RESUMEN
OBJECTIVES: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an autoimmune demyelinating disease rarely associated with malignancy. We report the clinical, MRI, immunopathology, and treatment response in a person with MOGAD and melanoma. METHODS: This is a case report of a person with a multidisciplinary evaluation at a tertiary referral center. RESULTS: A 52-year-old man presented with progressive encephalomyelitis that led to identification of metastatic melanoma. Investigations revealed positive MOG-IgG at high titers in serum (1:1,000; normal, <1:20) and CSF (1:4,096; normal, <1:2). MRI demonstrated multifocal T2 lesions with enhancement in the brain and spine. Brain biopsy showed demyelination and inflammation. MOG immunostaining was not present in the tumor tissue. He initially improved with methylprednisolone, plasmapheresis, prolonged oral steroid taper, and cancer-directed treatment with BRAF and MEK 1/2 inhibitors, but then developed bilateral optic neuritis. IV immunoglobulin (IVIG) was initiated. Five months later, he developed metastases and immune checkpoint inhibitor (ICI) treatment was started, which precipitated optic neuritis and myelitis despite IVIG and prednisone. Tocilizumab, an interleukin-6 receptor blocker, was started with excellent and sustained clinical and radiologic response. DISCUSSION: This case revealed a presentation of MOGAD concurrent with melanoma without tumor MOG immunostaining. We highlight tocilizumab as a dual-purpose treatment of MOGAD and the neurologic immune-related adverse effect of ICI.
Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Melanoma , Glicoproteína Mielina-Oligodendrócito , Humanos , Masculino , Melanoma/tratamiento farmacológico , Persona de Mediana Edad , Glicoproteína Mielina-Oligodendrócito/inmunología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Autoanticuerpos/sangre , Autoanticuerpos/líquido cefalorraquídeo , Enfermedades Autoinmunes Desmielinizantes SNC/inmunología , Enfermedades Autoinmunes Desmielinizantes SNC/tratamiento farmacológico , Enfermedades Autoinmunes Desmielinizantes SNC/inducido químicamenteRESUMEN
Anti-glial fibrillary acidic protein (GFAP) meningoencephalomyelitis (autoimmune GFAP astrocytopathy) is a new autoimmune central nervous system (CNS) disease diagnosable by the presence of anti-GFAP autoantibodies in the cerebrospinal fluid and presents as meningoencephalomyelitis in the majority of patients. Only few neuropathological reports are available and little is known about the pathogenic mechanisms. We performed a histopathological study of two autopsies and nine CNS biopsies of patients with anti-GFAP autoantibodies and found predominantly a lymphocytic and in one autopsy case a granulomatous inflammatory phenotype. Inflammatory infiltrates were composed of B and T cells, including tissue-resident memory T cells. Although obvious astrocytic damage was absent in the GFAP-staining, we found cytotoxic T cell-mediated reactions reflected by the presence of CD8+/perforin+/granzyme A/B+ cells, polarized towards astrocytes. MHC-class-I was upregulated in reactive astrocytes of all biopsies and two autopsies but not in healthy controls. Importantly, we observed a prominent immunoreactivity of astrocytes with the complement factor C4d. Finally, we provided insight into an early phase of GFAP autoimmunity in an autopsy of a pug dog encephalitis that was characterized by marked meningoencephalitis with selective astrocytic damage with loss of GFAP and AQP4 in the lesions.Our histopathological findings indicate that a cytotoxic T cell-mediated immune reaction is present in GFAP autoimmunity. Complement C4d deposition on astrocytes could either represent the cause or consequence of astrocytic reactivity. Selective astrocytic damage is prominent in the early phase of GFAP autoimmunity in a canine autopsy case, but mild or absent in subacute and chronic stages in human disease, probably due to the high regeneration potential of astrocytes. The lymphocytic and granulomatous phenotypes might reflect different stages of lesion development or patient-specific modifications of the immune response. Future studies will be necessary to investigate possible implications of pathological subtypes for clinical disease course and therapeutic strategies.
Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso , Encefalomielitis , Meningoencefalitis , Humanos , Animales , Perros , Proteína Ácida Fibrilar de la Glía/metabolismo , Encefalomielitis/patología , Astrocitos/patología , Enfermedades Autoinmunes del Sistema Nervioso/líquido cefalorraquídeo , Enfermedades Autoinmunes del Sistema Nervioso/terapia , Meningoencefalitis/líquido cefalorraquídeo , Meningoencefalitis/patología , AutoanticuerposRESUMEN
Multiple sclerosis (MS) is the leading cause of non-traumatic disability in young adults. New avenues are needed to help predict individuals at risk for developing MS and aid in diagnosis, prognosis, and outcome of therapeutic treatments. Previously, we showed that skin fibroblasts derived from patients with MS have altered signatures of cell stress and bioenergetics, which likely reflects changes in their protein, lipid, and biochemical profiles. Here, we used Fourier transform infrared (FTIR) spectroscopy to determine if the biochemical landscape of MS skin fibroblasts were altered when compared to age- and sex-matched controls (CTRL). More so, we sought to determine if FTIR spectroscopic signatures detected in MS skin fibroblasts are disease specific by comparing them to amyotrophic lateral sclerosis (ALS) skin fibroblasts. Spectral profiling of skin fibroblasts from MS individuals suggests significant alterations in lipid and protein organization and homeostasis, which may be affecting metabolic processes, cellular organization, and oxidation status. Sparse partial least squares-discriminant analysis of spectral profiles show that CTRL skin fibroblasts segregate well from diseased cells and that changes in MS and ALS may be unique. Differential changes in the spectral profile of CTRL, MS, and ALS cells support the development of FTIR spectroscopy to detect biomolecular modifications in patient-derived skin fibroblasts, which may eventually help establish novel peripheral biomarkers.
RESUMEN
OBJECTIVE: To describe demographic, clinical, and radiographic features of tumefactive demyelination (TD) and identify factors associated with severe attacks and poor outcomes. METHODS: Retrospective review of TD cases seen at Mayo Clinic, 1990-2021. RESULTS: Of 257 patients with TD, 183/257 (71%) fulfilled the 2017 multiple sclerosis (MS) McDonald criteria at the last follow-up, 12/257 (5%) had myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), 0 had aquaporin-4-IgG seropositive neuromyelitis optic spectrum disorders (AQP4+ NMOSD), and 62/257 (24%) were cryptogenic. Onset before age 18 was present in 18/257 (7%). Female to male ratio was 1.3:1. Cerebrospinal fluid oligoclonal (CSF) bands were present in 95/153 (62%). TD was the first demyelinating attack in 176/257 (69%). At presentation, 59/126 (47%) fulfilled Barkhof criteria for dissemination in space, 59/100 (59%) had apparent diffusion coefficient (ADC) restriction, and 57/126 (45%) had mass effect. Despite aggressive clinical presentation at onset, 181/257 (70%) of patients remained fully ambulatory (Expanded Disability Status Scale [EDSS] ≤4) after a 3.0-year median follow-up duration. Severe initial attack-related disability (EDSS ≥4) was more common in patients with motor symptoms (81/143 vs. 35/106, p < 0.0001), encephalopathy (20/143 vs. 2/106, p < 0.0001) and ADC restriction on initial MRI (42/63 vs. 15/33, p = 0.04). Poor long-term outcome (EDSS ≥4) was more common in patients with older onset age (41.9 ± 15 vs. 36.8 ± 15.6, p = 0.02) and motor symptoms at onset (49/76 vs. 66/171, p < 0.0001). INTERPRETATION: Most TD patients should be considered part of the MS spectrum after excluding MOGAD and NMOSD. Motor symptoms and older age at presentation portend a poor outcome.
