TNF-α and IL-10 downregulation and marked oxidative stress in Neuromyelitis Optica

<p>Abstract</p> <p>Background</p> <p>Neuromyelitis optica is a central nervous system demyelinating and inflammatory syndrome. The objective of this study is to identify cytokines related to the cellular immune response as well as blood brain barrier integrity and oxidative stress.</p> <p>Methods</p> <p>We performed a molecular characterization of cellular immune response and oxidative stress in serum from relapsing-NMO (R-NMO) patients and established the correlations between the clinical measurements and molecular parameters using the Bayesian approach.</p> <p>Serum samples from 11 patients with R-NMO diagnosed according to Wingerchuk criteria and matched in terms of age, gender and ethnicity with the healthy controls were analyzed. The levels of TNF-<it>α</it>, IFN-<it>γ</it>, IL-10, MMP-9, TIMP-1 and oxidative stress markers: malondialdehyde, advanced oxidation protein products, peroxidation potential, superoxide dismutase, catalase, and total hydroperoxides were measured.</p> <p>Results</p> <p>We found almost undetectable levels of TNF-<it>α</it>, a decreased production of IL-10 and a significant up-regulation of every oxidative stress biomarker studied. The insufficient production of TNF-<it>α </it>and IL-10 in R-NMO patients, which are two important players of T cell mediated immunoregulation, suggest an effector – regulator imbalance. The overproduction of oxygen reactive species as a consequence of the chronic inflammatory milieu is reflected on the excess of oxidative damage mediators detected. Furthermore, Multidimensional Scaling and a Bayesian linear regression model revealed a significant linear dependence between Expanded Disability Status Scale Kurtzke and TIMP-1; pointing to a possible predictive or prognostic value of this clinical-molecular relationship.</p> <p>Conclusion</p> <p>These results suggest that there is a breakdown in immunoregulatory mechanisms and noteworthy pro-oxidant environment contributing to NMO pathogenesis.</p

Experimental evidence for the preservation of U-Pb isotope ratios in mantle-recycled crustal zircon grains

Zircon of crustal origin found in mantle-derived rocks is of great interest because of the information it may provide about crust recycling and mantle dynamics. Consideration of this requires understanding of how mantle temperatures, notably higher than zircon crystallization temperatures, affected the recycled zircon grains, particularly their isotopic clocks. Since Pb2+ diffuses faster than U4+ and Th+4, it is generally believed that recycled zircon grains lose all radiogenic Pb after a few million years, thus limiting the time range over which they can be detected. Nonetheless, this might not be the case for zircon included in mantle minerals with low Pb2+ diffusivity and partitioning such as olivine and orthopyroxene because these may act as zircon sealants. Annealing experiments with natural zircon embedded in cristobalite (an effective zircon sealant) show that zircon grains do not lose Pb to their surroundings, although they may lose some Pb to molten inclusions. Diffusion tends to homogenize the Pb concentration in each grain changing the U-Pb and Th-Pb isotope ratios proportionally to the initial 206Pb, 207Pb and 208Pb concentration gradients (no gradient-no change) but in most cases the original age is still recognizable. It seems, therefore, that recycled crustal zircon grains can be detected, and even accurately dated, no matter how long they have dwelled in the mantle.This paper has been financed by the Spanish Grants CGL2013-40785-P and CGL2017-84469-P

IgG Antibodies against Measles, Rubella, and Varicella Zoster Virus Predict Conversion to Multiple Sclerosis in Clinically Isolated Syndrome

BACKGROUND:Multiple sclerosis (MS) is characterized by a polyspecific B-cell response to neurotropic viruses such as measles, rubella and varicella zoster, with the corresponding antibodies measurable in CSF as the so-called "MRZ reaction" (MRZR). We aimed to evaluate the relevance of MRZR to predict conversion of patients with clinically isolated syndrome (CIS) to MS, and to compare it to oligoclonal bands (OCB) and MRI. METHODOLOGY/PRINCIPAL FINDINGS:MRZR was determined in a prospective study over 2 years including 40 patients that remained CIS over follow-up (CIS-CIS) and 49 patients that developed MS (CIS-RRMS) using ELISA. Using logistic regression, a score (MRZS) balancing the predictive value of the antibody indices included in MRZR was defined (9 points measles, 8 points rubella, 1 point varicella zoster, cutpoint: sum of scores greater 10). MRZR and MRZS were significantly more frequent in CIS-RRMS as compared to CIS-CIS (p=0.04 and p=0.02). MRZS showed the best positive predictive value (PPV) of all parameters investigated (79%, 95%-CI: 54-94%), which could be further increased by combination with MRI (91%, 95%-CI: 59-99%). CONCLUSIONS/SIGNIFICANCE:Our data indicate the relevance of MRZR to predict conversion to MS. It furthermore shows the importance of weighting the different antibody indices included in MRZR and suggest that patients with positive MRZR are candidates for an early begin of immunomodulatory therapy

The intrathecal, polyspecific antiviral immune response in neurosarcoidosis, acute disseminated encephalomyelitis and autoimmune encephalitis compared to multiple sclerosis in a tertiary hospital cohort

