Increased circulating T cell reactivity to GM1 ganglioside in patients with Guillain-Barré syndrome.

This study was performed to determine whether increased ganglioside-specific T cell reactivity can be detected in the peripheral blood of patients with Guillain-Barre syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). T cell responsiveness to the gangliosides GM1, GM3, GD1a, GD1b, GD3, GT1b, GQ1b and sulphatide was assessed in peripheral blood mononuclear cells from untreated GBS patients (57), CIDP patients (43), patients with other peripheral neuropathies (55) and healthy control subjects (74) in a standard 6-day proliferation assay. Increased T cell reactivity to GM1 occurred in GBS patients compared to healthy controls and patients with other neuropathies. There was increased reactivity to GM3 in GBS patients compared to patients with other neuropathies but not compared to healthy controls. The frequencies of increased T cell reactivity to GM1 and GM3 in CIDP patients were intermediate between those of GBS patients and controls. We suggest that T cell reactivity to gangliosides might play a contributory role in the pathogenesis of GBS and perhaps CIDP.     

Increased circulating antiganglioside antibodies in primary and secondary progressive multiple sclerosis

Plasma samples from 70 patients with multiple sclerosis (MS), 41 patients with other neurological diseases (OND), and 38 healthy subjects were examined for antibodies against gangliosides GM1, GM3, GD1a, GD1b, and GD3 using enzyme-linked immunosorbent assays. The percentages of subjects with increased anti-GM3 responses were significantly higher in the primary progressive MS (56.3%) and secondary progressive MS (42.9%) groups than in the relapsing-remitting MS (2.9%), healthy subject (2.6%), and OND (14.6%) groups. Elevated antiganglioside antibodies may be secondary to axonal damage or may be a cause of axonal damage and accumulating disability in progressive MS. In either case, they may serve as a marker of axonal damage in MS.     

T cell vaccination in secondary progressive multiple sclerosis

Four secondary progressive MS patients were vaccinated with bovine myelin-reactive irradiated T cell lines from their peripheral blood. Patients were followed for 30-39 months, and monitored for immunological responses toward the vaccine, and for their clinical characteristics. Two patients showed stable EDSS score over time, one patient showed improvement by one EDSS step, and in the remaining patient her EDSS advanced over time. After the second inoculation there was a progressive decline of circulating whole myelin-reactive T cells, MBP143-168, PLP104-117, and MOG43-55-peptide-reactive T cells. In contrast the frequency of tetanus toxoid-reactive T cells remained unchanged. T cell vaccination (TCV) was also associated with a decline of myelin-specific IL-2- and IFN-gamma-secreting T cells. Twelve T cell lines (TCL) that recognize the inoculates were isolated from the peripheral blood of two patients. Ten of these TCL were CD8(+) and lysed the inoculates in a MHC Class I restricted manner. The remaining two TCL were CD4(+), and lysed the inoculates by MHC Class II restricted cytolytic activity. All T cell lines lysed not only myelin-reactive T cells, but also TCL specific for MBP143-168, PLP104-117 and MOG43-55 peptides. Control TCL specific for tetanus toxoid were not lysed. Neutralizing anti-Fas mAb did not influence the killing. Moreover, culture supernatants from two TCL which produce IL-10, were able to block the proliferation of myelin protein-specific TCL. This effect was abrogated using mAbs specific for IL-10. The data obtained indicated that TCV using autologous irradiated bovine myelin-reactive T cells promotes an effective depletion of T cells reactive against different myelin antigens.     

T cell receptor α chain polymorphisms in multiple sclerosis

Numerous studies have implicated the major histocompatibility complex (MHC) class II alleles, DR2 and DQw1, as multiple sclerosis (MS) susceptibility loci, however, the involvement of other loci is implied by twin studies and the relative lack of haplotype sharing for MHC. To evaluate the role that the TCR alpha chain genes may have in MS susceptibility, three variable (V) alpha polymorphisms were examined for associations in MS patients. Genotype and allele frequencies were compared to four different control groups: unaffected siblings and parents of the MS patients, patients with insulin-dependent diabetes mellitus (IDDM) and healthy unrelated Caucasians. No significant differences in allele and genotype frequencies at these three loci were observed in the MS population compared to the control groups. In addition, we analysed the distribution of haplotype sharing in affected sibling pairs. Among 30 informative families, there was no significant increase in haplotypes shared by affected siblings over that expected based on random segregation. Our results do not support suggestions that germline TCR alpha chain genes contribute to genetic susceptibility in MS.     

