Myelin P0 Research Articles

Antibiotics-Induced Intestinal Immunomodulation Attenuates Experimental Autoimmune Neuritis (EAN)

BackgroundThe composition of gut microbiota plays a pivotal role in priming the immune system and thus impacts autoimmune diseases. Data on the effects of gut bacteria eradication via systemic antibiotics on immune neuropathies are currently lacking. This study therefore assessed the effects of antibiotics-induced gut microbiota alterations on the severity of experimental autoimmune neuritis (EAN), a rat model of Guillain-Barré Syndrome (GBS). Myelin P0 peptide 180–199 (P0 180–199)-induced EAN severity was compared between adult Lewis rats (12 weeks old) that received drinking water with or without antibiotics (colistin, metronidazole, vancomycin) and healthy rats, beginning antibiotics treatment immediately after immunization (day 0), and continuing treatment for 14 consecutive days. Neuropathy severity was assessed via a modified clinical score, and then related to gut microbiota alterations observed after fecal 16S rRNA gene sequencing at baseline and after EAN induction. Effectors of gut mucosal and endoneurial immunity were assessed via immunostaining. EAN rats showed increased gut mucosal permeability alongside increased mucosal CD8+ T cells compared to healthy controls. Antibiotics treatment alleviated clinical EAN severity and reduced endoneurial T cell infiltration, decreased gut mucosal CD8+ T cells and increased gut bacteria that may be associated with anti-inflammatory mechanisms, like Lactobacillus or Parasutterella. Our findings point out a relation between gut mucosal immunity and the pathogenesis of EAN, and indicate that antibiotics-induced intestinal immunomodulation might be a therapeutic approach to alleviate autoimmunity in immune neuropathies. Further studies are warranted to evaluate the clinical transferability of these findings to patients with GBS.Graphical

Guillain-Barré syndrome: History, pathogenesis, treatment, and future directions.

Since its description by Guillain, Barré, and Strohl in 1916, Guillain-Barré syndrome (GBS) has attracted a large literature. The author reviews the history of research into its pathogenesis and treatment to highlight promising avenues for future research. This is a nonsystematic personal review. Since the early 1900s, the clinical picture of GBS has been illustrated in multiple series culminating in the ongoing International Guillain-Barré Syndrome study of 2000 patients. In the 1950s and 1960s, the inflammatory nature of the commonest form, acute inflammatory demyelinating polyradiculoneuropathy (AIDP), was described. In the 1990s, two axonal forms, acute motor-sensory axonal neuropathy and acute motor axonal neuropathy, were recognized. In the 1990s and early 2000s, these forms were shown to be due to antibodies against Campylobacter jejuni glycans cross-reacting with glycolipids on axonal membranes. The pathogenesis of AIDP remains unknown, but T-cell responses to the compact myelin proteins, P2 and P0, which cause experimental autoimmune neuritis, suggest that T cells are important. Randomized controlled trials in the 1970s and 1980s showed no benefit from corticosteroids. Trials in the 1980s showed benefit from plasma exchange and in the 1990s from intravenous immunoglobulin. Future research should seek biomarkers to identify subgroups with different treatment responses, define the true natural history of the disease with population-based epidemiological studies, study the pathology in autopsies early in the disease, seek causative antibodies and confirm autoimmune T-cell responses in AIDP, and expand treatment trials to include anti-T-cell agents.

Probing the Immunoreceptor Tyrosine-Based Inhibition Motif Interaction Protein Partners with Proteomics.

