Статті в журналах: "Multiple Sclerosis, Biomarkers, Immune response"

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Mathur, Deepali, Bikash Kumar Mishra, Soumyashree Rout, Francisco Jose Lopez-Iranzo, Gerardo Lopez-Rodas, Jayalakshmi Vallamkondu, Ramesh Kandimalla, and Bonaventura Casanova. "Potential Biomarkers Associated with Multiple Sclerosis Pathology." International Journal of Molecular Sciences 22, no. 19 (September 25, 2021): 10323. http://dx.doi.org/10.3390/ijms221910323.

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Multiple sclerosis (MS) is a complex disease of the central nervous system (CNS) that involves an intricate and aberrant interaction of immune cells leading to inflammation, demyelination, and neurodegeneration. Due to the heterogeneity of clinical subtypes, their diagnosis becomes challenging and the best treatment cannot be easily provided to patients. Biomarkers have been used to simplify the diagnosis and prognosis of MS, as well as to evaluate the results of clinical treatments. In recent years, research on biomarkers has advanced rapidly due to their ability to be easily and promptly measured, their specificity, and their reproducibility. Biomarkers are classified into several categories depending on whether they address personal or predictive susceptibility, diagnosis, prognosis, disease activity, or response to treatment in different clinical courses of MS. The identified members indicate a variety of pathological processes of MS, such as neuroaxonal damage, gliosis, demyelination, progression of disability, and remyelination, among others. The present review analyzes biomarkers in cerebrospinal fluid (CSF) and blood serum, the most promising imaging biomarkers used in clinical practice. Furthermore, it aims to shed light on the criteria and challenges that a biomarker must face to be considered as a standard in daily clinical practice.

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Puentes, Fabiola, Pascal Benkert, Sandra Amor, Jens Kuhle, and Gavin Giovannoni. "Antibodies to neurofilament light as potential biomarkers in multiple sclerosis." BMJ Neurology Open 3, no. 2 (November 2021): e000192. http://dx.doi.org/10.1136/bmjno-2021-000192.

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Background and objectiveThe concentration of neurofilament light (NfL) protein in cerebrospinal fluid (CSF) and blood is widely considered as a quantitative measure of neuro-axonal injury. Immune reactivity to NfL released into extracellular fluids induces specific autoantibody response. We investigated the levels and avidity of antibodies to NfL in patients with multiple sclerosis (MS) treated with disease-modifying therapies (DMTs) and their correlation with disease worsening and NfL protein concentration.MethodsWe conducted a prospective longitudinal study in 246 patients with MS (125 DMT-treated and 121 untreated at baseline). Serum levels of NfL antibodies, antibody avidity and immune complexes were determined by ELISA. NfL protein was measured using the Simoa platform. Clinical variables were tested for their association with the measured parameters in multivariate generalised estimating equation models.ResultsMultivariate analysis showed that levels of NfL antibodies were higher in progressive MS compared with clinically isolated syndrome (CIS)/relapsing remitting multiple sclerosis (RRMS) (p=0.010). Anti-NfL levels drop with increasing disability score (Expanded Disability Status Scale (EDSS)) (p=0.002), although conversely, were significantly elevated in CIS/RRMS after a recent EDSS increase (p=0.012). Patients receiving DMTs showed decreased levels of anti-NfL (p=0.008), high-avidity antibodies (p=0.017) and immune-complexes compared with untreated CIS/RRMS. Patients with MS switching to natalizumab showed lower levels of anti-NfL but higher immune complexes compared with healthy controls (p=0.0071). A weak association was observed between the levels of NfL protein and NfL antibodies.ConclusionsThese results support the potential usefulness of quantifying antibody response to NfL as potential markers of progression and treatment response in MS and need to be considered when interpreting peripheral blood NfL levels.

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Mycko, Marcin P., and Sergio E. Baranzini. "microRNA and exosome profiling in multiple sclerosis." Multiple Sclerosis Journal 26, no. 5 (January 22, 2020): 599–604. http://dx.doi.org/10.1177/1352458519879303.

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New DNA sequencing technologies have uncovered non-coding RNA (ncRNA) as a major player in regulating cellular processes and can no longer be dismissed as “junk” or “dark” RNA. Among the ncRNA, microRNA (miRNA) is arguably the most extensively characterized category and a number of studies have implicated them in regulating critical functions that can influence autoimmune demyelination. Of specific interest to multiple sclerosis (MS), miRNA have been implicated in both regulating immune responses and myelination, thus making them an attractive candidate for both pharmacological intervention and as disease biomarkers. In addition, exosomes, small vesicles secreted by most cell types and present in all body fluids, have been also shown to play roles in immune signaling, inflammation and angiogenesis. Therefore, exosomes are also being explored as tools for therapeutic delivery and as biomarkers. This article reviews the recent advances in miRNA and exosome profiling in MS and experimental models.

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Bose, Gauruv, Simon D. X. Thebault, Harold L. Atkins, and Mark S. Freedman. "Does Resetting the Immune System Fix Multiple Sclerosis?" Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 47, no. 1 (October 18, 2019): 1–10. http://dx.doi.org/10.1017/cjn.2019.294.

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Abstract:Multiple sclerosis is the leading non-traumatic cause of disability in young adults, affecting up to 100,000 Canadians. This chronic inflammatory and neurodegenerative disease of the central nervous system leads to irreversible neurologic disability if inadequately controlled. Though many current medications are available that reduce inflammatory damage, most patients continue to show some evidence of disease activity and accrue disability. In this review, we discuss the role of immune ablation followed by autologous hematopoietic stem cell transplantation (AHSCT), a therapeutic option for select patients with a more aggressive disease course. By “resetting” the immune system with a variety of ablative conditioning regimens, followed by immune reconstitution, this therapy has shown a durable response in halting evidence of inflammatory activity in most patients, without the need for continued disease-modifying therapies (DMT). Since the introduction of this therapy, there have been advances in patient selection and supportive care, such that morbidity has significantly declined and treatment-related mortality is minimized. Recent phase-II trials have shown excellent results in efficacy and safety of AHSCT; however, challenges exist which require ongoing study. The future challenges include comparing the variety of AHSCT conditioning regimens with each other as well as with existing highly effective DMT; identifying patients with an aggressive disease course through novel biomarkers who may benefit the most from AHSCT; and surveillance of long-term outcomes of different treatment protocols. In select patients, replacing the immune system with AHSCT holds promise of fundamentally altering the trajectory of their aggressive disease course.

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Feki, Sawsan, Salma Sakka, Sabrina Mejdoub, Mariem Damak, Hend Hachicha, Chokri Mhiri, and Hatem Masmoudi. "Biomarkers related to the intrathecal humoral immune response as laboratory tools for multiple sclerosis diagnosis." Journal of the Neurological Sciences 429 (October 2021): 118168. http://dx.doi.org/10.1016/j.jns.2021.118168.

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Harris, Violaine K., Nicola Donelan, Qi Jiang Yan, Kristi Clark, Amir Touray, Mustapha Rammal, and Saud A. Sadiq. "Cerebrospinal fluid fetuin-A is a biomarker of active multiple sclerosis." Multiple Sclerosis Journal 19, no. 11 (February 25, 2013): 1462–72. http://dx.doi.org/10.1177/1352458513477923.

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Background: There is an urgent need for biomarkers in multiple sclerosis (MS) that can reliably measure ongoing disease activity relative to inflammation, neurodegeneration, and demyelination/remyelination. Fetuin-A was recently identified as a potential biomarker in MS cerebrospinal fluid (CSF). Fetuin-A has diverse functions, including a role in immune pathways. Objective: The objective of this research is to investigate whether fetuin-A is a direct indicator of disease activity. Methods: We measured fetuin-A in CSF and plasma of patients with MS and correlated these findings to clinical disease activity and natalizumab response. Fetuin-A expression was characterized in MS brain tissue and in experimental autoimmune encephalomyelitis (EAE) mice. We also examined the pathogenic role of fetuin-A in EAE using fetuin-A-deficient mice. Results: Elevated CSF fetuin-A correlated with disease activity in MS. In natalizumab-treated patients, CSF fetuin-A levels were reduced one year post-treatment, correlating with therapeutic response. Fetuin-A was markedly elevated in demyelinated lesions and in gray matter within MS brain tissue. Similarly, fetuin-A was elevated in degenerating neurons around demyelinated lesions in EAE. Fetuin-A-deficient mice demonstrated delayed onset and reduced severity of EAE symptoms. Conclusions: Our results show that CSF fetuin-A is a biomarker of disease activity and natalizumab response in MS. Neuronal expression of fetuin-A suggests that fetuin-A may play a pathological role in the disease process.

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Gutiérrez-Fernández, María, Fernando de la Cuesta, Antonio Tallón, Inmaculada Cuesta, Mireya Fernández-Fournier, Fernando Laso-García, Mari Carmen Gómez-de Frutos, Exuperio Díez-Tejedor, and Laura Otero-Ortega. "Potential Roles of Extracellular Vesicles as Biomarkers and a Novel Treatment Approach in Multiple Sclerosis." International Journal of Molecular Sciences 22, no. 16 (August 20, 2021): 9011. http://dx.doi.org/10.3390/ijms22169011.

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Extracellular vesicles (EVs) are a heterogeneous group of bilayer membrane-wrapped molecules that play an important role in cell-to-cell communication, participating in many physiological processes and in the pathogenesis of several diseases, including multiple sclerosis (MS). In recent years, many studies have focused on EVs, with promising results indicating their potential role as biomarkers in MS and helping us better understand the pathogenesis of the disease. Recent evidence suggests that there are novel subpopulations of EVs according to cell origin, with those derived from cells belonging to the nervous and immune systems providing information regarding inflammation, demyelination, axonal damage, astrocyte and microglia reaction, blood–brain barrier permeability, leukocyte transendothelial migration, and ultimately synaptic loss and neuronal death in MS. These biomarkers can also provide insight into disease activity and progression and can differentiate patients’ disease phenotype. This information can enable new pathways for therapeutic target discovery, and consequently the development of novel treatments. Recent evidence also suggests that current disease modifying treatments (DMTs) for MS modify the levels and content of circulating EVs. EVs might also serve as biomarkers to help monitor the response to DMTs, which could improve medical decisions concerning DMT initiation, choice, escalation, and withdrawal. Furthermore, EVs could act not only as biomarkers but also as treatment for brain repair and immunomodulation in MS. EVs are considered excellent delivery vehicles. Studies in progress show that EVs containing myelin antigens could play a pivotal role in inducing antigen-specific tolerance of autoreactive T cells as a novel strategy for the treatment as “EV-based vaccines” for MS. This review explores the breakthrough role of nervous and immune system cell-derived EVs as markers of pathological disease mechanisms and potential biomarkers of treatment response in MS. In addition, this review explores the novel role of EVs as vehicles for antigen delivery as a therapeutic vaccine to restore immune tolerance in MS autoimmunity.

