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Article ; Online: Myelinodegeneration vs. Neurodegeneration in MS Progressive Forms

Serge Nataf

International Journal of Molecular Sciences, Vol 24, Iss 1596, p

2023 Volume 1596

Abstract: In MS patients with a progressive form of the disease, the slow deterioration of neurological functions is thought to result from a combination of neuronal cell death, axonal damages and synaptic dysfunctions [.] ...

Abstract	In MS patients with a progressive form of the disease, the slow deterioration of neurological functions is thought to result from a combination of neuronal cell death, axonal damages and synaptic dysfunctions [.]
Keywords	n/a ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Demonstration of an Aqp4/Tgf-Beta 1 Pathway in Murine Astrocytes Holds Implications for Both Neuromyelitis Optica and Progressive Multiple Sclerosis

Serge Nataf

International Journal of Molecular Sciences, Vol 21, Iss 3, p

2020 Volume 1035

Abstract: The role exerted by Aquaporin 4 (AQP4) as a regulator of astrocyte immune functions has been poorly explored. A recent report demonstrates that under neuroinflammatory conditions, the expression of Aqp4 on murine astrocytes is mandatory for the effective ...

Abstract	The role exerted by Aquaporin 4 (AQP4) as a regulator of astrocyte immune functions has been poorly explored. A recent report demonstrates that under neuroinflammatory conditions, the expression of Aqp4 on murine astrocytes is mandatory for the effective control of acute inflammation in the central nervous system. Such an immunomodulatory function appears to be mediated by a promotion of the transforming growth factor beta 1 (Tgfb1) pathway. Here, these results are discussed in the context of neuromyelitis optica (NMO) and multiple sclerosis (MS) progressive forms. It is proposed that NMO and progressive MS might rely on opposite molecular mechanisms involving, in NMO, an acutely-defective AQP4/TGFB1 pathway and, in progressive MS, a chronically-stimulated AQP4/TGFB1 pathway. Data supporting the involvement of angiotensin II as a molecular link between AQP4 and TGFB1 are also reviewed.
Keywords	aquaporin-4 ; tgf-beta 1 ; neuromyelitis optica: multiple sclerosis ; angiotensin ii ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2020-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Cord–Age–Gender Connections Shape the Pathophysiology of Multiple Sclerosis Progressive Forms

Serge Nataf

International Journal of Molecular Sciences, Vol 20, Iss 20, p

2019 Volume 5103

Abstract: There is increasing evidence that sex hormones, aging, and the occurrence of spinal cord (SC) tissue alterations exert combined effects on the development and outcome of multiple sclerosis (MS) progressive forms [.] ...

Abstract	There is increasing evidence that sex hormones, aging, and the occurrence of spinal cord (SC) tissue alterations exert combined effects on the development and outcome of multiple sclerosis (MS) progressive forms [.]
Keywords	n/a ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2019-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Evolution, immunity and the emergence of brain superautoantigens [version 1; referees

Serge Nataf

F1000Research, Vol

2 approved]

2017 Volume 6

Abstract: While some autoimmune disorders remain extremely rare, others largely predominate the epidemiology of human autoimmunity. Notably, these include psoriasis, diabetes, vitiligo, thyroiditis, rheumatoid arthritis and multiple sclerosis. Thus, despite the ... ...

Abstract	While some autoimmune disorders remain extremely rare, others largely predominate the epidemiology of human autoimmunity. Notably, these include psoriasis, diabetes, vitiligo, thyroiditis, rheumatoid arthritis and multiple sclerosis. Thus, despite the quasi-infinite number of "self" antigens that could theoretically trigger autoimmune responses, only a limited set of antigens, referred here as superautoantigens, induce pathogenic adaptive responses. Several lines of evidence reviewed in this paper indicate that, irrespective of the targeted organ (e.g. thyroid, pancreas, joints, brain or skin), a significant proportion of superautoantigens are highly expressed in the synaptic compartment of the central nervous system (CNS). Such an observation applies notably for GAD65, AchR, ribonucleoproteins, heat shock proteins, collagen IV, laminin, tyrosine hydroxylase and the acetylcholinesterase domain of thyroglobulin. It is also argued that cognitive alterations have been described in a number of autoimmune disorders, including psoriasis, rheumatoid arthritis, lupus, Crohn's disease and autoimmune thyroiditis. Finally, the present paper points out that a great majority of the "incidental" autoimmune conditions notably triggered by neoplasms, vaccinations or microbial infections are targeting the synaptic or myelin compartments. On this basis, the concept of an immunological homunculus, proposed by Irun Cohen more than 25 years ago, is extended here in a model where physiological autoimmunity against brain superautoantigens confers both: i) a crucial evolutionary-determined advantage via cognition-promoting autoimmunity; and ii) a major evolutionary-determined vulnerability, leading to the emergence of autoimmune disorders in Homo sapiens. Moreover, in this theoretical framework, the so called co-development/co-evolution model, both the development (at the scale of an individual) and evolution (at the scale of species) of the antibody and T-cell repertoires are coupled to those of the neural repertoires (i.e. the ...
Keywords	Autoimmunity ; Medicine ; R ; Science ; Q
Language	English
Publishing date	2017-02-01T00:00:00Z
Publisher	F1000 Research Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Molecular Insights into SARS-CoV2-Induced Alterations of the Gut/Brain Axis

