Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders

<p>Abstract</p> <p>Background</p> <p>Serum autoantibodies against the water channel aquaporin-4 (AQP4) are important diagnostic biomarkers and pathogenic factors for neuromyelitis optica (NMO). However, AQP4-IgG are absent in 5-40% of all NMO patients and the target of the autoimmune response in these patients is unknown. Since recent studies indicate that autoimmune responses to myelin oligodendrocyte glycoprotein (MOG) can induce an NMO-like disease in experimental animal models, we speculate that MOG might be an autoantigen in AQP4-IgG seronegative NMO. Although high-titer autoantibodies to human native MOG were mainly detected in a subgroup of pediatric acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) patients, their role in NMO and High-risk NMO (HR-NMO; recurrent optic neuritis-rON or longitudinally extensive transverse myelitis-LETM) remains unresolved.</p> <p>Results</p> <p>We analyzed patients with definite NMO (n = 45), HR-NMO (n = 53), ADEM (n = 33), clinically isolated syndromes presenting with myelitis or optic neuritis (CIS, n = 32), MS (n = 71) and controls (n = 101; 24 other neurological diseases-OND, 27 systemic lupus erythematosus-SLE and 50 healthy subjects) for serum IgG to MOG and AQP4. Furthermore, we investigated whether these antibodies can mediate complement dependent cytotoxicity (CDC). AQP4-IgG was found in patients with NMO (n = 43, 96%), HR-NMO (n = 32, 60%) and in one CIS patient (3%), but was absent in ADEM, MS and controls. High-titer MOG-IgG was found in patients with ADEM (n = 14, 42%), NMO (n = 3, 7%), HR-NMO (n = 7, 13%, 5 rON and 2 LETM), CIS (n = 2, 6%), MS (n = 2, 3%) and controls (n = 3, 3%, two SLE and one OND). Two of the three MOG-IgG positive NMO patients and all seven MOG-IgG positive HR-NMO patients were negative for AQP4-IgG. Thus, MOG-IgG were found in both AQP4-IgG seronegative NMO patients and seven of 21 (33%) AQP4-IgG negative HR-NMO patients. Antibodies to MOG and AQP4 were predominantly of the IgG1 subtype, and were able to mediate CDC at high-titer levels.</p> <p>Conclusions</p> <p>We could show for the first time that a subset of AQP4-IgG seronegative patients with NMO and HR-NMO exhibit a MOG-IgG mediated immune response, whereas MOG is not a target antigen in cases with an AQP4-directed humoral immune response.</p

Cerebrospinal Fluid B Cells Correlate with Early Brain Inflammation in Multiple Sclerosis

Background: There is accumulating evidence from immunological, pathological and therapeutic studies that B cells are key components in the pathophysiology of multiple sclerosis (MS). Methodology/Principal Findings: In this prospective study we have for the first time investigated the differences in the inflammatory response between relapsing and progressive MS by comparing cerebrospinal fluid (CSF) cell profiles from patients at the onset of the disease (clinically isolated syndrome, CIS), relapsing-remitting (RR) and chronic progressive (CP) MS by flow cytometry. As controls we have used patients with other neurological diseases. We have found a statistically significant accumulation of CSF mature B cells (CD19+CD1382) and plasma blasts (CD19+CD138+) in CIS and RRMS. Both B cell populations were, however, not significantly increased in CPMS. Further, this accumulation of B cells correlated with acute brain inflammation measured by magnetic resonance imaging and with inflammatory CSF parameters such as the number of CSF leukocytes, intrathecal immunoglobulin M and G synthesis and intrathecal production of matri

Minimum Information about a Biosynthetic Gene cluster

A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.Chemistry and Chemical Biolog

Ecological validity of walking capacity tests following rehabilitation in people with multiple sclerosis.

BackgroundWalking capacity tests are commonly used to evaluate interventions aiming at reducing walking impairment in people with multiple sclerosis (pwMS). However, their ecological validity has recently been questioned. The aim of the present study was to investigate the ecological validity of the 2- and 6-minutes walking tests (2MWT and 6MWT) and the timed 25-foot walk (T25FW) after 28 days of multidisciplinary inpatient rehabilitation (MIR) in pwMS using accelerometry.MethodsPwMS wore an accelerometer on 7 consecutive days within a 14-day period prior to MIR, performed 2/6MWT and T25FW at the beginning and at the end of MIR, followed by another 7 consecutive days of accelerometry.ResultsSignificant improvements in 2/6MWT and T25FW after MIR in a cohort of 76 pwMS (mean age = 47.9, SD 8.3 years) were overall correlated to a significant gain in everyday life mobility (total steps/day). However, the correlation was strongly dependent on pre-existing walking disability defined by EDSS and only pwMS with "mild" walking impairment (EDSS 2-3.5) were able to transfer benefits measurable by walking capacity tests into improved everyday life mobility, while pwMS with "moderate to severe" walking disability (EDSS 4-6.5) were not.ConclusionEcological validity of changes in walking capacity tests following MIR is strongly dependent on pre-existing walking impairment

Percentages of CD3+ T cells (A), CD19+CD138− mature B cells (B) and CD19+CD138+ plasma blasts (C) in the CSF of patients with a CIS, RRMS, CPMS and OND.

<p>Individual data points are shown as circles and horizontal bars indicate means. Data were compared using the Kruskal-Wallis test and Dunn's multiple comparison post-hoc test and overall p-values are shown in each figure. # = significant differences to the OND group.</p

Demographic, clinical and CSF data of analyzed patients.

<p><b>1</b> data are shown as median (range), p-value: groups were compared using <b>2</b> Qui-Square test or <b>3</b> Kruskal-Wallis test and Dunn's multiple comparison post-hoc test, # statistically significant different from OND control group.</p><p>Abbreviations: n = number of patients, y = years, EDSS = expanded disability status score, acute relapse = number of patients with an acute relapse, MRI Gd+ lesions = presence of gadolinium-enhancing lesions on T1-weighted MRI (neg = negative, pos = positive), ≥9 T2 MRI lesions = ≥9 lesions on T2-weighted MRI, OCB = oligoclonal bands, Q-Alb = albumin quotient, MMP = matrix metalloproteinase, ratio = CSF∶serum ratio, ns = statistically not significant.</p

CSF B cell subsets.

<p>(A) Dot plots of CSF leucocytes according to their CD45-PerCP versus side scatter properties (left panel) and forward versus side scatter properties (right panel). Region 1 (R1, left panel) was used for acquisition of a minimum number of 1000 events and region 2 (R2, right panel) was used for analysis. CSF analysis of representative patients with a CIS (B), RRMS (C), CPMS (D) and OND (E) for the presence of CD3+ T cells and CD19+ B cells (left panel), and CD19+CD138− mature B cells, CD19+CD138+ plasma blasts and CD19−CD138+ plasma cells (right panel). The numbers represent the relative percentages of these cell populations.</p