Autoimmune Neuritis Research Articles

Inhibition of immunoproteasome subunit low molecular mass polypeptide 7 with ONX-0914 improves hypoxic-ischemic brain damage via PI3K/Akt signaling.

The immunoproteasome subunit low molecular mass polypeptide 7 (LMP7) leads to brain injuries, such as autoimmune neuritis and ischemic stroke, by activating inflammation. However, the roles and mechanisms of LMP7 in hypoxic-ischemic brain damage (HIBD) remain unclear. This study explored these issues in a rat model of HIBD. Pathology was evaluated using hematoxylin-eosin staining. LMP7 expression was detected using western blot analysis, reverse transcription-quantitative PCR (RT-qPCR), and immunohistochemical staining. The presence of proinflammatory cytokines, including tumor necrosis factor-a, interleukin-6, and interleukin-1β, was tested using ELISA and RT-qPCR. Behavioral performance was evaluated using a short-term neurological function score and the Morris water maze test. Compared to those in the Sham group, the HIBD group exhibited obvious upregulated LMP7 and pro-inflammatory cytokine levels. HIBD rats exhibited severe pathological and behavioral damage. LMP7 inhibition with ONX-0914 reduced proinflammatory cytokine expression, attenuated pathological damage, and enhanced behavioral performance of rats with HIBD. Inhibition of phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling with LY29400 increased LMP7 expression and abolished the protective effects of ONX-0914 in HIBD rats. Our findings indicate that LMP7 aggravates brain injury by triggering inflammatory responses in HIBD rats. LMP7 inhibition with ONX-0914 exerts protective effects on HIBD rats, possibly via PI3K/Akt signaling.

Minocycline Treatment Reduces Mass and Force Output From Fast-Twitch Mouse Muscles and Inhibits Myosin Production in C2C12 Myotubes.

Minocycline, a tetracycline-class of antibiotic, has been tested with mixed effectiveness on neuromuscular disorders such as amyotrophic lateral sclerosis, autoimmune neuritis and muscular dystrophy. The independent effect of minocycline on skeletal muscle force production and signalling remain poorly understood. Our aim here is to investigate the effects of minocycline on muscle mass, force production, myosin heavy chain abundance and protein synthesis. Mice were injected with minocycline (40 mg/kg i.p.) daily for 5 days and sacrificed at day six. Fast-twitch EDL, TA muscles and slow-twitch soleus muscles were dissected out, the TA muscle was snap-frozen and the remaining muscles were attached to force transducer whilst maintained in an organ bath. In C2C12 myotubes, minocycline was applied to the media at a final concentration of 10 μg/mL for 48 h. In minocycline treated mice absolute maximal force was lower in fast-twitch EDL while in slow-twitch soleus there was an increase in the time to peak and relaxation of the twitch. There was no effect of minocycline treatment on the other contractile parameters measured in isolated fast- and slow-twitch muscles. In C2C12 cultured cells, minocycline treatment significantly reduced both myosin heavy chain content and protein synthesis without visible changes to myotube morphology. In the TA muscle there was no significant changes in myosin heavy chain content. These results indicate that high dose minocycline treatment can cause a reduction in maximal isometric force production and mass in fast-twitch EDL and impair protein synthesis during myogenesis in C2C12 cultured cells. These findings have important implications for future studies investigating the efficacy of minocycline treatment in neuromuscular or other muscle-atrophy inducing conditions.

Gypenosides Prevent H2O2-Induced Retinal Ganglion Cell Apoptosis by Concurrently Suppressing the Neuronal Oxidative Stress and Inflammatory Response

Our previous study demonstrated that gypenosides (Gp) exert protective effects on retinal nerve fibers and axons in a mouse model of experimental autoimmune optic neuritis. However, the therapeutic mechanisms remain unclear. Thus, in this study, a model of oxidative damage in retinal ganglion cells (RGCs) was established to investigate the protective effect of Gp, and its possible influence on oxidative stress in RGCs. Treatment of cells with H2O2 induced RGC injury owing to the generation of intracellular reactive oxygen species (ROS). In addition, the activities of antioxidative enzymes decreased and the expression of inflammatory factors increased, resulting in an increase in cellular apoptosis. Gp helped RGCs to become resistant to oxidation damage by directly reducing the amount of ROS in cells and exerting protective effects against H2O2-induced apoptosis. Treatment with Gp also reduced the generation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and increased nuclear respiratory factor 2 (Nrf-2) levels so as to increase the levels of heme oxygenase-1 (HO-1) and glutathione peroxidase 1/2 (Gpx1/2), which can enhance antioxidation in RGCs. In conclusion, our data indicate that neuroprotection by Gp involves its antioxidation and anti-inflammation effects. Gp prevents apoptosis through a mitochondrial apoptotic pathway. This finding might provide novel insights into understanding the mechanism of the neuroprotective effects of gypenosides in the treatment of optic neuritis.

