The protein component of the myelin layer is essential for all aspects of peripheral nerves, and its deficiency can lead to structural and functional impairment. The presence of peripheral myelin ...protein 2 (P2, PMP2, FABP8, M-FABP) in Schwann cells has been known for decades and shown recently to be involved in the lipid homeostasis in the peripheral neural system. However, its precise role during de- and remyelination has yet to be elucidated. To this end, we assessed remyelination after sciatic nerve crush injury in vivo, and in an experimental de/remyelination ex vivo myelinating culture model in P2-deficient
(P2
−/−
)
and wild-type (
WT
) animals. In vivo, the nerve crush paradigm revealed temporal structural and functional changes in
P2
−/−
mice as compared to
WT
animals. Concomitantly,
P2
−/−
DRG cultures demonstrated the presence of shorter internodes and enlarged nodes after ex vivo de/remyelination. Together, these data indicate that P2 may play a role in remyelination of the injured peripheral nervous system, presumably by affecting the nodal and internodal configuration.
Dimethyl fumarate (DMF), a fumaric acid ester, is a new orally available disease-modifying agent that was recently approved by the US FDA and the EMA for the management of relapsing forms of multiple ...sclerosis (MS). Fumaric acid has been used for the management of psoriasis, for more than 50 years. Because of the known anti-inflammatory properties of fumaric acid ester, DMF was brought into clinical development in MS. More recently, neuroprotective and myelin-protective mechanism actions have been proposed, making it a possible candidate for MS treatment. Two Phase III clinical trials (DEFINE, CONFIRM) have evaluated the safety and efficacy of DMF in patients with relapsing-remitting MS. Being an orally available agent with a favorable safety profile, it has become one of the most commonly prescribed disease-modifying agents in the USA and Europe.
Abstract Interleukin 17 (IL-17), produced by T cells, plays an important role in Multiple Sclerosis (MS) and its animal model, Experimental Autoimmune Encephalomyelitis (EAE). In contrast to ...IL-17-producing CD4 + T cells, the contribution of IL-17-producing CD8 + T cells (Tc17) in CNS autoimmunity has been investigated less intensively. Here we investigate the role of TC 17 in EAE. We compare different T cell populations and their cytokine pattern in the MOG35-55 - and MOG37-50 -induced EAE. We detected a similar cytokine phenotype for both EAE models in the autoimmune process assessed at different stages. Regarding the migratory activity, an involvement of IL-17 and IFN-γ in disease onset was suggested. Furthermore, we show that PAMPs have the ability to drive autoimmune process. To modify the cytokine pattern of different T cell populations, a combination of distinct factors is required (the activation of MyD88 or Syk, the genetic background, the presence of APCs and CD4 + T cells).
Objective
Some previous studies suggest modest to strong effects of 25‐hydroxyvitamin D (25(OH)D) on multiple sclerosis (MS) activity. The objective of this study was to explore the mechanistic ...rationale that may explain potential clinical effects of 25(OH)D.
Methods
This study measured serum 25(OH)D levels and global gene expression profiles over a course of up to 2 years in patients starting treatment with interferon beta‐1b (IFNB‐1b) after a clinically isolated syndrome. MS disease activity was assessed by the number of gadolinium‐enhancing lesions present on repeated magnetic resonance imaging (MRIs).
Results
The number of gadolinium‐enhancing lesions was highly significantly associated with 25(OH)D levels. Conducting various systems‐level analyses on the molecular level, multiple lines of evidence indicated that 25(OH)D regulates expression dynamics of a large gene–gene interaction system which primarily regulates immune modulatory processes modulating MS activity. The vitamin D response element was significantly enriched in this system, indicating a direct regulation of this gene interaction network through the vitamin D receptor. With increasing 25(OH)D levels, resulting regulation of this system was associated with a decrease in MS activity. Within the complex network of genes that are regulated by 25(OH)D, well‐described targets of IFNB‐1b and a regulator of sphingosine‐1‐phosphate bioavailability were found. The 25(OH)D effects on MS activity were additively enhanced by IFNB‐1b.
Interpretation
Here, we provide mechanistic evidence that an unbalanced 25(OH)D gene expression system may affect MS activity. Our findings support a potential benefit of monitoring and managing vitamin D levels (e.g., through supplementation) in early MS patients treated with IFN‐beta‐1b.
Experimental autoimmune encephalomyelitis (EAE) is--in certain aspects--regarded as an animal model of the human CNS autoimmune disease multiple sclerosis (MS). While in EAE CNS-autoantigen-specific ...immunity is induced in a defined way, the initial processes leading to CNS autoimmunity in humans are so far unknown. Despite essential restrictions, which exist regarding the interpretation of EAE data towards MS, EAE might be a useful model to study certain basic aspects of CNS autoimmunity. Studies in MS have demonstrated that established autoimmune pathology can be critically influenced by environmental factors, in particular viral and bacterial infections. To investigate this interaction, EAE as an instrument to study CNS autoimmunity under defined conditions appears to be a suitable experimental tool. For this reason, we here investigated the influence of the Toll-like-receptor (TLR) ligand CpG oligonucleotide (CpG) on already established CNS autoimmunity in murine proteolipid protein (PLP)-induced EAE in SJL mice. CpG were found to co-stimulate PLPp-specific IFN-γ production in the peripheral immune system and in the CNS. However, CpG induced Interleukin (IL)-17 production in the inflamed CNS both alone and in combination with additional PLPp stimulation. These findings might indicate a mechanism by which systemic infections and the microbial stimuli associated with them may influence already existing CNS autoimmune pathology.
