ABSTRACT
We compared cerebrospinal fluid levels of lactate, ß2-microglobulin and angiotensin-converting enzyme (ACE) between 438 untreated patients with multiple sclerosis and 276 patients with non-inflammatory neurological disorders. Age-adjusted ß2-microglobulin and lactate were significantly higher and ACE was significantly lower in MS patients than in controls. ß2-microglobulin and ACE positively correlated with high significance both in MS patients and controls. While disease duration negatively correlated and progression index, defined as EDSS score divided by disease duration in years, positively correlated with age-adjusted lactate levels, both did neither correlate with ß2-microglobulin nor with ACE. Both CSF ß2-microglobulin and ACE deserve further investigation as biomarkers of multiple sclerosis pathophysiology.
Subject(s)
Disease Progression , Lactic Acid/metabolism , Multiple Sclerosis/cerebrospinal fluid , Peptidyl-Dipeptidase A/cerebrospinal fluid , Severity of Illness Index , beta 2-Microglobulin/cerebrospinal fluid , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Biomarkers/cerebrospinal fluid , Cohort Studies , Female , Humans , Male , Middle Aged , Multiple Sclerosis/diagnosis , Retrospective Studies , Young AdultSubject(s)
Mitoxantrone , Multiple Sclerosis , Cohort Studies , Follow-Up Studies , Humans , RecurrenceABSTRACT
BACKGROUND: Autoantibodies, in particular those against aquaporin-4 and myelin-oligodendrocyte glycoprotein (MOG), aid as biomarkers in the differential diagnosis of demyelination. Here, we report on discovery of autoantibodies against flotillin in patients with multiple sclerosis (MS). METHODS: The target antigen was identified by histo-immunoprecipitation using the patients' sera and cryosections of rat or pig cerebellum combined with mass spectrometrical analysis. Correct identification was ascertained by indirect immunofluorescence and neutralization tests using the target antigens recombinantly expressed in HEK293 cells. RESULTS: Serum and CSF of the index patient produced a fine-granular IgG indirect immunofluorescence staining of the hippocampal and cerebellar molecular layers. Flotillin-1 and flotillin-2 were identified as target autoantigens. They also reacted with recombinant human flotillin-1/2 co-expressed in HEK293 cells, but not with the individual flotillins in fixed- and live-cell assays. Moreover, neutralization using flotillin-1/2, but not the single flotillins, abolished the tissue reactivity of patient serum. Screening of 521 patients, for whom anti-aquaporin-4 testing was requested and negative, revealed 8 additional patients with anti-flotillin-1/2 autoantibodies. All eight were negative for anti-MOG. Six patients ex post fulfilled the revised McDonald criteria for MS. Vice versa, screening of 538 MS sera revealed anti-flotillin-1/2 autoantibodies in eight patients. The autoantibodies were not found in a cohort of 67 patients with other neural autoantibody-associated syndromes and in 444 healthy blood donors. CONCLUSIONS: Autoantibodies against the flotillin-1/2 heterocomplex, a peripheral membrane protein that is involved in axon outgrowth and regeneration of the optic nerve, are present in 1-2% of patients with bona fide MS.
