myelin-basic-protein and Multiple-Sclerosis--Chronic-Progressive

Epigenetic changes influence gene expression without altering the DNA sequence. DNA methylation, histone modification and microRNA-associated post-transcriptional gene silencing are three key epigenetic mechanisms. Multiple sclerosis (MS) is a disease of the CNS with both inflammatory and neurodegenerative features. Although studies on epigenetic changes in MS only began in the past decade, a growing body of literature suggests that epigenetic changes may be involved in the development of MS, possibly by mediating the effects of environmental risk factors, such as smoking, vitamin D deficiency and Epstein-Barr virus infection. Such studies are also beginning to deliver important insights into the pathophysiology of MS. For example, inflammation and demyelination in relapsing-remitting MS may be related to the increased differentiation of T cells toward a T-helper 17 phenotype, which is an important epigenetically regulated pathophysiological mechanism. In progressive MS, other epigenetically regulated mechanisms, such as increased histone acetylation and citrullination of myelin basic protein, might exacerbate the disease course. In this Review, we summarize current knowledge on the role of epigenetic changes in the pathophysiology of MS.

Topics: Citrulline; Disease Progression; DNA Methylation; Epigenesis, Genetic; Forecasting; Gene-Environment Interaction; Histone Deacetylase Inhibitors; Humans; Inflammation Mediators; Lymphocyte Activation; Macrophage Activation; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Myelin Basic Protein; Neurotransmitter Agents; Oligonucleotides; Risk Factors; T-Lymphocytes, Helper-Inducer

Natalizumab inhibits the migration of systemic immune cells to the CNS and may be beneficial in progressive multiple sclerosis (MS). The objective of the study was to examine the effects of natalizumab in progressive MS.. In an open-label phase 2A study, 24 patients with progressive MS were included to receive natalizumab treatment for 60 weeks. Response to natalizumab was assessed in CSF and MRI studies. The primary endpoint was change in CSF osteopontin, a biomarker of intrathecal inflammation, from baseline to week 60.. Seventeen patients completed the study. No new safety issues were encountered. CSF osteopontin decreased by 65 ng/mL (95% confidence interval 34-96 ng/mL; p = 0.0004) from baseline to week 60 in conjunction with decreases in other CSF biomarkers of inflammation, axonal damage, and demyelination. Magnetization transfer ratio increased in both cortical gray and normal-appearing white matter and correlated with decreases in CSF neurofilament light chain.. Natalizumab treatment of progressive MS reduces intrathecal inflammation and tissue damage, supporting a beneficial effect of natalizumab treatment in progressive MS and suggesting that systemic inflammation contributes to the pathogenesis. Moreover, the study establishes the feasibility of using CSF biomarkers in proof-of-concept trials, allowing a low number of participants and short study duration.. This study provides Class IV evidence that in patients with progressive MS, natalizumab reduces biomarkers of intrathecal inflammation.

Topics: Adult; Antibodies, Monoclonal, Humanized; Cerebral Cortex; Chemokine CXCL13; Disability Evaluation; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Immunologic Factors; Magnetic Resonance Imaging; Male; Matrix Metalloproteinase 9; Middle Aged; Multiple Sclerosis, Chronic Progressive; Myelin Basic Protein; Natalizumab; Neurofilament Proteins; Osteopontin; Secondary Prevention; Treatment Outcome

To assess the safety, tolerability, and biologic and clinical activity of a solubilized complex comprised of human leukocyte antigen-DR2 with myelin basic protein84-102 (AG284)in patients with secondary progressive MS.. Soluble species-specific major histocompatibility complex myelin basic protein91-103 complexes ameliorate disease in a dose-dependent manner when administered to SJL/J mice with chronic relapsing experimental allergic encephalomyelitis. Preincubation with AG284 reduces the proliferative response of a DR2-restricted, myelin basic protein84-102-reactive T cell clone, derived from a MS patient, to myelin basic protein84-102 in the presence of autologous antigen-presenting cells.. Thirty-three patients with secondary progressive MS were randomly assigned to receive three alternate day IV doses of AG284 or placebo in a double-masked dose escalation study. The primary outcome was safety and tolerability. Secondary outcomes included a comparison of pre- and post-treatment gadolinium-enhanced brain MRI activity, Kurtzke Expanded Disability Status Scale, and Nine Hole Peg Test scores.. The frequency of adverse events was similar in the AG284 and placebo recipients. No significant treatment effect was detected by Expanded Disability Status Scale, Nine Hole Peg Test, or number of new gadolinium-enhancing MRI lesions.. AG284 as administered during this study was safe and well tolerated. Further studies are warranted to determine the biologic activity and clinical efficacy of this potential treatment for MS.