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Zhou, Qingqing, Rui Jia, and Jingxia Dang. "Correlation between the Neutrophil-to-Lymphocyte Ratio and Multiple Sclerosis: Recent Understanding and Potential Application Perspectives." Neurology Research International 2022 (October 26, 2022): 1–10. http://dx.doi.org/10.1155/2022/3265029.

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Multiple sclerosis (MS) is a chronic debilitating immune-mediated disease of the central nervous system, which causes demyelination and neuroaxonal damage. Low-grade systemic inflammation has been considered to lead to pathogenesis owing to the amplification of pathogenic immune response activation. However, there is a shortage of reliable systemic inflammatory biomarkers to predict the disease activity and progression of MS. In MS patients, a series of cytokines and chemokines promote the proliferation of neutrophils and lymphocytes and their transfer to the central nervous system. The neutrophil-to-lymphocyte ratio (NLR), which combines the information of the inherent and adaptive parts of the immune system, represents a reliable measure of the inflammatory burden. In this review, we aimed to discuss the inflammatory response in MS, mainly the function of lymphocytes and neutrophils, which can be implemented in the utility of NLR as a diagnostic tool in MS patients. The underlying pathophysiology is highlighted to identify new potential targets for neuroprotection and to develop novel therapeutic strategies.

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Mechelli, Rosella, Silvia Romano, Carmela Romano, Emanuele Morena, Maria Chiara Buscarinu, Rachele Bigi, Gianmarco Bellucci, et al. "MAIT Cells and Microbiota in Multiple Sclerosis and Other Autoimmune Diseases." Microorganisms 9, no. 6 (May 24, 2021): 1132. http://dx.doi.org/10.3390/microorganisms9061132.

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The functions of mucosal-associated invariant T (MAIT) cells in homeostatic conditions include the interaction with the microbiota and its products, the protection of body barriers, and the mounting of a tissue-repair response to injuries or infections. Dysfunction of MAIT cells and dysbiosis occur in common chronic diseases of inflammatory, metabolic, and tumor nature. This review is aimed at analyzing the changes of MAIT cells, as well as of the microbiota, in multiple sclerosis and other autoimmune disorders. Common features of dysbiosis in these conditions are the reduced richness of microbial species and the unbalance between pro-inflammatory and immune regulatory components of the gut microbiota. The literature concerning MAIT cells in these disorders is rather complex, and sometimes not consistent. In multiple sclerosis and other autoimmune conditions, several studies have been done, or are in progress, to find correlations between intestinal permeability, dysbiosis, MAIT cell responses, and clinical biomarkers in treated and treatment-naïve patients. The final aims are to explain what activates MAIT cells in diseases not primarily infective, which interactions with the microbiota are potentially pathogenic, and their dynamics related to disease course and disease-modifying treatments.

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Król-Grzymała, Angelika, Edyta Sienkiewicz-Szłapka, Ewa Fiedorowicz, Dominika Rozmus, Anna Cieślińska, and Andrzej Grzybowski. "Tear Biomarkers in Alzheimer’s and Parkinson’s Diseases, and Multiple Sclerosis: Implications for Diagnosis (Systematic Review)." International Journal of Molecular Sciences 23, no. 17 (September 4, 2022): 10123. http://dx.doi.org/10.3390/ijms231710123.

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Biological material is one of the most important aspects that allow for the correct diagnosis of the disease, and tears are an interesting subject of research because of the simplicity of collection, as the well as the relation to the components similar to other body fluids. In this review, biomarkers for Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS) in tears are investigated and analyzed. Records were obtained from the PubMed and Google Scholar databases in a timeline of 2015–2022. The keywords were: tear film/tear biochemistry/tear biomarkers + diseases (AD, PD, or MS). The recent original studies were analyzed, discussed, and biomarkers present in tears that can be used for the diagnosis and management of AD, PD, and MS diseases were shown. α-synTotal and α-synOligo, lactoferrin, norepinephrine, adrenaline, epinephrine, dopamine, α-2-macroglobulin, proteins involved in immune response, lipid metabolism and oxidative stress, apolipoprotein superfamily, and others were shown to be biomarkers in PD. For AD as potential biomarkers, there are: lipocalin-1, lysozyme-C, and lacritin, amyloid proteins, t-Tau, p-Tau; for MS there are: oligoclonal bands, lipids containing choline, free carnitine, acylcarnitines, and some amino acids. Information systematized in this review provides interesting data and new insight to help improve clinical outcomes for patients with neurodegenerative disorders.

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Arru, Giannina, Elia Sechi, Sara Mariotto, Alessia Farinazzo, Chiara Mancinelli, Daniela Alberti, Sergio Ferrari, et al. "Antibody response against HERV-W env surface peptides differentiates multiple sclerosis and neuromyelitis optica spectrum disorder." Multiple Sclerosis Journal - Experimental, Translational and Clinical 3, no. 4 (November 22, 2017): 205521731774242. http://dx.doi.org/10.1177/2055217317742425.

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Background A specific humoral immune response against HERV-W envelope surface (env-su) glycoprotein antigens has been reported in serum of patients with multiple sclerosis (MS). However, it has not been evaluated to date in patients with neuromyelitis optica spectrum disorder (NMOSD). Objective The objective of this paper is to investigate whether antibody (Ab) response against HERV-W env-su antigenic peptides differs between NMOSD and MS. Methods Serum samples were collected from 36 patients with NMOSD, 36 patients with MS and 36 healthy control individuals (HCs). An indirect ELISA was set up to detect specific Abs against HERV-W env-su peptides. Results Our data showed that two antigenic peptides, particularly HERV-Wenv93–108 and HERV-Wenv248–262, were statistically significantly present only in serum of MS compared to NMOSD and HCs. Thus, the specific humoral immune response against HERV-W env-su glycoprotein antigens found in MS is widely missing in NMOSD. Conclusion Increased circulating serum levels of these HERV-W Abs may be suitable as additional biomarkers to better differentiate MS from NMOSD.

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Carrithers, Michael D. "Differential activation of an innate immune signaling pathway in lymphocytes from patients with multiple sclerosis." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 182.71. http://dx.doi.org/10.4049/jimmunol.202.supp.182.71.

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Abstract Prior work demonstrated that epithelial V-like antigen (EVA), a cell surface adhesion molecule, is expressed in lymphocytes and is necessary for the efficacy of anti-alpha4integrin treatment of experimental autoimmune encephalomyelitis (EAE), a mouse model of human multiple sclerosis (MS). EVA deficiency is associated with a severe clinical phenotype of EAE in the presence or absence of treatment. Recent work demonstrates that EVA, which is encoded by the mpzl2 gene, also regulates expression of the anti-viral oligoadenylate synthase genes, Oas1 and Oas2. Here the EVA signaling pathway was assessed in patients with MS and healthy controls from the UIC Neuroimmunology Biobank. The goal of this initiative is to assess individual variation in innate immune responses that are associated with severe phenotypes of multiple sclerosis (MS) in underrepresented racial and ethnic minority groups. In response to treatment with the Tlr7/8 agonist R848, peripheral blood lymphocytes from MS patients demonstrated an increase in mpzl2 expression that was not observed in healthy controls. In addition, racial and ethnic differences were observed in the expression of Oas1and Oas2 genes. It is hypothesized that differential innate immune activation of these transcriptional pathways are novel biomarkers and modifiers of disease severity in MS. This work was funded by the Evelyn Garcia Research Fund at the University of Illinois College of Medicine, Chicago.

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Guedes, J., A. L. C. Cardoso, and M. C. Pedroso de Lima. "Involvement of MicroRNA in Microglia-Mediated Immune Response." Clinical and Developmental Immunology 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/186872.

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MicroRNAs (miRNAs) are an abundant class of small noncoding RNA molecules that play an important role in the regulation of gene expression at the posttranscriptional level. Due to their ability to simultaneously modulate the fate of different genes, these molecules are particularly well suited to act as key regulators during immune cell differentiation and activation, and their dysfunction can contribute to pathological conditions associated with neuroinflammation. Recent studies have addressed the role of miRNAs in the differentiation of progenitor cells into microglia and in the activation process, aiming at clarifying the origin of adult microglia cells and the contribution of the central nervous system (CNS) environment to microglia phenotype, in health and disease. Altered expression of several miRNAs has been associated with Alzheimer’s disease, multiple sclerosis, and ischemic injury, hence strongly advocating the use of these small molecules as disease markers and new therapeutic targets. This review summarizes the recent advances in the field of miRNA-mediated regulation of microglia development and activation. We discuss the role of specific miRNAs in the maintenance and switching of microglia activation states and illustrate the potential of this class of nucleic acids both as biomarkers of inflammation and new therapeutic tools for the modulation of microglia behavior in the CNS.

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Massacesi, Luca, Alice Mariottini, and Ferdinando Nicoletti. "Relevance of Pathogenetic Mechanisms to Clinical Effectiveness of B-Cell-Depleting Monoclonal Antibodies in Multiple Sclerosis." Journal of Clinical Medicine 11, no. 15 (July 23, 2022): 4288. http://dx.doi.org/10.3390/jcm11154288.

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Evidence of the effectiveness of B-cell-depleting monoclonal antibodies (mAbs) in multiple sclerosis (MS) prompted a partial revisitation of the pathogenetic paradigm of the disease, which was, so far, considered a T-cell-mediated autoimmune disorder. Mechanisms underlying the efficacy of B-cell-depleting mAbs in MS are still unknown. However, they likely involve the impairment of pleiotropic B-cell functions different from antibody secretion, such as their role as antigen-presenting cells during both the primary immune response in the periphery and the secondary response within the central nervous system (CNS). A potential impact of B-cell-depleting mAbs on inflammation compartmentalised within the CNS was also suggested, but little is known about the mechanism underlying this latter phenomenon as no definite evidence was provided so far on the ability of mAbs to cross the blood–brain barrier and reliable biomarkers of compartmentalised inflammation are lacking. The present paper briefly summarises the immunopathogenesis of MS with a focus on onset of autoimmunity and compartmentalisation of the immune response; mechanisms mediating B-cell depletion and underlying the effectiveness of B-cell-depleting mAbs are also discussed.

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Guerau-de-Arellano, Mireia, Amy Lovett-Racke, and Michael Racke. "T cell miRNA in multiple sclerosis pathogenesis (P5209)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 68.32. http://dx.doi.org/10.4049/jimmunol.190.supp.68.32.