Interferon beta-1b modulates serum sVCAM-1 levels in primary progressive multiple sclerosis

Endothelial activation is a key feature of multiple sclerosis (MS) pathogenesis. It is modulated by interferon beta-1b (IFNB-1b) treatment in relapsing-remitting MS (RRMS) patients. This particular pharmacodynamic effect still has to be proven in primary progressive MS (PPMS). In the current study, serum concentrations of soluble vascular cell adhesion molecule-1 (sVCAM-1) and sE-selectin were analyzed longitudinally in 18 PPMS patients before, during and after 12 months of treatment with IFNB-1b. During drug therapy there was a significant early and sustained increase of sVCAM-1 (overall P < 0.0001). Flu-like symptoms induced by IFNB-1b and also concomitant infections were associated with higher sVCAM-1 levels. Neutralizing antibodies to IFNB-1b were associated with lower sVCAM-1 levels. In conclusion, IFNB-1b modulates the adhesion cascade in patients with PPMS in a similar way it does in RRMS. Nevertheless, a clinical effect of IFNB in PPMS still has to be proven in a randomized controlled clinical trial.     

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.     

Acute oropharyngeal palsy is associated with antibodies to GQ1b and GT1a gangliosides.

Three patients with acute oropharyngeal palsy had high titre anti-GQ1b and anti-GT1a IgG antibodies. No patients had ophthalmoplegia or ptosis. In all patients limb ataxia or areflexia were present without notable limb weakness. These patients describe an oropharyngeal variant of Guillain-Barré syndrome in terms of anti-GQ1b antibody reactivity and show that high titre anti-GQ1b antibodies, serologically indistinguishable from those found in Miller Fisher syndrome, can occur in a clinical setting without ophthalmoplegia. The anti-GQ1b and anti-GT1a antibody assays may be helpful tests when considering the differential diagnosis of acute oropharyngeal palsy.     

Autoantibody synthesis in primary progressive multiple sclerosis patients treated with interferon beta-1b

Abstract We conducted an open-labeled clinical trial of interferon beta-1b (IFNB) treatment in 20 patients with primary progressive multiple sclerosis (PPMS) and longitudinally monitored autoantibodies against double-stranded DNA (dsDNA), thyroid peroxidase (TPO),myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), synapsin and S-100B. Before treatment, one patient had elevated TPO antibodies, four patients had elevated antibodies against S-100B, two patients against MOG or synapsin and one patient against MBP. In two patients we observed a continuous increase of dsDNA or TPO antibodies above the normal range. This rise paralleled IFNB treatment. In addition, 11 of 20 patients developed neutralizing antibodies against IFNB. There was no increase of autoantibodies directed against central nervous system antigens. Like patients with relapsing remitting or secondary progressive multiple sclerosis, PPMS patients may be at risk of an autoimmune response during IFNB treatment.     

Acute sensory ataxic neuropathy with antibodies to GD1b and GQ1b gangliosides and prompt recovery

Three patients developed acute pure sensory ataxic neuropathy. Two of the three patients had a recent Campylobacter jejuni infection. Patient 1 had monospecific IgG anti-GD1b. Patients 2 and 3 had cross-reactive IgG anti-GQ1b and anti-GD1b and patient 2 also had IgG anti-GT1a. Motor nerve conduction studies were completely normal. Sensory conductions showed reduced amplitude or absent sensory nerve action potentials with normal or slightly slowed conduction velocities. In patient 2, serial electrophysiological studies showed reappearance and improvement of sensory nerve potential amplitudes in 4 weeks. All patients recovered completely in 2 months and sensory potential amplitudes normalized in 3-5 months. Our findings: (1) confirm the existence of a pure acute sensory ataxic neuropathy with cross-reactive IgG anti-GQ1b and anti-GD1b as a variant of Guillain-Barré syndrome; (2) expand the clinical presentation of Guillain-Barré syndrome after C. jejuni infection and suggest that molecular mimicry is at the basis of acute sensory ataxic neuropathy; and (3) indicate that, in acute sensory ataxic neuropathy with prompt recovery, the site of the lesion is not in the primary sensory neurons and the pathophysiological mechanism may be functional in nature.     

