Immune regulation in multiple sclerosis : cytokines and metalloproteinases

Immunological mechanisms play a central role in the pathogenesis sclerosis (MS). In this study two groups of related immune variables are cytokines and metalloproteinases (MMPs), which regulate each other's production and activation. Cytokines play key role in pathogenesis and treatments of Cytokines are regulatory proteins secreted by a variety of cells. The pleiotropic action of cytokines include numerous effects on cells of the immune modulating immune responses. Cytokine receptors are crucial for the net effect of cytokines. The balance between Th1 and Th2 type cytokines might determine whether the immune response in MS is detrimental or beneficial. MMPs are a group of endopeptidases that degrade extracellular pro mechanisms in the genesis of inflammatory demyelination, such as recruitment, blood-brain barrier breakdown and myelin destruction are con be MMP-dependent processes.

Aims of the study: 1. To investigate the levels of cytokine secreting blood and cerebrospinal fluid mononuclear cells (MNC) in patients with MS and controls; 2. To define further the cytokine disbalance in MS by examining the levels of cytokine receptors that are important in the net effect of cytokine function; 3. To study the levels of blood and CSF MNC in MS expressing mRNA of MMPs and their inhibitors; and 4. To examine the effects of IFN-[beta] on cytokines and MMPs in MS.

Results: MS is associated with increased numbers of IL-6 and TNF-[alpha] secreting blood MNC and decreased numbers of IL-10 secreting cells compared to healthy subjects. In CSF, similar numbers of IL-6 and IL-10 secreting cells were observed in patients with MS and other neurological diseases (OND). Patients with MS also had higher levels of MMP-3, MMP-9 and tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA expressing blood MNC compared to controls. When patients with MS examined before vs. during 1 year of treatment with IFN-[beta], treatment resulted in decreased numbers of IL-6 and TNF-[alpha] secreting MNC and of MMP-3 and MMP mRNA expressing MNC compared to pretreatment levels. On the contrary, numbers of IL-10 secreting MNC and TIMP-1 mRNA expressing MNC were augmented IFN-[beta] therapy. IL-12 is a key cytokine for the development of Th1 type of immune response. ELISPOT assays were adopted to detect IL-12 secreting cells. In intracellular staining of IL-12 was measured by flow cytometry. Numbers of secreting blood MNC correlated with IL-12 positive blood MNC detected by flow cytometry. Utilizing IL-12 ELISPOT assays, elevated numbers of IL-12 secreting blood MNC were observed after stimulation with TNF-[alpha], IFN-[gamma], LPS, LPS+TNF-[alpha] or LPS+IFN-[gamma] compared to cultures without stimulation. When patients with MS were compared with controls, no difference was observed for numbers of IL-12 secreting blood MNC. In contrast, levels of IL-12 receptor (R)[beta]1 and -02 expressing T cells are higher in MS compared to controls, suggesting an elevated net effect of IL-12 in MS.

Conclusion: MS is associated with a disbalance of cytokines and of MMPs that may contribute to the pathogenesis of the disease. IFN-[beta] therapy seems to normalize altered levels of cytokines and MMPs observed in MS.

List of scientific papers

I. Özenci V, Kouwenhoven M, Huang YM, Xiao B, Kivisakk P, Fredrikson S, Link H (1999). Multiple sclerosis: levels of interleukin-10-secreting blood mononuclear cells are low in untreated patients but augmented during interferon-beta-1b treatment. Scand J Immunol. 49(5):554-561.
https://pubmed.ncbi.nlm.nih.gov/10320650

II. Özenci V, Kouwenhoven M, Huang YM, Kivisakk P, Link H (2000). Multiple sclerosis is associated with an imbalance between tumour necrosis factor-alpha (TNF-alpha)- and IL-10-secreting blood cells that is corrected by interferon-beta (IFN-beta) treatment. Clin Exp Immunol. 120(1):147-153.
https://pubmed.ncbi.nlm.nih.gov/10759776

III. Özenci V, Rinaldi L, Teleshova N, Matusevicius D, Kivisakk P, Kouwenhoven M, Link H (1999). Metalloproteinases and their tissue inhibitors in multiple sclerosis. J Autoimmun. 12(4):297-303.
https://pubmed.ncbi.nlm.nih.gov/10330301

IV. Özenci V, Kouwenhoven M, Teleshova N, Pashenkov M, Fredrikson S, Link H (2000). Multiple sclerosis: pro- and anti-inflammatory cytokines and metalloproteinases are affected differentially by treatment with IFN-beta. J Neuroimmunol. 108(1-2):236-243.
https://pubmed.ncbi.nlm.nih.gov/10900359

V. Özenci V, Kouwenhoven M, Press R, Link H, Huang YM (2000). IL-12 elispot assays to detect and enumerate IL-12 secreting cells. Cytokine. 12(8):1218-1224.
https://pubmed.ncbi.nlm.nih.gov/10930299

VI. Özenci V, Pashenkov M, Kouwenhoven M, Rinaldi L, Söderström M, Link H (2000). IL-12/IL-12R system in multiple sclerosis. [Submitted]