Topics: Adult; Autoantibodies; Brain; Dose-Response Relationship, Immunologic; Double-Blind Method; Female; HLA Antigens; HLA-DR2 Antigen; Humans; Immunotherapy; Interferon-gamma; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis, Chronic Progressive; Myelin Basic Protein; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; T-Lymphocytes; Treatment Outcome; Vaccines, Conjugate

Approximately 15% of multiple sclerosis (MS) patients develop a progressive form of disease from onset; this condition (primary progressive-PP) MS is difficult to diagnose and treat, and is associated with a poor prognosis. Extracellular vesicles (EVs) of brain origin isolated from blood and their protein cargoes could function as a biomarker of pathological conditions. We verified whether MBP and MOG content in oligodendrocytes-derived EVs (ODEVs) could be biomarkers of MS and could help in the differential diagnosis of clinical MS phenotypes. A total of 136 individuals (7 clinically isolated syndrome (CIS), 18 PPMS, 49 relapsing remitting (RRMS)) and 70 matched healthy controls (HC) were enrolled. ODEVs were enriched from serum by immune-capture with anti-MOG antibody; MBP and MOG protein cargoes were measured by ELISA. MBP concentration in ODEVs was significantly increased in CIS (p < 0.001), RRMS (p < 0.001) and PPMS (p < 0.001) compared to HC and was correlated with disease severity measured by EDSS and MSSS. Notably, MBP concentration in ODEVs was also significantly augmented in PPMS compared to RRMS (p = 0.004) and CIS (p = 0.03). Logistic regression and ROC analyses confirmed these results. A minimally invasive blood test measuring the concentration of MBP in ODEVs is a promising tool that could facilitate MS diagnosis.

Topics: Biomarkers; Extracellular Vesicles; Humans; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Myelin Basic Protein; Myelin-Oligodendrocyte Glycoprotein; Oligodendroglia; Pilot Projects; Prognosis

Despite accumulating evidence of intrathecal inflammation in patients with primary progressive multiple sclerosis (PPMS), immunomodulatory and suppressive treatment strategies have proven unsuccessful. With this study, we investigated the involvement of CD20. The main outcomes in this observational, case-control study were flow cytometry assessments of blood and CSF CD20. Assessing CD20. This study shows an association between intrathecal CD8

Topics: Case-Control Studies; CD8-Positive T-Lymphocytes; Dimethyl Fumarate; Humans; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Myelin Basic Protein; T-Lymphocytes

B cell-depleting therapies have recently proven to be clinically highly successful in the treatment of multiple sclerosis (MS). This study aimed to determine the effects of the novel type II anti-human CD20 (huCD20) monoclonal antibody (mAb) obinutuzumab (OBZ) on spinal cord degeneration in a B cell-dependent mouse model of MS. Double transgenic huCD20xHIGR3 (CD20dbtg) mice, which express human CD20, were immunised with the myelin fusion protein MP4 to induce experimental autoimmune encephalomyelitis (EAE). Both light and electron microscopy were used to assess myelination and axonal pathology in mice treated with OBZ during chronic EAE. Furthermore, the effects of the already established murine anti-CD20 antibody 18B12 were assessed in C57BL/6 wild-type (wt) mice. In both models (18B12/wt and OBZ/CD20dbtg) anti-CD20 treatment significantly diminished the extent of spinal cord pathology. While 18B12 treatment mainly reduced the extent of axonal pathology, a significant decrease in demyelination and increase in remyelination were additionally observed in OBZ-treated mice. Hence, the data suggest that OBZ could have neuroprotective effects on the CNS, setting the drug apart from the currently available type I anti-CD20 antibodies.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD20; Antineoplastic Agents, Immunological; Axons; B-Lymphocytes; Chronic Disease; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Electron; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Myelin Basic Protein; Myelin Proteolipid Protein; Neurofilament Proteins; Recombinant Fusion Proteins; Spinal Cord

