Tumor necrosis factor-alfa and interleukin-4 in cerbrospinal fluid and plasma in different clinical forms of multiple sclerosis

Abstract

Background/Aim. Multiple sclerosis (MS) is an immunemediated central nervous system disease characterized by inflammation, demyelination and axonal degeneration. Cytokines are proven mediators of immunological process in MS. The aim of this study was to investigate whether there is a difference in the production of the tumor necrosis factor alpha (TNF-alpha) and interleukin-4 (IL-4) in cerebrospinal fluid (CSF) and plasma in the MS patients and the controls (other neurological non-inflammatory diseases) and to determine a possible difference in these cytokines in plasma and CSF in different clinical forms of MS. Methods. This study involved 60 consecutive MS patients - 48 patients with relapsing-remitting MS (RRMS) and 12 patients with secondary progressive MS (SPMS). The control group consisted of 20, age and sex matched, nonimmunological, neurological patients. According to the clinical presentation of MS at the time of this investigation, 34 (56.7%) patients had relapse (RRMS), 14 (23.3%) were in remission (RRMS), while the rest of the patients, 12 (20.0%), were SPMS. TNF-alpha and IL-4 concentrations were measured in the same time in CSF and plasma in the MS patients and the controls. Extended disability status score (EDSS), albumin ratio and IgG index were determined in all MS patients. Results. The MS patients had significantly higher CSF and plasma levels of TNF-alpha than the controls (p < 0.001 for both samples). IL-4 CSF levels were significantly lower in the MS patients than in the controls (p < 0.001), however plasma levels were similar. The patients in relapse (RRMS) and with progressive disease (SPMS) had higher concentrations of CSF TNF-alpha levels than the patients in remission (p < 0.001). IL-4 CSF levels in relapse (RRMS) and SPMS groups were lower than in the patients in remission. The patients in remission had an unmeasurable plasma TNF-alpha level and the patients with SPMS had significantly lower IL-4 levels in plasma than the patients in relapse and remission (p < 0.001). The only significant correlation between cytokine level with either EDSS, or albumin ratio, or IgG index, was found between CSF TNF-alpha levels and albumin ratio in the patients with relapse (R square = 0.431, p < 0.001). Conclusion. According to the obtained data MS relapse was characterized by high concentrations of TNF-alpha in CSF and plasma and low concentrations of IL-4 in CSF. Remission was characterized by high concentrations of IL-4 and low concentrations of TNF-alpha both in CSF and plasma. SPMS was characterized with lower concentrations of TNF-alpha and IL-4 compared to relapse, both in CSF and plasma.Uvod/Cilj. Multipla skleroza (MS) je imunoloski posredovana bolest centralnog nervnog sistema koju karakterisu inflamacija, demijelinizacija, degenaracija aksona i glioza. Citokini su vazni medijatori imunoloskih procesa kod MS. Cilj ove studije bio je da se ispita postojanje razlike u produkciji inflamacijskog citokina faktora nekroze tumora alfa (TNF-alfa) i antiinflamacijskog citokina interleukina 4 (IL-4) u likvoru i plazmi bolesnika sa razlicitim klinickim faktorima MS i kod bolesnika sa drugim neuroloskim neinflamacijskim oboljenjima (kontrolna grupa). Metode. U studiju je bilo ukljuceno 60 bolesnika sa MS, 48 sa relapsno-remitentnom MS (RRMS) i 12 bolesnika sa sekundarno progresivnom MS (SPMS). Kontrolnu grupu je sacinjavalo 20 bolesnika sa neuroloskim, neimunoloskim bolestima. U vreme ispitivanja, 34 (56,7%) bolesnika bilo je u fazi pogorsanja, 14 (23,3%) u fazi remisije, dok je 12 (20%) bolesnika imalo SPMS. Citokini TNF-alpha i IL-4 odredjivani su istovremeno u plazmi i likvoru bolesnika sa MS i kontrolne grupe. Nivo neuroloskog poremecaja, izmeren koriscenjem The Expanded Disability Status Scale (EDSS), albuminski koeficijent i IgG indeks odredjivani su kod svih bolesnika sa MS. Rezultati. Bolesnici sa MS imali su znacajno vise koncentracije TNF-alfa i u likvoru i u plazmi, u poredjenju sa bolesnicima kontrolne grupe (p < 0,01). Koncentracija IL-4 u likvoru bila je znacajno niza kod bolesnika sa MS, nego kod bolesnika kontrolne grupe (p < 0,01), dok su koncentracije plazmatskih vrednosti bile slicne. Bolesnici u fazi pogorsanja (RRMS) i sa SPMS imali su vise koncentracije TNF-alfa u likvoru, nego bolesnici u fazi remisije bolesti (RRMS), (p < 0,01). Koncentracija IL-4 u likvoru bila je niza kod bolesnika sa RRMS u fazi pogorsanja i SPMS, nego kod bolesnika koji su bili u remisji bolesti (p < 0,01). Kod bolesnika u remisiji nije nadjen TNF-alfa u plazmi, dok su bolesnici sa SPMS imali znacajno nize koncentracije IL-4 u plazmi u poredjenju sa bolesnicima u fazi pogorsanja i u remisiji (p < 0.01). Jedina statisticki znacajna korelacija nadjena je izmedju koncentracije TNF-alfa u likvoru i albuminskog koeficijenta i to kod bolesnika u fazi pogorsanja bolesti (R square = 0,431, p < 0,01). Zakljucak. Prema rezultatima naseg istrazivanja, pogorsanje MS karakterisu visoke koncentracije TNF-alfa u likvoru i plazmi i niske koncentracije IL-4 u likvoru. Remisiju bolesti karakterisu visoke koncentracije IL-4 i niske koncentraije TNF-alfa i u plazmi i u likvoru. Progresivnu formu (SPMS) karakterisu nize koncentracije TNF-alfa i IL-4 u poredjenju sa relapsom, i to i u plazmi i u likvoru.