Altered Th17 cells and Th17/regulatory T-cell ratios indicate the subsequent conversion from undifferentiated connective tissue disease to definitive systemic autoimmune disorders

Abstract

A shift in the balance between Th17-cells and regulatory T-cells (Treg) is an important feature of systemic autoimmune diseases (SAID), and may also contribute to their development. Hereby, we assessed the distribution of peripheral Th17 and Treg-cells in patients with undifferentiated connective tissue disease (UCTD), the forerunner of SAIDs and followed these parameters during the development towards definitive SAIDs. Fifty-one UCTD patients were investigated and followed-up for 3 years. Flow cytometry was used to identify and follow three cell-populations: Th17-cells (CD4+IL-17+ T-cells), natural regulatory T-cells (CD4(+)CD25(bright)FoxP3(+); nTregs) and IL-10 producing Type-1 regulatory T-cells (CD4+IL-10+ T-cells; Tr1). Altogether 37.3% of these patients progressed into SAIDs. Th17-cells were increased in UCTD vs. controls, which further increased in those, whom developed SAIDs eventually. The Th17/nTreg ratio gradually increased from controls through UCTD patients, reaching the highest values in SAID-progressed patients. Regarding the Th17/Tr1 ratios, a similar tendency was observed moreover Th17/Tr1 could distinguish between UCTD patients with, or without subsequent SAID progression in a very early UCTD stage. Various immunoserological markers showed association with Th17 and Th17/nTreg at baseline, indicating the consecutive development of a distinct SAID. The derailed Th17/Treg balance may contribute to disease progression therefore could function as a prognostic marker.

Keywords: (Scleroderma-70 antigen, DNA Topoisomerase I); ANA; ANCA; APC; C-reactive protein; CCP; CNS; CRP; ELISA; ENA; FITC; IL-10 producing Type-1 regulatory T-cells; MCTD; NKT; PBMC; PE; PM/DM; RA; RF; SAID; SLE; SS; SSc; Scl-70; Sjögren’s syndrome; Sm; Smith antigen; T-helper cell; Tc-DTPA; Th; Tr1; Treg; U1 ribonucleoprotein; U1RNP; UCTD; aCL; allophycocyanin; anti-cardiolipin; anti-neutrophil cytoplasmic antibodies; anti-nuclear antibody; central nervous system; cyclic citrullinated peptide; double-stranded deoxyribonucleic acid; dsDNA; enzyme-linked immunosorbent assay; extractable nuclear antigen; fluorescein isothiocyanate; mixed connective tissue disease; nTreg; natural killer T cell; natural regulatory T cell; peripheral blood mononuclear cell; phycoerythrin; polymyositis/dermatomyositis; regulatory T cell; rheumatoid arthritis; rheumatoid factor; systemic autoimmune disease; systemic lupus erythematosus; systemic sclerosis; technetium-diethylene-triamine-pentaacetate; undifferentiated connective tissue disease.