2022 ACR Conference Blockbuster: CD8 T cell-Mediated Psoriatic Arthritis Subtype Newly Discovered in Mouse Models!

Background and purpose: A key clinical feature of psoriatic arthritis (PsA) is the presence of multiple areas (skin, joints, spine) and the prevalence of multi-regional involvement complicates
treatment.
Recent evidence supports that CD8 T cells play a major role in the pathogenesis of PsA, however, the specific role of these cells and serum factors in driving disease in individual regions is unclear
.
To fill this gap, we injected serum and peripheral blood mononuclear cells (PBMC) from patients with specific phenotypes (psoriasis simplex, psoriasis with non-erosive arthritis, psoriasis with erosive arthritis, dactylitis) into immunodeficient NSG-SGM3 mice to experimentally evaluate cells and serum factors
that promote regional inflammation in PsA.

Methods: Serum and PBMC were isolated from healthy controls (HC) for the treatment of active plaque and PsA
in patients with naïve psoriasis (Ps).
Three groups of NSG-SGM3 mice were intravenously injected with serum and PBMCs from healthy (HC), Ps, and PsA patients with primary dactylitis, nonerosive or erosive arthritis
.
Blood leukocytes, 3 mm skin, and synovial (posterior/anterior paw) biopsies were collected on day 30 post-transplantation and T cells
were quantified by flow cytometry and immunofluorescence.
We examined synovial CD8 T cells using GeoMx digital spatial analyzers and next-generation sequencing readouts in combination with nSolver software to determine their molecular profiles
.

Results: Only NSG-SGM3 injected with serum and PBMCs from patients injected with PsA showed psoriasis-like plaques and arthritis (Figure 1).

Mice injected with Ps patient cells and serum developed only psoriasis-like lesions
.
The disease phenotype (overt dactylitis, erosive or non-erosive arthritis) observed in one patient was also observed
in mice.
Flow cytometry analysis showed the percentage of effector memory (HU-PS; 37.
79%, hu-PsA; 22% Vs Ps; 16%, PsA 18%), decreased naïve CD8 T cells in mouse blood (Ps; 8.
91% vs.
hu-Ps;0.
48%, hi-PsA; 2.
6%）
。 Hu-PsA mice have ankle swelling with psoriasis-like lesions, dactylitis, and pleural infiltration
consisting of CD8 T cells, macrophages, and CD3 T cells that proliferate.
In contrast, Hu-Ps mice did not have ankle swelling or dactylitis
.
All hu-Ps and hu-PSA mice exhibited skin plaques with increased epidermal thickness (hu-HC 27.
6 μm2 vs.
hu-PsA 125 μm2, p = 0.
025) and proliferating CD3 T cells (hu-HC; 16 cells/µm2 vs.
hu-PsA 204 cells/µm2）
。 GeoMx digital spatial profilers and next-generation sequencing readouts showed enrichment of synovial CD8 T cells expressing IL32, GrzK, and GrzA in hu-PsA, but not
in hu-HC or hu-Ps.
Of note, serum and PBMCs metastases from PsA patients showed arthritis and psoriasis-like lesions in this model that could be completely eliminated
in patient and mouse models after anti-TNF therapy.

Figure 1 Serum soluble factors and PBMCs are critical
for PsA reproduction in humanized NSGSGM3 mice.
A) Skin pictures of hu-PsA mice showing psoriasis-like lesions
in mice injected with PsA patient serum and PBMCs.
B) Histological images of hu-PsA mice compared to hu-HC show increased epidermal thickness and significant accumulation of proliferating CD3* T cells (CD3: red, Ki67: white, smooth actin (SMA): green).

C) Hu-PsA-induced prominent synovial inflammation of the ankle joint in mice (dotted profile), type 1 CD3* T cell proliferation, CD8 T cells and CD14* cells colocalization
.
D) hu-PsA occurs with proliferative (Ki67-white) type 1 (T-betgreen) CD3* T cells (CD3-red) (dotted line).

Take 200x magnification pictures with a Zeiss Axioplan microscope, recorded
with a Hamamatsu camera.
Scale bar = 1000 μm

Conclusion: These data suggest that serum factors and CD8 T cells promote region-specific phenotypes
.
In addition, the model is expected to provide ideas
for patient-specific treatments and underlying disease mechanisms.

Original source:

Javier Rangel-Moreno, Ananta Paine,Soumyaroop Bhattacharya,et al.
Psoriatic Arthritis Disease Subtypes Mediated by CD8 T Cells Are Phenocopied in a Novel Humanized Murine Model of Psoriasis and Arthritis.
ACR Convergence 2022.
October 18, 2022.