Cerebrospinal fluid levels of myelin basic protein-like material and soluble interleukin-2 receptor in multiple sclerosis

The presence, level and disease activity relationships of soluble interleukin-2 receptor (sIL-2R) in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients are unresolved. We measured CSF immunoreactive myelin basic protein (MBP), a marker of acute myelin damage, and sIL-2R levels in the CSF from 11 patients with active relapsing remitting (RR) MS, five with stable RR MS, eight with chronic progressive (CP) MS, five with other neurologic diseases, and three normal controls. No measurable (less than 100 units/ml) sIL-2R was present in any of the samples. Conversely, MBP levels were elevated in the active RR group compared to the other four groups. These results indicate that, at the sensitivity of assays currently available, levels of CSF sIL-2R do not correlate with the diagnosis or disease activity of MS.     

Elevated serum levels of interleukin-12 in chronic progressive multiple sclerosis

The serum levels of the heterodimeric cytokine IL-12 were measured by solid-phase ELISA in a group of healthy subjects, multiple sclerosis (MS) patients with secondary chronic progressive course of the disease and patients suffering from other neurological diseases (OND). Serum levels of IL-12 higher than 5 pg/ml (limit of sensitivity of the assay) were only found in 2/30 (6.7%) of the healthy subjects and none of the 8 subjects with OND. In contrast, IL-12 was found in the majority of CPMS patients' sera (10/15, 66.7%) with values ranging between 5.5 and 18.6 pg/ml. These results are suggestive for an up-regulated production of IL-12 in CPMS.     

The relationship of interleukin-2 and soluble interleukin-2 receptors to intrathecal immunoglobulin synthesis in patients with multiple sclerosis

The in vivo relationship of interleukin-2 (IL-2) to the local humoral immune response within the central nervous system (CNS) in patients with multiple sclerosis (MS) is hitherto largely unknown. Intrathecal levels of IL-2 and soluble IL-2 receptors (sIL-2R) were correlated to the local CNS synthesis of immunoglobulin G, A, D, and M isotypes in 70 patients with clinically definite MS. Levels were also determined in 19 normal control subjects to establish normal reference limits. High cerebrospinal fluid levels of IL-2 and sIL-2R were detected mainly in patients with acute relapsing-remitting MS and were significantly higher than corresponding serum levels. Intrathecal levels of IL-2 significantly correlated with local CNS synthesis of IgD and IgM, while no correlation was found with either IgG or IgA. Similarly, intrathecal sIL-2R levels significantly correlated with local CNS production of IgD and IgM, but not IgG or IgA. These findings further extend previous reports and also suggest that IL-2 and sIL-2R are involved in the early intrathecal humoral immune response in MS.     

In vivo relationship of interleukin-2 and soluble IL-2 receptor to blood-brain barrier impairment in patients with active multiple sclerosis

Interleukin (IL)-2 has well-recognized effects on cerebral endothelial cells and, therefore, may mediate disruption of the blood-brain barrier in patients with multiple sclerosis (MS). To evaluate the in vivo relationship of the IL-2 system to blood-brain barrier impairment in MS, levels of IL-2 and soluble IL-2 receptors (sIL-2R) in cerebrospinal fluid (CSF) and serum samples from 50 patients with active MS and 49 controls were correlated with values of the CSF to serum albumin ratio. Intrathecal levels of IL-2 and sIL-2R were significantly higher in MS compared with the control groups and correlated with albumin ratios in MS patients. Intrathecal levels of IL-2 and sIL-2R also correlated with the degree of barrier damage in these patients. It is suggested that intrathecal levels of IL-2 and sIL-2R are related to barrier impairment in MS and may be important in understanding some of the pathological changes of this condition.     