Interferon beta-1a in primary progressive multiple sclerosis

There is currently no disease-modifying treatment proven to be of efficacy in primary progressive multiple sclerosis (PPMS). However, a number of therapeutic trials have recently been specifically designed for this group. These include a randomised controlled trial of interferon beta-1a which is discussed here. It is hoped that therapeutics in primary progressive multiple sclerosis will continue to expand and effective therapeutic agents will be developed.     

Secondary progressive multiple sclerosis in childhood--interferon beta 1b treatment

Multiple sclerosis (MS) is rare in children and the efficacy and safety of interferon beta 1b (IFN-beta 1b) treatment in childhood MS has not yet been established. We started to treat a boy who suffered from relapsing remitting MS with IFN-beta 1b at 8.5 years of age, because he had severe neurological disability in consequence of frequent relapses and incomplete remission. After initiating IFN-beta 1b treatment, his clinical course moved to secondary progressive (SP) MS, and he demonstrated poor improvement in degenerative progression and his disability continued to worsen. We could speculate that IFN-beta 1b was not effective regarding the degenerative component of childhood MS as in that of adult MS. SPMS is extremely rare in children, and this case would provide a very important implication to predict the tolerability of IFN-beta 1b treatment depending on the type of clinical course in childhood MS.     

格林—巴利综合征患者血清中的抗糖脂抗体

采用固相酶联免疫吸附法对３５例急性期格林－巴利综合征（ＧＢＳ）患者、２８例其他神经系统疾病患者和３０例健康体检者的血清中抗硫脂抗体，抗ＧＱ１ｂ及抗ＧＭ１抗体进行检测。结果：ＧＢＳ患者血清中抗硫脂ＩｇＭ抗体、抗ＧＱ１ｂＩｇＧ抗体和抗ＧＭ１ＩｇＧ抗体阳性率分别为３４％、１１％和３１％，均显著高于正常对照组。５６％的抗硫脂抗体阳性患者均有不同程度感觉障碍，而抗硫脂抗体阴性患者仅１６％（Ｐ＜０．０５）。５例有眼肌运动障碍的ＧＢＳ患者中，４例抗ＧＱ１ｂＩｇＧ抗体阳性，无眼肌麻痹的ＧＢＳ患者无１例抗ＧＱ１ｂ抗体阳性。提示不同的抗糖脂抗体可能在ＧＢＳ发病过程中起不同的作用。     

Immunologic factors in primary progressive multiple sclerosis

Primary progressive multiple sclerosis (PPMS) is clinically characterized by progression without remission or relapse, in contrast to relapsing forms of MS. Pathologic and imaging findings also indicate that PPMS differs from relapsing forms. Recent studies examining potential immunologic differences among MS forms suggest that cytokine and adhesion molecule expression profiles, but not chemokine receptor profiles, in PPMS patients resemble those in healthy controls more than those in patients with relapsing MS. However, the significance of these findings remains to be fully elucidated, and there is little additional evidence as yet of marked differences among MS forms based on immunologic characteristics. Of interest are the recent demonstrations that activated immune cells produce brain-derived neurotrophic factor (BDNF), a neuroprotective factor, in MS lesions, that BDNF receptors are located in MS tissue, and that glatiramer acetate (GA)-specific T cells produce BDNF irrespective of T helper cell Th1 or Th2 phenotype. These findings both support the concept of a protective inflammation in MS and suggest an additional mechanism of action for the clinical effects of GA therapy in MS. Whether and to what extent this mechanism is present in different MS forms remain to be clarified.     

Baseline T cell reactivity in multiple sclerosis is correlated to efficacy of interferon-beta

BACKGROUND: Measuring proliferative responses of T lymphocytes is a simple, reproducible and widely used assay of immune competence. Evidence suggests a role of T cell reactivity in autoimmune diseases. Interferon (IFN)-beta blocks in vitro proliferation of human T cells. OBJECTIVES: To assess (i) the relation between T cell proliferation and disease characteristics of MS patients, (ii) differences in T cell proliferation between subgroups and HC, and (iii) the predictive value of T cell proliferation for efficacy of IFN-beta. METHODS: Proliferative responses were measured in phytohaemagglutinin (PHA), anti-CD2/CD28 and anti-CD3 stimulated whole blood of 189 MS patients and 249 healthy controls (HC). Forty-eight patients started treatment with IFN-beta. Based on EDSS progression, number of relapses and steroid interventions, patients were classified as either clinical responder or nonresponder to IFN-beta. RESULTS: Significant differences between MS subgroups and HC were found in T cell responses upon both PHA stimulation (RR>HC: p=0.001 and SP>HC: p=0.001) and CD2/CD28 stimulation (RR>HC, SP>HC and PP>HC: all p values <0.001). No significant differences were found between the MS subgroups. A probability of 88% (95% CI, 71-95%) for a favorable response to IFN-beta was found with increased baseline proliferative T cell responses to PHA; a probability of only 16% (95% CI, 7-33%) with decreased values. CONCLUSION: Our results suggest that the level of T cell proliferation in whole blood predicts efficacy of IFN-beta in MS.     

