108 research outputs found
Aquaporin-4 prevents exaggerated astrocytosis and structural damage in retinal inflammation
No full textABSTRACT: Aquaporin-4 (AQP4) is the molecular target of the immune response in neuromyelitis optica (NMO) that leads to severe structural damage in the central nervous system (CNS) and in the retina. Conversely, AQP4 might be upregulated in astrocytes as a compensatory event in multiple sclerosis. Thus, the functional relevance of AQP4 in neuroinflammation needs to be defined. Here, we tested the role of AQP4 in the retina in MOG(35–55)-induced experimental autoimmune encephalomyelitis (EAE) using optical coherence tomography (OCT), OCT angiography, immunohistology, flow cytometry, and gene expression analysis in wild-type and Aqp4(–/–) mice. No direct infiltrates of inflammatory cells were detected in the retina. Yet, early retinal expression of TNF and Iba1 suggested that the retina participated in the inflammatory response during EAE in a similar way in wild-type and Aqp4(–/–) mice. While wild-type mice rapidly cleared retinal swelling, Aqp4(–/–) animals exhibited a sustainedly increased retinal thickness associated with retinal hyperperfusion, albumin extravasation, and upregulation of GFAP as a hallmark of retinal scarring at later stages of EAE. Eventually, the loss of retinal ganglion cells was higher in Aqp4(–/–) mice than in wild-type mice. Therefore, AQP4 expression might be critical for retinal Müller cells to clear the interstitial space from excess vasogenic edema and prevent maladaptive scarring in the retina during remote inflammatory processes of the CNS. KEY MESSAGES: Genetic ablation of AQP4 leads to a functional derangement of the retinal gliovascular unit with retinal hyperperfusion during autoimmune CNS inflammation. Genetic ablation of AQP4 results in a structural impairment of the blood retina barrier with extravasation of albumin during autoimmune CNS inflammation. Eventually, the lack of AQP4 in the retina during an inflammatory event prompts the exaggerated upregulation of GFAP as a hallmark of scarring as well as loss of retinal ganglion cells. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00109-022-02202-6
Retinal small vessel pathology is associated with disease burden in multiple sclerosis
No full textAlterations of the superficial retinal vasculature are commonly observed in multiple sclerosis (MS) and can be visualized through optical coherence tomography angiography (OCTA)
Supplemental material for Retinal inner nuclear layer volume reflects inflammatory disease activity in multiple sclerosis; a longitudinal OCT study
No full textSupplemental Material for Retinal inner nuclear layer volume reflects inflammatory disease activity in multiple sclerosis; a longitudinal OCT study by Lisanne J Balk, Danko Coric Benjamin Knier Hanna G Zimmermann Raed Behbehani Raed Alroughani Elena H Martinez-Lapiscina Alexander U Brandt Bernardo Sánchez-Dalmau Angela Vidal-Jordana Philipp Albrecht, Valeria Koska, Joachim Havla Marco Pisa Rachel C Nolan Letizia LeocaniFriedemann Paul, Orhan Xavier Montalban Aktas , Laura J Balcer Pablo Villoslada Olivier OutteryckThomas Korn, Axel Petzold and on behalf of the IMSVISUAL consortium in Multiple Sclerosis Journal – Experimental, Translational and Clinical</p
Optical coherence tomography angiography suggests different retinal pathologies in multiple sclerosis and Sjögren’s syndrome
No full textBackground While retinal vessel changes are evident in the eyes of patients with relapsing–remitting multiple sclerosis (RRMS), changes in the vasculature of possible MS mimics such as primary Sjögren’s syndrome (pSS) remain to be determined. We investigated the potential of retinal optical coherence tomography (OCT) angiography (OCTA) as diagnostic tool to differentiate between patients with RRMS and pSS. Methods This cross-sectional study included patients with RRMS ( n = 36), pSS ( n = 36) and healthy controls ( n = 30). Participants underwent clinical examination, assessment of visual acuity, retinal OCT, OCTA, and serum markers of glial and neuronal damage. We investigated the associations between OCTA parameters, visual functions, and serum markers. Eyes with a history of optic neuritis (ON) were excluded from analysis. Results We observed a significant thinning of the combined ganglion cell and inner plexiform layer in the eyes of patients with RRMS but not with pSS, when compared to healthy controls. Retinal vessel densities