Asunto(s)
Encefalopatías , Esclerosis Múltiple , Neuromielitis Óptica , Masculino , Femenino , Humanos , Estudios Retrospectivos , Neuromielitis Óptica/diagnóstico , Acuaporina 4 , Esclerosis Múltiple/complicacionesRESUMEN
BACKGROUND: MS is the most common CNS inflammatory demyelinating disease. Plasma exchange (PLEX) has well-demonstrated efficacy in acute corticosteroid-refractory attacks of demyelination but identifying the factors that predict favorable PLEX response remains elusive. We aimed to determine if apparent diffusion coefficient (ADC) restriction on brain MRI predicts clinical response to PLEX in individuals with an acute cerebral attack of MS. METHODS: Retrospective chart review of individuals with a cerebral attack of MS who underwent PLEX at Mayo Clinic. RESULTS: We identified 34 individuals who fulfilled the inclusion criteria. Twenty-seven (79%) responded to plasma exchange, with 16/34 (47%) having moderate and 11/34 (32%) marked improvement. Twenty-three (68%) people had ADC restriction on brain MRI prior to PLEX. ADC restriction did not predict response (p = 0.51). Several other pre-PLEX factors, including sex, Expanded Disability Status Scale (EDSS) at initial attack, time to PLEX, and concurrent spinal cord attack, also failed to predict response. Plasma-exchange responders had less disability at 6-month follow-up compared to non-responders (median EDSS 2.5 (range 1.0-10.0) vs. 7.5 (5.5-10.0), p<0.001). CONCLUSION: Acute cerebral attacks of MS have a high rate of plasma exchange response resulting in a lower EDSS at 6-months. ADC restriction does not predict response to plasma exchange.
Asunto(s)
Esclerosis Múltiple , Neuromielitis Óptica , Humanos , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/terapia , Intercambio Plasmático/métodos , Neuromielitis Óptica/terapia , Estudios Retrospectivos , Médula EspinalRESUMEN
Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an inflammatory demyelinating CNS condition characterized by the presence of MOG autoantibodies. We sought to investigate whether human MOG autoantibodies are capable of mediating damage to MOG-expressing cells through multiple mechanisms. We developed high-throughput assays to measure complement activity (CA), complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cellular cytotoxicity (ADCC) of live MOG-expressing cells. MOGAD patient sera effectively mediate all of these effector functions. Our collective analyses reveal that (a) cytotoxicity is not incumbent on MOG autoantibody quantity alone; (b) engagement of effector functions by MOGAD patient serum is bimodal, with some sera exhibiting cytotoxic capacity while others did not; (c) the magnitude of CDC and ADCP is elevated closer to relapse, while MOG-IgG binding is not; and (d) all IgG subclasses can damage MOG-expressing cells. Histopathology from a representative MOGAD case revealed congruence between lesion histology and serum CDC and ADCP, and we identified NK cells, mediators of ADCC, in the cerebrospinal fluid of relapsing patients with MOGAD. Thus, MOGAD-derived autoantibodies are cytotoxic to MOG-expressing cells through multiple mechanisms, and assays quantifying CDC and ADCP may prove to be effective tools for predicting risk of future relapses.
Asunto(s)
Autoanticuerpos , Inmunoglobulina G , Humanos , Glicoproteína Mielina-Oligodendrócito , Proteínas del Sistema Complemento , Fagocitosis , Citotoxicidad InmunológicaRESUMEN
BACKGROUND: Spinal cord lesions have been associated with progressive disease in individuals with typical relapsing remitting MS (RRMS). OBJECTIVE: In the current study, we aimed to determine if progressive disease is associated with spinal cord lesions in those with tumefactive multiple sclerosis (MS). METHODS: Retrospective chart review of individuals presenting to Mayo Clinic with tumefactive MS with spinal cord MRIs available (n=159). Clinical data were extracted by chart review. Brain and spinal cord MRIs were reviewed to characterize the tumefactive demyelinating lesion(s) and assess the burden of spinal cord disease. RESULTS: A total of 69 (43%) had spinal cord lesions. Progressive demyelinating disease was documented in 13 (8%); the majority (11/13) with secondary progressive disease. The method of progression was myelopathic in 8/13 (62%), cognitive in 3/13 (23%), motor from a supratentorial lesion in 2/13 (16%). EDSS at last follow-up was higher in those with progression than those without (median 6.0 (2.0-10.0) vs. 2.5 (0-10.0), p = < 0.001). Progressive demyelinating disease occurred in a minority. CONCLUSIONS: Patients with progression typically experienced progressive motor impairment, and this occurred exclusively in individuals with lesions in the corticospinal tracts of the brain and/or the spinal cord.
