Regulation of microglial TMEM119 and P2RY12 immunoreactivity in multiple sclerosis white and grey matter lesions is dependent on their inflammatory environment

AbstractMultiple Sclerosis (MS) is the most common cause of acquired neurological disability in young adults, pathologically characterized by leukocyte infiltration of the central nervous system, demyelination of the white and grey matter, and subsequent axonal loss. Microglia are proposed to play a role in MS lesion formation, however previous literature has not been able to distinguish infiltrated macrophages from microglia. Therefore, in this study we utilize the microglia-specific, homeostatic markers TMEM119 and P2RY12 to characterize their immunoreactivity in MS grey matter lesions in comparison to white matter lesions. Furthermore, we assessed the immunological status of the white and grey matter lesions, as well as the responsivity of human white and grey matter derived microglia to inflammatory mediators. We are the first to show that white and grey matter lesions in post-mortem human material differ in their immunoreactivity for the homeostatic microglia-specific markers TMEM119 and P2RY12. In particular, whereas immunoreactivity for TMEM119 and P2RY12 is decreased in the center of WMLs, immunoreactivity for both markers is not altered in GMLs. Based on data from post-mortem human microglia cultures, treated with IL-4 or IFNγ+LPS and on counts of CD3+ or CD20+ lymphocytes in lesions, we show that downregulation of TMEM119 and P2RY12 immunoreactivity in MS lesions corresponds with the presence of lymphocytes and lymphocyte-derived cytokines within the parenchyma but not in the meninges. Furthermore, the presence of TMEM119+ and partly P2RY12+ microglia in pre-active lesions as well as in the rim of active white and grey matter lesions, in addition to TMEM119+ and P2RY12+ rod-like microglia in subpial grey matter lesions suggest that blocking the entrance of lymphocytes into the CNS of MS patients may not interfere with all possible effects of TMEM119+ and P2RY12+ microglia in both white and grey matter MS lesions.

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Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

Science ◽

10.1126/science.aav7188 ◽

2019 ◽

Vol 365 (6460) ◽

pp. eaav7188 ◽

Cited By ~ 122

Author(s):

Keyword(s):

Multiple Sclerosis ◽

Immune Cells ◽

Expression Profiles ◽

Human Microglia ◽

Histocompatibility Complex ◽

The Central Nervous System ◽

Reference Map ◽

Peripheral Immune Cells ◽

Genomic Map ◽

Cellular Components

We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeting an autoimmune process to the central nervous system, although MS is most likely initially triggered by perturbation of peripheral immune responses.

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Modeling Resilience to Damage in Multiple Sclerosis: Plasticity Meets Connectivity

International Journal of Molecular Sciences ◽

10.3390/ijms21010143 ◽

2019 ◽

Vol 21 (1) ◽

pp. 143 ◽

Cited By ~ 1

Author(s):

Mario Stampanoni Bassi ◽

Ennio Iezzi ◽

Luigi Pavone ◽

Georgia Mandolesi ◽

Alessandra Musella ◽

...

Keyword(s):

Multiple Sclerosis ◽

Synaptic Plasticity ◽

Network Architecture ◽

White Matter Lesions ◽

Long Term Potentiation ◽

Chronic Inflammatory Disease ◽

Brain Network ◽

Term Potentiation ◽

The Central Nervous System ◽

Efficient Information

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelinating white matter lesions and neurodegeneration, with a variable clinical course. Brain network architecture provides efficient information processing and resilience to damage. The peculiar organization characterized by a low number of highly connected nodes (hubs) confers high resistance to random damage. Anti-homeostatic synaptic plasticity, in particular long-term potentiation (LTP), represents one of the main physiological mechanisms underlying clinical recovery after brain damage. Different types of synaptic plasticity, including both anti-homeostatic and homeostatic mechanisms (synaptic scaling), contribute to shape brain networks. In MS, altered synaptic functioning induced by inflammatory mediators may represent a further cause of brain network collapse in addition to demyelination and grey matter atrophy. We propose that impaired LTP expression and pathologically enhanced upscaling may contribute to disrupting brain network topology in MS, weakening resilience to damage and negatively influencing the disease course.