Phosphorylation of tyrosine is the basic mode of protein function and signal transduction in organisms. This process is regulated by protein tyrosine kinases (PTKs) and protein tyrosinases (PTPs). Immunoreceptor tyrosine-based inhibition motif (ITIM) has been considered as regulating the PTP activity through the interaction with the partner proteins in the cell signal pathway. The ITIM sequences need to be phosphorylated first to active the downstream signaling proteins. To explore potential regulatory mechanisms, the ITIM sequences of two transmembrane immunoglobulin proteins, myelin P0 protein-related protein (PZR) and programmed death 1 (PD-1), were analyzed to investigate their interaction with proteins involved in regulatory pathways. We discovered that phosphorylated ITIM sequences can selectively interact with the tyrosine phosphatase SHP2. Specifically, PZR-N-ITIM (pY) may be critical in the interaction between the ITIM and SH2 domains of SHP2, while PD1-C-ITSM (pY) may play a key role in the interaction between the ITIM and SH2 domains of SHP2. Quite a few proteins were identified containing the SH2 domain, exhibiting phosphorylation-mediated interaction with PZR-ITIM. In this study, 14 proteins with SH2 structural domains were identified by GO analysis on 339 proteins associated to the affinity pull-down of PZR-N-ITIM (pY). Through the SH2 domains, these proteins may interact with PZR-ITIM in a phosphorylation-dependent manner.

In vitro interaction of myelin proteins P0, P2, and MBP with F-actin

In vitro interaction of myelin proteins P0, P2, and MBP with F-actin

Complement-membrane regulatory proteins are absent from the nodes of Ranvier in the peripheral nervous system

BackgroundHomozygous CD59-deficient patients manifest with recurrent peripheral neuropathy resembling Guillain-Barré syndrome (GBS), hemolytic anemia and recurrent strokes. Variable mutations in CD59 leading to loss of function have been described and, overall, 17/18 of patients with any mutation presented with recurrent GBS. Here we determine the localization and possible role of membrane-bound complement regulators, including CD59, in the peripheral nervous systems (PNS) of mice and humans.MethodsWe examined the localization of membrane-bound complement regulators in the peripheral nerves of healthy humans and a CD59-deficient patient, as well as in wild-type (WT) and CD59a-deficient mice. Cross sections of teased sciatic nerves and myelinating dorsal root ganglia (DRG) neuron/Schwann cell cultures were examined by confocal and electron microscopy.ResultsWe demonstrate that CD59a-deficient mice display normal peripheral nerve morphology but develop myelin abnormalities in older age. They normally express myelin protein zero (P0), ankyrin G (AnkG), Caspr, dystroglycan, and neurofascin. Immunolabeling of WT nerves using antibodies to CD59 and myelin basic protein (MBP), P0, and AnkG revealed that CD59 was localized along the internode but was absent from the nodes of Ranvier. CD59 was also detected in blood vessels within the nerve. Finally, we show that the nodes of Ranvier lack other complement-membrane regulatory proteins, including CD46, CD55, CD35, and CR1-related gene-y (Crry), rendering this area highly exposed to complement attack.ConclusionThe Nodes of Ranvier lack CD59 and are hence not protected from complement terminal attack. The myelin unit in human PNS is protected by CD59 and CD55, but not by CD46 or CD35. This renders the nodes and myelin in the PNS vulnerable to complement attack and demyelination in autoinflammatory Guillain-Barré syndrome, as seen in CD59 deficiency.

Preclinical Assessment of EPO-Derived Peptide JM4 in Experimental Autoimmune Neuritis (P10-5.008)