Serge Nataf / Laurent Pays

International Journal of Molecular Sciences, Vol 22, Iss 10440, p

2021 Volume 10440

Abstract: For a yet unknown reason, a substantial share of patients suffering from COVID-19 develop long-lasting neuropsychiatric symptoms ranging from cognitive deficits to mood disorders and/or an extreme fatigue. We previously reported that in non-neural cells, ...

Abstract	For a yet unknown reason, a substantial share of patients suffering from COVID-19 develop long-lasting neuropsychiatric symptoms ranging from cognitive deficits to mood disorders and/or an extreme fatigue. We previously reported that in non-neural cells, angiotensin-1 converting enzyme 2 ( ACE2 ), the gene coding for the SARS-CoV2 host receptor, harbors tight co-expression links with dopa-decarboxylase ( DDC ), an enzyme involved in the metabolism of dopamine. Here, we mined and integrated data from distinct human expression atlases and found that, among a wide range of tissues and cells, enterocytes of the small intestine express the highest expression levels of ACE2 , DDC and several key genes supporting the metabolism of neurotransmitters. Based on these results, we performed co-expression analyses on a recently published set of RNA-seq data obtained from SARS-CoV2-infected human intestinal organoids. We observed that in SARS-CoV2-infected enterocytes, ACE2 co-regulates not only with DDC but also with a specific group of genes involved in (i) the dopamine/trace amines metabolic pathway, (ii) the absorption of microbiota-derived L-DOPA and (iii) the absorption of neutral amino acids serving as precursors to neurotransmitters. We conclude that in patients with long COVID, a chronic infection and inflammation of small intestine enterocytes might be indirectly responsible for prolonged brain alterations.
Keywords	COVID-19 ; SARS-CoV2 ; enterocytes ; long COVID ; brain ; trace amines ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	616
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Clonal selection versus clonal cooperation

Serge Nataf

F1000Research, Vol

the integrated perception of immune objects [version 1; referees: 2 approved]

2016 Volume 5

Abstract: Analogies between the immune and nervous systems were first envisioned by the immunologist Niels Jerne who introduced the concepts of antigen "recognition" and immune "memory". However, since then, it appears that only the cognitive immunology paradigm ... ...

Abstract	Analogies between the immune and nervous systems were first envisioned by the immunologist Niels Jerne who introduced the concepts of antigen "recognition" and immune "memory". However, since then, it appears that only the cognitive immunology paradigm proposed by Irun Cohen, attempted to further theorize the immune system functions through the prism of neurosciences. The present paper is aimed at revisiting this analogy-based reasoning. In particular, a parallel is drawn between the brain pathways of visual perception and the processes allowing the global perception of an "immune object". Thus, in the visual system, distinct features of a visual object (shape, color, motion) are perceived separately by distinct neuronal populations during a primary perception task. The output signals generated during this first step instruct then an integrated perception task performed by other neuronal networks. Such a higher order perception step is by essence a cooperative task that is mandatory for the global perception of visual objects. Based on a re-interpretation of recent experimental data, it is suggested that similar general principles drive the integrated perception of immune objects in secondary lymphoid organs (SLOs). In this scheme, the four main categories of signals characterizing an immune object (antigenic, contextual, temporal and localization signals) are first perceived separately by distinct networks of immunocompetent cells. Then, in a multitude of SLO niches, the output signals generated during this primary perception step are integrated by TH-cells at the single cell level. This process eventually generates a multitude of T-cell and B-cell clones that perform, at the scale of SLOs, an integrated perception of immune objects. Overall, this new framework proposes that integrated immune perception and, consequently, integrated immune responses, rely essentially on clonal cooperation rather than clonal selection.
Keywords	Antigen Processing & Recognition ; Immune Response ; Medicine ; R ; Science ; Q
Subject code	004
Language	English
Publishing date	2016-09-01T00:00:00Z
Publisher	F1000 Research Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Characterization of a Topically Testable Model of Burn Injury on Human Skin Explants

Olivia Gross-Amat / Marine Guillen / Damien Salmon / Serge Nataf / Céline Auxenfans

International Journal of Molecular Sciences, Vol 21, Iss 6956, p

2020 Volume 6956

Abstract: Severe burn injuries remain a major health problem due to high rates of mortality, residual morbidity, and/or aesthetic damages. To find new therapies aimed at promoting a harmonious healing of skin burns, it is important to develop models which take ... ...