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D313Y mutation in the differential diagnosis of white matter lesions: Experiences from a multiple sclerosis outpatient clinic

Multiple Sclerosis Journal ◽

10.1177/1352458516638747 ◽

2016 ◽

Vol 22 (11) ◽

pp. 1502-1505 ◽

Cited By ~ 5

Author(s):

Jana Becker ◽

Arndt Rolfs ◽

Nesrin Karabul ◽

Peter Berlit ◽

Markus Kraemer

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Neurological Disorders ◽

Lysosomal Storage Disorder ◽

White Matter Lesions ◽

Clinical Impact ◽

Lysosomal Storage ◽

Younger Patients ◽

Neural Damage ◽

The Central Nervous System

White matter lesions (WML) in younger patients might be due to a variety of neurological disorders. Fabry disease (FD), an x-linked inherited lysosomal storage disorder, happens to be misdiagnosed as multiple sclerosis (MS). In two middle-aged female patients, presenting bilateral WML, diagnosis of MS turned out to be doubtful. Human genetic analysis presented the Fabry mutation D313Y, in which clinical impact is still unclear. Disease manifestations outside the central nervous system were not detected. Our findings support the suspicion that Fabry mutation D313Y may be involved in neural damage resulting in WML.

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Age related susceptibility to grey matter demyelination and neurodegeneration is associated with meningeal neutrophil accumulation in an animal model of Multiple Sclerosis

10.1101/2021.12.23.474008 ◽

2021 ◽

Author(s):

Michelle Zuo ◽

Naomi Fettig ◽

Louis-Philippe Bernier ◽

Elisabeth Possnecker ◽

Shoshana Spring ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Th17 Cells ◽

Grey Matter ◽

Clinical Symptoms ◽

White Matter Lesions ◽

Neutrophil Accumulation ◽

Cns Inflammation ◽

Age Related ◽

Meningeal Inflammation

People living with multiple sclerosis (MS) experience episodic central nervous system (CNS) white matter lesions instigated by autoreactive T cells. With age, MS patients show evidence of grey matter demyelination and experience devastating non-remitting symptomology. What drives progression is unclear and has been hampered by the lack of suitable animal models. Here we show that passive experimental autoimmune encephalomyelitis (EAE) induced by an adoptive transfer of young Th17 cells induces a non-remitting clinical phenotype that is associated with persistent meningeal inflammation and cortical pathology in old, but not young SJL/J mice. While the quantity and quality of T cells did not differ in the brains of old vs young EAE mice, an increase in neutrophils and a decrease in B cells was observed in the brains of old mice. Neutrophils were also found in the meninges of a subset of progressive MS patient brains that showed evidence of meningeal inflammation and subpial cortical demyelination. Taken together, our data show that while Th17 cells initiate CNS inflammation, subsequent clinical symptoms and grey matter pathology are dictated by age and associated with other immune cells such as neutrophils.

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VITAMIN B12 AND NORMAL PRIONS: TWO FIELDS APPARENTLY SO FAR, BUT IN REALITY SO NEAR

Istituto Lombardo - Accademia di Scienze e Lettere - Rendiconti di Scienze ◽

10.4081/scie.2014.192 ◽

2014 ◽

Author(s):

Giuseppe Scalabrino ◽

Daniela Veber

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Nervous System ◽

Tumour Necrosis Factor ◽

Tumour Necrosis ◽

Post Mortem ◽

The Central Nervous System ◽

Epidermal Growth ◽

And Control ◽

Necrosis Factor

Cobalamin (Cbl) deficiency causes an imbalance in some cytokines and growth factors in the central nervous system and peripheral nervous system of the rat, and in the serum and cerebrospinal fluid (CSF) of adult Cbl-deficient (Cbl-D) patients. We hypothesized that an imbalance in normal prion (PrPC) levels and/or synthesis might be involved in the pathogenesis of Cbl-D neuropathy. Using different appropriate enzyme-linked immunosorbent assays (ELISAs), we determined the levels of Cbl, tumour necrosis factor-a, epidermal growth factor, and PrPC in spinal cord (SC) and CSF of Cbl-D rats treated or not with different molecules; in serum, CSF from Cbl-D or multiple sclerosis (MS) patients; and in post-mortem SC samples taken from MS patients and control patients. We have demonstrated that: (i) Cbl deficiency induces excess PrPC regions (particularly octapeptide repeated (OR) region) in rat SC; (ii) the SC increase is mediated by a local Cbl deficiency-induced excess of tumour necrosis factor- a; and (iii) CSF and serum PrPC concentrations in Cbl-D patients are significantly higher than in controls. CSF PrPC concentrations are significantly lower in MS patients than neurological controls. The Cbl, EGF, and PrPC levels were significantly decreased in post-mortem MS SCs in comparison with controls

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Gray matter atrophy in relapsing-remitting multiple sclerosis is associated with white matter lesions in connecting fibers

Multiple Sclerosis Journal ◽

10.1177/13524585211044957 ◽

2021 ◽

pp. 135245852110449

Author(s):

