Brain Advance Access originally published online on March 2, 2006
Brain 2006 129(5):1293-1305; doi:10.1093/brain/awl043
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Impaired maturation and altered regulatory function of plasmacytoid dendritic cells in multiple sclerosis
1 Department of Neurology, Medical University of Lodz, Lodz, Poland, 2 Department of Neurology, University of Würzburg, Würzburg and 3 Institute for MS Research, Medical Faculty of the University and Gemeinnuetzige Hertie-Stiftung, Goettingen, 4 Department of Neurology, Klinikum Augsburg, Germany
Correspondence to: Krzysztof W. Selmaj, MD, PhD, Department of Neurology, Medical University of Lodz, 22 Kopcinskiego Street, 90-153 Lodz, Poland E-mail: kselmaj{at}afazja.am.lodz.pl
Plasmacytoid dendritic cells (pDCs) represent a DC subtype that exerts divergent functions in innate and adoptive immunity including the immediate reaction to microbial factors and the induction of immunoregulatory responses. It is thought that different DC subtypes may be critically involved in the pathogenesis of multiple sclerosis (MS). In our study we assessed the phenotype, maturation and functional properties of peripheral blood pDCs from 35 clinically stable, untreated multiple sclerosis patients, 30 healthy controls and 9 patients with pneumonia, which was used as a non-specific inflammatory condition (NIC). Ex vivo expression of CD86 and 4-1BBL was significantly lower on pDCs from multiple sclerosis patients than from controls and patients with NIC (22 versus 47 versus 41% and 12 versus 35 versus 32%, respectively). When stimulated with IL-3 and CD40L, pDCs of multiple sclerosis patients showed inefficient maturation as demonstrated by significantly lower or delayed upregulation of CD86, 4-1BBL, CD40 and CD83. Additionally, in multiple sclerosis, stimulation of pDCs by unmethylated cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODN) resulted in a significantly lower interferon (IFN) alpha secretion than in controls. In multiple sclerosis, but not in controls, pDCs failed to upregulate proliferative responses and IFN-gamma secretion of autologous peripheral blood mononuclear cells (PBMC) in a co-culture system. Moreover, depletion of pDCs in multiple sclerosis patients, but not in controls, had no effect on generation of CD4+Foxp3+ regulatory T cells. We also provide data showing that glatiramer acetate (GA) treatment partially restores phenotype and function of pDCs in multiple sclerosis patients. These findings suggest functional abnormalities of pDCs in these patients, which might be of importance in the understanding of the development of immune dysregulation in this disease.
Key Words: multiple sclerosis; plasmacytoid dendritic cells; immunoregulation
Abbreviations: BDCA = blood dendritic cell antigen; CpG ODN = cytosine-phosphate-guanosine oligodeoxynucleotides; ELISA = enzyme-linked immunosorbent assay; FACS = fluorescence-activated cell sorting; GA = glatiramer acetate; IFN = interferon; IL = interleukin; mAb = monoclonal antibody; mDC = myeloid dendritic cell; NIC = non-specific inflammatory condition; PBMC = peripheral blood mononuclear cells; pDC = plasmacytoid dendritic cell
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Received July 26, 2005. Revised November 22, 2005. Accepted January 25, 2006.
*Both authors contributed equally to the work.
Both senior authors contributed equally to the work.