The Role of B Cells in Multiple Sclerosis Pathogenesis and Monoclonal Antibody Treatments Targeting B Cells

The presence of B cells, plasma cells and increased immunoglobulin (Ig) levels in multiple sclerosis (MS) lesions and cerebrospinal fluid (CSF) samples has suggested that the humoral immunity plays an important role in MS pathogenesis. Moreover, the demonstration of correlation of CSF B lymphocyte and Ig levels with the clinical course and prognosis of the disease has substantiated this notion. However, until the advent of clinical trials performed with B cell-targeting monoclonal antibodies, the role of B lymphocytes in MS pathogenesis has been a matter of controversy. Clinical trials testing the chimeric anti-CD20 monoclonal antibody rituximab and other monoclonal antibodies have shown that B-cell depletion significantly decreases MS relapse rate, disability progression and development of new contrast-enhancing MRI lesions. With the introduction of novel antibodies and fusion proteins that are currently being produced and tested, treatment methods with higher efficacy and lower side-effect profile are expected to be developed in the forthcoming years. (Archives of Neuropsychiatry 2011; 48 Supplement 2: 73-8

Neuronal acetylcholine receptor alpha 9-subunit: A possible central nervous system autoantigen

Nicotinic acetylcholine receptor (AChR) is a membrane glycoprotein composed of five subunits. Muscle AChR is consist of two alpha 1 and one each beta, delta, and epsilon subunits, whereas the neuronal AChR molecules are made up of various combinations of alpha (alpha 2-alpha 10) and beta (beta 1-beta 4) subunits. Myasthenia gravis (MG) develops as a result of an autoimmune attack against muscular AChR. While the prevailing symptom is muscle weakness, very rarely MG patients may develop additional central nervous system (CNS) symptoms. The majority of the anti-AChR antibodies responsible from disease induction is directed against alpha 1 subunit of AChR. There is considerable identity between muscular alpha 1 and neuronal alpha 9 subunits. Preliminary studies showed antibodies reactive with the CNS antigens in the serum samples of mice with experimental autoimmune myasthenia gravis (EAMG). Also, alpha 9 was present in the CNS in widespread locations and the binding pattern of anti-alpha 9 antibody was reminiscent of that of serum samples of some of the mice with EAMG. Serum anti-AChR antibodies of myasthenic patients might be cross-reacting with CNS AChR subunits and thus inducing CNS symptoms. Neuronal AChR alpha 9-subunit might be a major target antigen in this process. (c) 2006 Elsevier Ltd. All rights reserved

Anterior choroidal artery territory infarction: A case report and review

A patient was admitted with frequent episodes of transient neurologic symptoms formerly described as "capsular warning syndrome". The neurologic examination revealed right-sided hemiplegia, diminished pinprick, decreased light touch and extensor right plantar response. The only documented risk factor was hypertriglyceridemia, and diagnosis was anterior choroidal artery territory infarction, This report critically reviews the clinical features of this vascular lesion and the MRI findings

Steroid-Responsive Myeloneuropathy Associated With Antithyroid Antibodies

Background/Objective: To present information about 2 steroid-responsive, antithyroid antibody-positive patients with myeloneuropathy and myelopathy

Anti-Neuronal Autoantibodies Associated with Epilepsy and Related Neurological Syndromes

Autoimmunity and inflammation can be shown as causative factors of epilepsies of unknown cause. The clear relationship between seizures and certain autoimmune diseases has been revealed in recent years. The detection of autoantibodies in the serum of patients with epilepsy supports this notion. Most of the epilepsy-associated antibodies occur against molecules on the surface of neurons, whereas the remaining autoantibodies target intracellular antigens. In this article, we summarize anti-neuronal autoantibodies associated with epilepsy and associated neurological syndromes

Are linear AChR epitopes the real culprit in ocular myasthenia gravis?