Asunto(s)
Esclerosis Múltiple , Enfermedades de la Médula Espinal , Humanos , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Tractos Piramidales/diagnóstico por imagen , Estudios Retrospectivos , Progresión de la Enfermedad , Médula Espinal/diagnóstico por imagen , Médula Espinal/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Imagen por Resonancia Magnética/métodos , Enfermedades de la Médula Espinal/diagnóstico por imagen , Enfermedades de la Médula Espinal/patologíaRESUMEN
OBJECTIVE: In this observational study on a cohort of biopsy-proven central nervous system demyelinating disease consistent with MS, we examined the relationship between early-active demyelinating lesion immunopattern (IP) with subsequent clinical course, radiographic progression, and cognitive function. METHODS: Seventy-five patients had at least one early-active lesion on biopsy and were pathologically classified into three immunopatterns based on published criteria. The median time from biopsy at follow-up was 11 years, median age at biopsy - 41, EDSS - 4.0. At last follow-up, the median age was 50, EDSS - 3.0. Clinical examination, cognitive assessment (CogState battery), and 3-Tesla-MRI (MPRAGE/FLAIR/T2/DIR/PSIR/DTI) were obtained. RESULTS: IP-I was identified in 14/75 (19%), IP-II was identified in 41/75 (56%), and IP-III was identified in 18/75 (25%) patients. Patients did not differ significantly by immunopattern in clinical measures at onset or last follow-up. The proportions of disease courses after a median of 11 years were similar across immunopatterns, relapsing-remitting being most common (63%), followed by monophasic (32%). No differences in volumetric or DTI measures were found. CogState performance was similar for most tasks. A slight yet statistically significant difference was identified for episodic memory scores, with IP-III patients recalling one word less on average. INTERPRETATION: In this study, immunopathological heterogeneity of early-active MS lesions identified at biopsy does not correlate with different long-term clinical, neuroimaging or cognitive outcomes. This could be explained by the fact that while active white matter lesions are pathological substrates for relapses, MS progression is driven by mechanisms converging across immunopatterns, regardless of pathogenic mechanisms driving the acute demyelinated plaque.
Asunto(s)
Esclerosis Múltiple , Humanos , Persona de Mediana Edad , Esclerosis Múltiple/diagnóstico , Imagen por Resonancia Magnética/métodos , Sistema Nervioso Central , CogniciónRESUMEN
BACKGROUND AND OBJECTIVES: Studies on tumefactive brain lesions in myelin oligodendrocyte glycoprotein-immunoglobulin G (IgG)-associated disease (MOGAD) are lacking. We sought to characterize the frequency clinical, laboratory, and MRI features of these lesions in MOGAD and compare them with those in multiple sclerosis (MS) and aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD). METHODS: We retrospectively searched 194 patients with MOGAD and 359 patients with AQP4+NMOSD with clinical/MRI details available from the Mayo Clinic databases and included those with ≥1 tumefactive brain lesion (maximum transverse diameter ≥2 cm) on MRI. Patients with tumefactive MS were identified using the Mayo Clinic medical record linkage system. Binary