Multiple sclerosis: reduced proportion of circulating plasmacytoid dendritic cells expressing BDCA-2 and BDCA-4 and reduced production of IL-6 and IL-10 in response to herpes simplex virus type 1.
OBJECTIVE
We hypothesized that autoaggressive immune responses observed in multiple sclerosis (MS) could be associated with an imbalance in proportion of immune cell subsets and in cytokine production in response to infection, including viruses.


METHODS
We collected blood mononuclear cells (MNC) from 23 patients with MS and 23 sex- and age-matched healthy controls (HC) from the island of Sardinia, Italy, where the prevalence of MS is extraordinarily high. Using flow cytometry, we studied MNC for expression of blood dendritic cell antigens (BDCA)-2 and BDCA-4 surface markers reflecting the proportion of plasmacytoid dendritic cells (pDC) that produce type I interferons (IFNs) after virus challenge and promote Th2/anti-inflammtory cytokine production. In parallel, pro-inflammatory (interleukin [IL]-2, IL-12, IFN-gamma), anti-inflammatory (IL-4, IL-10), and immuno-regulatory/pleiotropic cytokines (type I IFNs including IFN-alpha and beta, IL-6) were measured before and after an in vitro exposure to herpes simplex virus type 1 (HSV-1).


RESULTS
The subset of lineage negative (lin(-)), BDCA-2(+) cells was lower in patients with MS compared with HC (0.08 + or - 0.02% vs 0.24 + or - 0.02%; P < 0.001). A similar pattern was observed for lin(-)BDCA-4(+) cells (0.08 + or - 0.02% vs 0.17% + or - 0.03; P < 0.01). Spontaneous productions of IL-6 (45 + or - 10 pg/mL vs 140 + or - 26 pg/mL; P < 0.01) and IL-10 (17 + or - 0.4 pg/mL vs 21 + or - 1 pg/mL; P < 0.05) by MNC were lower in patients with MS compared with HC. Spontaneous production of IL-6 (6.5 + or - 0.15 pg/mL vs 21 + or - 5 pg/mL; P < 0.01 and IL-10 (11 + or - 1 pg/mL vs 14 + or - 3 pg/mL; P < 0.05) by pDC was also lower in patients with MS compared with HC. Exposure of MNC to HSV-1 showed, in both patients with MS and HC, increased production of IFN-alpha, IL-6, and IL-10 but decreased production of IL-4. In response to HSV-1 exposure, productions of IL-6 (165 +or - 28 pg/mL vs 325 + or - 35 pg/mL; P < 0.01) and IL-10 (27 +or - 3 vs 33 + or - 3 P < 0.05) by MNC as well as by pDC (IL-6: 28 + or - 7 vs 39 + or - 12 P < 0.05; IL-10: 14 + or - 1 vs 16 + or - 3 P < 0.05) were lower in patients with MS compared with HC.


CONCLUSIONS
The results implicate a new evidence for altered immune cells and reduced immune responses in response to viral challenge in MS.
Sanna
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A
Department of Neuroscience, Institute of Clinical Neurology, University of Sassari, Sassari, Italy. alexsanna72@yahoo.it
Huang
Y M
YM
Arru
G
G
Fois
M L
ML
Link
H
H
Rosati
G
G
Sotgiu
S
S
D000328:Adult; D000954:Antigens, Surface / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D005260:Female; D006561:Herpes Simplex / Q000453:epidemiology / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000276:immunology*; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007558:Italy / Q000453:epidemiology; D037181:Lectins, C-Type / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000453:epidemiology / Q000276:immunology* / Q000821:virology*; D015995:Prevalence; D011971:Receptors, Immunologic / Q000378:metabolism; D055815:Young Adult
D000954:Antigens, Surface; D015415:Biomarkers; C443299:CLEC4C protein, human; C508609:IL10 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C478196:blood dendritic cell antigen 4, human; D016753:Interleukin-10