Circulating immune complexes in serum and in cerebrospinal fluid of patients with multiple sclerosis

We studied circulating immune complexes (IC) in the serum and cerebrospinal fluid (CSF) of patients with clinically defined multiple sclerosis (MS), in order to establish a correlation with the clinical course of the disease and to investigate the molecular composition of the IC isolated from patients in active phase of the disease. Serum IC levels were found to be significantly increased in patients from the progressive and active relapsing-remittent subgroups with both the CIC-conglutinin and C1q-binding methods. High levels of IC in CSF were detected only in the subgroup consisting of the relapsing-remittent patients in disease exacerbation when IC were determined by the C1q-binding test. No significant increase in serum or in CSF were found using the mRF-I test. The preliminary results of a qualitative investigation on serum IC in MS indicated that they are heterogeneous in nature, their size is mainly of the intermediate type, and they contain IgG, IgM, complement components and beta 2-microglobulins, the latter presenting an observation both new and interesting for studies on serum IC in MS patients.     

Lymphocyte subpopulations in cerebrospinal fluid and peripheral blood in multiple sclerosis

Lymphocytes subpopulations in cerebro-spinal fluid (CSF) and peripheral blood (PB) from multiple sclerosis (MS) patients were studied. PB of MS patients contains the same prevalence of E and EA rosette forming cells compared with controls, consisting of patients affected by various "nonimmunological" neuropsychiatric diseases. Cytochemical identification by the method of acid esterases in PB demonstrated in MS a prevalence of lymphocyte subpopulations similar to controls, and a relatively high percentage of macrophages compared with other methods, especially in MS patients: this may partially account for variable results obtained by various authors with the rosette technique. In CSF a significant decrease of total T, and particularly of T gamma cells, was found. Since T gamma lymphocytes have a suppressor effect on B cell proliferation and Ig synthesis, their decrease could be related with Ig hypersynthesis commonly found in the central nervous system of MS patients.     

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.     

Leukotrienes in the cerebrospinal fluid of multiple sclerosis patients

The concentration of the leukotrienes B4 (LTB4) and C4 (LTC4) was measured in the cerebrospinal fluid (CSF) of 38 multiple sclerosis (MS) patients and 51 with other neurological diseases. The LTB4 and LTC4 levels were significantly elevated in MS compared with the controls. The findings suggest that lipoxygenase products might play a pathogenetic role in the early, encephalitogenic phase of MS. The administration of lipoxygenase inhibitors or leukotriene antagonists might well open new perspectives for the treatment of MS.     

Immune complexes in serum and cerebrospinal fluid of multiple sclerosis patients and patients with other neurological diseases

Paired serum and cerebrospinal fluid (CSF) specimens from 30 multiple sclerosis (MS) patients and 30 patients with other neurological diseases (ONDs) were analyzed for the presence of immune complexes (ICs). With each of the 4 tests used, ICs were found more frequently in sera from both MS and OND patients than in sera from healthy blood donors. IC-positivity for MS and OND patient CSF varied from 10-33 % and from 10-17 % in different tests. The number of IC-positive sera or CSF in MS patients did not differ significantly from those in OND patients. For both MS and OND patients, the positivity pattern for serum and CSF specimens in each IC test was essentially unique. Furthermore, because several CSF IC-positive and serum IC-negative paired specimens were found, intrathecal IC formation may be independent of IC formation in peripheral blood. The presence of ICs in serum or CSF did not correlate with the clinical status of or laboratory data on the MS patients, nor was a correlation found with the diagnosis of the OND patients. In total, these results suggest that the presence or absence of ICs in MS or OND patients may simply reflect changes in the immunological regulation of individual patients.     

Lymphocyte subpopulations in the blood and cerebrospinal fluid of multiple sclerosis patients in active disease

Lymphocyte subpopulations (total T cells, active T cells and B cells) were simultaneously analyzed in peripheral blood and CSF of MS patients. All patients were in active disease, 3 to 4 weeks after first signs of disease activation appeared. Per cent levels and absolute numbers of examined lymphocyte subpopulations in the blood of MS patients were significantly lower than in healthy controls. In MS, the level of active T lymphocytes was lower in CSF than in peripheral blood. The results support our earlier observations relating to the role of active T lymphocytes in the clinical course of disease.     