<h3>Objective:</h3> Determine clinical efficacy of JM4, a synthetic erythropoietin-derived 19-mer peptide in experimental autoimmune neuritis (EAN). <h3>Background:</h3> Guillain-Barré syndrome, an acute inflammatory demyelinating polyneuropathy (AIDP), is an autoimmune disease causing injuries to myelinated nerves. Mild AIDP cases result in temporary motor and sensory deficits, but severe AIDP cases can also cause dysautonomia and respiratory failure leading to disability or death. Treatments include intravenous immune globulin or plasma exchange, but only 30–40% of patients experience clinical improvement. More effective interventions are needed to improve AIDP clinical outcomes. JM4 is a 19-mer peptide derived from human erythropoietin, which does not have an unwanted side effect of erythropoiesis. We demonstrated JM4 therapy had prolonged therapeutic benefits in an experimental autoimmune encephalomyelitis (EAE) model. Since inflammatory mechanisms underlying EAE are shared with EAN, an animal model for AIDP, we reasoned JM4 would also have clinical benefit in EAN. <h3>Design/Methods:</h3> EAN was induced in C57BL/6 mouse and in Lewis rat using murine peripheral nerve myelin P0 antigen and bovine myelin P2 peptide, respectively. EAN clinical scoring paradigm was used to assess neurological deficits. At deficit onset, EAN mice were administered JM4 intravenously (IV) for 10 days and EAN rats were administered JM4 IV for 3 days followed by intraperitoneal injection for 7 days. Sciatic nerves from EAN rodents were stained with Luxol fast blue to assess demyelination and with cresyl violet to assess mononuclear cell infiltration. <h3>Results:</h3> JM4 treatment reduced peak EAN clinical scores compared to sham treatment. Based on staining analysis, EAN induction caused mononuclear cell infiltration and demyelination in the sciatic nerve. <h3>Conclusions:</h3> Preliminary clinical scoring data from rodent models suggest JM4 may have therapeutic benefits in EAN models. Further studies are needed to correlate improvements in clinical scoring with histological analysis of demyelination, mononuclear cell infiltration and neuroinflammatory markers in EAN models. <b>Disclosure:</b> Dr. Arismendi has nothing to disclose. The institution of Dr. Choi has received research support from Department of Veterans Affairs. Dr. Husar has nothing to disclose. Peter C. Dowling, MD has nothing to disclose. Dr. Lu has nothing to disclose.

The therapeutic effects of ginkgolides in Guillain-Barré syndrome and experimental autoimmune neuritis

BackgroundGuillain-Barré syndrome (GBS) is an acquired immune-mediated inflammatory peripheral neuropathy. The immune regulation of ginkgolides have been revealed in recent years. We herein investigate the potential therapeutic effects of ginkgolides both on GBS and its animal model, experimental autoimmune neuritis (EAN). MethodsEAN in C57BL/6 mice induced by subcutaneous injection with peripheral nerve myelin P0 protein peptide 180–199 (P0 peptide) were treated with ginkgolides at three different doses. GBS patients were randomly divided into two groups, the experimental group and the control group. The experimental group were treated with ginkgolides as soon as diagnosed. ResultsOur data indicated that ginkgolides administration daily ameliorated the score of EAN and delayed the peak of disease in EAN mice. Ginkgolides also down-regulated the proportions of T helper (Th) 17 cells in EAN spleens. Furthermore, we also found that administration of ginkgolides significantly decreased the levels of interferon (IFN)-γ and interleukin-12 (IL)-12 in GBS patients. ConclusionsOur results suggested that ginkgolides ameliorated the clinical score of EAN through down-regulating the proportions of Th 17 cells. Ginkgolides also suppressed inflammation response by decreasing pro-inflammatory cytokines IFN-γ and IL-12, suggesting ginkgolides had potential therapeutic effects on GBS patients and EAN in the future.

Emerging Roles of Perivascular Mesenchymal Stem Cells in Synovial Joint Inflammation.

In contrast to the significant advances in our understanding of the mesenchymal stem cell (MSC) populations in bone marrow (BM), little is known about the MSCs that are resident in the synovial joint and their possible roles in the tissue homeostasis, chronic inflammation as well as in repair. Neural crest is a transient embryonic structure, generating multipotential MSC capable of migrating along peripheral nerves and blood vessels to colonize most tissue types. In adult, these MSC can provide functional stromal support as a stem cell niche for lymphocyte progenitors for instance in the BM and the thymus. Critically, MSC have major immunoregulatory activities to control adverse inflammation and infection. These MSC will remain associated to vessels (perivascular (p) MSC) and their unique expression of markers such as myelin P0 and transcription factors (e.g. Gli1 and FoxD1) has been instrumental to develop transgenic mice to trace the fate of these cells in health and disease conditions. Intriguingly, recent investigations of chronic inflammatory diseases argue for an emerging role of pMSC in several pathological processes. In response to tissue injuries and with the release of host cell debris (e.g. alarmins), pMSC can detach from vessels and proliferate to give rise to either lipofibroblasts, osteoblasts involved in the ossification of arteries and myofibroblasts contributing to fibrosis. This review will discuss currently available data that suggest a role of pMSC in tissue homeostasis and pathogenesis of the synovial tissue and joints. Graphical abstract.