Cyclophosphamide in chronic progressive multiple sclerosis: a comparative study

No effective treatment is presently available for progressive multiple sclerosis (MS). Cyclophosphamide (CFX), a cytotoxic immunosuppressive drug widely used in systemic dysimmune diseases, has been proposed for the treatment of multiple sclerosis with different schedules and controversial results. To evaluate the safety and clinical efficacy of CFX, we compared three different treatment schedules in patients with progressive MS: induction followed by bimonthly boosters for one year (17 patients); bimonthly boosters for one year without previous induction (15 patients); and monthly boosters for one year (21 patients). Survival analysis showed that the percentage of stable patients was significantly higher in the first and third treatment schedule groups. Myelotoxicity occurred in patients treated with induction and boosters (Group A). A high incidence of broncopneumonia was observed in patients undergoing the second treatment schedule (Group B). No major effects were observed in patients treated with monthly boosters (Group C). Response to treatment was limited to secondary progressive form. This study suggests that monthly treatment with CFX might be safely administered in progressive MS patients; its clinical efficacy must be confirmed by an appropriately designed clinical trial.     

Serum cytokine levels in chronic progressive multiple sclerosis: interleukin-2 levels parallel tumor necrosis factor-alpha levels

Serum levels of the cytokines interleukin-1 alpha (IL-I alpha), IL-1 beta, IL-2, IL-4, IL-6, tumor necrosis factor-alpha (TNF-alpha) and the soluble IL-2 receptor were measured in chronic progressive multiple sclerosis patients (CPMS) and normal, inflammatory, and noninflammatory disease controls. Serum IL-2 levels displayed the most consistent abnormalities in the group of tests for the CPMS group, and were the only cytokine levels to achieve significance in statistical group analyses. However, several patients with CPMS had normal serum IL-2 levels. An incidental finding was a statistical correlation between serum IL-2 and TNF-alpha levels among all groups tested. This finding was supported on analysis of serial serum samples from CPMS patients. These results suggest a linkage of IL-2 and TNF-alpha production, especially in pathological conditions.     

Serum uric acid, dehydroepiandrosterone sulphate, and apolipoprotein E genotype in benign vs. progressive multiple sclerosis

The majority of patients with multiple sclerosis (MS) experience gradual progression of disability, either as secondary progressive MS (SPMS) or primary progressive MS (PPMS). A subgroup with relapsing-remitting MS shows a benign course with little or no disease progression and minimal disability decades after the first manifestations, so called benign MS (BMS). In our search to identify factors that are associated with progression of MS, we investigated serum levels of uric acid and dehydroepiandrostenedione sulphate (DHEAS), and apolipoprotein (apo)E genotype in 28 patients with BMS, 33 with SPMS, 21 with PPMS, and 29 healthy individuals. We found no significant changes in uric acid levels and apoE genotype between the four groups. Mean DHEAS levels were lower in MS patients compared with healthy controls (P = 0.049), but there were no significant differences between the clinical subgroups of MS. In patients with SPMS and PPMS there was no correlation between progression rate and serum levels of either uric acid or DHEAS. Our results suggest that serum levels of uric acid and DHEAS, and apoE genotype do not differ between patients with a benign and progressive course of MS.     

Intravenous immunoglobulin, plasmalymphocytapheresis and azathioprine in chronic progressive multiple sclerosis

Five patients with a severe form of chronic progressive multiple sclerosis no longer responsive to steroid therapy were treated for six months with high-dose intravenous immunoglobulin associated with plasmalymphocytapheresis and azathioprine. In spite of an apparent initial stabilization of the course of the disease, EDSS assesment after six and twelve months of therapy revealed progressive disability in all patients.

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Sommario Cinque pazienti affetti da una grave forma di sclerosi multipla cronica progressiva (SMCP) resistente alla terapia steroidea sono stati trattati per sei mesi con IG e.v. ad alto dosaggio associate a plasmaferesi ed azatioprina. Durante il ciclo di trattamento, ben tollerato in tutti i pazienti, si è osservata una apparente riduzione della disabilità, ma l'osservazione clinica a sei mesi ed a un anno non ha confermato questo dato. L'associazione di IG e.v., plasmalinfocitoaferesi ed azatioprina, pur agendo verosimilmente su parte dei meccanismi umorali e cellulari coinvolti nel determinismo della malattia non sembra influenzare l'evoluzione clinica delle forme severe di SMCP.