Early alpha-lipoic acid therapy protects from degeneration of the inner retinal layers and vision loss in an experimental autoimmune encephalomyelitis-optic neuritis model

BackgroundIn multiple sclerosis (MS), neurodegeneration is the main reason for chronic disability. Alpha-lipoic acid (LA) is a naturally occurring antioxidant which has recently been demonstrated to reduce the rate of brain atrophy in progressive MS. However, it remains uncertain if it is also beneficial in the early, more inflammatory-driven phases. As clinical studies are costly and time consuming, optic neuritis (ON) is often used for investigating neuroprotective or regenerative therapeutics. We aimed to investigate the prospect for success of a clinical ON trial using an experimental autoimmune encephalomyelitis-optic neuritis (EAE-ON) model with visual system readouts adaptable to a clinical ON trial.MethodsUsing an in vitro cell culture model for endogenous oxidative stress, we compared the neuroprotective capacity of racemic LA with the R/S-enantiomers and its reduced form. In vivo, we analyzed retinal neurodegeneration using optical coherence tomography (OCT) and the visual function by optokinetic response (OKR) in MOG35–55-induced EAE-ON in C57BL/6J mice. Ganglion cell counts, inflammation, and demyelination were assessed by immunohistological staining of retinae and optic nerves.ResultsAll forms of LA provided equal neuroprotective capacities in vitro. In EAE-ON, prophylactic LA therapy attenuated the clinical EAE score and prevented the thinning of the inner retinal layer while therapeutic treatment was not protective on visual outcomes.ConclusionsA prophylactic LA treatment is necessary to protect from visual loss and retinal thinning in EAE-ON, suggesting that a clinical ON trial starting therapy after the onset of symptoms may not be successful.

How to Make a Non-Antigenic Protein (Auto) Antigenic: Molecular Complementarity Alters Antigen Processing and Activates Adaptive-Innate Immunity Synergy.

Evidence is reviewed that complementary proteins and peptides form complexes with increased antigenicity and/or autoimmunogenicity. Five case studies are highlighted: 1) diphtheria toxin-antitoxin (antibody), which induces immunity to the normally non-antigenic toxin, and autoimmune neuritis; 2) tryptophan peptide of myelin basic protein and muramyl dipeptide ("adjuvant peptide"), which form a complex that induces experimental allergic encephalomyelitis; 3) an insulin and glucagon complex that is far more antigenic than either component individually; 4) various causes of experimental autoimmune myocarditis such as C protein in combination with its antibody, or coxsackie B virus in combination with the coxsackie and adenovirus receptor; 5) influenza A virus haemagglutinin with the outer membrane protein of the Haemophilus influenzae, which increases antigenicity. Several mechanisms cooperate to alter immunogenicity. Complexation alters antigen processing, protecting the components against proteolysis, altering fragmentation and presenting novel antigens to the immune system. Complementary antigens induce complementary adaptive immune responses (complementary antibodies and/or T cell receptors) that produce circulating immune complexes (CIC). CIC stimulate innate immunity. Concurrently, complementary antigens stimulate multiple Toll-like receptors that synergize to over-produce cytokines, which further stimulate adaptive immunity. Thus innate and adaptive immunity form a positive feedback loop. If components of the complex mimic a host protein, then autoimmunity may result. Enhanced antigenicity for production of improved vaccines and/or therapeutic autoimmunity (e.g., against cancer cells) might be achieved by using information from antibody or TCR recognition sites to complement an antigen; by panning for complements in randomized peptide libraries; or using antisense peptide strategies to design complements.

Early signs of cellular stress in the induction phase of autoimmune optic neuritis

Early signs of cellular stress in the induction phase of autoimmune optic neuritis