multivariable stepwise logistic regression identified independent predictors of MOGAD diagnosis; Cox proportional regression models were used to assess the risk of relapsing disease and gait aid in patients with tumefactive MOGAD vs those with nontumefactive MOGAD. RESULTS: We included 108 patients with tumefactive demyelination (MOGAD = 43; AQP4+NMOSD = 16; and MS = 49). Tumefactive lesions were more frequent among those with MOGAD (43/194 [22%]) than among those with AQP4+NMOSD (16/359 [5%], p < 0.001). Risk of relapse and need for gait aid were similar in tumefactive and nontumefactive MOGAD. Clinical features more frequent in MOGAD than in MS included headache (18/43 [42%] vs 10/49 [20%]; p = 0.03) and somnolence (12/43 [28%] vs 2/49 [4%]; p = 0.003), the latter also more frequent than in AQP4+NMOSD (0/16 [0%]; p = 0.02). The presence of peripheral T2-hypointense rim, T1-hypointensity, diffusion restriction (particularly an arc pattern), ring enhancement, and Baló-like or cystic appearance favored MS over MOGAD (p ≤ 0.001). MRI features were broadly similar in MOGAD and AQP4+NMOSD, except for more frequent diffusion restriction in AQP4+NMOSD (10/15 [67%]) than in MOGAD (11/42 [26%], p = 0.005). CSF analysis revealed less frequent positive oligoclonal bands in MOGAD (2/37 [5%]) than in MS (30/43 [70%], p < 0.001) and higher median white cell count in MOGAD than in MS (33 vs 6 cells/µL, p < 0.001). At baseline, independent predictors of MOGAD diagnosis were the presence of somnolence/headache, absence of T2-hypointense rim, lack of T1-hypointensity, and no diffusion restriction (Nagelkerke R 2 = 0.67). Tumefactive lesion resolution was more common in MOGAD than in MS or AQP4+NMOSD and improved model performance. DISCUSSION: Tumefactive lesions are frequent in MOGAD but not associated with a worse prognosis. The clinical, MRI, and CSF attributes of tumefactive MOGAD differ from those of tumefactive MS and are more similar to those of tumefactive AQP4+NMOSD with the exception of lesion resolution, which favors MOGAD.
Asunto(s)
Esclerosis Múltiple , Neuromielitis Óptica , Humanos , Neuromielitis Óptica/diagnóstico por imagen , Esclerosis Múltiple/diagnóstico por imagen , Inmunoglobulina G , Estudios Retrospectivos , Somnolencia , Acuaporina 4 , Glicoproteína Mielina-Oligodendrócito , Recurrencia , AutoanticuerposRESUMEN
Cerebral cortical encephalitis (CCE) is a recently described myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) phenotype. In this observational retrospective study, we characterized 19 CCE patients (6.7% of our MOGAD cohort). Headache (n = 15, 79%), seizures (n = 13, 68%), and encephalopathy (n = 12, 63%) were frequent. Magnetic resonance imaging revealed unilateral (n = 12, 63%) or bilateral (n = 7, 37%) cortical T2 hyperintensity and leptomeningeal enhancement (n = 17, 89%). N-Methyl-D-aspartate receptor autoantibodies coexisted in 2 of 15 tested (13%). CCE pathology (n = 2) showed extensive subpial cortical demyelination (n = 2), microglial reactivity (n = 2), and inflammatory infiltrates (perivascular, n = 1; meningeal, n = 1). Most received high-dose steroids (n = 17, 89%), and all improved, but 3 had CCE relapses. This study highlights the CCE spectrum and provides insight into its pathogenesis. ANN NEUROL 2023;93:297-302.