Subject(s)
Autoantibodies/metabolism , Membrane Microdomains/metabolism , Membrane Proteins/metabolism , Multiple Sclerosis/metabolism , Adult , Animals , Autoantibodies/immunology , Female , HEK293 Cells , Humans , Male , Membrane Microdomains/immunology , Membrane Proteins/immunology , Middle Aged , Multiple Sclerosis/immunology , Multiple Sclerosis/pathology , Rats , SwineABSTRACT
OBJECTIVES: To explore long-term effects of treatment and prognostic relevance of variables assessed at baseline and during the European secondary progressive multiple sclerosis (SPMS) trial of interferon beta 1b (IFNB-1b). METHODS: We assessed 362 patients (60% female; median age 41 years; Expanded Disability Status Scale (EDSS): 5.5; 51% randomized to IFNB-1b) for their EDSS and treatment history after 10 years. Non-parametric analysis of covariance (ANCOVA) and multivariate linear regression models were applied. RESULTS: Median EDSS was 6.0 at the end of the randomized controlled trial (RCT), in the IFNB-1b and placebo groups, and 7.0 in long-term follow-up patients (those receiving IFNB-1b in the RCT were 6.5 and those receiving placebo in the RCT were 7.0; p = 0.086). 24 patients (6.6%) were deceased. The EDSS at baseline and the EDSS change during the RCT were the most important predictors of the EDSS 10 years later (partial R(2): 0.47). The ability to predict changes in EDSS 10 years after the RCT was limited (R(2): 0.12). Magnetic resonance imaging (MRI) measures remained in the predictive models, but explained < 5% of the variability. CONCLUSIONS: The results from this analysis did not provide convincing evidence to support a favorable long-term outcome in those patients allocated IFNB-1b during the RCT, in our SPMS cohort. The progressive stage of the disease remains largely unpredictable by clinical and conventional MRI measures, so better prognostic markers are needed.
Subject(s)
Immunologic Factors/therapeutic use , Interferon beta-1b/therapeutic use , Multiple Sclerosis, Chronic Progressive/drug therapy , Adult , Disability Evaluation , Disease Progression , Double-Blind Method , Europe , Female , Follow-Up Studies , Humans , Immunologic Factors/adverse effects , Interferon beta-1b/adverse effects , Linear Models , Magnetic Resonance Imaging , Male , Multiple Sclerosis, Chronic Progressive/diagnosis , Multiple Sclerosis, Chronic Progressive/mortality , Multivariate Analysis , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: Despite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. As sex hormones modify immunomodulatory apoE functions, they may explain contentious findings. This study aimed to investigate sex-specific effects of apoE on disease course of EAE and MS. METHODS: MOG(35-55) induced EAE in female and male apoE-deficient mice was assessed clinically and histopathologically. apoE expression was investigated by qPCR. The association of the MS severity score (MSSS) and APOE rs429358 and rs7412 was assessed across 3237 MS patients using linear regression analyses. RESULTS: EAE disease course was slightly attenuated in male apoE-deficient (apoE (-/-) ) mice compared to wildtype mice (cumulative median score: apoE (-/-) = 2 [IQR 0.0-4.5]; wildtype = 4 [IQR 1.0-5.0]; n = 10 each group, p = 0.0002). In contrast, EAE was more severe in female apoE (-/-) mice compared to wildtype mice (cumulative median score: apoE (-/-) = 3 [IQR 2.0-4.5]; wildtype = 3 [IQR 0.0-4.0]; n = 10, p = 0.003). In wildtype animals, apoE expression during the chronic EAE phase was increased in both females and males (in comparison to naïve animals; p < 0.001). However, in MS, we did not observe a significant association between MSSS and rs429358 or rs7412, neither in the overall analyses nor upon stratification for sex. CONCLUSIONS: apoE exerts moderate sex-specific effects on EAE severity. However, the results in the apoE knock-out model are not comparable to effects of polymorphic variants in the human APOE gene, thus pinpointing the challenge of translating findings from the EAE model to the human disease.