of the superficial vascular complex (SVC) were reduced in both patients with RRMS and pSS. However, retinal vessel rarefication of the deep vascular complex (DVC) was only evident in patients with pSS but not RRMS. Using multivariate regression analysis, we found that DVC vessel loss in pSS patients was associated with worse visual acuity. Conclusions Compared to patients with RRMS, rarefication of deep retinal vessels is a unique characteristic of pSS and associated with worse visual function. Assuming a disease-specific retinal vessel pathology, these data are indicative of a differential affliction of the gliovascular complex in the retina of RRMS and pSS patients.Open Access funding enabled and organized by Projekt DEAL.Deutsche Forschungsgemeinschafthttp://dx.doi.org/10.13039/501100001659Faculty of Medicine, Munich University of Technologyhttp://dx.doi.org/10.13039/501100009394Gemeinnützige Hertie-Stiftunghttp://dx.doi.org/10.13039/501100003493H2020 European Research Councilhttp://dx.doi.org/10.13039/100010663Bundesministerium für Bildung und Forschunghttp://dx.doi.org/10.13039/501100002347Else Kröner-Fresenius-Stiftunghttp://dx.doi.org/10.13039/501100003042Technische Universität München (1025
Optical coherence tomography angiography indicates subclinical retinal disease in neuromyelitis optica spectrum disorders
No full textBackground: Neuromyelitis optica spectrum disorders (NMOSD) are neuroinflammatory diseases of the central nervous system. Patients suffer from recurring relapses and it is unclear whether relapse-independent disease activity occurs and whether this is of clinical relevance. Objective: To detect disease-specific alterations of the retinal vasculature that reflect disease activity during NMOSD. Methods: Cross-sectional analysis of 16 patients with NMOSD, 21 patients with relapsing-remitting multiple sclerosis, and 21 healthy controls using retinal optical coherence tomography (OCT), optical coherence tomography angiography (OCT-A), measurement of glial fibrillary acidic protein (GFAP) serum levels, and assessment of visual acuity. Results: Patients with NMOSD but not multiple sclerosis revealed lower foveal thickness (FT) (p = 0.02) measures and an increase of the foveal avascular zone (FAZ) (p = 0.02) compared to healthy controls independent to optic neuritis. Reduced FT (p = 0.01), enlarged FAZ areas (p = 0.0001), and vessel loss of the superficial vascular complex (p = 0.01) were linked to higher serum GFAP levels and superficial vessel loss was associated with worse visual performance in patients with NMOSD irrespective of optic neuritis. Conclusion: Subclinical parafoveal retinal vessel loss might occur during NMOSD and might be linked to astrocyte damage and poor visual performance. OCT-A may be a tool to study subclinical disease activity during NMOSD
Dynamics of Retinal Vessel Loss After Acute Optic Neuritis in Patients With Relapsing Multiple Sclerosis
No full textBackground and Objectives Rarefication of the retinal vasculature as measured by optical coherence tomography angiography (OCT-A) is a novel finding in patients with multiple sclerosis (MS). This study aimed to analyze longitudinal dynamics of the retinal vasculature following an acute inflammatory relapse including acute optic neuritis (ON) and to search for associations with alterations of the retinal architecture and visual function. Methods This prospective longitudinal cohort study included patients with relapsing-remitting MS or clinically isolated syndrome having an acute ON (n = 20) or a non-ON relapse (n = 33). Patients underwent examinations at baseline and after 7, 14, 28, 90, and 180 days with OCT, OCT-A, and assessment of the high- (HCVA) and low-contrast visual acuity (LCVA). Results Retinal vessel loss of the superficial vascular complex (SVC) evolves early after ON and reaches a plateau between 90 and 180 days (relative vessel loss 15% +/- 8% [mean +/- SD]). In addition, an 18% +/- 18% intraindividual increase of the foveal avascular zone (FAZ) is evident within 180 days after acute ON. Both SVC thinning and FAZ enlargement were associated with worse HCVA and LCVA. Rarefication of the SVC evolved simultaneously to thinning of the common ganglion cell and inner plexiform layer (GCIP) after ON. No alterations of the deep vascular complex were seen in eyes with ON, and no alterations of the retinal vasculature were recognized in patients having acute non-ON relapses. Discussion Rarefication of the SVC and growing of the FAZ evolve rapidly after ON and are linked to persistent visual disability. ON-related SVC thinning might be closely linked to GCIP atrophy and might occur due to an altered local metabolic activity within inner retinal layers