Increased frequencies of serum antibodies to neurofilament light in patients with primary chronic progressive multiple sclerosis

We investigated whether serum and cerebrospinal fluid (CSF) antibodies to the light subunit of the NF protein (NF-L), a main component of the axonal cytoskeleton, may serve as biological markers for axonal pathology and/or disease progression in multiple sclerosis (MS). IgG to NF-L was measured in sera and CSF of MS patients, patients with inflammatory demyelinating diseases of the PNS, with acute inflammatory neurological diseases (including bacterial and viral meningitis), with neurodegenerative diseases, with acute noninflammatory neurological diseases (including stroke, headache and backache) and healthy controls by enzyme-linked immunosorbent assay. We found that serum anti-NF-L IgG antibodies were significantly elevated in MS patients with primary progressive disease course and we provide evidence for an intrathecal production of these antibodies. Our findings support the use of serum antibodies to NF-L as a marker for axonal destruction.     

Seasonal variation of interferon-γ production in progressive multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. There is increased interferon (IFN)-γ secretion in MS patients in vitro, and IFN-γ administration induces exacerbations of disease suggesting a link between IFN-γ and disease activity. We observed significantly increased IFN-γ production in the autumn and winter months compared with the spring and summer months in chronic progressive MS, and this increase was linked to endogenous interleukin (IL)-12 production. Increased seasonal IFN-γ was not observed in normal control subjects, and there were no seasonal changes in IL-10 in progressive MS. These results suggest a potential environmental link between dysregulated IFN-γ production and MS disease progression and pathogenesis.     

Cognitive impairment in primary and secondary progressive multiple sclerosis

The aim of this study was to use neuropsychological data to characterize two subtypes of multiple sclerosis (MS) patients in a large patient sample. We studied patients with primary-progressive MS (PPMS) and secondary-progressive MS (SPMS). A group of 121 MS patients (36 PPS, 85 SPMS) and 40 healthy controls were administered a brief battery of cognitive tests. Executive functioning, memory and attention were studied. Results demonstrate that PPMS patients exhibited slightly more impairment than patients with SPMS, although this difference is not significant (50% vs 37%). However, PPMS patients revealed a significantly poorer performance in verbal learning (p < 0.05) and in verbal fluency (p < 0.05). Whereas PPMS patients had significantly shorter disease durations (p < 0.05), there was no statistical difference in disability between both groups. We conclude from our study that cognitive deficits in progressive MS are frequent. Patients with PPMS tend to be more frequently and severely affected than SPMS patients. Our findings of high prevalence of cognitive involvement in PPMS have not been reported previously     

Abnormal tau phosphorylation in primary progressive multiple sclerosis

Although neurodegeneration is the pathological substrate of progression in multiple sclerosis (MS), the underlying mechanisms remain unresolved. Abnormal phosphorylation of tau, implicated in the aetiopathogenesis of a number of classic neurodegenerative disorders, has also recently been described in secondary progressive MS (SPMS). In contrast to SPMS, primary progressive MS (PPMS) represents a significant subset of patients with accumulating neurological disability from onset. The neuropathological relationship between SPMS and PPMS is unknown. Against this background, we investigated tau phosphorylation status in five cases of PPMS using immunohistochemical and biochemical methods. We report widespread abnormal tau hyperphosphorylation of the classic tau phospho-epitopes occurring in multiple cell types but with a clear immunohistochemical glial bias. In addition, biochemical analysis revealed abnormally phosphorylated insoluble tau in all cases. These findings establish a platform for further study of the role of insoluble tau formation, including determining the relevance of glial tau pathology, in the neurodegenerative phase of MS.