Asunto(s)
Encefalitis , Humanos , Glicoproteína Mielina-Oligodendrócito , Estudios Retrospectivos , Encefalitis/diagnóstico por imagen , Autoanticuerpos , Imagen por Resonancia MagnéticaRESUMEN
Multiple sclerosis (MS) is by far the most common central nervous system inflammatory demyelinating disease (CNS-IDD). It is diagnosed according to detailed criteria based on clinical definitions, magnetic resonance imaging (MRI) and cerebrospinal fluid findings. However, in rare instances, atypical syndromes associated with CNS demyelination, such as unusual MRI findings or poor response to standard treatment, may eventually necessitate a CNS biopsy with neuropathological examination. Pathology remains the gold standard in the differentiation of atypical CNS-IDDs, the recognition of which is essential for establishing the correct prognosis and optimal therapy. However, one must bear in mind that between different CNS-IDDs there are still overlapping features, even in the pathology. In this review, we compare and highlight contrasts within a spectrum of CNS-IDDs from the neuropathological perspective. We characterise pathological hallmarks of active vs chronic multiple sclerosis. Also, we define differences in the pathology of MS, acute disseminated encephalomyelitis (ADEM), aquaporin 4-IgG positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOsd), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Detailed description of the particular CNS-IDD pathology is crucial on an individual patient level (when clinically justified in atypical cases) but also from a broader perspective i.e. to advance our understanding of the complex disease mechanisms. Recent immunobiological and pathological discoveries have led to the description of novel inflammatory CNS disorders that were previously classified as rare MS variants, such as NMOsd and MOGAD. Multiple sclerosis remains an umbrella diagnosis, as there is profound heterogeneity between patients. Advances in neuropathology research are likely to disentangle and define further CNS-IDDs that used to be categorised as multiple sclerosis.
Asunto(s)
Enfermedades del Sistema Nervioso Central , Esclerosis Múltiple , Neuromielitis Óptica , Acuaporina 4 , Autoanticuerpos , Sistema Nervioso Central/diagnóstico por imagen , Sistema Nervioso Central/patología , Enfermedades del Sistema Nervioso Central/diagnóstico por imagen , Humanos , Inmunoglobulina G , Esclerosis Múltiple/diagnóstico por imagen , Neuromielitis Óptica/diagnóstico por imagen , Neuromielitis Óptica/patologíaRESUMEN
BACKGROUND: Haemorrhagic demyelinating lesions are rare, and little is known about the demyelinating diseases with which they are associated, or how lesional haemorrhage affects treatment and outcomes. OBJECTIVE: To examine the clinical characteristics and outcomes of patients with demyelinating lesions and magnetic resonance imaging (MRI) evidence of haemorrhage seen at the Mayo clinic between 1990 and 2018. METHODS: The Mayo Clinic's medical-record diagnostic-linkage system was used to identify patients with CNS demyelinating disease and parenchymal haemorrhage on brain MRI cross-referenced against a database of patients with pathologically confirmed CNS demyelinating disease. The clinical characteristics, diagnosis, MRI findings, brain histopathology, and outcomes of these patients were reviewed. RESULTS: Ten patients with haemorrhagic demyelination were identified, including three patients who underwent a brain biopsy. The main findings were that haemorrhagic demyelinating lesions most often occur in atypical forms of demyelination, especially acute haemorrhagic leukoencephalitis (AHL, or Weston-Hurst disease) and tumefactive demyelination, and rarely in multiple sclerosis. A spectrum of outcomes was observed for these patients ranging from complete remission through to high level disability. CONCLUSION: Lesional haemorrhage is uncommon in demyelinating disease where it is most closely associated with AHL. Bleeding within a demyelinating lesion does not always herald a poor prognosis.
Asunto(s)
Enfermedades Desmielinizantes , Esclerosis Múltiple , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Enfermedades Desmielinizantes/diagnóstico , Hemorragia , Humanos , Imagen por Resonancia Magnética/métodos , Esclerosis Múltiple/patologíaRESUMEN
Although major progress in multiple sclerosis research has been made during the last decades, key questions related to the cause and the mechanisms of brain and spinal cord pathology remain unresolved. These cover a broad range of topics, including disease aetiology, antigenic triggers of the immune response inside and/or outside the CNS and mechanisms of inflammation, demyelination neurodegeneration and tissue repair. Most of these questions can be addressed with novel molecular technologies in the injured CNS. Access to brain and spinal cord tissue from multiple sclerosis patients is, therefore, of critical importance. High-quality tissue is provided in part by the existing brain banks. However, material from early and highly active disease stages is limited. An initiative, realized under the patronage of the European Charcot Foundation, gathered together experts from different disciplines to analyse the current state of multiple sclerosis tissues collected post-mortem or as biopsies. Here, we present an account of what material is currently available and where it can be accessed. We also provide recommendations on how tissue donation from patients in early disease stages could be potentially increased and for procedures of tissue sampling and preservation. We also suggest to create a registry of the available tissues that, depending on the source (autopsy versus biopsy), could be made accessible to clinicians and researchers.