Primary progressive multiple sclerosis (PPMS) is a chronic demyelinating disease of the central nervous system (CNS) currently lacking any effective treatment. Promoting endogenous brain repair offers a potential strategy to halt and possibly restore neurologic function in PPMS. To understand how the microenvironment within white matter lesions plays a role in repair we have focused on neural progenitor cells (NPCs) since these are found in lesions in PPMS and have been found to influence oligodendrocyte progenitor cell maturation (OPCs). To better understand the cellular nature of NPCs in PPMS we developed iPS cells from blood samples of PPMS patients and age matched non-disease spouse or blood relative controls. Using these iPS cell lines we determined that the NPCs from PPMS cases provided no neuroprotection against active CNS demyelination compared to NPCs from control iPS lines which were capable of completely preventing injury. Conditioned media (CM) from PPMS NPCs provides no protection to OPCs and prevents maturation of OPCs into oligodendrocytes in vitro. We also found that CM from PPMS iPS NPCs elicited patient-specific differences in the response to compounds that should foster oligodendrocyte (OL) maturation. Together, these data establish a new model for understanding the nature of myelination defects in PPMS which may lead to novel targeted approaches for preventing demyelination in these patients.

Topics: Aged; Animals; Apoptosis; Axons; Cell Differentiation; Clemastine; Culture Media, Conditioned; Cuprizone; Female; Humans; Induced Pluripotent Stem Cells; Male; Mice, Inbred C57BL; Miconazole; Middle Aged; Monoamine Oxidase Inhibitors; Multiple Sclerosis, Chronic Progressive; Myelin Basic Protein; Myelin Sheath; Nerve Tissue Proteins; Oligodendroglia

Multiple sclerosis (MS) is associated with breakdown of the myelin sheath that coats neurons in the central nervous system. The cause of MS is not known, although the pathogenesis involves destruction of myelin by the immune system. It was the aim of this study to examine the abundant myelin protein, myelin basic protein (MBP), to determine if there are sites of modification that may be characteristic for MS. MBP from the cerebellum was examined from controls and MS patients across the age range using mass spectrometry and amino acid analysis. Amino acid racemization data indicated that myelin basic protein is long-lived and proteomic analysis of MBP showed it to be highly modified. A common modification of MBP was racemization of Asp and this was significantly greater in MS patients. In long-lived proteins, L-Asp and L-Asn can racemize to three other isomers, D-isoAsp, L-isoAsp and D-Asp and this is significant because isoAsp formation in peptides renders them immunogenic.Proteomic analysis revealed widespread modifications of MBP with two surface regions that are altered in MS. In particular, isoAsp was significantly elevated at these sites in MS patients. The generation of isoAsp could be responsible for eliciting an immune response to modified MBP and therefore be implicated in the etiology of MS.

Topics: Adult; Aged; Aging; Arginine; Aspartic Acid; Cerebellum; Glutamine; Humans; Isoaspartic Acid; Mass Spectrometry; Middle Aged; Models, Molecular; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Myelin Basic Protein; Protein Processing, Post-Translational; Proteolysis