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Abstract Multiple sclerosis (MS) is an immune-mediated disease that results in destruction of the myelin sheath and axonal degeneration. Interestingly, while myelin-specific T cells are present in peripheral blood mononuclear cells (PBMC) of both healthy controls and MS patients, they only become pathogenic in MS patients. This suggests that some regulatory checkpoint is bypassed in MS T cells, unleashing their autoimmune potential. By regulating protein-coding mRNAs, microRNAs (miRNAs) control important cellular processes. Specifically, we have previously shown that dysregulated miRNAs in MS patient’s naïve T cells promote pro-inflammatory Th1 immune responses. In this study, we explored whether differences in miRNA expression in memory T cells of MS patients further contribute to the pathogenesis of MS. Memory CD4 T cells were purified by magnetic bead sorting to 95% purity and subjected to a comprehensive Nanostring technology miRNA profiling. In a study on healthy (n=17) and seven MS patients (n=21), a number of miRs were found to be significantly different in MS compared to healthy controls. Among the identified miRs, many target genes known to be involved in T cell proliferation and apoptosis, activation, adhesion and regulation. These results identify miRNAs in memory T cells as MS biomarkers of biological significance and potential clinical value, and reveal potential new therapeutic targets in MS.

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Nuti, Francesca, Feliciana Real Fernandez, Giuseppina Sabatino, Elisa Peroni, Barbara Mulinacci, Ilaria Paolini, Margherita Di Pisa, et al. "A Multiple N-Glucosylated Peptide Epitope Efficiently Detecting Antibodies in Multiple Sclerosis." Brain Sciences 10, no. 7 (July 15, 2020): 453. http://dx.doi.org/10.3390/brainsci10070453.

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Diagnostics of Multiple Sclerosis (MS) are essentially based on the gold standard magnetic resonance imaging. Few alternative simple assays are available to follow up disease activity. Considering that the disease can remain elusive for years, identification of antibodies fluctuating in biological fluids as relevant biomarkers of immune response is a challenge. In previous studies, we reported that anti-N-glucosylated (N-Glc) peptide antibodies that can be easily detected in Solid-Phase Enzyme-Linked ImmunoSorbent Assays (SP-ELISA) on MS patients’ sera preferentially recognize hyperglucosylated adhesin of non-typeable Haemophilus Influenzae. Since multivalency can be useful for diagnostic purposes to allow an efficient coating in ELISA, we report herein the development of a collection of Multiple N-glucosylated Peptide Epitopes (N-Glc MEPs) to detect anti-N-Glc antibodies in MS. To this aim, a series of N-Glc peptide antigens to be represented in the N-GlcMEPs were tested in competitive ELISA. We confirmed that the epitope recognized by antibodies shall contain at least 5-mer sequences including the fundamental N-Glc moiety. Using a 4-branched dendrimeric lysine scaffold, we selected the N-Glc MEP 24, carrying the minimal epitope Asn(Glc) anchored to a polyethylene glycol-based spacer (PEG) containing a 19-atoms chain, as an efficient multivalent probe to reveal specific and high affinity anti-N-Glc antibodies in MS.

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Kharati, Maryam, Sanam Foroutanparsa, Mohammad Rabiee, Reza Salarian, Navid Rabiee, and Ghazal Rabiee. "Early Diagnosis of Multiple Sclerosis Based on Optical and Electrochemical Biosensors: Comprehensive Perspective." Current Analytical Chemistry 16, no. 5 (July 8, 2020): 557–69. http://dx.doi.org/10.2174/1573411014666180829111004.

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Background: Multiple Sclerosis (MS) involves an immune-mediated response in which body’s immune system destructs the protective sheath (myelin). Part of the known MS biomarkers are discovered in cerebrospinal fluid like oligoclonal lgG (OCGB), and also in blood like myelin Oligodendrocyte Glycoprotein (MOG). The conventional MS diagnostic methods often fail to detect the disease in early stages such as Clinically Isolated Syndrome (CIS), which considered as a concerning issue since CIS highlighted as a prognostic factor of MS development in most cases. Methods: MS diagnostic techniques include Magnetic Resonance Imaging (MRI) of the brain and spinal cord, lumbar puncture (or spinal tap) that evaluate cerebrospinal fluid, evoked potential testing revealing abnormalities in the brain and spinal cord. These conventional diagnostic methods have some negative points such as extensive processing time as well as restriction in the quantity of samples that can be analyzed concurrently. Scientists have focused on developing the detection methods especially early detection which belongs to ultra-sensitive, non-invasive and needed for the Point of Care (POC) diagnosis because the situation was complicated by false positive or negative results. Results: As a result, biosensors are utilized and investigated since they could be ultra-sensitive to specific compounds, cost effective devices, body-friendly and easy to implement. In addition, it has been proved that the biosensors on physiological fluids (blood, serum, urine, saliva, milk etc.) have quick response in a non-invasive rout. In general form, a biosensor system for diagnosis and early detection process usually involves; biomarker (target molecule), bio receptor (recognition element) and compatible bio transducer. Conclusion: Studies underlined that early treatment of patients with high possibility of MS can be advantageous by postponing further abnormalities on MRI and subsequent attacks. : This Review highlights variable disease diagnosis approaches such as Surface Plasmon Resonance (SPR), electrochemical biosensors, Microarrays and microbeads based Microarrays, which are considered as promising methods for detection and early detection of MS.

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Konen, Franz Felix, Malte Johannes Hannich, Philipp Schwenkenbecher, Matthias Grothe, Konrad Gag, Konstantin Fritz Jendretzky, Stefan Gingele, et al. "Diagnostic Cerebrospinal Fluid Biomarker in Early and Late Onset Multiple Sclerosis." Biomedicines 10, no. 7 (July 7, 2022): 1629. http://dx.doi.org/10.3390/biomedicines10071629.

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Background: The intrathecal humoral response is the characteristic diagnostic finding in the cerebrospinal fluid (CSF) analysis of patients with multiple sclerosis (MS). Although the average age of MS patients increases, little is known about the sensitivity of diagnostic markers in elderly MS patients. Methods: In this retrospective two-center study, intrathecal free light chains kappa fraction (FLCk IF) and oligoclonal bands (OCB) were studied in a large cohort of patients with early and late onset relapsing (RMS) and progressive (PMS) MS. Furthermore, the humoral immune profile in CSF was analyzed, including the polyspecific intrathecal immune response measured as the MRZ reaction. Results: While the frequency of CSF-specific OCB did not differ between early and late onset RMS and PMS, the sensitivity of positive FLCk IF and absolute FLCk IF values were lower in PMS. The positivity of the MRZ reaction was equally frequent in early and late onset RMS and PMS. PMS patients had higher local IgA concentrations than RMS patients (p = 0.0123). Conclusions: OCB are slightly superior to FLCk IF in progressive MS in terms of sensitivity for detecting intrathecal immunoglobulin synthesis. The MRZ reaction, as the most specific parameter for MS, is also applicable in patients with late onset and progressive MS.

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Dey, Adwitia, Lindsay Snyder, Veronika Weaver, Margherita T. Cantorna, and Pamela A. Hankey-Giblin. "The Ron receptor tyrosine kinase regulates inflammatory response in an experimental model of multiple sclerosis." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 188.13. http://dx.doi.org/10.4049/jimmunol.196.supp.188.13.

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Abstract In the experimental autoimmune encephalitis (EAE) murine model of multiple sclerosis (MS), both central nervous system (CNS)-resident macrophages (microglia) and infiltrating monocyte-derived macrophages contribute to disease progression. The Ron receptor tyrosine kinase is expressed on tissue resident macrophages including microglia and is involved in regulating inflammatory responses. An in vivo deletion of Ron (Ron KO) promotes inflammatory macrophage activation (M1) and limits a reparative macrophage phenotype (M2). Herein we investigated whether Ron expression plays a critical role in regulating disease progression in EAE. Ron KO mice exhibit delayed onset of EAE (day 14) compared to Wild-Type (WT) (day 10), however Ron KO mice exhibit greater peak severity at onset. Ron KO mice display T-cell mediated peripheral inflammation, as demonstrated by the significant increase in the secretion of interferon gamma (IFNγ) but not IL-17 and IL-10. At day 14, cultured lymph node cells from Ron KO mice exhibit increased expression of M1-macrophage mediated biomarkers iNOS, COX-2, IL-6, IL12B, IL1β and TNF-α. A likely cause of this increased inflammatory response can in part be attributed to a T-cell mediated increase in IFNγ. Furthermore, CNS tissues from Ron KO mice at day 14 have increased gene expression of hallmark inflammatory biomarkers iNOS, IL12B and COX-2. The results indicate an interplay between the innate and adaptive immune system in fostering an M1-macrophage mediated inflammatory state, as the underlying factor for the observed increase in disease severity in Ron KO mice. Maintenance of Ron expressing macrophages could then be a potential therapeutic approach to treating MS symptoms.

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Laroni, Alice, and Antonio Uccelli. "CD56bright Natural Killer Cells: A Possible Biomarker of Different Treatments in Multiple Sclerosis." Journal of Clinical Medicine 9, no. 5 (May 13, 2020): 1450. http://dx.doi.org/10.3390/jcm9051450.

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Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system, which leads, in many cases, to irreversible disability. More than 15 disease-modifying treatments (DMTs) are available for the treatment of MS. Clinical activity or activity at magnetic resonance imaging (MRI) are now used to assess the efficacy of DMTs, but are negative prognostic factors per se. Therefore, a biomarker permitting us to identify patients who respond to treatment before they develop clinical/radiological signs of MS activity would be of high importance. The number of circulating CD56bright natural killer (NK) cells may be such a biomarker. CD56bright NK cells are a regulatory immune population belonging to the innate immune system. The number of CD56bright NK cells increases upon treatment with interferon-beta, alemtuzumab, dimethyl fumarate, after autologous hematopoietic stem cell transplantation, and is higher in those who respond to fingolimod. In some cases, an increased number of CD56bright NK cells is associated with an increase in their regulatory function. In the current review, we will evaluate the known effect on CD56bright NK cells of DMTs for MS, and will discuss their possible role as a biomarker for treatment response in MS.

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Bărcuţean, Laura Iulia, Andreea Romaniuc, Smaranda Maier, Zoltan Bajko, Anca Moţăţăianu, Huţanu Adina, Iunius Simu, Sebastian Andone та Rodica Bălaşa. "Clinical and Serological Biomarkers of Treatment’s Response in Multiple Sclerosis Patients Treated Continuously with Interferonβ-1b for More than a Decade". CNS & Neurological Disorders - Drug Targets 17, № 10 (23 листопада 2018): 780–92. http://dx.doi.org/10.2174/1871527317666180917095256.

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Introduction: We evaluated the peripheral immune panel of Multiple Sclerosis (MS) patients treated for more than 10 years with interferon-beta1b (IFNβ-1b) and aimed to identify possible biomarkers of treatment response. Material and Methods: Serum samples from 70 MS patients treated with IFNβ-1b more than a decade were analysed for 15 cytokines, that were correlated with the disability score, annual relapse ratio (ARR): the total number of relapses-ARR_0, relapse on treatment-ARR_1 and demographic data. Two groups were defined based on the levels of disability, calculated using the Expanded Disability Status Scale (EDSS): G1 – recurrent-remissive and G2 – secondary-progressive. Furthermore, we split the patients based on gender (G1_f, G1_m, G2_f, G2_m). Results: The ARR was reduced after treatment was instituted. We found positive correlations between IL_25 and EDSS in G1_f and G2_f, tumor necrosis factor α (TNFα) and ARR_1 and ARR_0 in G1, and IL_17F with ARR_1. Negative correlations were for IL_25 and ARR_0 and ARR_1. SCD40L intensely positively correlated with IL_31 in G1 and G2. Conclusion: After more than a decade of treatment, IFNβ-1b offers good results by reducing relapses and slowing disability progression. Several biomarkers can be used to assess the patient’s response. High levels of IL_17 and TNFα will indicate a more active form of the disease. IL-25 may exert a positive influence in male MS patients and should be considered for future studies, together with the co-modulation between sCD40L and IL_31. Our method allowed us to screen the peripheral immune panel and can be used for assessing the peripheral levels of the above-mentioned cytokines.