Role of early activated microglia during onset of autoimmune optic neuritis

Role of early activated microglia during onset of autoimmune optic neuritis

Anti-MOG antibody in different types of immune-mediated optic neuritis

To investigate the expression of anti-myelin oligodendrocyte glycoprotein antibody (MOG-Ab) in different types of immune-mediated optic neuritis (IM-ON). Case-control and cross section study. The serum of 129 consecutive cases of immune-mediated optic neuritis (IM-ON group) seen in Neuro-ophthalmology clinic in Department of Neurology, Beijing Tongren Hospital during May 2010 and February 2011 were collected. All IM-ON cases were further classified into five different types as: 20 cases of multiple sclerosis related ON (MS-ON), 13 cases of neuromyelitis optical related ON (NMO-ON), 33 cases of autoimmune optic neuritis (AON), 43 cases of relapsing isolated optic neuritis (RION) and 20 cases of solitary isolated optic neuritis (SION). MOG-Ab was tested by ELISA. The positivity rate and titer of MOG-Ab among these groups were compared using chi-square test and ANOVA, t test by SPSS17.0 software. MOG-Ab was positive in 12 of all 129 tested IM-ON patients (9.3%), in which there were 5 of 20 MS-ON, none of 13 NMO-ON, 4 of 33 AON, 2 of 43 RION, and 1 of 20 SION patients. There were no statistical significant difference among five groups (Fisher's exact test, χ(2) = 7.051, P = 0.088), but MS-ON group showed statistically higher MOG-Ab positivity and titer than the "NMO spectrum optic neuritis" group which was merged from the other 4 IM-ON groups. MOG-Ab could be detected in different types of immune-mediated optic neuritis except NMO-ON and the expression of MOG-Ab was statistically higher in MS-ON group than the 'NMO spectrum optic neuritis' group.

MMP-mediated cleavage of β-dystroglycan in myelin sheath is involved in autoimmune neuritis

α-/β-Dystroglycans (DG) located at the outmost layer of myelin sheath play a critical role in its formation and stability in the peripheral nerve system. The demyelination of nerve fibers is present in autoimmune neuritis, however, it is not known about the molecular mechanisms underlying this pathological process. In an animal model of experimental autoimmune neuritis, we observed that β-DG cleavage was associated with the demyelination of peripheral nerves. The neuritis and β-DG cleavage were accompanied by matrix metalloproteinase (MMP)-2/-9 over-expressions and attenuated by captopril, a MMP inhibitor. The blockade of MMPs also improves clinical signs. Our results reveal a crucial role of MMP-mediated β-DG cleavage in autoimmune neuritis, such as Guillain–Barre’ syndrome, and bring insights into therapeutic strategies for autoimmune diseases.

Is Skin Biopsy a Useful Investigation in the Diagnosis of Idiopathic Optic Neuritis?

Previous studies have recommended skin biopsy (the immunofluorescent “band” test) as a valuable tool in the identification of cases of optic neuritis which are autoimmune. However in recent years the diagnostic spectrum of optic neuritis not associated with multiple sclerosis (MS) has considerably expanded both following the description of specific syndromes and also the discovery of other means of identifying autoimmune optic neuritis (such as detecting antibodies to Aquaporin 4). Furthermore the value of the immunofluorescent band test in the diagnosis of systemic autoimmune disorders such as systemic lupus erythematosis (SLE) has been questioned. However the test could still be useful if it can be shown that there are cases of autoimmune optic neuritis patients who have a positive skin biopsy but have serological evidence for neither SLE nor for neuromyelitis optica (NMO).

Flupirtine is a promising agent for the treatment of autoimmune optic neuritis

Flupirtine is a promising agent for the treatment of autoimmune optic neuritis

Complementary peptide epitopes and anti-idiotypic antibodies in autoimmunity.

Application of complementary B and T cell epitopes in inducing anti-idiotypic and anti-clonotypic antibodies capable of regulating or suppressing the autoimmune responses in experimental autoimmune myasthenia gravis (EAMG), allergic neuritis (EAN) and allergic encephalomyelitis (EAE) has been the stimulus of many research efforts. Studies on the idiotypic/anti-idiotypic network of anti-La/SSB positive sera from patients with Sjogren's Syndrome (SS) and Systemic Lupus Erythematosus (SLE) and on animals immunized with the complementary epitopes are presented.

Expression of interferon-gamma in the lens exacerbates anterior uveitis and induces retinal degenerative changes in transgenic Lewis rats.

Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that has been implicated in immunopathogenic mechanisms of a number of inflammatory diseases of autoimmune or infectious disease etiology. However, its exact role is still a matter of debate. In experimental mouse models, IFN-gamma has been shown to exacerbate autoimmune thyroiditis, insulin-dependent diabetes mellitus, and autoimmune neuritis while it confers protection against experimental allergic encephalomyelitis and experimental uveitis. In this study, we generated transgenic rats with constitutive expression of IFN-gamma in the eye to study its paracrine effects and to investigate whether local production of IFN-gamma also confers protection against uveitis in the rat species. We show here that chronic exposure of ocular cells to IFN-gamma results in apoptotic death of retinal ganglion cells, development of chronic choroiditis, formation of retinal in-foldings, and activation of proinflammatory genes. In contrast to its protective systemic effect in the mouse, constitutive secretion of IFN-gamma in the rat eye was found to predispose the development of severe anterior uveitis and induction of retinal degenerative processes that impair visual acuity. Our data underscore the danger in extrapolation of cytokine effects in the mouse to humans without corroborating evidence in other species.