Increased cerebrospinal fluid chitotriosidase index in patients with multiple sclerosis

Verbeek MM, Notting EA, Faas B, Claessens‐Linskens R, Jongen PJH. Increased cerebrospinal fluid chitotriosidase index in patients with multiple sclerosis.
Acta Neurol Scand: 2010: 121: 309–314.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective – To investigate chitotriosidase (CTTS) activity in serum and cerebrospinal fluid (CSF) in multiple sclerosis (MS) patients in relation to disease course and CSF markers for immune activation or inflammation. Materials and methods – We studied 80 patients with relapsing–remitting MS (RRMS), 24 with secondary progressive MS (SPMS), 20 with primary progressive MS (PPMS) and 29 patients with other neurological disorders (OND). We measured CTTS activity and studied the correlation with CSF mononuclear cell count (MNC) and intrathecal IgG production. Results – CTTS activity was significantly higher in CSF, but not in serum, from the total MS group compared with OND and controls. In RRMS and SPMS CTTS, index was increased compared with controls (RRMS, 0.10 ± 0.21; SPMS, 0.10 ± 0.15; controls, 0.021 ± 0.020), but not in PPMS (0.061 ± 0.052). CTTS index was higher in MS patients with elevated MNC or CSF‐restricted oligoclonal IgG bands than in MS patients without these CSF findings. Conclusions – CTTS index is elevated in RRMS and SPMS. The CTTS index is related to CSF markers of inflammation or immune activation.     

Amino acid concentrations in cerebrospinal fluid of patients with multiple sclerosis

As oligodendrocytes have binding sites for excitatory amino acids (glutamate, aspartate, serine, etc.), a role of these molecules in demyelinating disorders is possible. We measured the levels of amino acids in the cerebrospinal fluid (CSF) of patients with multiple sclerosis in comparison with CSF obtained by myelography from patients with lower back pain. There were no significant differences in the CSF concentrations of these amino acids between the two groups. Normal concentrations of excitotoxins do not exclude the role of these molecules in demyelinating disorders.     

Increased T-lymphocyte interleukin-6 binding in patients with multiple sclerosis.

Multiple sclerosis (MS) represents a T-cell-mediated autoimmune demyelinating disease of the central nervous system associated with altered immunoregulation. Interleukin (IL)-6 is a cytokine that has several effects on the neuroimmune system. Specific IL-6 receptors have been found in human lymphocytes and neuroglial cells. The aim of the present study was to assay IL-6 binding on peripheral blood T lymphocytes in MS patients. We found that T cells from MS patients had significantly more IL-6 receptors [Bmax: 279 +/- 7 vs. 246 +/- 8 (mean +/- SEM) receptors/cell, in patients and controls, respectively], whereas Kd values were similar to those of healthy subjects [26.8 +/- 0.7 vs. 25.4 +/- 0.6 (mean +/- SEM) pM, in patients and controls, respectively]. Significant (P < 0.05) differences in IL-6 binding values were observed between stable patients and those relapsing (272 +/- 9 vs. 300 +/- 12 (mean +/- SEM) receptors/cell, respectively). We found significantly (P < 0. 001) higher amounts of IL-6 receptors on CD4+ T cells from MS patients than on CD4+ lymphocytes from controls (434 +/- 11 vs. 363 +/- 9 (mean +/- SEM) receptors/cell, respectively); CD8+ T cells showed very few IL-6 receptors in both patients and controls. These data are discussed in terms of MS immune pathogenesis and pathophysiology, because T-cell activation seems to be linked to increased IL-6 binding. The upregulated IL-6 system might be involved in antibody-mediated demyelinating pathways, because IL-6 is well known to enhance humoral immune response.     

