Conformational epitopes of myelin oligodendrocyte glycoprotein are targets of potentially pathogenic antibody responses in multiple sclerosis

<p>Abstract</p> <p>Background</p> <p>Myelin/oligodendrocyte glycoprotein (MOG) is a putative autoantigen in multiple sclerosis (MS). Establishing the pathological relevance and validity of anti-MOG antibodies as biomarkers has yielded conflicting reports mainly due to different MOG isoforms used in different studies. Because epitope specificity may be a key factor determining anti-MOG reactivity we aimed at identifying <it>a priori </it>immunodominant MOG epitopes by monoclonal antibodies (mAbs) and at assessing clinical relevance of these epitopes in MS.</p> <p>Methods</p> <p>Sera of 325 MS patients, 69 patients with clinically isolated syndrome and 164 healthy controls were assayed by quantitative, high-throughput ELISA for reactivity to 3 different MOG isoforms, and quantitative titers correlated with clinical characteristics. mAbs defined unique immunodominant epitopes distinct to each of the isoforms.</p> <p>Results</p> <p>In the majority of human samples anti-MOG levels were skewed towards low titers. However, in 8.2% of samples high-titer anti-MOG antibodies were identified. In contrast to anti-MOG reactivity observed in a mouse model of MS, in patients with MS these never reacted with ubiquitously exposed epitopes. Moreover, in patients with relapsing-remitting MS high-titer anti-MOG IgG correlated with disability (EDSS; Spearman r = 0.574; p = 0.025).</p> <p>Conclusions</p> <p>Thus high-titer reactivity likely represents high-affinity antibodies against pathologically relevant MOG epitopes, that are only present in a small proportion of patients with MS. Our study provides valuable information about requirements of anti-MOG reactivity for being regarded as a prognostic biomarker in a subtype of MS.</p

Glatiramer acetate treatment does not modify the clinical course of (NZB × BXSB)F1 lupus murine model

Glatiramer acetate (GA, copolymer-1, Copaxone®), a therapy approved for treatment of multiple sclerosis (MS), prevents and reverses experimental autoimmune encephalomyelitis, the animal model of MS. In central nervous system autoimmune disease, GA is thought to act through modulation of antigen-presenting cells, such as monocytes, mediating an antigen-independent Th2 shift and development of FoxP3+ regulatory T cells. Recent reports indicate that GA may also be effective in models of other autoimmune diseases such as uveoretinitis, inflammatory bowel disease and graft rejection. To date, the potential effect of GA in lupus animal models has not been described. (NZB × BXSB)F1, male mice bearing Y-linked autoimmune acceleration , is a lupus-prone mouse model which is associated with a monocytosis accelerating disease progression. These mice were treated with GA before disease onset until death and both mortality rate and biological parameters were assessed to investigate whether GA may be beneficial in this spontaneous model of systemic lupus erythematosus. GA exerted no beneficial effect on the median survival after up to 7 months of treatment. Humoral and cellular parameters used as markers for lupus progression, such as anti-chromatin, anti-double-stranded DNA and anti-erythrocytes antibodies, hematocrit and monocytosis, were similarly unchanged. Our study demonstrates that GA has no significant effect on the progression of the (NZB × BXSB)F1 lupus-prone animal model. These results reinforce the hypothesis that GA may exert its beneficial effect in some specific autoimmune diseases onl

MHC class II–restricted antigen presentation by plasmacytoid dendritic cells inhibits T cell–mediated autoimmunity

Although plasmacytoid dendritic cells (pDCs) express major histocompatibility complex class II (MHCII) molecules, and can capture, process, and present antigens (Ags), direct demonstrations that they function as professional Ag-presenting cells (APCs) in vivo during ongoing immune responses remain lacking. We demonstrate that mice exhibiting a selective abrogation of MHCII expression by pDCs develop exacerbated experimental autoimmune encephalomyelitis (EAE) as a consequence of enhanced priming of encephalitogenic CD4+ T cell responses in secondary lymphoid tissues. After EAE induction, pDCs are recruited to lymph nodes and establish MHCII-dependent myelin-Ag–specific contacts with CD4+ T cells. These interactions promote the selective expansion of myelin-Ag–specific natural regulatory T cells that dampen the autoimmune T cell response. pDCs thus function as APCs during the course of EAE and confer a natural protection against autoimmune disease development that is mediated directly by their ability to present of Ags to CD4+ T cells in vivo