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Gambino, Caterina M., Bruna Lo Sasso, Giulia Bivona, Luisa Agnello, and Marcello Ciaccio. "Aging and Neuroinflammatory Disorders: New Biomarkers and Therapeutic Targets." Current Pharmaceutical Design 25, no. 39 (December 26, 2019): 4168–74. http://dx.doi.org/10.2174/1381612825666191112093034.

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: Chronic neuroinflammation is a common feature of the pathogenic mechanisms involved in various neurodegenerative age-associated disorders, such as Alzheimer's disease, multiple sclerosis, Parkinson’s disease, and dementia. : In particular, persistent low-grade inflammation may disrupt the brain endothelial barrier and cause a significant increase of pro-inflammatory cytokines and immune cells into the cerebral tissue that, in turn, leads to microglia dysfunction and loss of neuroprotective properties. : Nowadays, growing evidence highlights a strong association between persistent peripheral inflammation, as well as metabolic alterations, and neurodegenerative disorder susceptibility. The identification of common pathways involved in the development of these diseases, which modulate the signalling and immune response, is an important goal of ongoing research. : The aim of this review is to elucidate which inflammation-related molecules are robustly associated with the risk of neurodegenerative diseases. Of note, peripheral biomarkers may represent direct measures of pathophysiologic processes common of aging and neuroinflammatory processes. In addition, molecular changes associated with the neurodegenerative process might be present many decades before the disease onset. Therefore, the identification of a comprehensive markers panel, closely related to neuroinflammation, could be helpful for the early diagnosis, and the identification of therapeutic targets to counteract the underlying chronic inflammatory processes.

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Nuzziello, Nicoletta, Laura Vilardo, Paride Pelucchi, Arianna Consiglio, Sabino Liuni, Maria Trojano, and Maria Liguori. "Investigating the Role of MicroRNA and Transcription Factor Co-regulatory Networks in Multiple Sclerosis Pathogenesis." International Journal of Molecular Sciences 19, no. 11 (November 20, 2018): 3652. http://dx.doi.org/10.3390/ijms19113652.

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MicroRNAs (miRNAs) and transcription factors (TFs) play key roles in complex multifactorial diseases like multiple sclerosis (MS). Starting from the miRNomic profile previously associated with a cohort of pediatric MS (PedMS) patients, we applied a combined molecular and computational approach in order to verify published data in patients with adult-onset MS (AOMS). Six out of the 13 selected miRNAs (miR-320a, miR-125a-5p, miR-652-3p, miR-185-5p, miR-942-5p, miR-25-3p) were significantly upregulated in PedMS and AOMS patients, suggesting that they may be considered circulating biomarkers distinctive of the disease independently from age. A computational and unbiased miRNA-based screening of target genes not necessarily associated to MS was then performed in order to provide an extensive view of the genetic mechanisms underlying the disease. A comprehensive MS-specific miRNA-TF co-regulatory network was hypothesized; among others, SP1, RELA, NF-κB, TP53, AR, MYC, HDAC1, and STAT3 regulated the transcription of 61 targets. Interestingly, NF-κB and STAT3 cooperatively regulate the expression of immune response genes and control the cross-talk between inflammatory and immune cells. Further functional analysis will be performed on the identified critical hubs. Above all, in our view, this approach supports the need of multidisciplinary strategies for shedding light into the pathogenesis of MS.

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Lodde, Valeria, Giampaolo Murgia, Elena Rita Simula, Maristella Steri, Matteo Floris, and Maria Laura Idda. "Long Noncoding RNAs and Circular RNAs in Autoimmune Diseases." Biomolecules 10, no. 7 (July 14, 2020): 1044. http://dx.doi.org/10.3390/biom10071044.

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Immune responses are essential for the clearance of pathogens and the repair of injured tissues; however, if these responses are not properly controlled, autoimmune diseases can occur. Autoimmune diseases (ADs) are a family of disorders characterized by the body’s immune response being directed against its own tissues, with consequent chronic inflammation and tissue damage. Despite enormous efforts to identify new drug targets and develop new therapies to prevent and ameliorate AD symptoms, no definitive solutions are available today. Additionally, while substantial progress has been made in drug development for some ADs, most treatments only ameliorate symptoms and, in general, ADs are still incurable. Hundreds of genetic loci have been identified and associated with ADs by genome-wide association studies. However, the whole list of molecular factors that contribute to AD pathogenesis is still unknown. Noncoding (nc)RNAs, such as microRNAs, circular (circ)RNAs, and long noncoding (lnc)RNAs, regulate gene expression at different levels in various diseases, including ADs, and serve as potential drug targets as well as biomarkers for disease progression and response to therapy. In this review, we will focus on the potential roles and genetic regulation of ncRNA in four autoimmune diseases—systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes mellitus.

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Ortega Castro, R., F. U. Pilar, M. Martinez-Monllor, L. Muñoz-Barrera, I. Sanchez-Pareja, M. C. Ábalos-Aguilera, N. Barbarroja Puerto, et al. "POS0488 IDENTIFICATION OF NOVEL DISEASE BIOMARKERS IN SYSTEMIC SCLEROSIS THROUGH HIGH-THROUGHPUT PROTEOMICS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 498.3–499. http://dx.doi.org/10.1136/annrheumdis-2022-eular.4738.

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BackgroundSystemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, tissue fibrosis and activation of the innate and adaptive immune system. Clinical features of the disease consist of skin thickening and internal organ involvement. Due to the heterogeneous nature of the disease, there is an unmet need of biomarkers for diagnosis, disease progression and response to treatment.ObjectivesThe aim of this study was to explore new serum proteomic fingerprints of clinically defined forms of SSc.MethodsHighly specific detection of nighty two proteins from a panel related to organ damage was performed, by using the breakthrough technology proximity extension immunoassay (PEA, Olink), in the serum of 72 patients with SSC and 18 age-matched healthy donors (HD). Main disease complications in the SSC cohort, including lung fibrosis, skin fibrosis, renal, vascular, and esophageal involvement were assessed, and prevalence of circulating autoantibodies was tested, along with standard demographic and inflammatory parameters. Unsupervised hierarchical clustering methodologies were applied to identify subgroups of patients based on their proteomic profiles. Gene ontology enrichment was used to interrogate the biological meaning of the distinctive molecular signatures identified.ResultsSixteen circulating proteins related to organ damage were coordinately altered in the serum of SSc patients in relation to HD. Unsupervised clustering analyses differentiated 3 patients clusters presenting different proteomic profiles. Clinically, patients belonging to cluster 1 were characterized by a significant prevalence of multiple organ involvement (84%) in relation to clusters 2 (52%) and 3 (43%), mostly encompassing lung and skin fibrosis and esophageal dysmotility. Immunologically, cluster 1 further displayed the highest percentage of positivity for anti-scl70 antibodies.Nineteen serum proteins, not previously reported in the serum of SSC patients (BANK1, BID, CALR, ERBB2IP, FGR, FOSB, FOXO1, INPPL1, MAEA, MAGED1, MAP4K5, NBN, NCF2, PRKAB1, RASSF2, RCOR1, SMAD1, STXBP3, VASH1) were found deregulated between clusters, with a significant increase in the levels of all of them in cluster 1 compared with clusters 2 and 3. These deregulated proteins were mostly involved in biological processes such as cell proliferation, apoptosis, cell adhesion, migration, and immune response. Among them, two were functionally linked with cutaneous diseases [Calreticulin (CALR) and B-cell scaffold protein with ankryn repeats (BANK1)], two with digestive disorders (Tyrosine-protein kinase Fgr (FGR) and syntaxin-binding protein 3 (STXBP3)] and three with lung disfunction [protein FosB (FOSB), mothers against decapentaplegic homolog 1 (SMAD1) and forkhead box protein O1 (FOXO1)]. Interestingly, levels of some overexpressed proteins in C1 [BH3-interacting domain death agonist (BID), phosphatidylinositol 3,4,5-triphosphate 5-phosphatase 2 (INPPL1), Erbin (ERBB2IP), BANK1 and FOSB] were further related to the positivity for anti-scl70, the specific SSC-autoantibody known to be mostly associated to a bad prognosis and multiple organ involvement in SSC patients.Conclusion:1) Stratification based on serum proteomic profile could be of use for a better clinical classification of SSc patients, adding new insights to the underlying pathophysiological mechanisms.2) Combination of disease classifying autoantibodies with principal pathophysiological processes and serum proteomic profiles can help to elucidate and strengthen the diagnosis as well as the prognosis in SSC.AcknowledgementsSupported by ISCIII (RICOR-RD21/0002/0033) co-financed with FEDER.Disclosure of InterestsNone declared.

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Reder, A. T. "Neutralizing antibodies in multiple sclerosis: a complex impact on interferon responses, magnetic resonance imaging findings and clinical outcomes." Multiple Sclerosis Journal 13, no. 1_suppl (May 2007): 53–62. http://dx.doi.org/10.1177/1352458507076992.

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Interferon beta (IFN-β) therapy reduces relapse rate, MRI lesion development, and delays the progression of disability in relapsing forms of multiple sclerosis. As with other protein therapies, some patients develop neutralizing antibodies (NAbs) that could limit the efficacy of IFN-β. The clinical impact of NAbs is hotly debated. Non-standardized NAb assays, NAb persistence and disappearance, plus a six-month lag before a clinical effect, different IFN-β species and formulations, variable trial duration, have made interpretation of the significance of NAbs a challenging task. There is a correlation between the presence of NAb and reduced efficacy of IFN-β therapy in two- to four-year trials. However, patients destined to become NAb positive do better in the first year of IFN-β therapy. Patients with clinical worsening have surprisingly low NAb frequency and titers. Understanding the true clinical implications of NAbs will require well-controlled longitudinal studies instead of simple cross-sectional analyses, plus innovative trial designs with immune biomarkers. Multiple Sclerosis 2007; 13: S53—S62. http://msj.sagepub.com

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Ludwig, Michael D., Ian S. Zagon, and Patricia J. McLaughlin. "Featured Article: Serum [Met5]-enkephalin levels are reduced in multiple sclerosis and restored by low-dose naltrexone." Experimental Biology and Medicine 242, no. 15 (August 2, 2017): 1524–33. http://dx.doi.org/10.1177/1535370217724791.