BACKGROUND: A polyspecific, intrathecal humoral immune response against the neurotropic viruses, measles, rubella and varicella zoster virus, called “MRZ reaction” (MRZR), is present in the majority of patients with multiple sclerosis (MS). Neurosarcoidosis (NS) and acute disseminated encephalomyelitis (ADEM) are important clinical differential diagnoses of MS. Autoimmune encephalitis (AIE) represents a well characterized autoimmune CNS disorder with intrathecal antibody synthesis. The aim of this study was to investigate the specificity of MRZR for MS in patients with NS, ADEM and AIE for the first time, and to compare it with the diagnostic value of oligoclonal bands (OCB). PATIENTS AND METHODS: Twenty-two patients with NS, 17 with AIE, 8 with ADEM and 33 with MS serving as controls were analyzed for OCB and MRZR by calculation of the antibody index (AI) for each virus. MRZR was considered as positive if at least two AIs were ≥1.5. RESULTS: A positive MRZR was statistically significantly less frequent in NS (9 %), AIE (11 %) and ADEM (0 %) compared to MS patients (70 %; p < 0.001 each). The specificity of MRZR for MS was 92 % in the study cohort. In comparison to MRZR, the OCB showed a higher sensitivity (100 %), but a lower specificity (69 %) for MS. CONCLUSION: These results indicate that MRZR seems to be the most specific available CSF marker of MS

Intrathecal oligoclonal and polyspecific immune response in multiple sclerosis

Introduction. The intrathecal response of IgG, is the most frequent neuropathological sign in multiple sclerosis (MS)patients beside the detection of oligoclonal IgG bands in cerebrospinal fluid. At the same time the observation of an intrathecal antibody synthesis (antibody index > 1.4) against neurotropic viruses like measles, rubella, varicella zoster or herpes simple shows a higher frequency in MS than any other chronic disease (MRZH reaction). We report the intrathecal, polyspecific and oligoclonal immune response inpatients with definitive MS. Patients and methods. CSF and serum were tested for Albumin, IgG, IgM and IgA by standard immunochemical nephelometry assay while virus specific antibodies in CSF and serum samples were evaluated by ELISA and calculated as antibody index. Results. Oligoclonal IgG by, isoelectric focusing was detectable in all patients. A differential pattern of combined antibody index against neurotropic virus was observed. The largest frequency of a single species in the oligoclonal immune response was for measles antibodies, while the antibody response was found as a combination with increased rubella-antibody index and VZ-antibody index, respectively. Conclusion. Our results although preliminary for our country, enrich the criteria about that MRZH reaction provide a major neuroimmunological support to MS diagnosis

Intrathecal oligoclonal and polyspecific immune response in multiple sclerosis

Introduction. The intrathecal response of IgG, is the most frequent neuropathological sign in multiple sclerosis (MS)patients beside the detection of oligoclonal IgG bands in cerebrospinal fluid. At the same time the observation of an intrathecal antibody synthesis (antibody index > 1.4) against neurotropic viruses like measles, rubella, varicella zoster or herpes simple shows a higher frequency in MS than any other chronic disease (MRZH reaction). We report the intrathecal, polyspecific and oligoclonal immune response inpatients with definitive MS. Patients and methods. CSF and serum were tested for Albumin, IgG, IgM and IgA by standard immunochemical nephelometry assay while virus specific antibodies in CSF and serum samples were evaluated by ELISA and calculated as antibody index. Results. Oligoclonal IgG by, isoelectric focusing was detectable in all patients. A differential pattern of combined antibody index against neurotropic virus was observed. The largest frequency of a single species in the oligoclonal immune response was for measles antibodies, while the antibody response was found as a combination with increased rubella-antibody index and VZ-antibody index, respectively. Conclusion. Our results although preliminary for our country, enrich the criteria about that MRZH reaction provide a major neuroimmunological support to MS diagnosis

Follow-Up of Peripheral IL-1β and IL-6 and Relation with Apoptotic Death in Drug-Resistant Temporal Lobe Epilepsy Patients Submitted to Surgery

Increasing amounts of evidence support the role of inflammation in epilepsy. This study was done to evaluate serum follow-up of IL-1β and IL-6 levels, as well as their concentration in the neocortex, and the relationship of central inflammation with NF-κB and annexin V in drug-resistant temporal lobe epileptic (DRTLE) patients submitted to surgical treatment. Peripheral and central levels of IL-1β and IL-6were measured by ELISA in 10 DRTLE patients. The sera from patients were taken before surgery, and 12 and 24 months after surgical treatment. The neocortical expression of NF-κB was evaluated by western blotting and annexin V co-localization with synaptophysin by immunohistochemistry. The neocortical tissues from five patients who died by non-neurological causes were used as control. Decreased serum levels of IL-1 and IL-6 were observed after surgery; at this time, 70% of patients were seizure-free. No values of IL-1 and IL-6 were detected in neocortical control tissue, whereas cytokine levels were evidenced in DRTLE. Increased NF-κB neocortex expression was found and the positive annexin V neurons were more obvious in the DRTLE tissue, correlating with IL-6 levels. The follow-up study confirmed that the inflammatory alterations disappeared one year after surgery, when the majority of patients were seizure-free, and the apoptotic death process correlated with inflammation