Matthias Bussas ◽

Sophia Grahl ◽

Viola Pongratz ◽

Achim Berthele ◽

Christiane Gasperi ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Gray Matter ◽

White Matter Lesions ◽

Lesion Formation ◽

Brain White Matter ◽

Human Connectome Project ◽

Relapsing Remitting ◽

Healthy Control ◽

Relapsing Remitting Multiple Sclerosis

Background: Lesions of brain white matter (WM) and atrophy of brain gray matter (GM) are well-established surrogate parameters in multiple sclerosis (MS), but it is unclear how closely these parameters relate to each other. Objective: To assess across the whole cerebrum whether GM atrophy can be explained by lesions in connecting WM tracts. Methods: GM images of 600 patients with relapsing-remitting MS (women = 68%; median age = 33.0 years, median expanded disability status scale score = 1.5) were converted to atrophy maps by data from a healthy control cohort. An atlas of WM tracts from the Human Connectome Project and individual lesion maps were merged to identify potentially disconnected GM regions, leading to individual disconnectome maps. Across the whole cerebrum, GM atrophy and potentially disconnected GM were tested for association both cross-sectionally and longitudinally. Results: We found highly significant correlations between disconnection and atrophy across most of the cerebrum. Longitudinal analysis demonstrated a close temporal relation of WM lesion formation and GM atrophy in connecting fibers. Conclusion: GM atrophy is associated with WM lesions in connecting fibers. Caution is warranted when interpreting group differences in GM atrophy exclusively as differences in early neurodegeneration independent of WM lesion formation.

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Comparison of myelin water fraction values in periventricular white matter lesions between multiple sclerosis and neuromyelitis optica spectrum disorder

Multiple Sclerosis Journal ◽

10.1177/1352458516636247 ◽

2016 ◽

Vol 22 (12) ◽

pp. 1616-1620 ◽

Cited By ~ 12

Author(s):

In Hye Jeong ◽

Joon Yul Choi ◽

Su-Hyun Kim ◽

Jae-Won Hyun ◽

AeRan Joung ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Neuromyelitis Optica ◽

White Matter Lesions ◽

Spectrum Disorder ◽

Periventricular White Matter ◽

Neuromyelitis Optica Spectrum Disorder ◽

Water Fraction ◽

Myelin Water Fraction ◽

The Central Nervous System

Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are inflammatory autoimmune diseases of the central nervous system. We hypothesized that the degree of demyelination within lesions in MS and NMOSD would differ as the pathophysiology of the two diseases do. We used myelin water imaging to compare the myelin water fraction (MWF) in 106 periventricular white matter (PVWM) lesions in 27 MS patients and 51 PVWM lesions in 20 NMOSD patients. The MWF was significantly reduced in the MS compared with the NMOSD lesions, suggesting that myelin loss was more severe in MS than in NMOSD.

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Contrasting the brain imaging features of MOG-antibody disease, with AQP4-antibody NMOSD and multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/13524585211018987 ◽

2021 ◽

pp. 135245852110189

Author(s):

Silvia Messina ◽

Romina Mariano ◽

Adriana Roca-Fernandez ◽

Ana Cavey ◽

Maciej Jurynczyk ◽

...

Keyword(s):

Multiple Sclerosis ◽

Grey Matter ◽

Diffusion Imaging ◽

White Matter Lesions ◽

Lesion Volume ◽

Imaging Features ◽

Strongly Correlated ◽

Deep Grey Matter ◽

Magnetic Resonance Imaging Mri ◽

Aqp4 Antibody

Background: Identifying magnetic resonance imaging (MRI) markers in myelin-oligodendrocytes-glycoprotein antibody-associated disease (MOGAD), neuromyelitis optica spectrum disorder-aquaporin-4 positive (NMOSD-AQP4) and multiple sclerosis (MS) is essential for establishing objective outcome measures. Objectives: To quantify imaging patterns of central nervous system (CNS) damage in MOGAD during the remission stage, and to compare it with NMOSD-AQP4 and MS. Methods: 20 MOGAD, 19 NMOSD-AQP4, 18 MS in remission with brain or spinal cord involvement and 18 healthy controls (HC) were recruited. Volumetrics, lesions and cortical lesions, diffusion-imaging measures, were analysed. Results: Deep grey matter volumes were lower in MOGAD ( p = 0.02) and MS ( p = 0.0001), compared to HC and were strongly correlated with current lesion volume (MOGAD R = −0.93, p < 0.001, MS R = −0.65, p = 0.0034). Cortical/juxtacortical lesions were seen in a minority of MOGAD, in a majority of MS and in none of NMOSD-AQP4. Non-lesional tissue fractional anisotropy (FA) was only reduced in MS ( p = 0.01), although focal reductions were noted in NMOSD-AQP4, reflecting mainly optic nerve and corticospinal tract pathways. Conclusion: MOGAD patients are left with grey matter damage, and this may be related to persistent white matter lesions. NMOSD-AQP4 patients showed a relative sparing of deep grey matter volumes, but reduced non-lesional tissue FA. Observations from our study can be used to identify new markers of damage for future multicentre studies.