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Low-dose naltrexone is a widely used off-label therapeutic prescribed for a variety of immune-related disorders. The mechanism underlying low-dose naltrexone’s efficacy for fatigue, Crohn’s disease, fibromyalgia, and multiple sclerosis is, in part, intermittent blockade of opioid receptors followed by upregulation of endogenous opioids. Short, intermittent blockade by naltrexone specifically blocks the opioid growth factor receptor resulting in biofeedback events that increase production of the endogenous opioid growth factor (OGF) (chemically termed [Met5]-enkephalin) facilitating interactions between opioid growth factor and opioid growth factor receptor that ultimately, result in inhibited cell proliferation. Preclinical studies have reported that enkephalin levels are deficient in animal models of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Our hypothesis is that serum enkephalin levels are diminished in humans with multiple sclerosis and experimental autoimmune encephalomyelitis mice, and that change in serum opioid growth factor levels may serve as a reasonable candidate biomarker for the onset of experimental autoimmune encephalomyelitis and response to therapy. To address this, we designed a two-part study to measure endogenous opioids in multiple sclerosis patients, and to investigate the temporal pattern of decline in serum enkephalin concentrations in mice with chronic progressive experimental autoimmune encephalomyelitis and treated with low-dose naltrexone. For comparison, we investigated whether low-dose naltrexone exposure in normal mice also resulted in altered enkephalin levels. In both animal models, we monitored tactile and heat sensitivity, as well as differential white blood cell counts as indicators of inflammation. Serum [Met5]-enkephalin levels were lower in humans with multiple sclerosis relative to non-multiple sclerosis patients, and low-dose naltrexone restored their levels. In experimental autoimmune encephalomyelitis mice, [Met5]-enkephalin levels were depressed prior to the appearance of clinical disease, and were restored with low-dose naltrexone treatment. Low-dose naltrexone therapy had no effect on serum [Met5]-enkephalin or β-endorphin in normal mice. Thus, [Met5]-enkephalin (i.e. opioid growth factor) may be a reasonable candidate biomarker for multiple sclerosis, and may signal new pathways for treatment of autoimmune disorders. Impact statement This report presents human and animal data identifying a novel biomarker for the onset and progression of multiple sclerosis (MS). Humans diagnosed with MS have reduced serum levels of OGF (i.e. [Met5]-enkephalin) relative to non-MS neurologic patients, and low-dose naltrexone (LDN) therapy restored their enkephalin levels. Serum OGF levels were reduced in mice immunized with MOG35-55 prior to any clinical behavioral sign of experimental autoimmune encephalomyelitis, and LDN therapy restored their serum OGF levels. β-endorphin concentrations were not altered by LDN in humans or mice. Thus, blood levels of OGF may serve as a new, selective biomarker for the progression of MS, as well as response to therapy.

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Maier, Smaranda, Mihaela Simu, Adina Hutanu, Laura Barcutean, Septimiu Voidazan, Zoltan Bajko, Anca Motataianu, Irina Lata, and Rodica Balasa. "Clinical Immunological Correlations in Patients with Multiple Sclerosis Treated with Natalizumab." Brain Sciences 10, no. 11 (October 30, 2020): 802. http://dx.doi.org/10.3390/brainsci10110802.

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Natalizumab (NAT) was the first disease modifying therapy used for the treatment of relapsing-remitting multiple sclerosis (MS) that was designed with a specific mechanism of action that targets an important step of the MS immunopathology, directly blocking the T lymphocyte intrusion in the central nervous system. Initially, it was considered that NAT carried no biological effects on the peripheral immune response. The purpose of our study was to assess the effects of NAT on the peripheral pro and anti-inflammatory cytokines and to reveal possible correlations between them and the clinical activity of the disease. We noticed a significant decrease in interleukin (IL)-17, tumor necrosis factor-alpha (TNF-α) and IL-31 serum levels in treated patients. The lack of relapses during the study was associated with low baseline IL-17 level. The patients that had an increase in the disability score during the study had significantly lower IL-17 and higher IL-1β baseline levels. IL-17 can be used as a biomarker for disease activity but also for progression assessment in NAT treated patients. NAT has a far more complex mechanism compared to what was initially believed, besides modulating lymphocyte trafficking through the blood–brain barrier, it also changes the peripheral levels of pro and anti-inflammatory cytokines in MS patients.

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Schulze-Topphoff, Ulf, Simona Casazza, Michel Varrin-Doyer, Kara Pekarek, Raymond A. Sobel, Stephen L. Hauser, Jorge R. Oksenberg, Scott S. Zamvil, and Sergio E. Baranzini. "Tob1 plays a critical role in the activation of encephalitogenic T cells in CNS autoimmunity." Journal of Experimental Medicine 210, no. 7 (June 24, 2013): 1301–9. http://dx.doi.org/10.1084/jem.20121611.

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Reliable biomarkers corresponding to disease progression or therapeutic responsiveness in multiple sclerosis (MS) have not been yet identified. We previously reported that low expression of the antiproliferative gene TOB1 in CD4+ T cells of individuals presenting with an initial central nervous system (CNS) demyelinating event (a clinically isolated syndrome), correlated with high risk for progression to MS. We report that experimental autoimmune encephalomyelitis (EAE) in Tob1−/− mice was associated with augmented CNS inflammation, increased infiltrating CD4+ and CD8+ T cell counts, and increased myelin-reactive Th1 and Th17 cells, with reduced numbers of regulatory T cells. Reconstitution of Rag1−/− mice with Tob1−/− CD4+ T cells recapitulated the aggressive EAE phenotype observed in Tob1−/− mice. Furthermore, severe spontaneous EAE was observed when Tob1−/− mice were crossed to myelin oligodendrocyte glycoprotein–specific T cell receptor transgenic (2D2) mice. Collectively, our results reveal a critical role for Tob1 in adaptive T cell immune responses that drive development of EAE, thus providing support for the development of Tob1 as a biomarker for demyelinating disease activity.

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Abarca-Zabalía, Judith, Ma Isabel García, Alberto Lozano Ros, Ignacio Marín-Jiménez, Maria L. Martínez-Ginés, Beatriz López-Cauce, María L. Martín-Barbero, et al. "Differential Expression of SMAD Genes and S1PR1 on Circulating CD4+ T Cells in Multiple Sclerosis and Crohn’s Disease." International Journal of Molecular Sciences 21, no. 2 (January 20, 2020): 676. http://dx.doi.org/10.3390/ijms21020676.

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The Th17 immune response plays a key role in autoimmune diseases such as multiple sclerosis (MS) and inflammatory bowel disease (IBD). Expression of Th17-related genes in inflamed tissues has been reported in autoimmune diseases. However, values are frequently obtained using invasive methods. We aimed to identify biomarkers of MS in an accessible sample, such as blood, by quantifying the relative expression of 91 Th17-related genes in CD4+ T lymphocytes from patients with MS during a relapse or during a remitting phase. We also compared our findings with those of healthy controls. After confirmation in a validation cohort, expression of SMAD7 and S1PR1 mRNAs was decreased in remitting disease (–2.3-fold and –1.3-fold, respectively) and relapsing disease (–2.2-fold and –1.3-fold, respectively). No differential expression was observed for other SMAD7-related genes, namely, SMAD2, SMAD3, and SMAD4. Under-regulation of SMAD7 and S1PR1 was also observed in another autoimmune disease, Crohn’s disease (CD) (−4.6-fold, -1.6-fold, respectively), suggesting the presence of common markers for autoimmune diseases. In addition, expression of TNF, SMAD2, SMAD3, and SMAD4 were also decreased in CD (–2.2-fold, –1.4-fold, –1.6-fold, and –1.6-fold, respectively). Our study suggests that expression of SMAD7 and S1PR1 mRNA in blood samples are markers for MS and CD, and TNF, SMAD2, SMAD3, and SMAD4 for CD. These genes could prove useful as markers of autoimmune diseases, thus obviating the need for invasive methods.

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Seiberl, Michael, Julia Feige, Patrick Hilpold, Wolfgang Hitzl, Lukas Machegger, Arabella Buchmann, Michael Khalil, et al. "Serum Neurofilament Light Chain as Biomarker for Cladribine-Treated Multiple Sclerosis Patients in a Real-World Setting." International Journal of Molecular Sciences 24, no. 4 (February 17, 2023): 4067. http://dx.doi.org/10.3390/ijms24044067.

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Serum neurofilament light chain (sNfL) is an intensely investigated biomarker in multiple sclerosis (MS). The aim of this study was to explore the impact of cladribine (CLAD) on sNfL and the potential of sNfL as a predictor of long-term treatment response. Data were gathered from a prospective, real-world CLAD cohort. We measured sNfL at baseline (BL-sNfL) and 12 months (12Mo-sNfL) after CLAD start by SIMOA. Clinical and radiological assessments determined fulfilment of “no evidence of disease activity” (NEDA-3). We evaluated BL-sNfL, 12M-sNfL and BL/12M sNfL ratio (sNfL-ratio) as predictors for treatment response. We followed 14 patients for a median of 41.5 months (range 24.0–50.0). NEDA-3 was fulfilled by 71%, 57% and 36% for a period of 12, 24 and 36 months, respectively. We observed clinical relapses in four (29%), MRI activity in six (43%) and EDSS progression in five (36%) patients. CLAD significantly reduced sNfL (BL-sNfL: mean 24.7 pg/mL (SD ± 23.8); 12Mo-sNfL: mean 8.8 pg/mL (SD ± 6.2); p = 0.0008). We found no correlation between BL-sNfL, 12Mo-sNfL and ratio-sNfL and the time until loss of NEDA-3, the occurrence of relapses, MRI activity, EDSS progression, treatment switch or sustained NEDA-3. We corroborate that CLAD decreases neuroaxonal damage in MS patients as determined by sNfL. However, sNfL at baseline and at 12 months failed to predict clinical and radiological treatment response in our real-world cohort. Long-term sNfL assessments in larger studies are essential to explore the predictive utility of sNfL in patients treated with immune reconstitution therapies.

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Parnell, Grant P., Prudence N. Gatt, Fiona C. McKay, Stephen Schibeci, Malgorzata Krupa, Joseph E. Powell, Peter M. Visscher, et al. "Ribosomal protein S6 mRNA is a biomarker upregulated in multiple sclerosis, downregulated by interferon treatment, and affected by season." Multiple Sclerosis Journal 20, no. 6 (October 14, 2013): 675–85. http://dx.doi.org/10.1177/1352458513507819.

