Characterization and modulation of immunoregulatory molecules in neuroinflammation

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease affecting the central nervous system (CNS). Several lines of evidence suggest that MS is an immune-mediated disorder characterized by active and inactive phases, where changes in disease activity are reflected by changes in the expression patterns of immunoregulatory molecules.

T cell immunoglobulin- and mucin-domain-containing molecules (TIMs) were recently described as associated with the regulation of cytokine differentiation. The in vitro expression of human TIM-1 and TIM-3 was examined using Th 1 and Th2 cell lines and real time RT-PCR. The ex vivo expression was determined in mononuclear cells derived from peripheral blood (PBMC) and cerebrospinal fluid (CSF-MC) of persons with MS and noninflammatory controls. A differential expression of TIM-1 and TIM-3 was demonstrated by human Th2 and Th1/ThO cell lines, respectively, in vitro. The expression of TIM-3 correlated well ex vivo with the expression of inflammatory Th1 cytokines (IFN-gamma and TNF-alpha) in MS CSF-MC. Conversely, TIM-1 was increased in CSF-MC during the inactive, but not the clinically active, phase of MS.

Interestingly, high TIM-1 was associated with low IFN-gamma expression, further supporting a role for TIMs in cytokine regulation in general and in MS in particular. Immune reactions in the CNS may not only mediate disease, but also convey neuroprotective effects. It is therefore conceivable that the expression of neurotrophic factors in immune cells may be of relevance for the relative protection of neurons during CNSinflammation. We examined the ex vivo expression of neurotrophin mRNAs in PBMC from persons with MS. Brain-derived neurotrophic factor (BDNF) mRNA was increased in MS compared with non-inflammatory controls. This is consistent with an active role of BDNF in MS, possibly as a compensatory, restorative and/or immunomodulatory mediator.

The cytokine IFN-beta has the potential to alter the disease course of MS, by reducing the number of relapses and by slowing the progression of neurological disability. A potential mechanism via which IFNbeta may act is through an antagonistic effect on IFN-gamma, a key proinflammatory cytokine. Reduced levels of both pro- and anti-inflammatory cytokines were detected after 6 months of IFN-beta treatment, but not after 2 weeks of treatment. There was no evidence to support an associated shift from the production of Th1- to Th2-cytokines.

Progressive muscular weakness, disabling fatigue and pain occurring decades after acute poliomyelitis clinically characterize the post-polio syndrome (PPS). Previously, increased numbers of CSF-MC expressing mRNA for inflammatory cytokines have been demonstrated in PPS. Here, immunomodulatory effects of intravenous immunoglobulin (Ivlg) in PPS were examined. The expression of TNF-alpha, IFNgamma, LL-10 and IL-4 mRNA was measured by real time RT-PCR in PBMC and CSF-MC of patients with PPS before, and 6-8 weeks after IvIg treatment. TNF-alpha, IFN-gamma, and IL-10 CSF mRNA levels were elevated in samples from untreated patients with PPS compared to persons with other neurological diseases. Upon IvIg treatment, IFN-gamma and TNF-alpha mRNA levels were dramatically reduced, while IL-10 remained unchanged. We conclude that CSF-MC expression of cytokines in PPS can be downmodulated with lvlg by treatment.

In conclusion, key immunoregulatory molecules are possible to target in human neuroinflammation, for both therapeutic and etiopathological studies.

List of scientific papers

I. Khademi M, Illes Z, Gielen AW, Marta M, Takazawa N, Baecher-Allan C, Brundin L, Hannerz J, Martin C, Harris RA, Hafler DA, Kuchroo VK, Olsson T, Piehl F, Wallstrom E (2004). T Cell Ig- and mucin-domain-containing molecule-3 (TIM-3) and TIM-1 molecules are differentially expressed on human Th1 and Th2 cells and in cerebrospinal fluid-derived mononuclear cells in multiple sclerosis. J Immunol. 172(11): 7169-76.
https://pubmed.ncbi.nlm.nih.gov/15153541

II. Gielen A, Khademi M, Muhallab S, Olsson T, Piehl F (2003). Increased brain-derived neurotrophic factor expression in white blood cells of relapsing-remitting multiple sclerosis patients. Scand J Immunol. 57(5): 493-7.
https://pubmed.ncbi.nlm.nih.gov/12753507

III. Khademi M, Wallstrom E, Andersson M, Piehl F, Di Marco R, Olsson T (2000). Reduction of both pro- and anti-inflammatory cytokines after 6 months of interferon beta-1a treatment of multiple sclerosis. J Neuroimmunol. 103(2): 202-10.
https://pubmed.ncbi.nlm.nih.gov/10696916

IV. Gonzalez H, Khademi M, Andersson M, Piehl F, Wallstrom E, Borg K, Olsson T (2004). Prior poliomyelitis-IVIg treatment reduces proinflammatory cytokine production. J Neuroimmunol. 150(1-2): 139-44.
https://pubmed.ncbi.nlm.nih.gov/15081258