BACKGROUND: The expression of aquaporin 4 (AQP4) and intermediate filament (IF) proteins is altered in malignant glioblastoma (GBM), yet the expression of the major IF-based cytolinker, plectin (PLEC), and its contribution to GBM migration and invasiveness, are unknown. Here, we assessed the contribution of plectin in affecting the distribution of plasmalemmal AQP4 aggregates, migratory properties, and regulation of cell volume in astrocytes. METHODS: In human GBM, the expression of glial fibrillary acidic protein (GFAP), AQP4 and PLEC transcripts was analyzed using publicly available datasets, and the colocalization of PLEC with AQP4 and with GFAP was determined by immunohistochemistry. We performed experiments on wild-type and plectin-deficient primary and immortalized mouse astrocytes, human astrocytes and permanent cell lines (U-251 MG and T98G) derived from a human malignant GBM. The expression of plectin isoforms in mouse astrocytes was assessed by quantitative real-time PCR. Transfection, immunolabeling and confocal microscopy were used to assess plectin-induced alterations in the distribution of the cytoskeleton, the influence of plectin and its isoforms on the abundance and size of plasmalemmal AQP4 aggregates, and the presence of plectin at the plasma membrane. The release of plectin from cells was measured by ELISA. The migration and dynamics of cell volume regulation of immortalized astrocytes were assessed by the wound-healing assay and calcein labeling, respectively. RESULTS: A positive correlation was found between plectin and AQP4 at the level of gene expression and protein localization in tumorous brain samples. Deficiency of plectin led to a decrease in the abundance and size of plasmalemmal AQP4 aggregates and altered distribution and bundling of the cytoskeleton. Astrocytes predominantly expressed P1c, P1e, and P1g plectin isoforms. The predominant plectin isoform associated with plasmalemmal AQP4 aggregates was P1c, which also affected the mobility of astrocytes most prominently. In the absence of plectin, the collective migration of astrocytes was impaired and the dynamics of cytoplasmic volume changes in peripheral cell regions decreased. Plectin's abundance on the plasma membrane surface and its release from cells were increased in the GBM cell lines. CONCLUSIONS: Plectin affects cellular properties that contribute to the pathology of GBM. The observed increase in both cell surface and released plectin levels represents a potential biomarker and therapeutic target in the diagnostics and treatment of GBMs.
Inebilizumab, a humanized, glycoengineered, IgG1 monoclonal antibody that depletes CD19+ B-cells, is approved to treat aquaporin 4 (AQP4) IgG-seropositive neuromyelitis optica spectrum disorder (NMOSD). Inebilizumab is afucosylated and engineered for enhanced affinity to Fc receptor III-A (FCGR3A) receptors on natural killer cells to maximize antibody-dependent cellular cytotoxicity. Previously, the F allele polymorphism at amino acid 158 of the FCGR3A gene (F158) was shown to decrease IgG-binding affinity and reduce rituximab (anti-CD20) efficacy for NMOSD attack prevention. In contrast, our current findings from inebilizumab-treated NMOSD patients indicate similar clinical outcomes between those with F158 and V158 allele genotypes.
Leukoencefalopatie mohou představovat v řadě případů obtížný diagnostický problém. Při diagnostice je nutné se zaměřit zejména na léčitelné příčiny. Kromě cévních, infekčních a autoimunitních ale narůstá i počet léčitelných genetických onemocnění. V případě autoimunitních encefalopatií se v posledních letech zlepšila diagnostika a léčba, díky čemuž mohou být pacienti rychleji a účinněji léčeni. Byť stále zůstává mnoho nevyřešených otázek ohledně přesného mechanismu, jakým imunitní systém napadá mozkovou tkáň, lepší pochopení těchto mechanismů umožňuje cílené zvolení imunoterapie i zabránění možnému zhoršení nemoci nesprávnou léčbou. Cílem článku je upozornit na vzácnější zánětlivé autoimunitní leukoencefalopatie s dominujícím postižením mozku se zaměřením na cíle a mechanismy imunitní reakce a napomoci s často obtížnou diagnostikou těchto onemocnění.
Leukoencephalopathies can be difficult to diagnose. Diagnosis must focus on treatable causes. However, in addition to vascular, infectious and autoimmune causes, there are an increasing number of treatable genetic disorders. In the case of autoimmune encephalopathies, diagnosis and treatment have improved in recent years, allowing patients to be treated more quickly and effectively. Although there are still many unanswered questions about the mechanism by which the immune system attacks brain tissue, a better understanding of this mechanism will enable targeted immunotherapy to be chosen and prevent the possible worsening of the disease if the wrong treatment is applied. The aim of this article is to highlight the rarer inflammatory autoimmune leukoencephalopathies with predominant brain involvement, focusing on the targets and mechanisms of the immune response, and to help in the often difficult diagnosis of these entities.