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Background: Multiple Sclerosis (MS) is an immune-mediated disease of the central nervous system which responds to therapies targeting circulating immune cells. Objective: Our aim was to test if the T-cell activation gene expression pattern (TCAGE) we had previously described from whole blood was replicated in an independent cohort. Methods: We used RNA-seq to interrogate the whole blood transcriptomes of 72 individuals (40 healthy controls, 32 untreated MS). A cohort of 862 control individuals from the Brisbane Systems Genetics Study (BSGS) was used to assess heritability and seasonal expression. The effect of interferon beta (IFNB) therapy on expression was evaluated. Results: The MS/TCAGE association was replicated and rationalized to a single marker, ribosomal protein S6 (RPS6). Expression of RPS6 was higher in MS than controls ( p<0.0004), and lower in winter than summer ( p<4.6E-06). The seasonal pattern correlated with monthly UV light index ( R=0.82, p<0.002), and was also identified in the BSGS cohort ( p<0.0016). Variation in expression of RPS6 was not strongly heritable. RPS6 expression was reduced by IFNB therapy. Conclusions: These data support investigation of RPS6 as a potential therapeutic target and candidate biomarker for measuring clinical response to IFNB and other MS therapies, and of MS disease heterogeneity.

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Dumbrava, Ecaterina Elena, Michael L. Dougan, Sarthak Gupta, Laura Cappelli, Tamiko R. Katsumoto, Osama E. Rahma, Jeane Painter, et al. "A phase 1b study of nivolumab in patients with autoimmune disorders and advanced malignancies (AIM-NIVO)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): TPS2676. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps2676.

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TPS2676 Background: Nivolumab is an anti-PD1 monoclonal antibody approved for treatment of an increasing number of solid tumors and hematological malignancies. However, patients (pts) with history of autoimmune disorders are excluded from the majority of clinical trials testing immune-checkpoint inhibitors (ICI) such as anti-PD1/anti-PD-L1 antibodies. Consequently, the risks of flare ups, worsening of pre-existing autoimmune disorders or risk of de-novo immune related adverse events (irAEs) in pts with dysfunctional immune systems and tumor types who otherwise stand to benefit from ICI therapy are largely unknown, posing a challenge for oncologists. We are conducting a phase Ib study to test the hypothesis that nivolumab can be safely administered to pts with varying severity of Dermatomyositis, Systemic Sclerosis, Rheumatoid Arthritis, Systemic Lupus Erythematosus, Inflammatory Bowel Disease, Multiple Sclerosis and other autoimmune disorders (AIM-Nivo). Methods: AIM-Nivo is an open-label, multi-center ongoing phase Ib study with nivolumab 480mg IV every 28 days in pts with autoimmune diseases and advanced malignancies (NCT03816345). The study has autoimmune disease-specific cohorts overseen by a multidisciplinary group of experts. The primary objective is to assess the overall safety and toxicity profile of nivolumab in pts with autoimmune disorders and advanced malignancies. Secondary objectives are to evaluate the antitumor efficacy; the impact of nivolumab on the autoimmune disease severity indices; and to explore potential biomarkers of response, resistance, or toxicity for each of the autoimmune disease-specific cohorts. Key overall inclusion criteria include age ≥18 years, histologically confirmed advanced or metastatic malignancies in which ICI are approved or have shown clinical activity. Key overall exclusion criteria include prior therapy with anti-PD-1/PD-L1 antibodies. Specific eligibility criteria are defined for each disease-specific cohort. For each autoimmune disorder, severity level of the disease as defined by disease-specific severity indices will be assessed, and up to a total of 12 pts will be included in each disease cohort at each severity level (max 36 pts per cohort). Primary endpoints are dose-limiting toxicities, adverse events (AEs) and serious AEs. Continuous monitoring of toxicity will be conducted. Key secondary endpoints are best objective response per RECIST1.1; progression free and overall survival; and cohort specific tumor tissue, blood, and non-tumor tissue-based biomarkers. The AIM-Nivo trial opened in May 2019 and is enrolling pts through the National Cancer Institute Experimental Therapeutics Clinical Trials Network (ETCTN), Early Drug Development Opportunity Program (EDDOP), and Create Access to Targeted Cancer Therapy for Underserved Populations (CATCH-UP) sites. Clinical trial information: NCT03816345.

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Wagner, Martin, and Peter Fickert. "Drug Therapies for Chronic Cholestatic Liver Diseases." Annual Review of Pharmacology and Toxicology 60, no. 1 (January 6, 2020): 503–27. http://dx.doi.org/10.1146/annurev-pharmtox-010818-021059.

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Though ursodeoxycholic acid (UDCA) remains the baseline treatment for most cholestatic liver diseases, UDCA treatment leaves approximately one-third of patients with primary biliary cholangitis (PBC) and all patients with primary sclerosing cholangitis (PSC) at risk for disease progression. New anticholestatic agents, including nuclear receptor agonists, choleretics, and bile acid synthesis suppressors, will likely increase response rates to therapy in PBC and PSC. Strategies that target early immune-mediated injury have so far been disappointing, hampered by the lack of biomarkers to detect early disease states, which then could profit from immunomodulatory therapy. Future concepts need to personalize treatments according to disease stage, progression, and phase, and to combine multiple drugs to target different pathogenic pathways.

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Kearns, Patrick K. A., Sarah J. Martin, Jessie Chang, Rozanna Meijboom, Elizabeth N. York, Yingdi Chen, Christine Weaver, et al. "FutureMS cohort profile: a Scottish multicentre inception cohort study of relapsing-remitting multiple sclerosis." BMJ Open 12, no. 6 (June 2022): e058506. http://dx.doi.org/10.1136/bmjopen-2021-058506.

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PurposeMultiple sclerosis (MS) is an immune-mediated, neuroinflammatory disease of the central nervous system and in industrialised countries is the most common cause of progressive neurological disability in working age persons. While treatable, there is substantial interindividual heterogeneity in disease activity and response to treatment. Currently, the ability to predict at diagnosis who will have a benign, intermediate or aggressive disease course is very limited. There is, therefore, a need for integrated predictive tools to inform individualised treatment decision making.ParticipantsEstablished with the aim of addressing this need for individualised predictive tools, FutureMS is a nationally representative, prospective observational cohort study of 440 adults with a new diagnosis of relapsing-remitting MS living in Scotland at the time of diagnosis between May 2016 and March 2019.Findings to dateThe study aims to explore the pathobiology and determinants of disease heterogeneity in MS and combines detailed clinical phenotyping with imaging, genetic and biomarker metrics of disease activity and progression. Recruitment, baseline assessment and follow-up at year 1 is complete. Here, we describe the cohort design and present a profile of the participants at baseline and 1 year of follow-up.Future plansA third follow-up wave for the cohort has recently begun at 5 years after first visit and a further wave of follow-up is funded for year 10. Longer-term follow-up is anticipated thereafter.

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Grigorov, Boncho, Anastasiya Trenova, Antonia Grigorova, and Spaska Stanilova. "IL-18 PROMOTER POLYMORPHISM AND IL-18 SERUM LEVELS IN ASSOCIATION WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS." Journal of IMAB - Annual Proceeding (Scientific Papers) 26, no. 4 (December 1, 2020): 3475–80. http://dx.doi.org/10.5272/jimab.2020264.3475.

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Purpose: Multiple sclerosis is the immune-mediated disorder whose etiology is not completely understood. The present study aimed to survey association between the promoter polymorphism IL18 -607C/A (rs1946518), the serum concentration of IL-18 and susceptibility to relapsing-remitting multiple sclerosis (RRMS) in Bulgarian patients Material and Methods: This case-control study includes 159 RRMS patients with disease-modifying therapy (DMT) and 162 age-sex-matched healthy volunteers. All included subjects were genotyped by ARMS-PCR while serum levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: Our results revealed significant differences in the serum levels of IL-18 according to the gender, the onset of disease and the type of disease-modifying therapy. The serum levels of IL-18 are significantly higher in RRMS men compared to RRMS women and the RRMS men with late-onset of the disease (above 30 years) also demonstrated significantly increased serum levels than the women with late-onset of disease and even with healthy men. The RRMS patients treated with interferon-beta showed significantly increased IL-18 serum level than those treated with glatiramer acetate. Conclusions: Our study shows that the promoter polymorphism IL18 -607C/A is not associated with susceptibility to RRMS in Bulgarian patients as well as the serum level of the cytokine. The observed differences in the serum level of IL-18 in RRMS patients according to gender and the response to therapy could be used as a biomarker to the course of the disease.

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Brahmajothi, Mulugu V., and Mohamed Bahie Abou-Donia. "Autoantibodies to myelin proteins as biomarkers to identify nervous system injuries in Gulf War Illness and other neuromuscular disorders." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 166.62. http://dx.doi.org/10.4049/jimmunol.200.supp.166.62.

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Abstract A study on veterans with Gulf War Illness (GWI) from Madison VA Hospital demonstrated a widespread disruption of damages to the white matter using magnetic resonance brain imaging suggesting a cause of prolonged chronic musculoskeletal pain. We hypothesized that exposure to various chemicals could cause delayed neurotoxicity and that myelin is an important white matter component, which play a critical role in neural function and plasticity. Any disruption to myelin may result in reduced brain connectivity, musculoskeletal pain, and cognitive dysfunction. Since myelin is composed of various proteins, dysregulation or damage over a period will form a distinguishable biomarker in CSF and in serum/plasma. Further, continued damage could elicit an immune response. With these reasoning, we measured serum/plasma levels of myelin proteins and autoantibodies specific to myelin proteins by ELISA in Veterans with Gulf War Illness (GWI) and other patients with neuronal disorders (Multiple Sclerosis (MS), Parkinson’s disease (PD), mild Traumatic Brain Injury (TBI), Flight Crews with chronic pain and veterans with Chronic Fatigue Syndrome (CFS) and Lupus (SLE)). We quantitated several myelin proteins (MPZ, MAG, MBP MOG, MOBP, PMP2, and NF155) to determine the intensity of disruption. Autoantibody levels in MS patients were used as positive control and since all the samples (n=10) tested showed the highest level of IgG specific autoantibodies compared to other cohorts. Significantly increased levels of NF155, MOG, MOBP, and MAG were observed among all groups compared to controls (p<0.001). Elevated levels of MPZ and PMP2 characterized PD and SLE (p<0.01) and GWI veterans showed elevated levels of MBP compared CFS and healthy cohorts.

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Ileana Dumbrava, Ecaterina Elena, Maria E. Suarez-Almazor, Jeane Painter, Tanner Johanns, Michael L. Dougan, Laura Cappelli, Clifton O. Bingham, et al. "A phase Ib study of nivolumab in patients with autoimmune disorders and advanced malignancies (AIM-NIVO)." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): TPS3158. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps3158.