In the current exploratory study, we longitudinally measured immune parameters in the blood of individuals with relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS), and investigated their relationship to disease duration and clinical and radiologic measures of CNS injury.. Peripheral blood mononuclear cells (PBMCs) and plasma were obtained from subjects with RRMS, SPMS, and from healthy controls on a monthly basis over the course of 1 year. MRI and Expanded Disability Status Scale evaluations were performed serially. PBMCs were analyzed by enzyme-linked immunosorbent spot assay to enumerate myelin basic protein-specific interleukin (IL)-17- and interferon (IFN)-γ-producing cells. Plasma concentrations of proinflammatory factors were measured using customized Luminex panels.. Frequencies of myelin basic protein-specific IL-17- and IFN-γ-producing PBMCs were higher in individuals with RRMS and SPMS compared to healthy controls. Patients with SPMS expressed elevated levels of IL-17-inducible chemokines that activate and recruit myeloid cells. In the cohort of patients with SPMS without inflammatory activity, upregulation of myeloid-related factors correlated directly with MRI T2 lesion burden and inversely with brain parenchymal tissue volume.. The results of this exploratory study raise the possibility that Th17 responses and IL-17-inducible myeloid factors are elevated during SPMS compared with RRMS, and correlate with lesion burden. Our data endorse further investigation of Th17- and myeloid-related factors as candidate therapeutic targets in SPMS.

Topics: Adult; Aged; Cytokines; Disability Evaluation; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interferon-gamma; Interleukin-17; Interleukin-23; Leukocytes, Mononuclear; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Myelin Basic Protein

Topics: Biomarkers; Cytokines; Female; Humans; Leukocytes, Mononuclear; Male; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Myelin Basic Protein

One of the auto-antigens aberrantly targeted in Multiple sclerosis is myelin basic protein (MBP). In this study, chronic progressive multiple sclerosis (CPMS) patients receiving the experimental drug MBP8298, on a compassionate care trial, were examined before and after high dose peptide treatment for their circulating regulatory T-cell numbers and their responses to the common mitogens, phytohemagglutinin and poke-weed mitogen. Peripheral blood mononuclear cells (PBMCs) isolated from these patients before treatment displayed anergy upon stimulation with phytohemagglutinin; measured through reduced proliferation, IFN-γ and IL-17A secretion in an in vitro cell culture system. 6 Weeks and 6months after treatment their PBMCs displayed a reversal of anergy with phytohemagglutinin stimulation. There was also a marked increase in their CD4(+)CD25(+hi)FoxP3(+) T-cells regulatory T-cells. These results suggest that high dose MBP8298 treatment has a profound effect on the circulating T-cells of CPMS patients, capable of reversing peripheral anergy and establishing T regulation.

Topics: CD4 Lymphocyte Count; Clonal Anergy; Compassionate Use Trials; Dose-Response Relationship, Immunologic; Follow-Up Studies; Humans; Immunotherapy; Interferon-gamma; Interleukin-17; Interleukin-2 Receptor alpha Subunit; Multiple Sclerosis, Chronic Progressive; Myelin Basic Protein; Peptide Fragments; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Treatment Outcome

The pathological basis of diffusely abnormal white matter (DAWM) in multiple sclerosis (MS) has not been elucidated in detail, but may be an important element in disability and clinical progression.. Fifty-three subjects with MS were examined with T₁, multi-echo T₂ and magnetization transfer (MT). Twenty-three samples of formalin-fixed MS brain tissue were examined with multi-echo T₂ and subsequently stained for myelin phospholipids using luxol fast blue, for axons using Bielschowsky, immunohistochemically for the myelin proteins myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3' phosphohydrolase (CNP) and for astrocytes using glial fibrillary acidic protein (GFAP). Regions of interest in DAWM were compared with normal appearing white matter.. Fourteen of 53 subjects with MS in the in vivo study showed the presence of DAWM. Subjects with DAWM were found to have a significantly lower Expanded Disability Status Scale (EDSS) and shorter disease duration (DD) when compared with subjects without DAWM (EDSS: 1.5 versus 3.0, p = 0.031; DD: 5.4 versus 10.3 years, p = 0.045). DAWM in vivo had reduced myelin water and MT ratio, and increased T₂ and water content. Histological analysis suggests DAWM, which shows a reduction of the myelin water fraction, is characterized by selective reduction of myelin phospholipids, but with a relative preservation of myelin proteins and axons.. These findings suggest that the primary abnormality in DAWM is a reduction or perturbation of myelin phospholipids that correlates with a reduction of the myelin water fraction.