- MeSH
- akvaporin 4 MeSH
- autoimunitní nemoci nervového systému * diagnostické zobrazování klasifikace patologie MeSH
- diferenciální diagnóza MeSH
- glykoprotein v myelinu oligodendrocytů MeSH
- leukoencefalopatie * diagnostické zobrazování klasifikace patologie MeSH
- lidé MeSH
- neurologické manifestace MeSH
- neuromyelitis optica patologie MeSH
- Susacův syndrom diagnostické zobrazování patologie MeSH
- systémový lupus erythematodes patologie MeSH
- vaskulitida centrálního nervového systému epidemiologie etiologie klasifikace patologie MeSH
- vzácné nemoci diagnostické zobrazování klasifikace patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
OBJECTIVE: To investigate relationships between serum neurofilament light chain (sNfL), ubiquitin C-terminal hydrolase L1 (sUCHL1), tau (sTau) and glial fibrillary acidic protein (sGFAP) levels and disease activity/disability in neuromyelitis optica spectrum disorder (NMOSD), and the effects of inebilizumab on these biomarkers in N-MOmentum. METHODS: N-MOmentum randomised participants to receive inebilizumab or placebo with a randomised controlled period (RCP) of 28 weeks and an open-label follow-up period of ≥2 years. The sNfL, sUCHL1, sTau and sGFAP were measured using single-molecule arrays in 1260 scheduled and attack-related samples from N-MOmentum participants (immunoglobulin G (IgG) autoantibodies to aquaporin-4-positive, myelin oligodendrocyte glycoprotein-IgG-positive or double autoantibody-negative) and two control groups (healthy donors and patients with relapsing-remitting multiple sclerosis). RESULTS: The concentration of all four biomarkers increased during NMOSD attacks. At attack, sNfL had the strongest correlation with disability worsening during attacks (Spearman R2=0.40; p=0.01) and prediction of disability worsening after attacks (sNfL cut-off 32 pg/mL; area under the curve 0.71 (95% CI 0.51 to 0.89); p=0.02), but only sGFAP predicted upcoming attacks. At RCP end, fewer inebilizumab-treated than placebo-treated participants had sNfL>16 pg/mL (22% vs 45%; OR 0.36 (95% CI 0.17 to 0.76); p=0.004). CONCLUSIONS: Compared with sGFAP, sTau and sUCHL1, sNfL at attack was the strongest predictor of disability worsening at attack and follow-up, suggesting a role for identifying participants with NMOSD at risk of limited post-relapse recovery. Treatment with inebilizumab was associated with lower levels of sGFAP and sNfL than placebo. TRIAL REGISTRATION NUMBER: NCT02200770.
BACKGROUND: The N-MOmentum trial, a double-blind, randomized, placebo-controlled, phase 2/3 study of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD), enrolled participants who were aquaporin-4-immunoglobulin G (AQP4-IgG)-seropositive (AQP4+) or -seronegative (AQP4-). This article reports AQP4- participant outcomes. METHODS: AQP4-IgG serostatus was determined for all screened participants by a central laboratory, using a validated, fluorescence-observation cell-binding assay. Medical histories and screening data for AQP4- participants were assessed independently by an eligibility committee of three clinical experts during screening. Diagnosis of NMOSD was confirmed by majority decision using the 2006 neuromyelitis optica criteria. Myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) serology (using a clinically validated, flow cytometry assay) and annualized attack rates (AARs) were evaluated post hoc. Efficacy outcomes were assessed by comparing pre-study and on-study AARs in treated participants. RESULTS: Only 18/50 AQP4- screened participants (36%) were initially considered eligible for randomization; 16 were randomized and received full treatment, 4 to placebo (1 MOG-IgG-seropositive [MOG+]) and 12 to inebilizumab (6 MOG+). The most common reason for failure to pass screening among prospective AQP4- participants was failure to fulfill the 2006 NMO MRI criteria. In inebilizumab-treated AQP4- participants, on-study AARs (95% confidence interval [CI]) calculated from treatment initiation (whether from randomization or when received at the start of the open-label period) to the end of study were lower than pre-study rates: for all AQP4- participants (n = 16), mean (95% CI) AAR was 0.048 (0.02-0.15) versus 1.70 (0.74-2.66), respectively. For the subset of AQP4-/MOG+ participants (n = 7), AAR was 0.043 (0.006-0.302) after treatment versus 1.93 (1.10-3.14) before the study. For the subset of AQP4-/MOG- participants (n = 9), post-treatment AAR was 0.051 (0.013-0.204) versus 1.60 (1.02-2.38). Three attacks occurred during the randomized controlled period in the AQP4- inebilizumab group and were of mild severity; no attacks occurred in the AQP4- placebo group. The low number of participants receiving placebo (n = 4) confounds direct comparison with the inebilizumab group. No attacks were seen in any AQP4- participant after the second infusion of inebilizumab. Inebilizumab was generally well tolerated by AQP4- participants and the adverse event profile observed was similar to that of AQP4+ participants. CONCLUSION: The high rate of rejection of AQP4- participants from enrollment into the study highlights the challenges of implementing the diagnostic criteria of AQP4- NMOSD. An apparent reduction of AAR in participants with AQP4- NMOSD who received inebilizumab warrants further investigation.
