The role of antibodies in multiple sclerosis

AbstractB cells, plasma cells, and antibodies are commonly found in active central nervous system (CNS) lesions in patients with multiple sclerosis (MS). B cells isolated from CNS lesions as well as from the cerebrospinal fluid (CSF) show signs of clonal expansion and hypermutation, suggesting their local activation. Plasma blasts and plasma cells maturating from these B cells were recently identified to contribute to the development of oligoclonal antibodies produced within the CSF, which remain a diagnostic hallmark finding in MS. Within the CNS, antibody deposition is associated with complement activation and demyelination, indicating antigen recognition-associated effector function. While some studies indeed implied a disease-intrinsic and possibly pathogenic role of antibodies directed against components of the myelin sheath, no unequivocal results on a decisive target antigen within the CNS persisted to date. The notion of a pathogenic role for antibodies in MS is nevertheless empirically supported by the clinical benefit of plasma exchange in patients with histologic signs of antibody deposition within the CNS. Further, such evidence derives from the animal model of MS, experimental autoimmune encephalomyelitis (EAE). In transgenic mice endogenously producing myelin-specific antibodies, EAE severity was substantially increased accompanied by enhanced CNS demyelination. Further, genetic engineering in mice adding T cells that recognize the same myelin antigen resulted in spontaneous EAE development, indicating that the coexistence of myelin-specific B cells, T cells, and antibodies was sufficient to trigger CNS autoimmune disease. In conclusion, various pathological, clinical, immunological, and experimental findings collectively indicate a pathogenic role of antibodies in MS, whereas several conceptual challenges, above all uncovering potential target antigens of the antibody response within the CNS, remain to be overcome

A Systematic Assessment of Prevalence, Incidence and Regional Distribution of Multiple Sclerosis in Bavaria From 2006 to 2015

Introduction: Worldwide, incidence and prevalence of multiple sclerosis (MS) have increased over the last decades. We present a systematic epidemiological study with recent prevalence and incidence rates of MS in Bavaria. Methods: Incidence and prevalence of MS stratified by gender, age groups and region were analyzed by data records from 2006 to 2015 of more than 10 million people insured by the Bavarian Association of Statutory Health Insurance Physicians. Official statistics of the German Federal Ministry of Health provided the size of the general population. Future prevalence was estimated with a predictive model. Results: From 2006 to 2015 prevalence of MS in Bavaria increased from 171 per 100,000 to 277 per 100,000, while incidence rates remained relatively stable (range 16-18 per 100,000 inhabitants with a female to male ratio between 2.4:1 and 2:1). Incidence and prevalence were higher in urban than urbanized and rural areas. The prevalence is expected to increase to 374 per 100,000 in 2040 with the highest prevalence rates between 50 and 65 years. Conclusion: The prevalence of MS in Bavaria is among the highest worldwide and will further rise over the next two decades. This demonstrates a need to strengthen healthcare provision systems due to the increasing numbers of particularly older patients with MS in the future

Sensing external spins with nitrogen-vacancy diamond

A single nitrogen-vacancy (NV) center is used to sense individual, as well as small ensembles of, electron spins placed outside the diamond lattice. Applying double electron–electron resonance techniques, we were able to observe Rabi nutations of these external spins as well as the coupling strength between the external spins and the NV sensor, via modulations and accelerated decay of the NV spin echo. Echo modulation frequencies as large as 600 kHz have been observed, being equivalent to a few nanometers distance between the NV and an unpaired electron spin. Upon surface modification, the coupling disappears, suggesting the spins to be localized at surface defects. The present study is important for understanding the properties of diamond surface spins so that their effects on NV sensors can eventually be mitigated. This would enable potential applications such as the imaging and tracking of single atoms and molecules in living cells or the use of NVs on scanning probe tips to entangle remote spins for scalable room temperature quantum computers

contribution of individual amino acids within mhc molecule or antigenic peptide to tcr ligand potency

The TCR recognition of peptides bound to MHC class II molecules is highly flexible in some T cells. Although progress has been made in understanding the interactions within the trimolecular complex, to what extent the individual components and their amino acid composition contribute to ligand recognition by individual T cells is not completely understood. We investigated how single amino acid residues influence Ag recognition of T cells by combining several experimental approaches. We defined TCR motifs for CD4+ T cells using peptide synthetic combinatorial libraries in the positional scanning format (PS-SCL) and single amino acid-modified peptide analogues. The similarity of the TCR motifs defined by both methods and the identification of stimulatory antigenic peptides by the PS-SCL approach argue for a contribution of each amino acid residue to the overall potency of the antigenic peptide ligand. In some instances, however, motifs are formed by adjacent amino acids, and their combined influence is superimposed on the overall contribution of each amino acid within the peptide epitope. In contrast to the flexibility of the TCR to interact with different peptides, recognition was very sensitive toward modifications of the MHC-restriction element. Exchanges of just one amino acid of the MHC molecule drastically reduced the number of peptides recognized. The results indicate that a specific MHC molecule not only selects certain peptides, but also is crucial for setting an affinity threshold for TCR recognition, which determines the flexibility in peptide recognition for a given TCR

Alteration of T cell cytokine production in PLPp-139-151-induced EAE in SJL mice by an immunostimulatory CpG Oligonucleotide

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

No evidence of an association of multiple sclerosis (MS) with Borna disease virus 1 (BoDV-1) infections in patients within an endemic region: a retrospective pilot study

Background Borna disease virus 1 (BoDV-1) causes rare human infections within endemic regions in southern and eastern Germany. The infections reported to date have been linked to severe courses of encephalitis with high mortality and mostly irreversible symptoms. Whether BoDV-1 could act as a trigger for other neurological conditions, is, however, incompletely understood. Objectives and methods In this study, we addressed the question of whether the presentation of a clinically isolated syndrome (CIS) or of multiple sclerosis (MS) might be associated with a milder course of BoDV-1 infections. Serum samples of 100 patients with CIS or MS diagnosed at a tertiary neurological care center within an endemic region in southern Germany and of 50 control patients suffering from headache were retrospectively tested for BoDV-1 infections. Results In none of the tested sera, confirmed positive results of anti-BoDV-1-IgG antibodies were retrieved. Our results support the conclusion that human BoDV-1 infections primarily lead to severe encephalitis with high mortality

CSF Protein Concentration Shows No Correlation With Brain Volume Measures

Background: CSF protein concentrations vary greatly among individuals. Accounting for brain volume may lower the variance and increase the diagnostic value of CSF protein concentrations.Objective: To determine the relation between CSF protein concentrations and brain volume.Methods: Brain volumes (total intracranial, gray matter, white matter volumes) derived from brain MRI and CSF protein concentrations (total protein, albumin, albumin CSF/serum ratio) of 29 control patients and 497 patients with clinically isolated syndrome or multiple sclerosis were studied.Finding: We found significant positive correlations of CSF protein concentrations with intracranial, gray matter, and white matter volumes. None of the correlations remained significant after correction for age and sex.Conclusion: Accounting for brain volume derived from brain MRI is unlikely to improve the diagnostic value of protein concentrations in CSF