Topics: 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; Adult; Aged; Astrocytes; Axons; Brain; Brain Chemistry; Disability Evaluation; Female; Glial Fibrillary Acidic Protein; Humans; Immunohistochemistry; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Myelin Basic Protein; Nerve Tissue Proteins; Phospholipids; Phosphoric Diester Hydrolases; Predictive Value of Tests; Staining and Labeling; Transcription Factors; Water; Young Adult

The disease mechanism of multiple sclerosis (MS) involves inflammation, demyelination and neurodegeneration. The relation between these components is not completely understood, but recent experiences with aggressive anti-inflammatory treatment suggest that inflammation drives neuronal damage in patients with relapsing remitting MS. Although infiltration of lymphocytes into the brain parenchyma was recognized as a key event in the pathogenesis of MS more than 120 years ago, important aspects of the mechanisms triggering and sustaining this immune response remain unknown. Furthermore, studies of MS lesions and evidence from therapeutic trials suggest that the disease mechanism may vary both throughout the disease course and between patients. The understanding of MS as an autoimmune disease targeting myelin proteins is shaped by the animal model experimental autoimmune encephalomyelitis (EAE), but translation from EAE to MS has proven to be difficult. Although both the EAE model and the prominent association to HLA class II molecules suggest a key role for CD4+ T helper cells, it is not known if or how their tolerance to myelin proteins or other putative autoantigens are broken in MS. This paper reviews some important concepts and controversies in the understanding of the immunological basis for MS and its treatment.

Topics: Animals; Antigen Presentation; B-Lymphocytes; CD4-Positive T-Lymphocytes; Encephalomyelitis, Autoimmune, Experimental; Herpesvirus 4, Human; HLA Antigens; Humans; Immune Tolerance; Immunity, Cellular; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Myelin Basic Protein; Myelin Sheath; Vitamin D Deficiency

Autoimmune reactions associated with MS involve genetic and environmental factors. Because murine coronaviruses induce an MS-like disease, the human coronaviruses (HCoV) are attractive candidates as environmental factors involved in a demyelinating pathology. We previously reported the isolation of HCoV-229E/myelin basic protein (MBP) cross-reactive T-cell lines (TCL) in MS patients. To investigate antigenic cross-reactivity at the molecular level, 155 long-term T-cell clones (TCC) were derived from 32 MS patients by in vitro selection with MBP, proteolipid protein (PLP) or HCoV (strains 229E and OC43). Overall, 114 TCC were virus-specific, 31 were specific for myelin Ag and 10 other were HCoV/myelin cross-reactive. Twenty-eight virus-specific TCC and 7 myelin-specific TCC were obtained from six healthy donors. RACE RT-PCR amplification of the Vbeta chains of five of ten the cross-reactive TCC confirmed clonality and sequencing identified the CDR3 region associated with cross-reactivity. Our findings have promising implications in the investigation of the role of molecular mimicry between coronaviruses and myelin in MS as a mechanism related to disease initiation or relapses.

Topics: Adult; Aged; Amino Acid Sequence; Antigen-Presenting Cells; Antigens, Viral; Cell Proliferation; Clone Cells; Coronavirus; Epitopes; Female; Humans; Lymphocyte Activation; Male; Middle Aged; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Myelin Basic Protein; Myelin Proteolipid Protein; Myelin Sheath; Receptors, Antigen, T-Cell, alpha-beta; Reverse Transcriptase Polymerase Chain Reaction; T-Cell Antigen Receptor Specificity; T-Lymphocytes; Time Factors

Topics: Alleles; Antigen Presentation; Epistasis, Genetic; Genome; Haplotypes; Humans; Linkage Disequilibrium; Models, Biological; Models, Genetic; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Myelin Basic Protein; Peptides; Polymorphism, Genetic

To characterize T cell and antibody responses in remitting-relapsing experimental autoimmune encephalomyelitis (RR-EAE), we compared myelin oligodendrocyte glycoprotein (MOG)-induced RR-EAE in C57BL/6 (B6) x SJL (F1) mice and chronic-progressive EAE (CP-EAE) in B6 mice at week 8 p.i. when clinical scores were comparable. Although these two strains exhibited similar inflammation/demyelination pattern and MOG-induced T cell responses, RR-EAE mice produced significantly higher levels of anti-MOG IgG1/IgG2a antibodies. Further, lymphocytes of RR-EAE mice proliferated vigorously to the secondary epitope myelin basic protein (MBP) 1-11. These results support a potential involvement of anti-MOG antibodies and epitope spreading in T cell responses in the development of MOG-induced RR-EAE model.