     

Serum sAPO-1/Fas levels in multiple sclerosis

Soluble APO-1 (sAPO-1) may prevent apoptosis of lymphocytes induced by activation of the APO-1/Fas receptor. Objectives – To determine sAPO-1 levels in the serum of multiple sclerosis (MS) patients and controls in order to investigate if abnormal lymphocyte apoptosis occurs in this disease. Methods – Serum samples from patients with MS, other neurological diseases, systemic lupus erythematosus and healthy controls were determined by enzyme-linked immunosorbent assay. Results – We did not detect differences in mean serum sAPO-1 levels between patients with multiple sclerosis and controls. Conclusions – This preliminary study suggests that resistance of peripheral blood lymphocytes to apoptosis mediated by sAPO-1 is not likely to be a major factor in the development of autoreactive cells in MS.     

抑郁症首次发病维吾尔族、汉族患者血清白介素-2、6及其可溶性受体水平的对照研究

目的:探讨抑郁症首次发病的维吾尔族(维族)、汉族患者血清白介素(IL)-2、IL-6及其可溶性受体(sIL-2R、sIL-6R)水平的变化。方法:对117例首次发病的抑郁症患者(抑郁症组,维族亚组57例,汉族亚组60例)给予文拉法辛治疗4周。治疗前后采用汉密尔顿抑郁量表(HAMD)-17项评定病情,采用酶联免疫吸附法(ELISA)检测血清IL-2、IL-6及sIL-2R、sIL-6R水平;并与性别、年龄相匹配的正常对照组(维族、汉族各55例)比较。结果:抑郁症维族及汉族亚组HAMD评分治疗后较治疗前显著下降(P均0.01),两亚组间差异无统计学意义。抑郁症组治疗前血清IL-2、IL-6及sIL-2R、sIL-6R水平明显高于正常对照组(P均0.01),且IL-2、sIL-6R水平在维族与汉族亚组间差异有统计学意义(P均0.01);治疗后血清IL-2、IL-6及sIL-2R、sIL-6R水平较治疗前明显下降(P均0.01)。结论:维族和汉族抑郁症患者均有免疫失调;文拉法辛治疗能改善抑郁症病情及免疫失调。     

Course and prognosis of chronic progressive multiple sclerosis: Results of an epidemiological study

In studies on the natural course of multiple sclerosis (MS), several forms of the disease are distinguished. The most important are the relapsing remitting and the chronic progressive forms. The relationship between these remains unclear. In a prospective epidemiological survey we studied the course of MS using the year in which the chronic-progressive phase started as a landmark. The reliability of this "year of progression" was examined in an observer agreement study. Data were acquired from 342 patients. Progression of the handicap was most rapid in case of a secondary progressive course, female sex, high relapse rate in the preceding remitting phase and "year of progression" at a higher age. Survival after the "year of progression" was lowest in the secondary progressive group. Determining the "year of progression" seems to be significant for the prognosis.     

Lymphocyte activating factor activity in the serum and cerebrospinal fluid of patients with multiple sclerosis

Serum and cerebrospinal fluid (CSF) from patients with multiple sclerosis (MS), patients with other (non-inflammatory) neurological diseases (OND), patients with non-inflammatory non-neurological diseases, and normal controls were assayed for lymphocyte activiting factor (LAF) activity by thymocyte costimulation. LAF activity was detected in normal control sera, which did not differ significantly in this respect from MS or OND patient sera. Not were there significant differences by stage of MS (chronic progressive MS, MS in relapse and MS in remission) or between MS patients and the non-inflammatory non-neurological controls. Almost all the CFSs assayed presented lower values than did the corresponding sera. Serum and CSF after fractionation showed no significant increase in LAF activity except in the 2 MS patients in remission. From these data it may be assumed that LAF activity does not necessarily correspond to the clinical phase of MS. The possible role of LAF activity as a marker of MS progression has yet to be determined.

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Sommario La capacità di co-stimolare la proliferazione timocitaria (attività LAF) è stata valutata nel siero e nel liquor di pazienti con sclerosi a placche e con altre malattie neurologiche non infiammatorie. La valutazione è stata anche fatta in pazienti senza malattie neurologiche né infiammatorie, considerati come controlli ed in soggetti normali. I sieri di questi ultimi presentavano un certo grado di attività LAF e non è stata trovata alcuna differenza significativa tra questo gruppo e tra i sieri dei pazienti con sclerosi a placche e quelli dei pazienti con altre malattie neurologiche. Inoltre, non vi era alcuna differenza significativa tra i sieri dei pazienti con sclerosi a placche in vari stadi della malattia. Anche nei campioni di liquor non è stata trovata alcuna differenza significativa e comunque quasi tutti i liquor esaminati presentavano una minore attività LAF dei rispettivi sieri. L'attività LAF dopo frazionamento non aumentava significativamente ad eccezione dei due sieri di pazienti con sclerosi a placche in remissione. Alla luce di questi dati si può concludere che l'attività LAF non è correlata necessariamente alla fase clinica della sclerosi a placche.