Formation and immunomodulatory function of meningeal B-cell aggregates in progressive CNS autoimmunity
No full textMeningeal B lymphocyte aggregates have been described in autopsy material of patients with chronic Multiple Sclerosis. The presence of meningeal B cell aggregates has been correlated with worse disease. However, the functional role of these meningeal B cell aggregates is not understood. Here, we use a mouse model of Multiple Sclerosis, the spontaneous opticospinal encephalomyelitis model, which is built on the double transgenic expression of myelin oligodendrocyte glycoprotein-specific T cell- and B cell-receptors, to show that the formation of meningeal B cell aggregates is dependent on the expression of α4 integrins by antigen-specific T cells. T cell-conditional genetic ablation of α4 integrins in opticospinal encephalomyelitis mice impaired the formation of meningeal B cell aggregates, and surprisingly, led to a higher disease incidence as compared to opticospinal encephalomyelitis mice with α4 integrin-sufficient T cells. B cell-conditional ablation of α4 integrins in opticospinal encephalomyelitis mice resulted in the entire abrogation of the formation of meningeal B cell aggregates, and opticospinal encephalomyelitis mice with α4 integrin-deficient B cells suffered from a higher disease burden than regular opticospinal encephalomyelitis mice. While anti-CD20 antibody-mediated systemic depletion of B cells in opticospinal encephalomyelitis mice after onset of disease failed to efficiently decrease meningeal B cell aggregates without significantly modulating disease progression, treatment with anti-CD19 chimeric antigen receptor-T cells eliminated meningeal B cell aggregates and exacerbated clinical disease in opticospinal encephalomyelitis mice. Since about 20 percent of B cells in organised meningeal B cell aggregates produced either IL-10 or IL-35, we propose that meningeal B cell aggregates might also have an immunoregulatory function as to the immunopathology in adjacent spinal cord white matter. The immunoregulatory function of meningeal B cell aggregates needs to be considered when designing highly efficient therapies directed against meningeal B cell aggregates for clinical application in Multiple Sclerosis
The Campfire as Pentecostal Vision in Hemingway\u27s Works
No full textErnest Hemingway\u27s main concern in representing human life through fictional forms, has consistently been to see man against the background of his world and universe, to examine the human situation from various points of view. The author\u27s prime goal is to depict the education of his hero. Within the text and the time of a given story Hemingway allows his hero to either accept or to reject the proper attitude in life. That portrayal of the acceptance or rejection enunciates another portion of the Hemingway code
The glioblastoma multiforme tumor site promotes the commitment of tumor-infiltrating lymphocytes to the T(H)17 lineage in humans
No full textAlthough glioblastoma multiforme (GBM) is not an invariably cold tumor, checkpoint inhibition has largely failed in GBM. In order to investigate T cell–intrinsic properties that contribute to the resistance of GBM to endogenous or therapeutically enhanced adaptive immune responses, we sorted CD4(+) and CD8(+) T cells from the peripheral blood, normal-appearing brain tissue, and tumor bed of nine treatment-naive patients with GBM. Bulk RNA sequencing of highly pure T cell populations from these different compartments was used to obtain deep transcriptomes of tumor-infiltrating T cells (TILs). While the transcriptome of CD8(+) TILs suggested that they were partly locked in a dysfunctional state, CD4(+) TILs showed a robust commitment to the type 17 T helper cell (T(H)17) lineage, which was corroborated by flow cytometry in four additional GBM cases. Therefore, our study illustrates that the brain tumor environment in GBM might instruct T(H)17 commitment of infiltrating T helper cells. Whether these properties of CD4(+) TILs facilitate a tumor-promoting milieu and thus could be a target for adjuvant anti-T(H)17 cell interventions needs to be further investigated
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