Melanoma Cell Adhesion Molecule Expressing Helper T Cells in CNS Inflammatory Demyelinating Diseases.

BACKGROUND AND OBJECTIVE: To elucidate the relationship between melanoma cell adhesion molecule (MCAM)-expressing lymphocytes and pathogenesis of CNS inflammatory demyelinating diseases (IDDs). METHODS: Patients with multiple sclerosis (MS) (n = 72) and neuromyelitis optica spectrum disorder (NMOSD, n = 29) were included. We analyzed the frequency and absolute numbers of MCAM+ lymphocytes (memory helper T [mTh] cells, naive helper T cells, CD8+ T cells, and B cells) in the peripheral blood (PB) and the CSF of patients with MS and NMOSD, treated with/without disease-modifying drugs (DMDs) or steroids, using flow cytometry. RESULTS: The frequency of MCAM+ cells was higher in the mTh cell subset than that in other lymphocyte subsets. A significant increase in the frequency and the absolute number of MCAM+ mTh cells was observed in the PB of patients with NMOSD, whereas no increase was observed in the PB of patients with MS. The frequency of CSF MCAM+ mTh cells was higher in relapsing patients with MS and NMOSD than that in the control group. Although there was no difference in the frequencies of MCAM+ lymphocytes among the DMD-treated groups, fingolimod decreased the absolute number of MCAM+ lymphocytes. DISCUSSION: MCAM+ mTh cells were elevated in the CSF of relapsing patients with MS and in both the PB and CSF of patients with NMOSD. These results indicate that MCAM contributes to the pathogenesis of MS and NMOSD through different mechanisms. MCAM could be a therapeutic target of CNS IDDs, and further study is needed to elucidate the underlying mechanism of MCAM in CNS IDD pathogenesis.

[Myasthenia gravis and sleep]. / Myasthenia gravis und Schlaf.

In myasthenia gravis respiratory function is often disturbed in the night, especially during REM sleep, despite of normal daytime respiratory function. Nevertheless, nocturnal respiratory problems are rarely diagnosed. Sleepiness, concentration and memory problems can be symptoms of a sleep related breathing disorder. Reports of reduction of REM sleep, memory dysfunction, and detection of acetylcholine receptor (AchR)-antibodies in the cerebrospinal fluid have lead to the hypothesis of a central nervous system involvement in myasthenia gravis. Possible mechanisms are centrally acting AchR-antibodies, unspecifically acting cytokines and hypoxia, possibly the most important influence upon REM sleep reduction and impaired cognitive function. In a patient presenting possible CNS-involvement (cephalea, fatigue, concentration and memory problems), a polysomnographic investigation should therefore be performed to detect a sleep related breathing disorder.

Elevated cerebrospinal fluid CD4+/CD8+ T cell ratio in myasthenia gravis.

The proportions of CD2+, CD4+ and CD8+ lymphocytes were determined with the 3-layer indirect immunoperoxidase technique in the cerebrospinal fluid (CSF) of 31 patients with myasthenia gravis (MG) and 21 control subjects without autoimmune or central nervous system (CNS) diseases. None of the MG patients were using immunosuppressive drugs and all were thymectomized shortly after CSF sampling. Analysis of the reference population showed that the percentage of CD4+ lymphocytes and accordingly the CD4+/CD8+ T cell ratio is normally higher in CSF than in peripheral blood (PB). Compared to the controls, the mean percentage of CD4+ lymphocytes and the mean CD4+/CD8+ ratio in CSF were significantly higher in MG patients. In addition, the CD4+/CD8+ ratio was elevated in the CSF of 15 MG patients (48%) as a result of an elevation in the proportion of CD4+ and/or a decrease in CD8+ T cells. Among MG subjects the mean proportion of CD4+ lymphocytes was higher in the CSF of patients with also an elevated number of enlarged stimulated lymphoid cells in their CSF, which implies that these lymphocytes are often of the CD4+ phenotype. The percentage of CD4+ T cells in CSF was significantly higher in MG patients with a hyperplastic thymus or a thymoma than in those with an involuted thymus. Neither in MG patients nor in the reference population could an association be observed between CSF and PB lymphocyte subsets. In the controls this suggests that immunologic events of the CNS are normally not directly reflected in PB.(ABSTRACT TRUNCATED AT 250 WORDS)

Oligoclonal immunoglobulin G in cerebrospinal fluid of myasthenia gravis patients.

Immunoglobulin G (IgG) band patterns were investigated in cerebrospinal fluid (CSF) from 19 patients with myasthenia gravis (MG) in a search for abnormalities indicating central nervous system (CNS) involvement in this disorder. Using the isoelectric focusing (IEF) technique and antiserum immunoblotting against IgG, we found no evidence of the presence of oligoclonal IgG in CSF from most of MG patients. In 2 cases, the positive findings of oligoclonal IgG in CSF may have reflected a manifestation of an associated disease, which has already been associated with immune abnormalities within the CNS. Further investigations with more sophisticated techniques are required to give additional insight into humoral immune events within the CNS in MG patients.

[Leukotrienes and neurological diseases]. / Leukotrienler ve nörolojik hastaliklar.

Assessment of Leukotriene C4 (LTC4) activity in the serum and cerebrospinal fluid (CSF) specimens of patients with multiple sclerosis (MS), Parkinson's disease, amyotrophic lateral sclerosis (ALS), Myasthenia gravis (MG), Behçet's disease and neuro-Behçet, as well as in normal controls were carried out in order to determine its role in the pathogenesis of neurologic disorders. LTC4 levels were found to be elevated in MS and Behçet patient in comparison with controls. Augmentation of LTC4 levels underlines the fact that leukotrienes may be held responsible the pathogenesis of these disorders.