Subject(s)
Apolipoproteins E/genetics , Encephalomyelitis, Autoimmune, Experimental/genetics , Multiple Sclerosis/genetics , Animals , Apolipoproteins E/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Fluorescent Antibody Technique , Genotype , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Real-Time Polymerase Chain Reaction , Sex FactorsSubject(s)
Multiple Sclerosis/chemically induced , Papillomavirus Vaccines/adverse effects , Adolescent , Adult , Child , Cohort Studies , Denmark , Female , Follow-Up Studies , Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18 , Humans , Incidence , Multiple Sclerosis/epidemiology , Risk Assessment/statistics & numerical data , Sweden , Young AdultSubject(s)
4-Aminopyridine/therapeutic use , Evoked Potentials, Motor , Multiple Sclerosis/drug therapy , Multiple Sclerosis/physiopathology , Potassium Channel Blockers/therapeutic use , Walking , 4-Aminopyridine/administration & dosage , 4-Aminopyridine/pharmacology , Adult , Aged , Drug Administration Schedule , Female , Humans , Leg/innervation , Male , Middle Aged , Neural Conduction/drug effects , Potassium Channel Blockers/administration & dosage , Potassium Channel Blockers/pharmacology , Predictive Value of Tests , Prospective StudiesABSTRACT
Recombinant monoclonal antibodies break new ground in the treatment of immune-mediated nerve and muscle disorders but also of neurodegenerative diseases, in the field of neuro-oncology and in pain therapy, as they allow molecular targeting of defined cell populations or key pathophysiological molecules. However, safety risks might accompany a high efficacy. Basic understanding of this increasingly important class of agents and a steady update of knowledge, in particular on safety aspects, are therefore key requirements for responsible use based on an individual benefit-risk assessment.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Central Nervous System Diseases/drug therapy , Alemtuzumab , Alzheimer Disease/diagnosis , Alzheimer Disease/drug therapy , Alzheimer Disease/immunology , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Antibodies, Monoclonal, Murine-Derived , Antibodies, Neoplasm/adverse effects , Antibodies, Neoplasm/therapeutic use , Central Nervous System Diseases/diagnosis , Central Nervous System Diseases/immunology , Central Nervous System Neoplasms/drug therapy , Clinical Trials as Topic , Drug Approval , Humans , Multiple Sclerosis/drug therapy , Natalizumab , Opportunistic Infections/etiology , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic use , RituximabSubject(s)
Antibodies, Neutralizing/blood , Interferon-beta/immunology , Interferon-beta/metabolism , Multiple Sclerosis/drug therapy , Multiple Sclerosis/immunology , Antibodies, Neutralizing/biosynthesis , Antibodies, Neutralizing/metabolism , Binding Sites, Antibody/drug effects , Binding Sites, Antibody/immunology , Humans , Immunosuppressive Agents/therapeutic use , Interferon-beta/therapeutic use , Methylprednisolone/administration & dosage , Multiple Sclerosis/metabolismSubject(s)
Acids/analysis , Adjuvants, Immunologic/adverse effects , Injections, Subcutaneous , Interferon-beta/adverse effects , Multiple Sclerosis/drug therapy , Pain/chemically induced , Adjuvants, Immunologic/administration & dosage , Adjuvants, Immunologic/chemistry , Humans , Hydrogen-Ion Concentration , Interferon beta-1a , Interferon-beta/administration & dosage , Interferon-beta/chemistry , Single-Blind MethodSubject(s)
Amyloidosis/complications , Leukemia, B-Cell/complications , Mutation , Polyneuropathies/complications , Polyneuropathies/genetics , Prealbumin/genetics , Aged , Amyloidosis/genetics , Amyloidosis/pathology , Germany , Heterozygote , Humans , Immunohistochemistry , Leukemia, B-Cell/pathology , Male , Methionine/metabolism , Polyneuropathies/pathology , Prealbumin/analysis , Valine/metabolismABSTRACT
NF-ATc, an inducibly expressed transcription factor, controls gene expression in T lymphocytes and cardiomyocytes. We show here that the transcriptional co-activators CBP/p300 bind to and control the activity of the inducible N-terminal transactivation domain of NF-ATc, TAD-A. Similar to the N terminal transactivation domain of c-Jun, TAD-A is inducibly phosphorylated, but this phosphorylation is dispensable for the interaction with CBP/p300. Constitutive active versions of c-Raf and Rac synergistically enhance the CBP/p300-mediated increase of TAD-A activity, indicating the important role CBP/p300 plays in the integration of T cell activation signals. Since a mutation of CBP abolishing HAT activity is almost as active as wild-type CBP in T cells, functions of CBP/p300 other than histone acetylation appear to control the NF-AT-dependent transcription in T cells.