RESUMEN
Astrocytes utilize both glycolytic and mitochondrial pathways to power cellular processes that are vital to maintaining normal CNS functions. These cells also mount inflammatory and acute phase reactive programs in response to diverse stimuli. While the metabolic functions of astrocytes under homeostatic conditions are well-studied, the role of cellular bioenergetics in astrocyte reactivity is poorly understood. Teriflunomide exerts immunomodulatory effects in diseases such as multiple sclerosis by metabolically reprogramming lymphocytes and myeloid cells. We hypothesized that teriflunomide would constrain astrocytic inflammatory responses. Purified murine astrocytes were grown under serum-free conditions to prevent acquisition of a spontaneous reactive state. Stimulation with TNFα activated NFκB and increased secretion of Lcn2. TNFα stimulation increased basal respiration, maximal respiration, and ATP production in astrocytes, as assessed by oxygen consumption rate. TNFα also increased glycolytic reserve and glycolytic capacity of astrocytes but did not change the basal glycolytic rate, as assessed by measuring the extracellular acidification rate. TNFα specifically increased mitochondrial ATP production and secretion of Lcn2 required ATP generated by oxidative phosphorylation. Inhibition of dihydroorotate dehydrogenase via teriflunomide transiently increased both oxidative phosphorylation and glycolysis in quiescent astrocytes, but only the increased glycolytic ATP production was sustained over time, resulting in a bias away from mitochondrial ATP production even at doses down to 1 µM. Preconditioning with teriflunomide prevented the TNFα-induced skew toward oxidative phosphorylation, reduced mitochondrial ATP production, and reduced astrocytic inflammatory responses, suggesting that this drug may limit neuroinflammation by acting as a metabolomodulator.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Astrocitos/metabolismo , Crotonatos/farmacología , Hidroxibutiratos/farmacología , Inflamación/metabolismo , Nitrilos/farmacología , Toluidinas/farmacología , Factor de Necrosis Tumoral alfa/farmacología , Adenosina Trifosfato/metabolismo , Animales , Animales Recién Nacidos , Astrocitos/citología , Astrocitos/efectos de los fármacos , Células Cultivadas , Quimiocinas/metabolismo , Metabolismo Energético/efectos de los fármacos , Glucólisis/efectos de los fármacos , Lipocalina 2/metabolismo , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Oxidación-Reducción/efectos de los fármacos , Fosforilación Oxidativa/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The antigen specificity of Anti-Neuronal Nuclear Antibody-type 3 (ANNA3)-IgG is unknown. We identified Dachshund-homolog 1 (DACH1) as the ANNA3 autoantigen and confirmed it by antigen-specific assays, immunohistochemical colocalization and immune absorption experiments. Patients' median age was 63.5 years (range, 49-88); 67% were female. Neurological manifestations (information available for 30 patients) included one or more of neuropathy, 12; cognitive difficulties, 11; ataxia, 8; dysautonomia, 7. Evidence of a neoplasm was present in 27 of 30 (90%), most of neuroendocrine lineage. DACH1-IgG is rare and represents a novel proposed biomarker of neurological autoimmunity and cancer. ANN NEUROL 2022;91:670-675.