Effects of an Intratympanic Injection of Dexamethasone Combined with Gentamicin on the Expression Level of Serum P0 Protein Antibodies in Patients with Meniere's Disease

OBJECTIVES:To investigate the effects of an intratympanic injection of dexamethasone combined with gentamicin on the expression level of serum P0 protein antibodies in patients with Meniere’s disease (MD).METHODS:A total of 136 patients with MD treated in our hospital were enrolled in this study. Among them, 68 patients were treated with an intratympanic injection of dexamethasone combined with gentamicin (observation group). Another 68 patients were treated with gentamicin alone (control group).RESULTS:After treatment, the expression levels of IgG and IgM in the two groups significantly decreased (p<0.05); the levels in the observation group were significantly lower than those in the control group (p<0.05). The incidences of vertigo, tinnitus, and gait instability in the observation group were significantly lower than those in the control group (p<0.05). Vestibular symptom index (VSI) scores in the observation group were significantly lower than those in the control group (p<0.05). We observed no significant difference between the two groups in the number of vertigo attacks 6 months after treatment (p>0.05).CONCLUSION:For patients with MD, dexamethasone combined with gentamicin can reduce the incidence of vertigo, tinnitus, and gait instability, but it has no effect on the efficacy or number of vertigo attacks 6 months after treatment. Therefore, the levels of myelin P0 protein antibodies after treatment can be used as predictors of vertigo at 6 months after treatment.

Bovine mucous membranes as a source of antimicrobial compounds

Loss of food quality, deterioration of organoleptic properties and accumulation of anti-alimentary compounds are in focus of modern food science. Nowadays, such traditional methods as processing, physical and chemical treatment are used for improving of shelf life. An alternative ways of shelf life increasing are quite a sharp problem. Antimicrobial peptides (AMPs) could be an actual alternative. According to Antimicrobial Peptide Database (http://aps.unmc.edu/AP/main.php), 2884 antimicrobial peptides from six kingdoms were found and identified. Mucous membranes of farm animals due to their border position and intensive contact with different pathogens could be a capacious source of such substances. Objects of the study were bovine oral cavity mucosa, nasal cavity mucosa, tracheal cavity mucosa, rectal mucosa, tongue mucosa, saliva gland and submandibular lymph nodes. Two-dimensional electrophoresis (2DE) was performed according to the method of O'Farrell, 35 protein fractions were identified by MALDI-TOF MS and MS/MS mass spectrometry. A number of qualitative and quantitative differences were revealed. A large number of histones (H2bd-like, H2BC, HIST1H2BD, HIST2H2AC, HIST1H2AH, histone H3.3 and H2bl-like, HIST2H2AC and histone H3.3, mixture HIST1H2AJ, HIST2H2BE and histone H2A type 2-C) were found in all mucous membranes as well as several tissue-specific proteins (proteins S100-A12 and AGR2, isoforms of ribosomal proteins, myelin P2, odorant-binding protein, secretoglobin), which could be a precusors of bioactive peptides

Phylogenetically Conserved Sequences Around Myelin P0 Stop Codon are Essential for Translational Readthrough to Produce L-MPZ.

Myelin protein zero (P0, MPZ) is the main cell adhesion molecule in peripheral myelin, the sequence of which is evolutionarily highly conserved. Large myelin protein zero (L-MPZ) is a novel translational readthrough molecule in mammals in a physiological status and is encoded by the P0 mRNA with an extra domain. The sequence similarities in the L-MPZ-specific region are found in humans and frogs but not in fish P0 cDNA. Actual synthesis of L-MPZ has been detected in rat and mouse sciatic nerve but not yet evaluated in frogs and humans. The production mechanism and physiological functions of L-MPZ remain unknown. Additionally, the sequence context around the canonical stop codon is significant for readthrough in viruses and yeast, but the correlation between the sequence around P0 stop codon and L-MPZ synthesis is unclear. Here, we focused on the phylogenetic pathways in L-MPZ synthesis. We have shown that L-MPZ is widely produced from frogs to humans using western blotting against L-MPZ. Mutation analysis of the sequence around the stop codon for L-MPZ synthesis using a mammalian in vitro transcription/translation system revealed that the evolutionarily conserved sequence around P0 stop codon is susceptible to readthrough and is similar to the consensus motif in viruses and yeast UAG stop codon type molecules. Our results demonstrate that the phylogenetically conserved sequence around the canonical P0 stop codon is essential for L-MPZ synthesis, suggesting that phylogenetic emergence of L-MPZ in amphibians may be related to particular distribution and/or function in the PNS myelin.

