The Role of Matrix Metalloproteinase 3 and 9 in the Pathogenesis of Acute Neuroinflammation. Implications for Disease Modifying Therapy.

Matrix metalloproteinases (MMPs) are proteolytic enzymes that are involved in a variety of physiological and pathological processes, including those in CNS. In this study, plasma values of MMP-3 and MMP-9 have been compared in clinically isolated syndrome (CIS) and relapsing-remitting multiple sclerosis (RRMS) patients during their acute attacks, in relation to the biological activity of disease. Therefore, we compared the MMPs plasma values regarding Expanded Disability Status Scale (EDSS), progression index of disease (PID), acute brain lesion volume seen on magnetic resonance imaging (MRI) and index of blood-brain barrier (BBB) permeability destruction. The obtained results demonstrated higher plasma values of MMPs in both study groups than control values (p < 0.05). No statistical significances have been detected comparing the obtained values of both enzymes between CIS and RRMS group (p > 0.05). In both CIS and RRMS groups, the patients with higher EDSS showed higher MMPs plasma values (p < 0.05). The MMPs values were also significantly higher in both study patients with higher total number comparing to those with lower number of MRI brain lesion (p < 0.05) (beyond MMP-3 in RRMS). All obtained correlations, between MMPs and EDSS, PID, volume of MRI Gd-enhancement brain lesions, and index of BBB permeability, were positive (p < 0.05.) This study demonstrates alterations of both tested MMPs with closed correlation with the disease biological activity. Although MMPs are being implicated in the pathogenesis of acute neuroinflammation, the MMPs modulation might be useful in the future design of disease modifying therapy with the specific target profile.

IL-17 and glutamate excitotoxicity in the pathogenesis of multiple sclerosis.

Immunoinflammatory-mediated demyelination, the main pathological feature of multiple sclerosis (MS), is regularly accompanied by neurodegenerative processes, mostly in the form of axonal degeneration, which could be initiated by glutamate excitotoxicity. In the current study, the relationship between Th17-mediated inflammatory and excitotoxic events was investigated during an active phase of MS. Cerebrospinal fluid (CSF) of patients with MS and control subjects was collected, and IL-17A and glutamate levels were determined. IL-17A level was significantly higher in patients with MS; whereas no statistically significant changes in glutamate concentrations were found. There was a direct correlation between IL-17A and glutamate levels; IL-17A levels were also associated with the neutrophil expansion in CSF and blood-brain barrier disruption. However, IL-17A level and the number of neutrophils tended to fall with disease duration. The results suggest that Th17 cells might enhance and use glutamate excitotoxicity as an effector mechanism in the MS pathogenesis. Furthermore, Th17 immune response, as well as neutrophils, could be more important for MS onset rather than further disease development and progression, what could explain why some MS clinical trials, targeting Th17 cells in the later stage of the disease, failed to provide any clinical benefit.

[Peripheral blood T lymphocyte subtypes in multiple sclerosis--dependance of clinical course and duration of the disease]. / Subpopulacije limfocita T periferne krvi kod multiple skleroze--zavisnost od klinicke forme i trajanja bolesti.

Multiple sclerosis is a disease mediated by immunological mechanisms, with characteristics of an autoimmune prosses. We registered changes in distribution of immunophenotipisation markers CD2, CD3, CD4, CD8, CD56 and DR, by indirect immunoflourescence assay, on immune cells of peripheral blood. We tested 20 patients with clinically definite category of illness, in exacerbation, and 10 healthy individuals. Multiple sclerosis patients had changes in distribution of T cell subtypes in exacerbation, which correlated with clinical course and duration of the disease. Relapsing-remitting course of disease is followed by decrease of activated T lymphocytes and fluctuation of CD4+ T lymphocytes, while there are no changes in studied markers at patients with progressive course. Duration of the disease over 10 years is followed by decreases of CD4+ and CD8+ T lymphocytes, independent of course of the disease.

[Changes in surface markers on peripheral blood lymphocytes, caused by thymic extract in breast cancer patients]. / Promene povrsinskih markera limfocita periferne krvi izazvane primenom ekstrakta timusa kod bolesnica s karcinomom dojke.

A quantification of peripheral blood CD2, CD3, CD4, CD8 i CDDR positive cells was performed to evaluate effectiveness of a bovine thymic extract, TFX-thymomodulin in expresing those surface markers, modulated by postoperative radiotherapy in breast cancer patients. Twenty patients with histologically proven breast cancer, assigned to clinical stage II using the criteria of TNM (Tumour Node Metastasis) classification were divided into two compatative groups: the first one was treated with radiotherapy only, whereas the second one was additionally treated with TFX-thymomodulin. The quantification of CD2, CD3, CD4, CD8 and CDDR positive peripheral blood cells was performed before and after treatment in both comparative groups, using the indirect immunofluorescent technique. We found significantly lower reduction in CD4 and CDDR positive cells in the breast cancer patient group, treated with radioimmunotherapy, compared to the group, treated with radiotherapy only. TFX-thumomodulin could be effective in reducing the changes of examined surface markers, caused by radiotherapy in breast cancer patients.