Topics: Analysis of Variance; Animals; Antibodies; Cells, Cultured; Cytokines; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Glycoproteins; Histological Techniques; Immunization; Immunoglobulin G; Lymphocyte Activation; Mice; Mice, Inbred Strains; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Myelin Basic Protein; Myelin Proteolipid Protein; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Spinal Cord; T-Lymphocytes; Time Factors

Although multiple sclerosis is considered to be an autoimmune disease in the CNS, the immune responses that take place in the CNS and lymphoid organs remain to be elucidated. Here, we have successfully induced various subtypes of experimental autoimmune encephalitis (EAE) in LEW.1AV1 rats carrying RT1(av1) on the Lewis background genes by immunization with recombinant rat myelin oligodendrocyte glycoprotein (MOG) in various solutions with adjuvants. The purpose of the present study was to analyse in more detail the clinical and immunopathological features of MOG-induced EAE in LEW.1AV1 rats. Immunization with high doses of soluble MOG with pertussis toxin induced acute, frequently fatal EAE, whereas medium doses of partially aggregated MOG without pertussis toxin produced relapsing and remitting EAE. Secondary progressive EAE was induced in some rats by immunization with the immunization protocol having an intermediate nature between the above two. The optic nerve (approximately 60% of the immunized rats) and spinal cord (100%) were frequently involved and detectable both clinically and pathologically, while there was no lesion in the cerebrum. Histological examination revealed that, despite variety in the clinical subtypes, progression of the pathological processes was strikingly uniform, i.e. initial inflammation with minimal demyelination followed by predominant demyelination with minimal lymphocyte infiltration. These findings suggest that the lesion during the later stage is maintained by humoral factors. Taken together, this experimental system can serve as a model of neuromyelitis optica. Further analysis will provide useful information to elucidate the pathogenesis and to develop immunotherapy for neuromyelitis optica and multiple sclerosis.

Topics: Animals; Antibodies; Brain Stem; Encephalomyelitis, Autoimmune, Experimental; Immunization; Immunohistochemistry; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Myelin Basic Protein; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Neuromyelitis Optica; Optic Nerve; Pertussis Vaccine; Rats; Rats, Inbred Lew; Spinal Cord

In this study, we analysed the recall antigen-induced cytokine production by peripheral blood mononuclear cells (PBMC) from 31 patients with multiple sclerosis (MS) with a relapsing-remitting (rr) and a relapsing-progressive (rp) course and from 40 healthy controls. Cells were stimulated with purified protein derivative (PPD; type 1 response) and tetanus toxoid (TT; type 2 response). Cytokines were determined in the supernatants by ELISA. One of the interesting findings was that healthy controls showed more frequently an IL-5 production after incubation with TT than MS-patients (68% vs.37%; p<0.01), while the type 1 reactivity was only slightly enhanced in MS patients as compared to the controls. However, within the MS patients, there was a significant difference in the incidence of the type 1 reactivity comparing patients with an rp and an rr course (60% vs. 24%; p<0.05). Furthermore, the frequency of a type 0 profile (simultaneous PPD-induced IFN-gamma and TT-induced IL-5 production) was fourfold higher in rr than in the rp patients (43% vs. 10%, p<0.05). In vitro analysis of cytokine profiles in MS could therefore be an interesting approach to evaluate the prognosis of MS (rr vs. rp) already at the beginning of the disease. Thus, it seems that the presence of a type 0 profile is a valid indicator for a favorable course, while a type 1 profile is rather associated with rp MS.