Friedreich Ataxia: Developmental Failure of the Dorsal Root Entry Zone.

Dorsal root ganglia, dorsal roots (DR), and dorsal root entry zones (DREZ) are vulnerable to frataxin deficiency in Friedreich ataxia (FA). A previously unrecognized abnormality is the intrusion of astroglial tissue into DR. Segments of formalin-fixed upper lumbar spinal cord of 13 homozygous and 2 compound heterozygous FA patients were sectioned longitudinally to represent DREZ and stained for glial fibrillary acidic protein (GFAP), S100, vimentin, the central nervous system (CNS)-specific myelin protein proteolipid protein, the peripheral nervous system (PNS) myelin proteins PMP-22 and P0, and the Schwann cell proteins laminin, alpha-dystroglycan, and periaxin. Normal DREZ showed short, sharply demarcated, dome-like extensions of CNS tissue into DR. The Schwann cell-related proteins formed tight caps around these domes. In FA, GFAP-, S100-, and vimentin-reactive CNS tissue extended across DREZ and into DR over much longer distances by breaching the CNS-PNS barrier. The transition between PNS and CNS myelin proteins was disorganized. During development, neural-crest derived boundary cap cells provide guidance to dorsal root ganglia axons growing into the dorsal spinal cord and at the same time block the inappropriate intrusion of CNS glia into DR. It is likely that frataxin is required during a critical period of permissive (axons) and nonpermissive (astroglia) border-control.

De novo PMP2 mutations in families with type 1 Charcot-Marie-Tooth disease.

We performed whole exome sequencing on a patient with Charcot-Marie-Tooth disease type 1 and identified a de novo mutation in PMP2, the gene that encodes the myelin P2 protein. This mutation (p.Ile52Thr) was passed from the proband to his one affected son, and segregates with clinical and electrophysiological evidence of demyelinating neuropathy. We then screened a cohort of 136 European probands with uncharacterized genetic cause of Charcot-Marie-Tooth disease and identified another family with Charcot-Marie-Tooth disease type 1 that has a mutation affecting an adjacent amino acid (p.Thr51Pro), which segregates with disease. Our genetic and clinical findings in these kindred demonstrate that dominant PMP2 mutations cause Charcot-Marie-Tooth disease type 1.

Bowman–Birk inhibitor concentrate suppresses experimental autoimmune neuritis via shifting macrophages from M1 to M2 subtype

BackgroundIn the present study, we investigated the immuno-regulatory and therapeutic effects of Bowman–Birk inhibitor concentrate (BBIC) on experimental autoimmune neuritis (EAN), an animal model of Guillain–Barré syndrome (GBS) in human. MethodsEAN in Lewis rats induced by inoculation with peripheral nerve myelin P0 protein peptide 180-199 (P0 peptide) was treated with BBIC at two different therapeutic regimens. ResultsOur data indicated that the administration of BBIC daily orally effectively inhibited and ameliorated the clinical and pathological signs of EAN. The suppression of EAN was associated with an insufficiency of autoreactive T cells, as reflected by inhibited P0 peptide-specific mononuclear cell proliferation and decreased in CD4 and CD8T cells infiltrating into the peripheral nervous system (PNS). BBIC might mediate its therapeutic effects by shifting macrophages from M1 to M2 subtype as evidenced by increasing Arg-1, CD206 and IL-10 and inhibiting IFN-γ, TNF-α, IL-12, iNOS and CD40 expressions on macrophages as well as enhancing anti-inflammatory cytokines IL-4 and IL-10 and decreasing inflammatory cytokines, IFN-γ, TNF-α and IL-17 in the PNS. ConclusionOur results suggest that BBIC may have therapeutic potential in human GBS and other autoimmune diseases in the future.