- MeSH
- akvaporin 4 MeSH
- autoprotilátky MeSH
- humanizované monoklonální protilátky MeSH
- imunoglobulin G MeSH
- lidé MeSH
- neuromyelitis optica * diagnostické zobrazování farmakoterapie MeSH
- prospektivní studie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
Neuromyelitis optica (NMO) a spektrum ochorení NMO (neuromyelitis optica spectrum disorders – NMOSD) sa na základe klinických a paraklinických kritérií, predovšetkým MR a prítomnosti protilátok proti akvaporínu 4 (AQP4), jasne odčlenili od sclerosis multiplex (SM) ako samostatná nozologická jednotka. Možnosti MR spolu so sérologickým testovaním protilátok proti AQP4 a myelínovému oligodendrocytovému glykoproteínu (MOG), zohrávajú dôležitú úlohu v diagnostike a diferenciálnej diagnostike NMOSD od SM a MOGAD – myelin ologodendrocyte glycoprotein associated disease.
Neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorders (NMOSD) have been clearly separated from sclerosis multiplex (SM) as a distinct nosological entity based on clinical and paraclinical criteria, particularly MRI and the presence of antibodies to aquaporin-4 (AQP4). The capabilities of MRI, together with serological testing for antibodies to AQP4 and myelin oligodendrocyte glycoprotein (MOG), play an important role in the diagnosis and differential diagnosis of NMOSD from SM and MOGAD-myelin oligodendrocyte glycoprotein associated disease.
- MeSH
- akvaporin 4 imunologie MeSH
- centrální nervový systém diagnostické zobrazování patologie MeSH
- diferenciální diagnóza MeSH
- lidé MeSH
- magnetická rezonanční tomografie * MeSH
- mozek diagnostické zobrazování patologie MeSH
- myelinový oligodendrocytární glykoprotein MeSH
- neuromyelitis optica * diagnostické zobrazování klasifikace patologie MeSH
- senioři MeSH
- transverzální myelitida diagnostické zobrazování klasifikace patologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- kazuistiky MeSH
There is no consensus regarding the classification of optic neuritis, and precise diagnostic criteria are not available. This reality means that the diagnosis of disorders that have optic neuritis as the first manifestation can be challenging. Accurate diagnosis of optic neuritis at presentation can facilitate the timely treatment of individuals with multiple sclerosis, neuromyelitis optica spectrum disorder, or myelin oligodendrocyte glycoprotein antibody-associated disease. Epidemiological data show that, cumulatively, optic neuritis is most frequently caused by many conditions other than multiple sclerosis. Worldwide, the cause and management of optic neuritis varies with geographical location, treatment availability, and ethnic background. We have developed diagnostic criteria for optic neuritis and a classification of optic neuritis subgroups. Our diagnostic criteria are based on clinical features that permit a diagnosis of possible optic neuritis; further paraclinical tests, utilising brain, orbital, and retinal imaging, together with antibody and other protein biomarker data, can lead to a diagnosis of definite optic neuritis. Paraclinical tests can also be applied retrospectively on stored samples and historical brain or retinal scans, which will be useful for future validation studies. Our criteria have the potential to reduce the risk of misdiagnosis, provide information on optic neuritis disease course that can guide future treatment trial design, and enable physicians to judge the likelihood of a need for long-term pharmacological management, which might differ according to optic neuritis subgroups.
