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1.
J Neuroimmunol ; 280: 36-42, 2015 Mar 15.
Article in English | MEDLINE | ID: mdl-25773153

ABSTRACT

BACKGROUND/OBJECTIVE: Data from animal models of MS suggest that GM-CSF(+)CD4(+)T cells are pathogenic cells. Therefore, GM-CSF production by CD4(+)T cells of MS patients and their susceptibility to regulatory mechanisms were investigated. METHODS: Intracellular flowcytometry was performed to determine the GM-CSF(+)CD4(+)T cell fraction in PBMC and CSF of MS patients and controls. The effect of regulatory T cells (Tregs) on GM-CSF production by CD4(+)T cells was studied in MS patients using a proliferation-suppression assay. Finally, GM-CSF(+)CD4(+)T cell fraction and GM-CSF protein levels in supernatant were assessed in anti-CD3-stimulated CD4(+)T cell cultures derived from healthy controls and MS patients, in the presence or absence of the active vitamin D metabolite calcitriol. RESULTS: The GM-CSF(+)CD4(+)T cell fraction in the peripheral blood did not differ between controls and MS patients. This T cell population could also be detected in the CSF of both subjects with MS as well as subjects with another diagnosis. In the CSF, it comprised a significant fraction of the T cell population. Upon in vitro stimulation of PBMC with anti-CD3 antibody, no differences were observed in GM-CSF(+)CD4(+)T cell frequencies. GM-CSF secretion was susceptible to regulation by Treg and vitamin D. Suppression of GM-CSF secretion by vitamin D was reduced in MS patients. CONCLUSIONS: Our study showed no elevation in GM-CSF(+)CD4(+)T cell fractions in MS patients compared to controls. Furthermore, GM-CSF secretion was prone to regulation by Treg and vitamin D, the latter being less effective in MS patients.


Subject(s)
CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/metabolism , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Multiple Sclerosis/pathology , T-Lymphocytes, Regulatory/physiology , Vitamin D/pharmacology , Adult , Cytokines/metabolism , Female , Flow Cytometry , Humans , Male , Middle Aged , Statistics, Nonparametric , Time Factors , Young Adult
2.
Mol Immunol ; 63(2): 521-9, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25458313

ABSTRACT

The NLRP3 inflammasome is a macromolecular complex importantly involved in IL-1ß processing. A role for this has been described in multiple sclerosis (MS). One mechanism by which IL-1ß might be involved in MS is by inducing pathogenic Th17 cells, i.e. GM-CSF+ Th17 cells. In the present study, we show that expression of the inflammasome related genes, NLRP3, caspase-1, IL-1ß and the IL-1ß/IL-1Ra ratio, was increased in PBMC from MS patients compared to healthy controls (HC). However, in an in vitro inflammasome activity assay with PBMC, IL-1ß protein secretion and the IL-1ß/IL-1Ra protein ratio were similar in MS patients and HC. Th cells cultured in the presence of supernatant derived from LPS/ATP inflammasome activated PBMC showed increased Th17 and GM-CSF+ Th17 cell frequencies in HC and MS patients and decreased anti-inflammatory IL-10+Th cell frequency in HC compared to Th cells cultured in the presence of control supernatant. Moreover, addition of the immune modulator calcitriol to the former condition resulted in reduced frequencies of Th17 and GM-CSF+Th17 cells, and also of IL-10+ Th cells. Evidently, our data indicate that inflammasome activity can skew the Th cell population toward a more pro-inflammatory composition, an effect that might be inhibited by vitamin D, and that might be importantly involved in inflammation within the central nervous system.


Subject(s)
Gene Expression Profiling , Inflammasomes/genetics , Leukocytes, Mononuclear/metabolism , Multiple Sclerosis/genetics , Multiple Sclerosis/immunology , Th17 Cells/immunology , Adenosine Triphosphate/pharmacology , Adult , Case-Control Studies , Cell Differentiation/drug effects , Cell Differentiation/genetics , Down-Regulation/drug effects , Female , Gene Expression Regulation/drug effects , Humans , Inflammasomes/metabolism , Interleukin 1 Receptor Antagonist Protein/metabolism , Interleukin-10/metabolism , Interleukin-17/metabolism , Interleukin-1beta/blood , Interleukin-1beta/metabolism , Leukocytes, Mononuclear/drug effects , Lipopolysaccharides/pharmacology , Male , Middle Aged , Multiple Sclerosis/blood , Subcellular Fractions/drug effects , Subcellular Fractions/metabolism , Th17 Cells/drug effects , Th17 Cells/pathology , Vitamin D/pharmacology , Young Adult
3.
J Neuroimmunol ; 258(1-2): 77-84, 2013 May 15.
Article in English | MEDLINE | ID: mdl-23517930

ABSTRACT

In the present study, circulating proportions of CD8(+) T (Tc) cell subsets, including IL-17 (Tc17) and IL-10 (Tc10) producing cells, were assessed in relapsing-remitting MS (RRMS) patients and a possible effect of beta interferon (IFN-ß), glatiramer acetate (GA), and vitamin D (VitD) on these cell subsets was investigated. We show that both Tc17 and Tc10 cell fractions are elevated in the circulation of RRMS patients in remission compared to healthy subjects and that these Tc subsets remain unaffected by current immune modulating regimens.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Multiple Sclerosis, Relapsing-Remitting/immunology , T-Lymphocyte Subsets/immunology , Adult , Female , Flow Cytometry , Glatiramer Acetate , Humans , Immunosuppressive Agents/therapeutic use , Interferon-beta/therapeutic use , Interleukin-10/immunology , Interleukin-17/immunology , Male , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Peptides/therapeutic use , Radioimmunoassay , Recurrence , Remission Induction , Vitamin D/blood
4.
Eur J Clin Microbiol Infect Dis ; 32(1): 61-9, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22875191

ABSTRACT

Vitamin D skews the immune system towards a more tolerogenic state. Therefore, a relatively high vitamin D status, i.e., within the normal physiological range, might result in a lower antibody response to infection and vaccination. We hypothesized, however, that vitamin D is primarily important in establishing immune homeostasis, implying that a relatively high vitamin D status would not hamper an adequate antibody response against pathogens. Our results show that the vitamin D status did not differ between responders and hypo-responders in patients infected with Streptococcus pneumoniae, as well as patients vaccinated against S. pneumoniae, Neisseria meningitidis type C (MenC), and/or Haemophilus influenzae type b (Hib). Furthermore, specific IgG titers were not associated with the vitamin D status in patients vaccinated against S. pneumoniae and MenC, while there was a weak inverse association in Hib-vaccinated patients. These data indicate that a relatively high vitamin D status does not seem to hamper an adequate antibody response upon infection or vaccination, suggesting that vitamin D, in this setting, is not immunosuppressive.


Subject(s)
Antibodies, Bacterial/blood , Antibody Formation , Haemophilus influenzae/immunology , Neisseria meningitidis/immunology , Streptococcus pneumoniae/immunology , Vitamin D/blood , Adult , Bacterial Infections/immunology , Bacterial Vaccines/immunology , Cohort Studies , Female , Humans , Immunoglobulin G/blood , Male , Middle Aged , Serum/immunology
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