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TPS3158 Background: Immune checkpoint inhibitors (ICI) such as anti-PD-1/PD-L1 antibodies have become a pivotal approach to cancer therapy. Nivolumab is an anti-PD1 antibody approved for an increasing number of solid tumors and hematological malignancies. However, patients (pts) with history of autoimmune disorders are excluded from the majority of clinical trials testing ICI. Consequently, the risks of flares and worsening of pre-existing autoimmune disorders in pts with tumor types who otherwise stand to benefit from ICI therapy are largely unknown, posing a challenge for oncologists. We are conducting a phase Ib study to test the hypothesis that nivolumab can be safely administered to pts with varying severity of Dermatomyositis, Systemic Sclerosis, Rheumatoid Arthritis, Systemic Lupus Erythematosus, Inflammatory Bowel Disease, Multiple Sclerosis, Sjögren's Syndrome and Other Autoimmune Disorders (AIM-Nivo). Methods: AIM-Nivo is an open-label, multi-center ongoing phase Ib study with nivolumab 480mg IV every 28 days in pts with autoimmune diseases and advanced malignancies (NCT03816345). The study has autoimmune disease-specific cohorts overseen by a multidisciplinary group of experts. The primary objective is to assess the overall safety and toxicity profile of nivolumab in pts with autoimmune disorders and advanced malignancies. Secondary objectives are to evaluate the antitumor efficacy, the impact of nivolumab on the autoimmune disease severity indices, and to explore potential biomarkers of response, resistance or toxicity. Key overall inclusion criteria include age ≥18 years, histologically confirmed advanced malignancies in which ICI are approved or have shown clinical activity. Key overall exclusion criteria include prior therapy with anti-PD-1/PD-L1 antibodies. Specific eligibility criteria are defined for each disease-specific cohort. For each autoimmune disorder, severity level of the disease as defined by disease-specific severity indices will be assessed, and up to a total of 12 pts will be included in each disease cohort at each severity level. Primary endpoints are dose-limiting toxicities, adverse events (AEs) and serious AEs. Continuous monitoring of toxicity will be conducted. Key secondary endpoints are best objective response, progression free and overall survival and cohort specific tumor tissue, blood and non-tumor tissue-based biomarkers. The AIM-Nivo trial opened in May 2019 and is enrolling pts through the National Cancer Institute Experimental Therapeutics Clinical Trials Network (ETCTN). Clinical trial information: NCT03816345 .

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Zheng, B., K. Keen, M. Fritzler, C. Ryerson, P. Wilcox, B. Whalen, B. Sahin, et al. "POS0869 CYTOKINES IN SYSTEMIC SCLEROSIS RELATED INTERSTITIAL LUNG DISEASE AND IDIOPATHIC PULMONARY FIBROSIS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 729.1–729. http://dx.doi.org/10.1136/annrheumdis-2022-eular.1905.

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BackgroundImmune pathways have been implicated in both systemic sclerosis (SSc)-related interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF). Determination of blood cytokine differences in these two disorders need to be elucidated to better understand potential biological processes and common pathogenic pathways.ObjectivesThis study compared 87 circulating cytokine levels amongst healthy controls and both SSc-ILD and IPF. There was also exploration of the association between cytokine levels and disease progression based on the annualized rate of decline of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO).MethodsLevels of 87 plasma cytokines were measured using commercial panels for consecutive SSc-ILD, IPF, and healthy individuals recruited at a Canadian tertiary-care center. Pulmonary function tests were performed as clinically indicated every 3-12 months. Cytokine levels are compared using the Wilcoxon rank sum test for two samples pairwise. The association between differentially expressed cytokines with both percent predicted annualized FVC and DLCO change was assessed within each disease group using multiple linear models adjusted for age, sex, baseline FVC, and immunosuppressive or anti-fibrotic treatment at sampling. Correction for multiplicity of testing was by Holm’s method.ResultsThere were 19 healthy controls, 40 SSc-ILD, and 17 IPF participants with clinical features shown in Table 1. Eotaxin-1 and interleukin 6 (IL-6) were significantly elevated in both SSc-ILD and IPF compared to healthy controls (Figure 1). SSc-ILD had significantly lower soluble epidermal growth factor receptor (sEGFR) and higher levels of both soluble tumor necrosis factor receptor type II (sTNFRII) and soluble vascular endothelial growth factor receptor-1 (sVEGFR1) compared to healthy controls. IPF cases were distinguished from healthy controls by significantly higher monocyte chemoattractant protein-1 (MCP-1) and monokine induced by gamma interferon (MIG, also known as CXCL9) levels. No significant association was found for any of the cytokines with ILD progression based on annualized rates of either FVC or DLCO change.Table 1.Baseline patient characteristics stratified by disease groupsHealthy control(n = 19)SSc-ILD(n = 40)IPF(n = 17)Age, year51 ± 1956 ± 1273 ± 7Male, count (%)6 (32)12 (30)12 (71)Disease duration, yearNA6.41 (7.81)1.76 (2.14)Ever smoker, count (%)2 (11)19 (48)14 (82)•4 (82)oker0.4 [0, 1]11 [4, 29]19 [11, 35]Treatment presence, count (%)NA16 (40)7 (41)Baseline FVC %NA80 ± 2285 ± 21Baseline DLCO %NA51 ± 1749 ± 11Annualized FVC % changeNA-1.7 ± 8.2-6.2 ± 13.6Annualized DLCO % changeNA-0.5 ± 6.2-7.8 ± 18.6The number (%), mean ± standard deviation, and median [interquartile range] are shown. Disease duration is defined as time of ILD first seen on HRCT in IPF and time from first non-Raynaud’s phenomenon in SSc-ILD. Treatment includes presence of ILD therapies: nintedanib, pirfenidone, mycophenolate mofetil, azathioprine, rituximab. FVC = forced vital capacity, DLCO = diffusing capacity for carbon monoxideFigure 1.Notched box plots of cytokine differences between disease groups. All cytokine levels are shown on a log scale. Overlap of notches indicates lack of a statistically significant difference in medians in a pairwise comparison. P-values are for SSc-ILD or IPF compared to healthy controls using Wilcoxon rank sum two-sample test corrected for multiple testing using Holms method.ConclusionDifferences in seven circulating cytokines between healthy controls with both SSc-ILD and IPF show evidence of systemic cytokine activation. All seven cytokines have a role in immune cell extravasation and pro-fibrotic signaling, which provides further evidence of immune pathways involved in pulmonary fibrosis. Further studies will be pursued of longitudinal change of these biomarkers for halting or slowing disease progression and improving response to treatment.Disclosure of InterestsBoyang Zheng: None declared, Kevin Keen Grant/research support from: Merck Canada Inc, Marvin Fritzler Shareholder of: Abbott Laboratories; Roche Holdings; Abcellera; Moderna, Speakers bureau: For diagnostic company: Werfen, Consultant of: For diagnostic company: Werfen; Aesku, Employee of: Medical Director of Mitogen Diagnostics, Christopher Ryerson Speakers bureau: Boehringer Ingelheim, Hoffmann-La Roche, Consultant of: Boehringer Ingelheim, Hoffmann-La Roche, Veracyte, Astra Zeneca, Grant/research support from: Boehringer Ingelheim, Hoffmann-La Roche, Pearce Wilcox Speakers bureau: Vertex, Valeo, Boehringer, Beth Whalen: None declared, Basak Sahin: None declared, Haiyan Hou Employee of: Mitogen Diagnostics, Penny Latham Employee of: Eve technologies, Mei Feng Zhang Employee of: Mitogen diagnostics, Iris Yao: None declared, James Dunne: None declared

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Kersh, Anna. "CD4 T Cell reactivity to both native and citrullinated-MOG epitopes identified in HLA-DR4 mouse model Of demyelinating disease (BA11P.137)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 184.19. http://dx.doi.org/10.4049/jimmunol.194.supp.184.19.

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Abstract Multiple sclerosis (MS) is an autoimmune disease characterized by inflammation and demyelination in the central nervous system (CNS). HLA-DR4 is an MHC class II gene associated with increased risk for MS. Humanized HLA-DR4-transgenic mice were used to probe T cell specificity and affinity during demyelinating disease progression in response to myelin oligodendrocyte glycoprotein (MOG). Using the micropipette adhesion frequency assay to obtain sensitive, physiologically relevant measurements, only 26% of CNS-infiltrating CD4 T cells are reactive to MOG in symptomatic HLA-DR4-expressing mice. Moreover T cells probed for specificity to a modified MOG peptide containing a citrulline residue in position 101 instead of arginine revealed T cells reactive to MOG alone, citrulline-modified MOG, or to both. Of importance, the citrullinated-MOG peptide does not induce paralytic disease on its own. We believe that these results are the first demonstration of T cell reactivity to citrullinated-MOG epitopes in the context of HLA-DR4 presentation to T cells. We suggest that T cell cross-reactivity to native and citrullinated epitopes of MOG provides a mechanism of disease progression and escape from immune tolerance. Further, reactivity to the citrullinated neoepitope has great implications for use as a potential biomarker of disease therapeutic efficacy since citrullination is the result of a deimination reaction that occurs during prolonged inflammation.

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Rajathilagam T, Rajathilagam T., Thuthi Mohan Thuthi Mohan, Aruna B Patil, Mohanavalli S. Mohanavalli S, and Seethalakshmi S. Seethalakshmi S. "IL-6, a Therapeutic Target and Omega-3 PUFA, a Host Modulator in Chronic Periodontitis." Biomedical and Pharmacology Journal 14, no. 4 (December 30, 2021): 2307–18. http://dx.doi.org/10.13005/bpj/2332.

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Periodontitis is a common multifactorial inflammatory disease with gradual loss of supportive tissues around the teeth which eventually leads to decrease in the quality of life. Blocking Interleukin-6 (IL-6), a multifunctional cytokine with pro-inflammatory properties has demonstrated therapeutic efficacy in inflammatory diseases like Rheumatoid arthritis, SLE and multiple sclerosis. Host immune response, the underlying cause for this progressive disease is targeted by Host modulatory therapy (HMT), an emerging treatment modality. Omega-3 polyunsaturated fatty acids (ώ 3 PUFAs), one of the relatively safe HMTs, reduces tissue destruction, stabilizes or even regenerates the periodontium through its anti-inflammatory & immunoregulatory properties. ώ 3 PUFAs are essential for the synthesis of eicosanoids which are involved in anti-inflammatory, antiplatelet aggregatory, vasodilation, vasoconstriction, immune response, cell growth and proliferation. The key factor examined and extrapolated in this study is the anti-inflammatory property of ώ 3 PUFA. The aim of the study was to evaluate the immunological and clinical response to ώ 3 PUFA supplementation therapy in chronic periodontitis by measuring the inflammatory cytokine, IL-6 levels in serum. In this open label exploratory study, 40 patients with a Female: Male ratio of 4:1were enrolled and assessed clinically by measuring Oral Hygiene Index-Simplified (OHI-S), Probing Pocket Depth (PPD), Clinical Attachment Level (CAL) and their serum for IL-6 levels. Subsequently 300 mg (concentration of EPA 180/DHA120) of ώ 3 PUFA was prescribed twice daily for 3 months and periodically reviewed to assess their IL-6 levels and periodontal status. IL-6 levels which were at a maximum mean of 10.2 pg/ml prior to treatment, showed a gradual and notable reduction to 2.3 pg/ml at the end of the study following ώ 3 PUFA supplementation therapy. The coefficient of variation R2 and ANOVA showed statistically significant periodic variation in biomarker IL-6 and in all clinical measurements at all time intervals. ώ 3 PUFA adjunctive therapy significantly reduces the inflammatory cytokine (IL-6) levels and causes noteworthy improvement of the most relevant clinical parameters (OHI-S, PPD, CAL). Hence ώ 3 PUFA can be recommended as a dietary supplementation and a safe host modulatory treatment in chronic periodontitis.