[Intrathecal immunoactivation in the patients with myasthenia gravis--autoantibodies in the cerebrospinal fluid].

We examined the cerebrospinal fluid (CSF) of 17 myasthenia gravis (MG) patients for certain immunological parameters in order to assess signs of intrathecal immunoactivation. We have found oligoclonal IgG bands in the CSF of 6 of 17 by the agarose gel electrophoresis and enlarged lymphoid cells in CSF of 8 of 17 patients of MG. We measured anti-nicotinic acetylcholine receptor (AChR) antibody and anti-striational muscle antibody (AMA) in serum and CSF from MG patients and compared the serum: CSF ratio with total IgG. No evidence of intrathecal anti-AChR antibody synthesis was demonstrated while AMA was partly (50%) synthesized in myasthenic CSF. This difference suggested that there is either different immunological regulation in synthesis between anti-AChR antibody and AMA in the CSF or the different behavior after transfer to CSF.

Muscle antibodies in the cerebrospinal fluid from patients with myasthenia gravis.

IgG antibodies to nicotinic acetylcholine receptor (AChR) and to a muscle antigen extracted by citric acid, were quantified in serum and cerebrospinal fluid (CSF) from 28 patients with myasthenia gravis, and the serum:CSF ratios compared with those of total IgG. Agarose-electrophoresis and calculations of the IgG index and Tourtellotte's formula were performed. No evidence of intrathecal antibody synthesis was demonstrated. Compared to the total IgG concentrations in serum and CSF, the CSF concentrations of IgG AChR antibodies were lower than expected.

The cerebrospinal fluid in myasthenia gravis.

We examined the number of leucocytes and the concentration of total protein, albumin and IgG in the cerebrospinal fluid (CSF) from 46 patients with myasthenia gravis (MG) and 50 controls. Mean leucocyte number in the MG patients was 1634 cells/ml (controls 1244), mean total protein 0.38 g/l (controls 0.32), mean IgG 0.034 g/l (controls 0.025) and mean albumin 0.199 g/l (controls 0.176). No evidence of intrathecal IgG synthesis was demonstrated. The CSF was normal in most cases. When pathological changes occurred they were slight and could be attributed to associated diseases or to iatrogenic blood contamination of the CSF. We demonstrated that an artificial blood contamination of the CSF, although macroscopically undetectable, increased the CSF albumin concentration and the CSF albumin/serum albumin ratio considerably.

Lymphocyte subpopulations and IgG concentrations in cerebrospinal fluid and blood from patients with myasthenia gravis.

Twelve patients with myasthenia gravis (MG) were examined for cerebrospinal fluid (CSF) T lymphocytes and for peripheral blood lymphocyte subpopulations (E-, EAET-, EA- and EAC-rosette-forming cells). The patients had a significantly increased percentage of CSF T cells (88.2 +/- 8.7%) when compared with controls (78.0 +/- 9.1%). Absolute concentrations of CSF T cells were not significantly increased. In peripheral blood no significant change in lymphocyte subpopulations was observed, but there was a slight leucocytosis in the patient group. The patients had increased CSF IgG concentrations, CSF IgG to protein ratio, and CSF to serum IgG ratio, indicating an intrathecal production of IgG. No oligoclonal bands could be demonstrated in the agarose gel electrophoresis. The two patients with thymoma had anti-muscle antibodies in CSF and serum, with ratios of 1:256 and 1:1024, respectively. Serum IgG levels were increased, but not significantly, in the patient group. These results suggest an involvement also of the central nervous system in some patients with MG.

Quantitation of IgG, IgA and IgM in the CSF by radioimmunoassay.

A radioimmunoassay (RIA) for quantitating IgG, IgA and IgM in unconcentrated CSF has been developed. The amounts and percentages of these immunoglobulins in CSF from 31 normal individuals were determined. Using these values as normal, CSF from patients with syphilis, encephalitis, subacute sclerosing panencephalitis (SSPE), and multiple sclerosis (MS) was studied. Abnormalities were detected, indicating the potential relevance of more extensive study of the CSF immunoglobulins. CSF from patients with myotonic dystrophy and myasthenia gravis was normal. RIA was compared with rocket electroimmunodiffusion (EID) for the quantitation of IgG. Although RIA consistently gave lower absolute values, both assays reliably detect elevated IgG in CSF. However, an advantage of RIA is its capacity to quantitate IgA and IgM.

Determination of acetylcholine receptor antibody in myasthenia gravis: clinical usefulness and pathogenetic implications.

Antibodies to cholinergic receptor structures were found in 75% of 76 Finnish and 93% of 175 Swedish patients with myasthenia gravis. The amount of antibodies showed a positive correlation to the severity of the disease, and was reduced during immunosuppressive treatment, and by thymectomy. Thymoma patients had high values. The antibody was also found in the cerebrospinal fluid. Two healthy newborn babies of myasthenic mothers had antibodies during the first weeks of life, in spite of no clinical symptoms. The occurrence of IgM antibodies before IgM antibodies in two patients during the early stages of myasthenia gravis suggests that the antibody is not a primary cause of the disease.

[Preliminary study on immunoglobulins G in the cerebrospinal fluid of neurological patients]. / Studio preliminare sulle immunoglobuline G nel liquido cefalo-rachidiano di malati neurologici

The preliminary data from a study of the cerebrospinal fluid IgG of 76 neurological patients are reported. The radial immunodiffusion method was employed. The absolute and percentage increase of IgG with respect to total proteins in the various diagnostic classes involved in the series was considered. The most significant increases were encountered in M.S., in neuropathies and radiculopathies and in tumor involving the subarachnoid spaces. The high percentage is, however, characteristic of M.S. The method is thus particularly useful in diagnosing M.S. and in differentiating it from other neurological diseases.