BACKGROUND: Serum antibodies to myelin-oligodendrocyte glycoprotein (MOG) are biomarkers of MOG-IgG-associated disorder (MOGAD), a demyelinating disease distinct from both multiple sclerosis and aquaporin-4-IgG neuromyelitis optica spectrum disorder. The phenotype of MOGAD is broad and includes optic neuritis, transverse myelitis, and acute demyelinating encephalomyelitis. Myelitis is common with MOGAD and typically results in acute and severe disability, although prospects for recovery are often favorable with prompt immunotherapy. CASE PRESENTATION: This contribution presents a unique case report of a young male patient exhibiting relapsing myelitis with normal spinal cord and brain magnetic resonance imaging. Comprehensive diagnostic assessment revealed myelin-oligodendrocyte glycoprotein-IgG-associated disorder. CONCLUSION: MOGAD is one of the conditions which should be considered in MRI-negative myelitis. The diagnosis, however, may prove difficult, especially if the patient is not exhibiting other neurological symptoms of MOGAD. Conus or epiconus involvement is common in MOGAD; the patient reported herein exhibited incomplete rostral epiconus symptoms which, together with somatosensory evoked potential abnormalities, led to the diagnosis.
- MeSH
- akvaporin 4 MeSH
- autoprotilátky MeSH
- glykoprotein v myelinu oligodendrocytů MeSH
- imunoglobulin G MeSH
- lidé MeSH
- lokální recidiva nádoru MeSH
- magnetická rezonanční tomografie MeSH
- neuromyelitis optica * MeSH
- transverzální myelitida * diagnostické zobrazování MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
Ocrelizumab, rituximab, ofatumumab, ublituximab, inebilizumab, and evobrutinib are immunotherapies that target various B cell-related proteins. Most of these treatments have proven efficacy in relapsing and progressive forms of MS and neuromyelitis optica spectrum disease (NMOSD) or are in advanced stages of clinical development. Currently, ocrelizumab and inebilizumab are licensed for treatment of MS and NMOSD, respectively. This part of the review focuses on monoclonal antibody B cell-depleting strategies in NMOSD and the emerging related myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G-associated disease (MOGAD). Case series and phase 2/3 studies in these inflammatory disorders are assessed. The safety profile of long-term B-cell depletion in MS, NMOSD, and MOGAD will be highlighted. Finally implications of the current coronavirus disease 2019 pandemic on the management of patients with these disorders and the use of B cell-depleting agents will be discussed.
- MeSH
- akvaporin 4 MeSH
- B-lymfocyty MeSH
- COVID-19 * MeSH
- lidé MeSH
- neuromyelitis optica * farmakoterapie MeSH
- SARS-CoV-2 MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Satralizumab je humanizovaná monoklonální protilátka proti receptoru pro interleukin 6, která redukuje riziko relapsu u pacientů s neuromyelitis optica a onemocněními jejího širšího spektra (NMOSD). NMOSD patří mezi vzácná chronická autoimunitní onemocnění centrálního nervového systému, která se odlišují od roztroušené sklerózy a jsou asociována s protilátkami proti akvaporinu 4 (AQP4-IgG) u více než dvou třetin pacientů. Interleukin 6 hraje významnou roli v patogenezi těchto poruch. Mezi typické klinické projevy patří ataky optických neuritid, myelitid, syndromu area postrema (singultus, nauzea, zvracení). Ataky onemocnění způsobují výraznou invaliditu pacienta, která přetrvává i přes akutní terapii. Prevence rozvoje a zmínění tíže atak je hlavním cílem chronické léčby.
Satralizumab, a humanized monoclonal antibody targeting the interleukin-6 receptor, reduced the risk of relapse in patients with neuromyelitis optica spectrum disorder (NMOSD). NMOSD are rare chronic inflammatory central nervous system diseases distinct from multiple sclerosis and are associated with autoantibodies to aquaporin-4 (AQP4-IgG) in approximately two thirds of patients. Interleukin-6 is involved in the pathogenesis of the disorders. In NMOSD, most common symptoms are optic neuritis, acute myelitis or signs of brainstem involvement like persistent hiccup, nausea or vomiting (area postrema syndrome). Attacks in NMOSD are often characterized by severe neurologic deficits with poor recovery. Frequently, a significant disability persists after an attack. Therefore, attack occurrence and severity prevention is the key issue of chronic treatment strategy.
- Klíčová slova
- satralizumab,
- MeSH
- akvaporin 4 imunologie MeSH
- humanizované monoklonální protilátky aplikace a dávkování farmakokinetika terapeutické užití MeSH
- klinické zkoušky, fáze III jako téma MeSH
- lidé MeSH
- neuromyelitis optica * farmakoterapie patofyziologie MeSH
- přežití po terapii bez příznaků nemoci MeSH
- receptory interleukinu-6 * antagonisté a inhibitory MeSH
- Check Tag
- lidé MeSH