Abstract	Severe burn injuries remain a major health problem due to high rates of mortality, residual morbidity, and/or aesthetic damages. To find new therapies aimed at promoting a harmonious healing of skin burns, it is important to develop models which take into account the unique properties of the human skin. Based on previously described models of burn injury performed on human skin explants, we hypothesized that maintaining explants under constant tension forces would allow to more closely reproduce the pathophysiological processes of skin remodeling. We thus. Here, we set up and characterized an improved model of deep second-degree burn injury on ex vivo cultured human skin explants at air-liquid interface and maintained under conditions of constant tension forces. A spontaneous re-epithelialization of the lesion was observed 8 to 9 days post burn and was found to rely on the proliferation of basal keratinocytes at the wound edges. Collagen VII at the dermo-epidermal junction reformed along with the progression of re-epithelializatio and a synthesis of procollagen III was observed in the dermis at the wound site. These findings indicate that our model is suitable for the assessment of clinically-relevant therapies aimed at modulating the kinetics of re-epithelialization and/or the activation of fibroblasts following skin burn injuries. In this regard, we evaluated the use of a thermoreversible poloxamer hydrogel as a vehicle for topically-testable therapeutic molecules. Our data showed that, although useful for drug formulation, the p407/p188 poloxamer hydrogel induces a delay of skin re-epithelialization in humans skin explants submitted to experimental burn injury.
Keywords	burn ; human skin ; ex vivo ; wound healing ; poloxamer hydrogel ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	571
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A Unique TGFB1-Driven Genomic Program Links Astrocytosis, Low-Grade Inflammation and Partial Demyelination in Spinal Cord Periplaques from Progressive Multiple Sclerosis Patients

Serge Nataf / Marc Barritault / Laurent Pays

International Journal of Molecular Sciences, Vol 18, Iss 10, p

2017 Volume 2097

Abstract: We previously reported that, in multiple sclerosis (MS) patients with a progressive form of the disease, spinal cord periplaques extend distance away from plaque borders and are characterized by the co-occurrence of partial demyelination, astrocytosis ... ...

Abstract	We previously reported that, in multiple sclerosis (MS) patients with a progressive form of the disease, spinal cord periplaques extend distance away from plaque borders and are characterized by the co-occurrence of partial demyelination, astrocytosis and low-grade inflammation. However, transcriptomic analyses did not allow providing a comprehensive view of molecular events in astrocytes vs. oligodendrocytes. Here, we re-assessed our transcriptomic data and performed co-expression analyses to characterize astrocyte vs. oligodendrocyte molecular signatures in periplaques. We identified an astrocytosis-related co-expression module whose central hub was the astrocyte gene Cx43/GJA1 (connexin-43, also named gap junction protein α-1). Such a module comprised GFAP (glial fibrillary acidic protein) and a unique set of transcripts forming a TGFB/SMAD1/SMAD2 (transforming growth factor β/SMAD family member 1/SMAD family member 2) genomic signature. Partial demyelination was characterized by a co-expression network whose central hub was the oligodendrocyte gene NDRG1 (N-myc downstream regulated 1), a gene previously shown to be specifically silenced in the normal-appearing white matter (NAWM) of MS patients. Surprisingly, besides myelin genes, the NDRG1 co-expression module comprised a highly significant number of translation/elongation-related genes. To identify a putative cause of NDRG1 downregulation in periplaques, we then sought to identify the cytokine/chemokine genes whose mRNA levels inversely correlated with those of NDRG1. Following this approach, we found five candidate immune-related genes whose upregulation associated with NDRG1 downregulation: TGFB1 (transforming growth factor β 1), PDGFC (platelet derived growth factor C), IL17D (interleukin 17D), IL33 (interleukin 33), and IL12A (interleukin 12A). From these results, we propose that, in the spinal cord periplaques of progressive MS patients, TGFB1 may limit acute inflammation but concurrently induce astrocytosis and an alteration of the ...
Keywords	multiple sclerosis ; neuroinflammation ; astrocytes ; myelin ; bioinformatics ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	616
Language	English
Publishing date	2017-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Molecular Mapping of Hydrogen Sulfide Targets in Normal Human Keratinocytes

Olivia Gross-Amat / Marine Guillen / Jean-Pascal Gimeno / Michel Salzet / Nicolas Lebonvallet / Laurent Misery / Céline Auxenfans / Serge Nataf

International Journal of Molecular Sciences, Vol 21, Iss 4648, p

2020 Volume 4648

Abstract: Although sulfur-rich thermal waters have ancestrally been used in the context of dermatological conditions, a global mapping of the molecular effects exerted by H 2 S on human keratinocytes is still lacking. To fill this knowledge gap, we subjected ... ...

