Session Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's I
Session Type: Abstract Submissions (ACR)
Background/Purpose: Anti-topoisomerase-1 (Topo-1 or Scl70) autoantibodies are present in 30-45% of scleroderma (SSc) patients and identify a more aggressive disease phenotype with worse clinical outcome and reduced survival. While autoreactive T cells may be involved in SSc pathogenesis driving tissue inflammation and damage, no study has to date reliably quantified and functionally characterized topo-1-specific T cells in SSc patients.
Methods: Peripheral blood mononuclear cells from 27 (15 Scl70-positive and 12 Scl70-negative) consecutive patients and 4 healthy donors (HD) were stimulated with topoisomerase-1 purified from baculovirus-infected insect cells in the presence of anti-CD40 blocking antibodies and autologous serum. Topo-1-responsive T cells were defined based on the expression of activation markers CD154 and CD69, and their frequency calculated as percentage of CD4+ cells. The polarized functional phenotype (Th1, Th2, Th17, Th1/17) of autoreactive T cells was further determined by the surface expression of specific chemokine receptors (CXCR3, CCR6, CCR4) and their cytokine secretion profile (IFNγ, IL-4, IL-17) quantified by ELISA and qPCR after cell sorting. Comprehensive clinical data were obtained at the time of blood draws.
Results: Topo-1-reactive CD4+ T cells were found in all topo-1-positive subjects compared to one topo-1-negative patient and no HD [p=<0.001 and p=0.005 respectively] with a frequency ranging between 0.11% and 0.42% of CD4+ T cells. Anti-HLA-DR antibodies effectively inhibited topo-1 presentation and the activation of topo-1-responsive CD4+ T cells. Topo-1-specific T cells exhibited a predominant Th17 phenotype compared to the parent CD4+ T cell population [37±16% vs 8±5%, p=0.001]. Among topo-1-positive patients, higher levels of topo-1-reactive CD4+ T cells were associated with presence of interstitial lung disease [p=0.03], lower forced vital capacity (FVC) [rho=-0.657, p=0.011], and lower carbon monoxide diffusing capacity (DLco) [rho=-0.592, p=0.026].
Conclusion: This study establishes a robust and sensitive assay to measure topo-1-reactive T cells, and suggests that Th17 differentiation may be of importance in SSc pathogenesis.
Q. R. Liu,
F. M. Wigley,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/topoisomerase-1-specific-t-cells-exhibit-a-proinflammatory-th17-phenotype-and-are-associated-with-interstitial-lung-disease-in-scleroderma/