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Asgharzadeh, Mohammad, Mir Reza Valiallahzadeh, Zahra Taghinejad, Behroz Mahdavi Poor, Hossein Samadi Kafil, Vahid Asgharzadeh, and Jalil Rashedi. "Diagnostic biomarkers of multiple sclerosis." Romanian Journal of Neurology 20, no. 4 (December 31, 2021): 418–23. http://dx.doi.org/10.37897/rjn.2021.4.2.

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Multiple sclerosis (MS) is a chronic and inflammatory disease of the central nervous system (CNS) that is common in people between the ages of 20 and 40. Although the exact cause of MS is still unknown, evidences shows that genetic and environmental factors have a role in activating immune cells to attack the myelin sheath of the neurons, and causing them to be damaged. In order to control and reduce the disease prevalence, early identification of at risk people and patients in the early stages of the disease is important. Measurement of interferon gamma (IFN-γ), vitamin D, melatonin, neurofilaments, micro RNA-132 (miR-132), miR-155, determination of antibody titer against Epstein-Barr virus (EBV) and human leukocyte antigen (HLA) typing are appropriate methods to diagnose the disease, and ultimately prevent its recurrence.

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Michaličková, Danica, Öztürk Kübra, Debanjan Das, Bukhari Osama, and Ondřej Slanař. "Molecular biomarkers in multiple sclerosis." Arhiv za farmaciju 72, no. 2 (2022): 127–48. http://dx.doi.org/10.5937/arhfarm72-36165.

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Multiple sclerosis (MS) is a highly heterogenous disease regarding radiological, pathological, and clinical characteristics and therapeutic response, including both the efficacy and safety profile of treatments. Accordingly, there is a high demand for biomarkers that sensitively and specifically apprehend the distinctive aspects of the MS heterogeneity, and that can aid in better understanding of the disease diagnosis, prognosis, prediction of the treatment response, and, finally, in the development of new treatments. Currently, clinical characteristics (e.g., relapse rate and disease progression) and magnetic resonance imaging play the most important role in the clinical classification of MS and assessment of its course. Molecular biomarkers (e.g., immunoglobulin G (IgG) oligoclonal bands, IgG index, anti-aquaporin-4 antibodies, neutralizing antibodies against interferon-beta and natalizumab, anti-varicella zoster virus and anti-John Cunningham (JC) virus antibodies) complement these markers excellently. This review provides an overview of exploratory, validated and clinically useful molecular biomarkers in MS which are used for prediction, diagnosis, disease activity and treatment response.

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Pastare, Daina, Mohamed Ridha Bennour, Elīna Polunosika, and Guntis Karelis. "Biomarkers of Multiple Sclerosis." Open Immunology Journal 9, no. 1 (December 20, 2019): 1–13. http://dx.doi.org/10.2174/1874226201909010001.

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The search for an ideal multiple sclerosis biomarker with good diagnostic value, prognostic reference and an impact on clinical outcome has yet to be realized and is still ongoing. The aim of this review is to establish an overview of the frequent biomarkers for multiple sclerosis that exist to date. The review summarizes the results obtained from electronic databases, as well as thorough manual searches. In this review the sources and methods of biomarkers extraction are described; in addition to the description of each biomarker, determination of the prognostic, diagnostic, disease monitoring and treatment response values besides clinical impact they might possess. We divided the biomarkers into three categories according to the achievement method: laboratory markers, genetic-immunogenetic markers and imaging markers. We have found two biomarkers at the time being considered the gold standard for MS diagnostics. Unfortunately, there does not exist a single solitary marker being able to present reliable diagnostic value, prognostic value, high sensitivity and specificity as well as clinical impact. We need more studies to find the best biomarker for MS.

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Rodríguez Murúa, Sofía, Mauricio F. Farez, and Francisco J. Quintana. "The Immune Response in Multiple Sclerosis." Annual Review of Pathology: Mechanisms of Disease 17, no. 1 (January 24, 2022): 121–39. http://dx.doi.org/10.1146/annurev-pathol-052920-040318.

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Multiple sclerosis (MS) is a chronic autoimmune, inflammatory, and neurodegenerative disease that affects the central nervous system (CNS). MS is characterized by immune dysregulation, which results in the infiltration of the CNS by immune cells, triggering demyelination, axonal damage, and neurodegeneration. Although the exact causes of MS are not fully understood, genetic and environmental factors are thought to control MS onset and progression. In this article, we review the main immunological mechanisms involved in MS pathogenesis.

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Buck, Dorothea, and Bernhard Hemmer. "Biomarkers of treatment response in multiple sclerosis." Expert Review of Neurotherapeutics 14, no. 2 (January 6, 2014): 165–72. http://dx.doi.org/10.1586/14737175.2014.874289.

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Wipfler, P., K. Oppermann, G. Pilz, S. Afazel, E. Haschke-Becher, A. Harrer, M. Huemer, et al. "Adhesion molecules are promising candidates to establish surrogate markers for natalizumab treatment." Multiple Sclerosis Journal 17, no. 1 (October 11, 2010): 16–23. http://dx.doi.org/10.1177/1352458510383075.

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Background: Natalizumab is the first monoclonal antibody therapy approved for multiple sclerosis (MS). Its therapeutic mechanism is the blockade of the α4-integrin subunit of the adhesion molecule (AM) very late activation antigen-4 (VLA-4), which leads to an inhibition of immune cell extravasation into the central nervous system (CNS). Methods: We investigated changes in the expression levels of unblocked α4-integrin and further AM (intercellular adhesion molecule-1, -2, -3 (cICAM-1, -2, -3), leukocyte function associated antigen-1 (LFA-1)) on peripheral blood mononuclear cells (PBMC) determined by flow cytometry from 25 patients with MS before the first natalizumab infusion and before the fourth infusion. In 15 MS patients AM expression was evaluated every 3 months over 1 year. Results:We found a significant decrease ( p < 0.0001) of unblocked α4-integrin cell surface expression on all investigated PBMC subsets (T cells −61.7%, B cells −69.1%, monocytes/macrophages −46.4%) in the blood of MS patients after 3 months of natalizumab treatment. Moreover, a continuous decrease ( p < 0.05) of unblocked α4-integrin expression levels was seen after 3, 6, 9, and 12 months. As a secondary effect, expression levels of the other investigated AM were differentially affected. Conclusions:Results show a sustained decrease of unblocked α4-integrin expression not only in all patients but also in all investigated PBMC subsets. This probably results in a continuously decreasing transmigration of PBMC into the CNS and may explain the improved clinical efficacy in the second treatment year and also the increasing risk of progressive multifocal leukoencephalopathy during long-term natalizumab therapy. We conclude that AM expression profiles are promising candidates for the development of a biomarker system to determine both natalizumab treatment response and patients at risk for opportunistic CNS infections.

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Dillenseger, Anja, Marie Luise Weidemann, Katrin Trentzsch, Hernan Inojosa, Rocco Haase, Dirk Schriefer, Isabel Voigt, Maria Scholz, Katja Akgün, and Tjalf Ziemssen. "Digital Biomarkers in Multiple Sclerosis." Brain Sciences 11, no. 11 (November 16, 2021): 1519. http://dx.doi.org/10.3390/brainsci11111519.

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For incurable diseases, such as multiple sclerosis (MS), the prevention of progression and the preservation of quality of life play a crucial role over the entire therapy period. In MS, patients tend to become ill at a younger age and are so variable in terms of their disease course that there is no standard therapy. Therefore, it is necessary to enable a therapy that is as personalized as possible and to respond promptly to any changes, whether with noticeable symptoms or symptomless. Here, measurable parameters of biological processes can be used, which provide good information with regard to prognostic and diagnostic aspects, disease activity and response to therapy, so-called biomarkers Increasing digitalization and the availability of easy-to-use devices and technology also enable healthcare professionals to use a new class of digital biomarkers—digital health technologies—to explain, influence and/or predict health-related outcomes. The technology and devices from which these digital biomarkers stem are quite broad, and range from wearables that collect patients’ activity during digitalized functional tests (e.g., the Multiple Sclerosis Performance Test, dual-tasking performance and speech) to digitalized diagnostic procedures (e.g., optical coherence tomography) and software-supported magnetic resonance imaging evaluation. These technologies offer a timesaving way to collect valuable data on a regular basis over a long period of time, not only once or twice a year during patients’ routine visit at the clinic. Therefore, they lead to real-life data acquisition, closer patient monitoring and thus a patient dataset useful for precision medicine. Despite the great benefit of such increasing digitalization, for now, the path to implementing digital biomarkers is widely unknown or inconsistent. Challenges around validation, infrastructure, evidence generation, consistent data collection and analysis still persist. In this narrative review, we explore existing and future opportunities to capture clinical digital biomarkers in the care of people with MS, which may lead to a digital twin of the patient. To do this, we searched published papers for existing opportunities to capture clinical digital biomarkers for different functional systems in the context of MS, and also gathered perspectives on digital biomarkers under development or already existing as a research approach.

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Harris, Violaine K., and Saud A. Sadiq. "Biomarkers of Therapeutic Response in Multiple Sclerosis: Current Status." Molecular Diagnosis & Therapy 18, no. 6 (August 28, 2014): 605–17. http://dx.doi.org/10.1007/s40291-014-0117-0.

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Hernández-Pedro, Norma Y., Guillermo Espinosa-Ramirez, Verónica Pérez de la Cruz, Benjamín Pineda, and Julio Sotelo. "Initial Immunopathogenesis of Multiple Sclerosis: Innate Immune Response." Clinical and Developmental Immunology 2013 (2013): 1–15. http://dx.doi.org/10.1155/2013/413465.

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Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. The hallmark to MS is the demyelinated plaque, which consists of a well-demarcated hypocellular area characterized by the loss of myelin, the formation of astrocytic scars, and the mononuclear cell infiltrates concentrated in perivascular spaces composed of T cells, B lymphocytes, plasma cells, and macrophages. Activation of resident cells initiates an inflammatory cascade, leading to tissue destruction, demyelination, and neurological deficit. The immunological phenomena that lead to the activation of autoreactive T cells to myelin sheath components are the result of multiple and complex interactions between environment and genetic background conferring individual susceptibility. Within the CNS, an increase of TLR expression during MS is observed, even in the absence of any apparent microbial involvement. In the present review, we focus on the role of the innate immune system, the first line of defense of the organism, as promoter and mediator of cross reactions that generate molecular mimicry triggering the inflammatory response through an adaptive cytotoxic response in MS.

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