Interferon beta (IFNbeta) therapy for multiple sclerosis (MS) is associated with a potential for the development of neutralising antibodies (NAbs) that negatively affect therapy. Several factors ...influence the development of NAbs, such as lack of complete sequence homology with the endogenous IFNbeta sequence, frequency of administration, level of dose and formulation of IFNbeta. Taken together, the evidence that NAb status reduces clinical efficacy in MS patients is strong. Standardised assays for NAbs are lacking, and titres vary over time. NAb testing is a critical component of care for MS patients because it provides information on one of the most important factors determining clinical responsiveness to IFNbeta therapy. This expert panel report attempts to move the field towards resolution of the remaining issues and considers several aspects of NAbs, including their clinical relevance, factors influencing immunogenicity, assays to quantify NAbs and the definition of clinically relevant titres.
Zusammenfassung
Die Multiple Sklerose ist eine komplexe, autoimmun vermittelte Erkrankung des zentralen Nervensystems, charakterisiert durch inflammatorische Demyelinisierung sowie ...axonalen/neuronalen Schaden. Die Zulassung verschiedener verlaufsmodifizierender Therapien und unser verbessertes Verständnis der Krankheitsmechanismen und -entwicklung in den letzten Jahren haben die Prognose und den Verlauf der Erkrankung deutlich verändert. Diese Aktualisierung der Behandlungsempfehlung der Multiple Sklerose Therapie Konsensus Gruppe konzentriert sich auf die wichtigsten Empfehlungen für verlaufsmodifizierende Therapien der Multiplen Sklerose im Jahr 2021. Unsere Empfehlungen basieren auf aktuellen wissenschaftlichen Erkenntnissen und gelten für diejenigen Medikamente, die in weiten Teilen Europas, insbesondere in den deutschsprachigen Ländern (Deutschland, Österreich, Schweiz), zugelassen sind.
Patients with primary progressive MS who received the anti-CD20+ humanized antibody ocrelizumab were less likely to have clinical deterioration that was sustained for 12 weeks than those who received ...placebo. The drug was associated with decreased lesion activity on MRI.
Primary progressive multiple sclerosis accounts for 10 to 15% of the overall population with multiple sclerosis.
1
The course of this disease differs from those of relapsing–remitting and secondary progressive forms of multiple sclerosis in that progression consists mainly of gradual worsening of neurologic disability from symptom onset, although relapses may occur.
1
Phase 3 trials in primary progressive multiple sclerosis have been unsuccessful,
2
–
4
and no disease-modifying treatments have been approved.
B cells contribute to the pathogenesis of multiple sclerosis, including the primary progressive form.
5
Although the mechanisms of tissue injury in multiple sclerosis are uncertain, B cells may influence pathogenesis . . .
In two trials involving patients with relapsing multiple sclerosis, the anti-CD20+ monoclonal antibody ocrelizumab was associated with lower annualized relapse rates, lower risk of disability ...progression, and better MRI features than interferon beta-1a.
Despite the availability of several disease-modifying treatments for relapsing forms of multiple sclerosis, patients often continue to have clinical and subclinical disease activity, and neurologic disability continues to accrue. Thus, there is a need for more effective treatments with acceptable safety profiles.
1
–
3
B cells are thought to influence the underlying pathogenesis of multiple sclerosis by means of antigen presentation,
4
autoantibody production,
5
,
6
cytokine regulation,
4
and the formation of ectopic lymphoid aggregates in the meninges, which possibly contribute to cortical demyelination and neurodegeneration.
7
,
8
Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20, a cell-surface antigen that is expressed . . .
Experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats by active immunization with myelin from guinea pig spinal cord by the encephalitogenic myelin basic protein or by adoptive ...transfer using myelin basic protein-specific CD4-positive T cells. Treatment with purified monoclonal antibody (1A-29) to the intercellular adhesion molecule-1 and its F(ab')2 fragments efficiently suppressed active EAE. Control treatment with an irrelevant antibody or saline did not alter the course of the disease. Histological sections of the central nervous system showed a pronounced reduction of inflammatory infiltrates during treatment with antibody to intercellular adhesion molecule-1. In the adoptive transfer model of EAE, 1A-29 had only a minor effect. Proliferation assays on lymph node cells ex vivo from 1A-29- and saline-treated animals were performed. Administration of 1A-29 suppressed antigen-specific T-cell proliferation. The differential effects in EAE versus adoptive transfer EAE suggest that 1A-29 acts predominantly on the induction phase of the immune response and, to a lesser extent, on the transendothelial migration of T cells. We conclude that intercellular adhesion molecule-1-dependent pathways are critically involved in the pathogenesis of EAE and that antibodies to leukocyte adhesion molecules could be a novel therapeutic approach to autoimmune disease of the central nervous system.
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