Repetitive Pertussis Toxin Promotes Development of Regulatory T Cells and Prevents Central Nervous System Autoimmune Disease

Bacterial and viral infections have long been implicated in pathogenesis and progression of multiple sclerosis (MS). Incidence and severity of its animal model experimental autoimmune encephalomyelitis (EAE) can be enhanced by concomitant administration of pertussis toxin (PTx), the major virulence factor of Bordetella pertussis. Its adjuvant effect at the time of immunization with myelin antigen is attributed to an unspecific activation and facilitated migration of immune cells across the blood brain barrier into the central nervous system (CNS). In order to evaluate whether recurring exposure to bacterial antigen may have a differential effect on development of CNS autoimmunity, we repetitively administered PTx prior to immunization. Mice weekly injected with PTx were largely protected from subsequent EAE induction which was reflected by a decreased proliferation and pro-inflammatory differentiation of myelin-reactive T cells. Splenocytes isolated from EAE-resistant mice predominantly produced IL-10 upon re-stimulation with PTx, while non-specific immune responses were unchanged. Longitudinal analyses revealed that repetitive exposure of mice to PTx gradually elevated serum levels for TGF-β and IL-10 which was associated with an expansion of peripheral CD4+CD25+FoxP3+ regulatory T cells (Treg). Increased frequency of Treg persisted upon immunization and thereafter. Collectively, these data suggest a scenario in which repetitive PTx treatment protects mice from development of CNS autoimmune disease through upregulation of regulatory cytokines and expansion of CD4+CD25+FoxP3+ Treg. Besides its therapeutic implication, this finding suggests that encounter of the immune system with microbial products may not only be part of CNS autoimmune disease pathogenesis but also of its regulation

Paroxysmal painful tonic spasms in neuromyelitis optica spectrum disorder

Background: Recently, an association between painful tonic spasms (PTS) and Neuromyelitis Optica Spectrum Disorder (NMOSD) was established. Objective: To describe the clinical characteristics of PTS in NMOSD based on a video recording and to provide a literature review on the topic. Methods: We report a case of a 38 years-old woman with a diagnosis of NMOSD and positive aquaporin-4 IgG antibody status who developed PTS five weeks after an episode of longitudinal extensive transverse myelitis (LETM). Results: Repetitive, brief, and painful episodes of muscle contraction were observed on the patient's left hand, spreading to the left arm, and then extending to the four limbs. While pregabalin and topiramate had no influence on these episodes, the patient responded to carbamazepine (CBZ), without symptom recurrence after one year. Conclusions: PTS in association with LETM can be considered typical for NMOSD. Although the exact mechanism is unknown, ephaptic transmission after spinal cord damage and excitatory soluble factors released during acute inflammation responses are sought to be involved. Symptomatic treatment with CBZ achieved remission of spams in our case

Cerebrospinal fluid angiotensin-converting enzyme for diagnosis of neurosarcoidosis

Neurosarcoidosis (NS) is a rare condition that may mimic central nervous system (CNS) infection, neoplasia and other inflammatory disorders of the CNS such as multiple sclerosis, encephalitis and vasculitis. Diagnosis is challenging in cases with minimal or absent systemic involvement. Cerebrospinal fluid (CSF) angiotensin-converting enzyme (c-ACE) has been claimed as a valuable diagnostic tool for NS. However, there is little data evaluating its performance in routine clinical practice

Mild clinical expression of Lambert–Eaton myasthenic syndrome in a patient with HIV infection

Neuromuscular complications of HIV are related to immunodeficiency, direct cytotoxicity of the virus or side effect of the treatments. Autoimmune disorders involving the nervous system, including Guillain–Barre syndrome, myositis and vasculitis, have been described in association with HIV. Neuromuscular junction autoimmune diseases such as myasthenia gravis have been occasionally reported in patients with HIV, whereas the Lambert–Eaton myasthenic syndrome (LEMS) has never been described. We report an unusual case of paucisymptomatic LEMS in a patient with HIV infection