Topics: Adult; Cell Division; Cytokines; Female; Humans; Immunosuppressive Agents; Leukocytes, Mononuclear; Male; Middle Aged; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Myelin Basic Protein; Phytohemagglutinins; Pokeweed Mitogens; Predictive Value of Tests; Prognosis; Tetanus Toxin; Th1 Cells; Tuberculin; Up-Regulation

A significant correlation exists between disability and the volume of black holes (BHL VOL), defined as hypointense lesions on T1-weighted cranial magnetic resonance imaging. A consistent correlation has also been reported between urinary myelin basic protein-like material (MBPLM) and the transition toward secondary progression (SP) from relapsing-remitting (RR) multiple sclerosis (MS).. To improve the management of MS through a noninvasive and cost-effective test for monitoring disease activity or disease status.. From 662 patients with MS (86 with RR MS, 259 with SP MS without continued attacks, and 317 with SP MS with continued attacks), 24-hour urine samples were obtained at enrollment in the phase 3 Linomide (roquinimex) drug study. The urine specimens were analyzed for MBPLM and correlated with clinical features and findings on cranial magnetic resonance imaging.. Significant but weak correlations existed between urinary MBPLM and BHL VOL in all patients with MS (r = 0.114, P =.003; n = 662), patients with SP MS without attacks (r = 0.185, P =.003; n = 259), and all patients with SP MS (r = 0.122, P =.003; n = 576). No significant correlations were detected in the RR MS group or any of the disease groups or subgroups whose Expanded Disability Status Scale score was 5.0 or lower. In subgroup analysis, the most significant correlation was detected between urinary MBPLM after adjustment for creatinine and BHL VOL in patients with SP MS with an Expanded Disability Status Scale score of 5.5 or higher but without continued relapses (r = 0.417, P<.001; n = 138).. In patients with advanced SP MS, urinary MBPLM may possibly serve as an indicator of failed remission and axonal damage. Urinary MBPLM correlates with disease status in MS, especially the transition of RR MS to SP MS with advancing disability.

Topics: Adjuvants, Immunologic; Axons; Brain; Cost-Benefit Analysis; Cross-Sectional Studies; Disability Evaluation; Disease Progression; Female; Humans; Hydroxyquinolines; Magnetic Resonance Imaging; Male; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Myelin Basic Protein; Predictive Value of Tests; Randomized Controlled Trials as Topic; Severity of Illness Index

In this study, we investigated the in vitro proliferative response of peripheral blood T lymphocytes from MS patients and controls to MBP and MOG either in the absence or in the presence of the conditioning factor IL-7. In the absence of IL-7, T-cell reactivity to MOG and MBP was similar in MS patients and controls even if an increased MBP response was found in a subgroup of patients with active disease. In the presence of IL-7, increased T-cell reactivity to MBP was observed in MS patients suggesting that their MBP-specific T cells are in a different functional state.

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; In Vitro Techniques; Interleukin-7; Male; Middle Aged; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Myelin Basic Protein; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; T-Lymphocytes

Human myelin basic protein (hMBP) gene is one of the candidate genes in the complex mosaic of multiple sclerosis (MS) susceptibility. In this study we verified the distribution of the polymorphism of the region 5' flanking the first exon of the hMBP gene, in 97 relapsing remitting, 74 primary progressive Italian MS patients, and in 236 healthy controls, using polymerase chain reaction (PCR) and gel electrophoresis analysis in this region from 1116 - 1540 nt. Three different band patterns were observed: one homozygote with a 354 bp long fragment, one homozygote with 424 bp long fragment and one heterozygote with both bands present. The short fragment was statistically more frequent in RRMS patients than in HC (P<0.05). The long fragment was more present in HC. Similarly the short homozygous pattern (354 bp/354 bp) was significantly higher in the RRMS patients versus the healthy controls (P<0.01). The sequence analysis of the hMBP alleles showed that while the long fragments matched the prototype sequence completely, all the short fragments showed a deletion of 70 bp from nt 1177 to nt 1247, which explains the short 354 bp allele detected by PCR. Moreover two single mismatches in positions 1386 (T-->C) and 1431 (G-->A), were present only in the short hMBP fragment.