     

Nitric oxide metabolites and interleukin-6 in cerebrospinal fluid from multiple sclerosis patients

Interleukin-6 (IL-6) and nitric oxide (NO) are implicated in the pathology of multiple sclerosis (MS). We have investigated the levels of these mediators in the cerebrospinal fluid (CSF) from 50 patients with MS and 23 control subjects. Mean CSF IL-6 level was higher in the total MS group in comparison with controls, but not significantly, whilst the difference between patients with stable MS and controls reached the level of statistical significance. Mean CSF nitrite/nitrate level was significantly higher in the total MS group compared with the control group, as well as in active MS patients versus controls. There was significant difference neither in the mean CSF IL-6 nor in nitrite/nitrate levels between active and stable MS patients. Interestingly, we observed a significant negative correlation between IL-6 and nitrite/nitrate levels in the CSF in the total MS group. Such a trend existed in both subgroups with active and stable MS, but without reaching the level of statistical significance. Our data further support the involvement of IL-6 and NO in ongoing pathological processes in MS, suggesting their potential interplay within the central nervous system in this disease.     

Elevated soluble interleukin-2 receptor levels in patients with active multiple sclerosis

The level of soluble interleukin-2 receptor (sIL-2R) was quantitated with enzyme-linked immunosorbent assay in serum and cerebrospinal fluid obtained from 24 patients with multiple sclerosis and 10 patients with other neurological disorders in whom immunological mechanisms are unlikely to participate. The sIL-2R level in the serum and cerebrospinal fluid of patients with multiple sclerosis in relapse was significantly higher compared with patients with multiple sclerosis in remission and with controls. The sIL-2R level, especially in the cerebrospinal fluid, showed higher sensitivity and specificity than other clinical parameters including the cerebrospinal fluid IgG ratio, peripheral lymphocyte CD4/CD8 ratio, cerebrospinal fluid myelin basic protein and oligoclonal bands. Our data suggest that measurement of the sIL-2R level may be useful in evaluating disease activity in patients with multiple sclerosis.     

Interleukin-8 and RANTES levels in patients with relapsing-remitting multiple sclerosis (RR-MS) treated with cladribine

OBJECTIVE: Chemokines are involved in the pathogenesis of multiple sclerosis. The aim of the study was to evaluate the effects of immunosuppressive therapy on production of two proinflammatory chemokines--interleukin-8 (IL-8) and RANTES (regulated on activation, normal T cell expressed and secreted). MATERIALS AND METHODS: Twenty-five patients with relapsing-remitting multiple sclerosis were treated with 2-chlorodeoxyadenosine (Cladribine), administered subcutaneously in 6 cycles repeated every 5 weeks. IL-8 and RANTES levels were measured by the enzyme-linked immunoassay (ELISA) method in serum and cerebrospinal fluid (CSF) before and after treatment. RESULTS: After Cladribine treatment the levels of IL-8 decreased significantly in CSF only, whereas the RANTES levels decreased significantly both in CSF and serum. CONCLUSION: Our results suggest that Cladribine therapy might modify the circulating level of RANTES.     

Interferon-beta1b treatment modulates cytokines in patients with primary progressive multiple sclerosis

OBJECTIVES: It is unknown whether the immunological effects of beta-interferon (IFN-beta) differ in primary progressive multiple sclerosis (PPMS) when compared with relapsing-remitting multiple sclerosis (RRMS). Therefore, we investigated the effects of IFN-beta1b treatment in PPMS on proliferation and cytokine pattern of peripheral blood mononuclear cells (PBMC) and interleukin-10 (IL-10) serum level. METHODS: Eighteen patients were treated with IFN-beta1b for 12 months in an open-label trial. Serum and PBMC were collected longitudinally. RESULTS: Interleukin-10 serum levels increased (P = 0.02) during treatment. Tumor necrosis factor-alpha was increased in anti CD3 (OKT3) antibody stimulated PBMC during treatment (P = 0.04), whereas secretion of IL-10 was decreased in OKT3 (P = 0.04), but increased in concavalin A stimulated PBMC (P = 0.02). CONCLUSIONS: Interleukin-10 serum levels rose in IFN-beta1b-treated patients as has been observed in RRMS. The changes in cytokine patterns secreted by T-lymphocytes of PPMS patients, however, differ from effects observed in RRMS supporting the hypothesis that PPMS differs in some immunological aspects from RRMS.     