多发性硬化病人血清和脑脊液壳三糖苷酶活性的研究

目的探讨多发性硬化(MS)病人血清和脑脊液(CSF)壳三糖苷酶(CTTS)活性以及CSF免疫活化和炎症标志物。方法选择三所医院178例MS病人,其中复发缓解型MS(RRMS)120例,继发进展型MS(SPMS)32例,原发进展型MS(PPMS)26例,并选取40例其他神经疾患(OND)和30非神经疾患病人作为对照组,检测血清和CSF中CTTS活性及CSF单核细胞数(MNC)和鞘内IgG产物。结果 MS病人与OND组和对照组比较,CSF中CTTS活性明显升高,但血清不升高。RRMS和SPMS组CTTS指数高于对照组,但PPMS组正常。在伴有MNC升高或CSF寡克隆IgG区带的MS病人,CTTS指数高于无此表现者。结论 RRMS和SPMS病人CCTS指数升高,CCTS指数与CSF炎症或免疫活化标志物有关。     

Immune complexes and the complement factors C4 and C3 in cerebrospinal fluid and serum from patients with chronic progressive multiple sclerosis

Immune complexes (IC) have been found in both serum and cerebrospinal fluid (CSF) in multiple sclerosis (MS). The complement system is known to play a major role as a mediator of inflammation in immune complex disease. Therefore, we have investigated paired samples of serum and CSF from 32 patients with progressive MS for IC, the levels of the complement factors C4 and C3, and presence of their activation products (AP). IC was found in serum from 17 of the 32 MS patients (53%) and in CSF from 9 of 31 MS patients (29%). No correlation was found between the occurrence of IC in serum and in CSF. The levels of C3 in serum and CSF from the MS patients did not differ from the levels in a control group, whereas the levels of C4 in MS-serum were elevated and the C4 levels in MS-CSF reduced. A low level of CSF-C4 correlated significantly to the occurrence of CSF-IC. AP of C4 and C3 in serum were seen in 11 of the 32 patients (34%), appearing significantly more frequently among patients with circulating IC. No C4- or C3AP could be identified in CSF.     

Tau protein concentrations in cerebrospinal fluid of patients with multiple sclerosis

FUNDAMENTALS AND OBJECTIVE: Multiple sclerosis (MS) is the prototype of demyelinating disease, but recently, it has been shown that the existence of axonal lesions contribute to irreversible central nervous system damage in this disease. Tau proteins are considered to be important for maintaining the stability of axonal microtubules involved in the mediation of fast axonal transport of synaptic constituents. There have been reports of increased cerebrospinal fluid (CSF) tau concentrations in patients with MS, and it has been suggested that this could be a marker of axonal damage. The objective of the present study was to elucidate whether CSF tau levels could be a marker of MS activity. PATIENT AND METHODS: We measured tau concentrations in the CSF of 20 patients with MS (nine in the first, seven in the second, one in the fourth exacerbation, and three patients with chronic progressive course) and 32 age- and sex-matched controls, using a specific enzyme-linked immunosorbent assay method. RESULTS: The CSF tau concentrations of patients with MS did not differ from those of controls, and they were not correlated with age at onset and duration of the disease. CONCLUSION: CSF tau concentrations are not a marker of MS activity.     

Essential fatty acids in the serum and cerebrospinal fluid of multiple sclerosis patients

ABSTRACT- Statistical evaluation of essential fatty acids (determined by gas chromatography) in the serum and cerebrospinal fluid of patients with definite MS and acute CCT showed marked differences as compared to healthy subjects. It was also evident that the decrease of essential fatty acids in MS patients differed from that of CCT patients. Whereas the fatty acid levels in the serum of MS patients revealed only minor differences as compared to the controls and CCT patients, MS patients did show a clear decrease, especially of linoleic and arachidonic acids, in the CSF. This difference was most pronounced in cholesterol esters in the CSF. One absorption study with safflower oil demonstrated normal enteral absorption of essential fatty acids and the ability to cross the blood-CSF barrier.     