Morphological study of Schwann cells remyelination in contused spinal cord of rats

ObjectiveTo study the role and effect of Schwann cells (SCs) remyelination in contused spinal cord. MethodsGreen fluorescence protein expressing-SCs were transplanted into the epicenter, rostral and caudal tissues of the injury site at 1 week after the spinal cords were contused. At 6 weeks, the spinal cords were removed for cryosections, semithin sections and ultrathin sections, and then immunocytochemical staining of myelin basic protein (MBP), P0 protein (P0) and S100 protein (S100) was carried out on the cryosections. Qualitative and semiquantitative analyses were performed on the cryosections and semithin sections. Ultrastructure of myelinated fibers was observed on the ultrathin sections under electron microscope. ResultsTransplanted SCs and myelinated fibers immunocytochemically labeled by MBP, P0 as well as S100 distributed in whole injured area. The quantity of myelinated fibers labeled by the three myelin proteins showed no statistical difference, however, which was significantly larger than that of controls. On the semithin sections, the experimental group demonstrated more myelinated fibers in the injured area than the controls, but the fibers had smaller diameter and thinner myelin sheath under electron microscope. ConclusionSCs can promote regeneration of injured nerve fibers and enhance remyelination, which may be histological basis of SCs-mediated functional repair of injured spinal cords.

Effect of low temperature on Schwann-like cell differentiation of bone marrow mesenchymal stem cells

Mesenchymal stem cells (MSCs) are multipotent stromal cells that can differentiate into a variety of cell types. The potential of MSCs for differentiation and proliferation depends on the control of various processes. In this study, we have investigated the effects of low temperature on the Schwann-like cell differentiation of human bone marrow mesenchymal stem cells (BM-MSCs). The growth of BM-MSCs decreased at low temperature, but increased Schwann-like cell differentiation. The expression of cell surface antigen decreased CD73, CD105, and CD90, which are known markers of MSCs at 35°C. Also, the levels of matrix RNA [S100, glial fibrillary acidic protein (GFAP), p75, myelin basic protein, P0, and others] at 35°C in the differentiation culture were higher than those at 37°C in the differentiation culture, and S100, p75, and GFAP proteins were expressed more than at 37°C. GFAP and S100 were stained strongly at 35°C by immunohistochemical examination. These data demonstrate that culturing BM-MSCs at reduced temperature can improve differentiation into Schwann-like cells.

Dynamics of the Peripheral Membrane Protein P2 from Human Myelin Measured by Neutron Scattering—A Comparison between Wild-Type Protein and a Hinge Mutant

Myelin protein P2 is a fatty acid-binding structural component of the myelin sheath in the peripheral nervous system, and its function is related to its membrane binding capacity. Here, the link between P2 protein dynamics and structure and function was studied using elastic incoherent neutron scattering (EINS). The P38G mutation, at the hinge between the β barrel and the α-helical lid, increased the lipid stacking capacity of human P2 in vitro, and the mutated protein was also functional in cultured cells. The P38G mutation did not change the overall structure of the protein. For a deeper insight into P2 structure-function relationships, information on protein dynamics in the 10 ps to 1 ns time scale was obtained using EINS. Values of mean square displacements mainly from protein H atoms were extracted for wild-type P2 and the P38G mutant and compared. Our results show that at physiological temperatures, the P38G mutant is more dynamic than the wild-type P2 protein, especially on a slow 1-ns time scale. Molecular dynamics simulations confirmed the enhanced dynamics of the mutant variant, especially within the portal region in the presence of bound fatty acid. The increased softness of the hinge mutant of human myelin P2 protein is likely related to an enhanced flexibility of the portal region of this fatty acid-binding protein, as well as to its interactions with the lipid bilayer surface requiring conformational adaptations.

Impaired dendritic cell function in a spontaneous autoimmune polyneuropathy.