Asunto(s)
Autoinmunidad , Neoplasias , Animales , Autoantígenos , Biomarcadores , Perros , Femenino , Humanos , Inmunoglobulina G , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: To report the expanded neurological presentations and oncological associations of tripartite motif-containing protein 46 (TRIM46)-IgG seropositive patients. METHODS: Archived sera/cerebrospinal fluid (CSF) were evaluated by tissue-based immunofluorescence assay to identify patients with identical axon initial segment (AIS)-specific staining pattern. Phage immunoprecipitation sequencing (PhIP-Seq) was used to identify the putative autoantigen. RESULTS: IgG in serum (17) and/or CSF (16) from 25 patients yielded unique AIS-specific staining on murine central nervous system (CNS) tissue. An autoantibody specific for TRIM46 was identified by PhIP-Seq, and autoantigen specificity was confirmed by transfected COS7 cell-based assay. Clinical information was available for 22 TRIM46-IgG seropositive patients. Fifteen were female (68%). Median age was 67 years (range 25-87). Fifteen (68%) patients presented with subacute cerebellar syndrome (six isolated; nine with CNS accompaniments: encephalopathy (three), brainstem signs (two), myelopathy (two), parkinsonism (one)). Other phenotypes included limbic encephalitis (three), encephalopathy with/without seizures (two), myelopathy (two). Eighteen (82%) had cancer: neuroendocrine carcinomas (9; pancreatic (3), small-cell lung (4), oesophagus (1), endometrium (1)), adenocarcinomas (6; lung (2), ovarian (2), endometrial (1), breast (1)), sarcoma (2) and gastrointestinal tumour (1). Neurological symptoms in three followed immune checkpoint inhibitor (ICI) administration. CONCLUSIONS: This study supports TRIM46-IgG being a biomarker of paraneoplastic CNS disorders and expands the neurological phenotypes, oncological and ICI-related adverse event associations.
Asunto(s)
Autoanticuerpos/líquido cefalorraquídeo , Proteínas del Tejido Nervioso/líquido cefalorraquídeo , Síndromes Paraneoplásicos del Sistema Nervioso/líquido cefalorraquídeo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/líquido cefalorraquídeo , Femenino , Humanos , Encefalitis Límbica/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND AND PURPOSE: Tumefactive demyelination (TD) presents with large inflammatory lesions mimicking tumors or other space-occupying lesions. Limited epidemiological, clinical and radiological data exist for TD. We aimed to report the incidence rate, and clinical and radiological features of TD in Olmsted County, Minnesota. METHODS: We retrospectively reviewed patients with central nervous system inflammatory demyelination-related diagnostic codes (January 1, 1998 to December 31, 2018) in the Rochester Epidemiology Project database, and adjusted incidence rates by age and sex to the 2010 US total population. We used the Expanded Disability Status Scale (EDSS) to assess outcomes (index attack and last follow-up). RESULTS: Of 792 multiple sclerosis (MS) patients, 15 (eight males, seven females) had tumefactive MS, representing 1.9% of the MS population. The median (range) age at attack onset was 34.2 (2-61) years. Tumefactive lesion was the first clinical MS attack in 8/16 patients. Cerebrospinal fluid oligoclonal bands (OCBs) were present in 8/12 patients and 11/16 patients met the Barkhof criteria for dissemination in space. Most patients remained fully ambulatory (EDSS score ≤4 in 13/16 patients [81%]) after a median (range) follow-up duration of 10.5 (1-20.5) years. Age-adjusted annual incidence rates were 0.46/100,000 (95% confidence interval [CI] 0.12-0.81) for female patients, 0.66/100,000 (95% CI 0.23-1.02) for male patients, and 0.56/100,000 [95% CI 0.28-0.83] overall. When age- and sex-adjusted to the 2010 US total population, the overall annual incidence rate was 0.57 (95% CI 0.28-0.84). Despite aggressive clinical presentation at disease onset, most patients remained fully ambulatory (EDSS score ≤4 in 13/16 patients) with a relapsing-remitting course. CONCLUSIONS: Although incidence is rare, TD should be suspected in patients presenting with subacutely progressive neurological deficits associated with magnetic resonance imaging findings of ring enhancement, apparent diffusion coefficient restriction, and OCB on spinal fluid analysis.