Extraocular muscle weakness occurs in most of the myasthenia gravis (MG) patients and it is often the initial complaint. Approximately 10-20% of MG patients with extraocular muscle weakness display only ocular symptoms and rest of the patients subsequently develop generalized muscle weakness. It is not entirely clear why some MG patients develop only ocular symptoms and why extraocular muscle weakness almost always precedes generalized muscle weakness. These facts are often explained by increased susceptibility of extraocular muscles due to their reduced endplate safety factor and lower complement inhibitor expression. Findings of a recently developed animal model of ocular MG suggest that additional factors might be in play. While immunization of HLA transgenic and wild-type (WT) mice with the native acetylcholine receptor (AChR) pentamer carrying conformational epitopes generates severe generalized muscle weakness, immunization of the same mouse strains with recombinant unfolded AChR subunits containing linear epitopes induces ptosis with or without mild generalized muscle weakness. Notably, immunization of mice with deficient T helper cell-mediated antigen presentation with recombinant AChR subunits or whole native AChR pentamer also induces ocular symptoms, AChR-reactive B cells and AChR antibodies. Based on these findings, we hypothesize that ocular symptoms observed in the earlier stages of MG might be triggered by linear and non-conformational AChR epitopes expressed by thymic cells or invading microorganisms. This initial AChR autoimmunity might be managed by T cell independent and B cell mediated mechanisms yielding low affinity AChR antibodies. These antibodies are putatively capable of inducing muscle weakness only in extraocular muscles which have increased vulnerability due to their inherent biological properties. After this initial attack, as AChR bearing immune complexes form and the immune system gains access to the native AChR expressed by muscle and thymic myoid cells, a more robust anti-AChR autoimmunity develops giving way to high affinity AChR antibodies, thymic germinal center formation and severe generalized muscle weakness. Accurate characterization of chain if events leading to ocular and generalized symptoms in MG might enable development of novel therapeutics that might prevent the transition from mild ocular symptoms to severe generalized weakness in earlier stages of the disease. (C) 2016 Elsevier Ltd. All rights reserved

Complement associated pathogenic mechanisms in myasthenia gravis

The complement system is profoundly involved in the pathogenesis of acetylcholine receptor (AChR) antibody (Ab) related myasthenia gravis (MG) and its animal model experimental autoimmune myasthenia gravis (EAMG). The most characteristic finding of muscle pathology in both MG and EAMG is the abundance of IgG and complement deposits at the nerve-muscle junction (NMJ), suggesting that AChR-Ab induces muscle weakness by complement pathway activation and consequent membrane attack complex (MAC) formation. This assumption has been supported with EAMG resistance of complement factor C3 knockout (KO), C4 KO and C5 deficient mice and amelioration of EAMG symptoms following treatment with complement inhibitors such as cobra venom factor, soluble complement receptor 1, anti-C1q, anti-C5 and anti-C6 Abs. Moreover, the complement inhibitor decay accelerating factor (DAF) KO mice exhibit increased susceptibility to EAMG. These findings have brought forward improvisation of novel therapy methods based on inhibition of classical and common complement pathways in MG treatment. (C) 2013 Elsevier B.V. All rights reserved

Inflammatory biomarkers in epilepsy

Epilepsy affects millions of people worldwide and has a great burden on world health. Improvement of seizure outcomes mostly relies on establishment of individualized risk factors for epileptogenesis and drug resistance. Several circulating molecules could serve as diagnostic and prognostic biomarkers at different stages of the disease. Inflammatory markers, blood-brain barrier markers, oxidative stress markers, microRNAs, autoantibodies, hormones and growth factors are promising fields of research for biomarkers in epilepsy. Several experimental studies and only a few clinical studies have revealed associations between inflammatory biomarkers and clinical outcomes of epilepsy. Herein, we detail the clinical and immunological significance of several factors of inflammation that may in due time serve as biomarkers of epilepsy in an effort to potentially inspire the researchers towards the development of reliable prognostic biomarkers for epilepsy

Limbic encephalitis and variants: Classification, diagnosis and treatment

Background and Objective: Recent studies suggest that a substantial number of patients with autoimmune limbic encephalitis may improve if properly diagnosed and treated. This is due, in part, to the increasing recognition of disorders that associate with antibodies to neuronal cell membrane antigens. This review focuses in these disorders, trained in a clinically useful immunologic classification of limbic encephalitis