Spontaneous autoimmune polyneuropathy (SAP) in B7-2 knockout NOD mice mimics the progressive form of chronic inflammatory demyelinating polyradiculoneuropathy, and is mediated by myelin protein zero (P0)-reactive Th1 cells. In this study, we focused on the effect of B7-2 deletion on the function of dendritic cells (DCs) within the context of SAP. We found that development of SAP was associated with a preponderance or increase of CD11b(+) DCs in peripheral lymph nodes and sciatic nerves. B7-2 deletion led to altered immunophenotypic properties that differ between CD11b(+) DCs and CD8α(+) DCs. Both DC subsets from B7-2 knockout NOD mice exhibited impaired capacity to capture fluorophore-labeled myelin P0, but diminished Ag-presenting function was observed only in CD11b(+) DCs. Clinical assessment, electrophysiologic studies, and splenocyte proliferation studies revealed that absence of B7-2 on DCs was sufficient to cause impaired ability to induce tolerance to P0, which could be overcome by preconditioning with IL-10. Tolerance induction by Ag-pulsed wild-type NOD DCs was dependent on IL-10 and was associated with increased CD4(+) regulatory T cells, whereas tolerance induction by IL-10-conditioned B7-2-deficient DCs was associated with increased percentages of both regulatory T cells and B10 cells in the spleen. We conclude that B7-2 deletion has an impact on the distribution of DC subsets in lymphoid organs and alters the expression of costimulatory molecules, but functional consequences are not uniform across DC subsets. Defective tolerance induction in the absence of B7-2 can be restored by preconditioning of DCs with IL-10.

Characterization of Myelin P2 and Slitrk Echinoderm Genes and Their Expression During Enteric Nervous System Regeneration

Holuthuria glaberrima is an echinoderm known for its ability to regenerate its internal organs including its enteric nervous system (ENS). Unfortunately, there is a limited amount of nervous component markers and many of the molecular events that occur during the regeneration of this system in the sea cucumber are still unknown. New insights into the regeneration of the holothurian ENS may be provided by determining the genes involved and differentially expressed in this process. Using a database generated by Next Generation Sequencing (NGS), we identified two genes that might be associated with regeneration: Slitrk and the gene that encodes Myelin P2 protein. Slitrk proteins have been shown to modulate neurite outgrowth in vertebrate animals. Myelin P2 protein is one of the components of the myelin sheath in vertebrate glial cells, and holothurian glia has been shown to play an important role in the regeneration of the holothurian CNS. We have shown that these genes are present and expressed in normal and regenerating sea cucumber by using various bioinformatic tools, sqPCR and immunohistochemistry. We established a gene expression profile of various tissues and at different stages of intestinal regeneration. To view the spatial localization of Myelin P2 protein, we developed an antibody and localized its expression to the ceolomic epithelium of the intestine and muscle. Finally, our work also explores the evolution of myelin‐related proteins, an interesting development from our findings, since myelin is not found in invertebrate nervous systems. In conclusion, we believe that understanding the role of these genes may aid in the elucidation of possible patterns of ENS regeneration of H. glaberrima.

Efficiency of long-term treatment with intravenous immunoglobulins correlates with reduced autoreactive T cell responses in chronic inflammatory demyelinating polyneuropathy patients.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare disease of the peripheral nervous system, characterized by gradual increasing weakness of the limbs, with more than 50% of patients experiencing marked disability 1. The underlying pathophysiological mechanism of CIDP remains unknown; however, studies have shown activated T cells in the circulation of CIDP patients 2–4. In addition, patient studies suggest a key role for autoreactive T cell responses against peripheral myelin antigens such as P0, P1, P2 and peripheral myelin protein PMP-22 5,6. Mechanism-of-action studies in other chronic autoimmune diseases have shown that the T cell memory compartment influences antigen responses by showing up-regulation of CD4+ or CD8+ T effector memory (TEM) cells 7,8. Recently, published data from a randomized, placebo-controlled clinical trial demonstrated the long-term efficacy and safety of intravenous immunoglobulin (IVIg) treatment in CIDP patients 9. However, the underlying mechanism of action of IVIg in the treatment of CIDP remains unclear 10,11. The aim of this study was to investigate the course of autoreactive T cell responses against the two peripheral myelin antigens P2 and PMP-22 in addition to the frequency of memory T cell subsets during IVIg treatment in CIDP patients 12.