Lymphocyte subpopulations in the cerebrospinal fluid and peripheral blood in multiple sclerosis

Subpopulations of lymphocytes in the CSF and peripheral blood were studied in 30 patients with MS, 16 with other neurologcial diseases (OND) and 15 control subjects without any neurological abnormalities. In patients with relapse of MS, the absolute numbers of total lymphocytes, alpha-naphthyl acid esterase (ANAE) positive, E-rosette forming and bearing the "avid"FcIgG receptor lymphocytes were significantly increased in the CSF as compared with stable or slowly progressive MS patients, patients with other OND and control subjects.
The relative number of ANAE-positive cells was higher, and "avid"FcIgG receptor bearing cells lower in the CSF of all patients with MS than in the two other groups. The significance of the finding is unclear. The imbalance between lymphocyte subpopulations may reflect a primary defect in MS, or may be secondary, due to the presence of circulating immune complexes. In peripheral blood no substantial differences in lymphocyte behavior were observed between MS patients and other groups.     

Multimodal evoked responses and cerebrospinal fluid oligoclonal immunoglobulins in patients with multiple sclerosis

One hundred patients with possible, probable and definite multiple sclerosis (MS) were examined with somatosensory (SER), visual (VER) and brain stem auditory (BAER) evoked responses. Paired samples of cerebrospinal fluid (CSF) and serum were examined with agarose gel electrophoresis to detect intrathecally synthesized oligoclonal immunoglobin bands. Comparison of the number of abnormal CSF and evoked response tests showed that the CSF examination was slightly more sensitive in all diagnostic groups when compared to the results of multimodal evoked responses but that the two sets of test were in part supplementary. Oligoclonal immunoglobulin bands in the CSF were present in all patients with a duration of the disease of less than six months. VER seemed to be the most sensitive of the evoked tests in this particular group of patients.     

Neutral protease in cerebrospinal fluid from patients with multiple sclerosis and other neurological diseases

Neutral protease activity was significantly elevated in the cerebro-spinal fluid of patients with multiple sclerosis (MS) in exacerbation and in the acute phase of acute viral meningoencephalitis (AME) compared with that of MS in remission, amyotrophic lateral sclerosis or psychosomatic disease. Since in each relapse of MS, protease activity was higher in exacerbation than in remission, this activity may be one good marker of disease activity in MS. One hundred micro molar of FOY305, synthetic protease inhibitor, inhibited in vitro increased neutral protease activity in MS in exacerbation, which suggests the possibility of a clinical application of this protease inhibitor for MS.     

Soluble L-selectin levels in serum and cerebrospinal fluid in patients with multiple sclerosis and systemic lupus erythematosus

Soluble L-selectin (sL-selectin) concentrations were measured in paired samples of serum and cerebrospinal fluid by an ELISA method. Patients with several forms of multiple sclerosis (MS) and systemic lupus erythematosus with central nervous system involvement (SLE-CNS) were investigated. Elevated CSF sL-selectin concentrations were found in patients with SLE-CNS (7.62 +/- 3.31 ng/ml) and with relapsing-remitting form of MS (6.99 +/- 4.72 ng/ml) compared to the control group (4.00 +/- 0.95 ng/ml). The data presented suggest some similarities between inflammatory/immunological events in the central nervous system in patients with SLE-CNS and relapsing-remitting form of MS. Immunological heterogeneity in MS is suspected.     

Soluble immune complexes in cerebrospinal fluid of patients with multiple sclerosis and other neurological diseases

The occurrence of soluble immune complexes (IC) in the cerebrospinal fluid (CSF) of 14 multiple sclerosis (MS) patients, four acute polyradiculoneuritis patients, 30 patients with other neurological diseases (OND) and 30 patients with disc prolapse (DP) was examined by a solid phase C1q-protein A binding assay (C1q-PABA) and a complement consumption test. IC-positive reactions were observed only in the C1q-PABA. The binding indices determined by the C1q-PABA differed significantly ( P < 0.01) when the MS or the OND patient groups were compared to the DP group. No significant ( P < 0.1) difference was observed between the indices in the MS and OND groups. Binding indices in C1q-PABA showed no correlation either to IgG concentration, total protein concentration or cell counts in CSF of MS patients. Three of the four polyradiculoneuritis patients were strongly IC-positive while the fourth patient was negative. Filtration and PEG-precipitation data indicated that a major part of the IgG-containing IC in CSF detected by C1q-PABA was of macromolecular nature.