Abstract	Although sulfur-rich thermal waters have ancestrally been used in the context of dermatological conditions, a global mapping of the molecular effects exerted by H 2 S on human keratinocytes is still lacking. To fill this knowledge gap, we subjected cultured human keratinocytes to distinct amounts of the non-gaseous hydrogen sulfur donor NaHS. We first checked that H 2 S accumulated in the cytoplasm of keratinocytes under our experimental conditions andused a combination of proteomics, genomics and biochemical approaches to unravel functionally relevant H 2 S targets in human keratinocytes. We found that the identified targets fall into two main categories: (i) the oxidative stress response molecules superoxide dismutase 2 (SOD2), NAD(P)H quinone dehydrogenase 1 (NQO1) and culin 3 (CUL3) and (ii) the chemokines interleukin-8 (IL-8) and CXCL2. Interestingly, NaHS also stimulated the caspase-1 inflammasome pathway, leading to increased secretion of the pro-inflammatory molecule interleukin-18 (IL-18). Interestingly, the secretion of interleukin-1 beta (IL-1β) was only modestly impacted by NaHS exposure despite a significant accumulation of IL-1β pro-form. Finally, we observed that NaHS significantly hampered the growth of human keratinocyte progenitors and stem cells cultured under clonogenic conditions or as epidermal cell sheets. We conclude that H 2 S exerts specific molecular effects on normal human keratinocytes.
Keywords	human keratinocyte ; H2S ; RNAseq ; proteomics ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2020-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Preserving Basement Membranes during Detachment of Cultivated Oral Mucosal Epithelial Cell Sheets for the Treatment of Total Bilateral Limbal Stem Cell Deficiency

Marie-Rose Rovere / Patricia Rousselle / Marek Haftek / Bruce Charleux / Viridiana Kocaba / Céline Auxenfans / Serge Nataf / Odile Damour

Cell Transplantation, Vol

2018 Volume 27

Abstract: Total bilateral limbal stem cell deficiency leading to loss of corneal clarity, potential vision loss, pain, photophobia, and keratoplasty failure cannot be treated by autologous limbal transplantation, and allogeneic limbal transplantation requires ... ...

Abstract	Total bilateral limbal stem cell deficiency leading to loss of corneal clarity, potential vision loss, pain, photophobia, and keratoplasty failure cannot be treated by autologous limbal transplantation, and allogeneic limbal transplantation requires subsequent immunosuppressive treatment. Cultured autologous oral mucosal epithelial cells have been shown to be safe and effective alternatives. These cells can be transplanted on supports or without support after detachment from the culture dishes. Dispase, known for epidermal sheet detachment, is reported as not usable for oral mucosa. The objective was to find an optimized detachment method providing a sufficiently resistant and adhesive cultured oral mucosal epithelium (COME), which can be grafted without sutures. Enzymatic treatments (dispase or collagenase at different concentrations) were compared to enzyme-free mechanical detachment. Histological immunofluorescence (IF) and Western blotting (WB) were used to examine the impact on adhesion markers (laminin-332, β1-integrin, and type VII collagen) and junctional markers (E-cadherin, P-cadherin). Finally, the COME ability to adhere to the cornea and produce a differentiated epithelium 15 d after grafting onto an ex vivo porcine stroma model were investigated by histology, IF, and transmission electron microscopy. Collagenase at 0.5 mg/mL and dispase at 5 mg/mL were selected for comparative study on adhesive expression marker by IF and WB showed that levels of basement membrane proteins and cell–cell and cell–matrix junction proteins were not significantly different between the 3 detachment methods. Collagenase 0.5 mg/mL was selected for the next step validation because of the better reproducibility, 100% success (vs. 33% with dispase 5 mg/mL). Grafted onto porcine de-epithelialized corneal stroma, collagenase 0.5 mg/mL detached COME were found to adhere, stratify, and continue to ensure renewal of the epithelium. For COME, collagenase 0.5 mg/mL enzymatic detachment was selected and validated on its resistance and adhesive marker expression as well as their anchorage onto our new ex vivo de-epithelialized stroma model.
Keywords	Medicine ; R
Subject code	571
Language	English
Publishing date	2018-02-01T00:00:00Z
Publisher	SAGE Publishing
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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