The effects of interferon-β on interleukin-10 in multiple sclerosis patients

The incidence of the neuropathological lesions and the severity of the clinical symptoms in multiple sclerosis (MS) are correlated with the amount of the transferred autoreactive T cells. The balance between the T helper 1 (Th1) and T helper 2 (Th2) cytokine phenotypes may affect the activity of the disease in MS patients. Interleukin-10 (IL-10) is a cytokine secreted by Th2 cells. Thus, it has been thought that inducing IL-10 may have therapeutic effects in the treatment of MS patients. In this study, in order determine whether different types of prophylaxis change the secretion of IL-10, we measured the levels of IL-10 in relapsing-remitting type multiple sclerosis (RRMS) patients receiving interferon-beta 1b (IFN-beta 1b) or azathioprine (AZA). Our study consisted of RRMS patients (n=45) and healthy subjects (n=15) as control group. Patients were categorized into three groups as those receiving either IFN-beta 1b or AZA and those not receiving prophylaxis. Each group was compared with the control group. Serum IL-10 levels were determined using ELISA method. IL-10 levels of those receiving IFN-beta 1b were found to be significantly higher than that of other groups. These results support that the ability of inducing anti-inflammatory cytokine IL-10 plays a role in the clinical advantage of IFN-beta 1b in MS treatment.     

Chemokine CCL2 and chemokine receptor CCR2 in early active multiple sclerosis

The chemokine monocyte chemoattractant protein (MCP)-1/CCL2 and its receptor CCR2 have been strongly implicated in disease pathogenesis in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS), whereas data on the CCL2-CCR2 axis are scarce in MS. We studied the expression of CCR2 on leukocytes in blood and cerebrospinal fluid (CSF) from patients with monosymptomatic optic neuritis and MS, and the concentration of CCL2 in the CSF from these patients. Results were compared with the results in non-inflammatory neurological controls and were correlated with other parameters (magnetic resonance imaging and CSF data). Our findings suggest a limited role for CCL2/CCR2 in early active MS.     

Serum uric acid levels in multiple sclerosis patients correlate with activity of disease and blood–brain barrier dysfunction

Several findings suggest lower levels of serum uric acid in multiple sclerosis (MS) patients. The aim of this study is to investigate relationships of uric acid serum levels in relapse-remitting (RR) MS patients with clinical activity of disease and blood-brain barrier (BBB) condition. Sixty-three definite RRMS patients and 40 controls divided into two groups: 20 healthy donors and 20 patients with other inflammatory neurological diseases (OINDs) were analysed. By using a quantitative enzymatic assay according to the manufacture's protocol and a commercial uric acid standard solution, serum uric acid levels were measured and the results were standardized. To investigate BBB function, magnetic resonance imaging after administration of gadolinium was used. MS patients were found to have significantly lower serum uric acid levels (193.89 +/- 49.05 micromol/l; mean value +/-SD) in comparison with healthy donors (292.7 +/- 58.65 micromol/l; P=0.000) and OIND patients (242.7 +/- 46.66 micromol/l; P=0.001). We found that MS patients with relapse had significantly lower serum uric acid levels (161.49 +/- 23.61 micromol/l) than MS patients with remission (234.39 +/- 41.96 micromol/l; P=0.000) and more over, MS patients with BBB disruption had significantly lower serum uric acid levels (163.95 +/- 26.07 micromol/l) than those with normal BBB (252.48 +/- 25.94 micromol/l; P=0.000). Further, we also found that serum uric acid level independently correlated with disease activity, BBB disruption, and gender. These results indicate that lower uric acid levels in MS patients are associated with relapse and suggest that uric acid might be beneficial in the treatment of MS.