Topics: Alleles; Amino Acid Sequence; DNA Mutational Analysis; Female; Gene Deletion; Genetic Predisposition to Disease; Humans; Italy; Male; Molecular Sequence Data; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Myelin Basic Protein; Polymorphism, Genetic; Repetitive Sequences, Nucleic Acid

Myelin basic protein (MBP), a candidate autoantigen in multiple sclerosis (MS), exists in different isoforms and charge isomers generated by differential splicing of exons and by a combination of posttranslational modifications, respectively. These various isoforms and charge isomers of MBP vary in abundance and most likely serve different functions during myelinogenesis and remyelination. The least cationic among the charge isomers of MBP is citrullinated and is referred to as MBP-C8. MBP-C8 is relatively increased in the population of MBP isomers in more developmentally immature myelin and in MS brain tissue. In a previous study, we found that MBP-C8-reactive T cells could be detected in CD4+ T cell lines (TCL) generated with MBP from both MS patients and normal controls. Here, we examined the frequency and peptide specificity of MBP-C8-specific TCL generated with MBP-C8 in MS patients and controls. Ten subjects grouped in five sets, each an MS patient and a control, were studied. In all cases, the MS patient had either a higher overall number of MBP-C8-responding lines, responded with greater sensitivity to the MBP-C8 antigen or both. Few lines responded to the MBP-C8 peptides but, if they did, they appeared to be specific to the carboxyl-half of the MBP-C8 molecule. Given the large amounts of citrullinated MBP in MS brain tissue, a preferential T cell response to MBP-C8 may be involved in the induction and perpetuation of this disease. Multiple Sclerosis (2000) 6 220 - 225

Topics: Adult; Cell Line; Citrulline; Humans; Male; Middle Aged; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Myelin Basic Protein; Peptide Fragments; Reference Values; T-Lymphocytes

To compare the clinical and laboratory features of primary progressive (PP) and secondary progressive (SP) MS, to evaluate the role of CSF and urine myelin basic protein-like material (MBPLM) in differentiating PP from SP MS, and to assess the utility of urine MBPLM as a surrogate marker of disease activity in progressive MS.. The current categorization of subtypes of MS is based solely on clinical and temporal characteristics of the disease. Laboratory markers are needed that can differentiate reliably the subtypes of MS and serve as surrogate markers of disease progression.. Clinical and paraclinical data of 51 PPMS and 140 SPMS patients were reviewed retrospectively. CSF and urine MBPLM were measured using a double-antibody radioimmunoassay.. PPMS was more likely to present with progressive myelopathy (p < or = 0.001) after the age of 40 years (p = < or = 0.001), and it affected men relatively more often than SPMS (male-to-female ratio, 1:1.7 versus 1:3.2 respectively). Ambulatory assistance was required by PP patients more often and earlier than in those with SPMS. The incidence of abnormal CSF, evoked potential, and cranial MRI studies was similar in the two groups. Spinal cord MRI abnormalities were noted significantly more often in SP disease. There was an insignificant trend of higher CSF MBPLM in SPMS compared with PPMS. Urine MBPLM and MBPLM/creatinine were significantly higher in SPMS than in PPMS. However, the values of urine MBPLM and MBPLM/creatinine at the initial visits of patients with PPMS and SPMS were not significantly different. Urine MBPLM/creatinine was significantly higher in both PPMS and SPMS compared with normal control subjects. No correlation was found between urine MBPLM and disease duration or between urine MBPLM and clinical disability. There was no correlation between urine MBPLM/creatinine and either disease duration or clinical disability.. These findings provide additional evidence of the differences in PPMS and SPMS, notably in the associated changes in MBPLM in urine, and also suggest a possible role for urine MBPLM in identifying patient cohorts. The high urine MBPLM levels in progressive MS patients indicate a potential role of this marker for assessing responsiveness to therapeutic interventions.

Topics: Adult; Age of Onset; Biomarkers; Female; Humans; Male; Middle Aged; Multiple Sclerosis, Chronic Progressive; Myelin Basic Protein; Radioimmunoassay