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Myelin Quantification in White Matter Pathology of Progressive Multiple Sclerosis Post-Mortem Brain Samples: A New Approach for Quantifying Remyelination

International Journal of Molecular Sciences ◽

10.3390/ijms222312634 ◽

2021 ◽

Vol 22 (23) ◽

pp. 12634

Author(s):

Marije J. D. Huitema ◽

Eva M. M. Strijbis ◽

Antonio Luchicchi ◽

John G. J. M. Bol ◽

Jason R. Plemel ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

High Reliability ◽

Progressive Multiple Sclerosis ◽

Measurement Tool ◽

Post Mortem ◽

New Approach ◽

Tissue Sections ◽

Post Mortem Brain ◽

The Central Nervous System

Multiple sclerosis (MS) is a demyelinating and neurodegenerative disease of the central nervous system (CNS). Repair through remyelination can be extensive, but quantification of remyelination remains challenging. To date, no method for standardized digital quantification of remyelination of MS lesions exists. This methodological study aims to present and validate a novel standardized method for myelin quantification in progressive MS brains to study myelin content more precisely. Fifty-five MS lesions in 32 tissue blocks from 14 progressive MS cases and five tissue blocks from 5 non-neurological controls were sampled. MS lesions were selected by macroscopic investigation of WM by standard histopathological methods. Tissue sections were stained for myelin with luxol fast blue (LFB) and histological assessment of de- or remyelination was performed by light microscopy. The myelin quantity was estimated with a novel myelin quantification method (MQM) in ImageJ. Three independent raters applied the MQM and the inter-rater reliability was calculated. We extended the method to diffusely appearing white matter (DAWM) and encephalitis to test potential wider applicability of the method. Inter-rater agreement was excellent (ICC = 0.96) and there was a high reliability with a lower- and upper limit of agreement up to −5.93% to 18.43% variation in myelin quantity. This study builds on the established concepts of histopathological semi-quantitative assessment of myelin and adds a novel, reliable and accurate quantitative measurement tool for the assessment of myelination in human post-mortem samples.

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Metabolites predict lesion formation and severity in relapsing-remitting multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458517702534 ◽

2017 ◽

Vol 24 (4) ◽

pp. 491-500 ◽

Cited By ~ 9

Author(s):

Antoine M Klauser ◽

Oliver T Wiebenga ◽

Anand JC Eijlers ◽

Menno M Schoonheim ◽

Bernard MJ Uitdehaag ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Magnetic Resonance ◽

Diffusion Tensor ◽

White Matter Lesions ◽

Radial Diffusivity ◽

Lesion Formation ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis

Background: Multiple sclerosis is characterized by white matter lesions, which are visualized with conventional T2-weighted magnetic resonance imaging (MRI). Little is known about local metabolic processes preceding the appearance and during the pathological development of new lesions. Objective: To identify metabolite changes preceding white matter (WM) lesions and pathological severity of lesions over time. Methods: A total of 59 relapsing-remitting multiple sclerosis (MS) patients were scanned four times, with 6-month intervals. Imaging included short-TE magnetic resonance spectroscopic imaging (MRSI) and diffusion tensor imaging (DTI). Results: A total of 16 new lesions appeared within the MRSI slab in 12 patients. Glutamate increased (+1.0 mM (+19%), p = 0.039) 12 and 6 months before new lesions appeared. In these areas, the increase in creatine and choline 6 months before until lesion appearance was negatively correlated with radial diffusivity (ρ = −0.73, p = 0.002 and ρ = −0.72, p = 0.002). Increase in creatine also correlated with the increase of axial diffusivity in the same period (ρ = −0.53, p = 0.034). When splitting the lesions into “mild” and “severe” based on radial diffusivity, only mild lesions showed an increase in creatine and choline during lesion formation ( p = 0.039 and p = 0.008, respectively). Conclusion: Increased glutamate heralded the appearance of new T2-visible WM lesions. In pathologically “mild” lesions, an increase in creatine and choline was found during lesion formation.

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