (CXCR3-/CCR4+), and double positives (DP; CXCR3+/CCR4+), and the CCR6- subsets, i.e. Th1 (CXCR3+/CCR4-), and Th2 (CXCR3-/CCR4+). In addition, we looked at cutaneous lymphocyte-associated antigen (CLA), a skin lymphocyte homing receptor. The percentage of these Th-subsets (normalized to untreated LECs), that were generated upon co-incubation with LECs, were statistically tested using 2-way ANOVA.

Results: SDTCs upregulated CLA-expression upon incubation on LECs that underwent pretreatment with SF-RA and SF-PsA, as compared to LECs preincubated with TNF or IL-17A. In contrast, this effect was not observed in PBMCs. The increase of normalized mean fluorescence intensity (MFI) for CLA-expression in SDTCs was more pronounced in LECs preincubated with SF-PsA versus SF-RA, and increased 3.3-fold, 2.8-fold and 3.1-fold in the total CD4+ compartment, Th17.1 and DP subsets respectively (P<0.01 for all as compared to SF-RA). This finding was not explained by an increase in the proportion of the total CD4+ compartment or Th17.1 and DP subsets within the CLA+ SDTC population.

Conclusion: LECs are directly involved in T-cell homing capabilities, as shown by CLA regulation at the time of STDC activation. CLA regulation occurs in a highly tissue-selective manner. Thus, preincubation of dermal LECs with SF-PsA and to a lesser extent SF-RA reinforced CLA expression particularly in CCR6+ T-cell subsets that are abundant in psoriatic skin. This effect was not seen in CD3-enriched PBMCs, where the CLA+ T-cell proportion is far less. Further studies are underway to show that LECs derived from relevant biological tissues from PsA patients including skin, lymph nodes and synovium may be critical for inducing tissue-imprinting receptors at the time of T-cell activation, and for tissue-restricted migration to both skin and synovial joints and entheses in PsO and PsA.

« Back to 2016 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-lymphatic-system-a-gatekeeper-for-migration-of-pathogenic-t-cells-towards-synovial-joints-and-entheses-in-psoriasis/