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International Immunology Advance Access originally published online on June 11, 2008
International Immunology 2008 20(8):971-979; doi:10.1093/intimm/dxn056
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Progressive divergent shifts in natural and induced T-regulatory cells signify the transition from undifferentiated to definitive connective tissue disease

Peter Szodoray1,*, Britt Nakken2,*, Sandor Barath1, Janos Gaal3, Magdolna Aleksza1, Margit Zeher1, Sandor Sipka1, Anna Szilagyi1, Eva Zold1, Gyula Szegedi1,4 and Edit Bodolay1

1 Division of Clinical Immunology, 3rd Department of Medicine
2 Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary
3 Department of Rheumatology, Kenezy County Hospital, Debrecen, Hungary
4 Research Group of Autoimmune Diseases, Hungarian Academy of Sciences, Budapest, Hungary

Correspondence to: P. Szodoray; E-mail: szodoray{at}gmail.com

The objectives of the study is to determine clinical signs and distribution of peripheral T-cell subsets, B cells and T regulatory cells in patients with undifferentiated connective tissue disease (UCTD) and during the development toward well-established connective tissue diseases (CTD). The methods include 46 patients with UCTD were followed and investigated for differentiation into defined CTDs for 2 years. Cell subsets were determined on the basis of cell surface markers, intracellular cytokine production by flow cytometry and serum cytokine levels by ELISA. The results are as follows: 45.6% of UCTD patients developed into a defined CTD. The number and percentage of activated T cells, memory T cells and NKT cells were increased in patients compared with controls. In addition, in patients with UCTD, the percentage of CD4+/IFN{gamma}+ Th1 was significantly higher compared with controls and further increased in patients that developed CTDs. The percentage and absolute number of CD4+CD25+Foxp3+ regulatory T cells (Tregs) were diminished in UCTD patients compared with healthy controls, while the number of CD4+/IL-10+ Tregs increased. The conclusions are Overproduction of IFN{gamma} and the decrease of natural (Foxp3+) Tregs seem to be characteristic features of UCTD patients. The increased IL-10 production of CD4+ T cells might be a compensatory suppressive mechanism; however, it is probably not able to balance the overproduction of IFN{gamma} and the observed decrease of Foxp3+ Tregs. The shift toward Th1 with increased IFN{gamma} production in patients with UCTD combined with the degree of immunoregulatory disturbances characterized by the progressive divergent shifts in natural and induced T-regulatory cell populations signify the transition from undifferentiated to definitive CTD.

Keywords: clinical signs, cytokines, definitive connective tissue diseases, regulatory T cells, undifferentiated connective tissue disease

* The first two authors contributed equally to this work.

Transmitting editor: A. Falus

Received 11 September 2007, accepted 14 May 2008.


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