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Autoimmunity in the Nervous Systems: Multiple Sclerosis and Beyond 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (10 March 2023) | Viewed by 9552

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Special Issue Editors

Dr. Maria Liguori

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Consiglio Nazionale delle Ricerche, Institute of Biomedical Technologies, Bari Unit, Bari, Italy
Interests: neurosciences; multiple sclerosis; neurodegenerative diseases; genomics, transcriptomics; neuroimaging; genotype-phenotype correlations; pharmacogenomics
Special Issues, Collections and Topics in MDPI journals

Dr. Maria Rosaria Coscia

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Guest Editor

National Research Council of Italy, Institute of Biochemistry and Cell Biology, Via P. Castellino 111, 80131 Naples, Italy
Interests: comparative immunology; immunoglobulin genes; adaptive immunity; molecular biology; biochemistry; genome evolution; engineered monoclonal antibodies

Special Issue Information

Dear Colleagues,

Several cellular and molecular mechanisms—e.g., molecular mimicry, cytokine dysregulation, dendritic cell apoptosis, and defective autophagy—underlie autoimmunity, in which factors such as sex, genes, and the environment can play different roles. Since females have been reported to be affected more often by autoimmune diseases, much attention has been given to the biological analysis of the observed sex bias and its impact on immune-mediated diseases.

One of the most recognizable and studied autoimmune diseases of the central nervous system is multiple sclerosis (MS); however, several other syndromes have been recognized, depending on the target of the immunological reaction. Interestingly, sometimes, the molecular mechanisms underlying these disorders overlap due to their common pathogenic pathways. For example, conditional deletions of autophagy-related proteins seem to protect from experimental autoimmune encephalomyelitis (the animal model of MS) and experimental arthritis. Furthermore, single-nucleotide polymorphisms (SNPs) of autophagy-related genes have been reported to be associated with susceptibility to both systemic lupus erythematosus and Crohn’s disease. In our opinion, looking into these types of interactions will also help to disentangle the complex regulation of autoimmunity, as well as providing valuable support for addressing possible novel targeted therapeutic efforts.

Following the previous Special Issue, in this new edition, we aim to broaden the current picture of autoimmunity by also considering the proven impact of gut microbiota in the immunological balance of the nervous system. Once more, particular interest will be given to novel and original data reporting significant sex differences in the autoimmune pathogenic mechanisms of the most well-known neurological diseases.

Dr. Maria Liguori
Dr. Maria Rosaria Coscia
Guest Editors

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Keywords

molecular basis of immune mechanisms
genetics and epigenetics of autoimmune diseases
immune dysregulation
sex differences of self-tolerance and other pathogenic mechanisms
autoimmunity and neurodegeneration
environmental modulation of immune response
microbiome and nervous systems
multiple sclerosis and other autoimmune diseases
immunotherapy
biomarkers
computational biology

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Autoimmunity in the Nervous Systems: Multiple Sclerosis and Beyond in International Journal of Molecular Sciences (6 articles)

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Research

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11 pages, 1205 KiB

Open AccessArticle

Immunomodulatory Aspects of Therapeutic Plasma Exchange in Neurological Disorders—A Pilot Study

by Fabian Foettinger, Georg Pilz, Peter Wipfler, Andrea Harrer, Jan Marco Kern, Eugen Trinka and Tobias Moser

Int. J. Mol. Sci. 2023, 24(7), 6552; https://doi.org/10.3390/ijms24076552 - 31 Mar 2023

Cited by 2 | Viewed by 2296

Abstract

Therapeutic plasma exchange (TPE) is used for drug-resistant neuroimmunological disorders, but its mechanism of action remains poorly understood. We therefore prospectively explored changes in soluble, humoral, and cellular immune components associated with TPE. We included ten patients with neurological autoimmune disorders that underwent TPE and assessed a panel of clinically relevant pathogen-specific antibodies, total serum immunoglobulin (Ig) levels, interleukin-6 (IL-6, pg/mL), C-reactive protein (CRP, mg/dL), procalcitonin (PCT, µg/L) and major lymphocyte subpopulations (cells/µL). Blood was collected prior to TPE (pre-TPE, baseline), immediately after TPE (post-TPE), as well as five weeks (follow-up1) and 130 days (follow-up2) following TPE. Pathogen-specific antibody levels were reduced by −86% (p < 0.05) post-TPE and recovered to 55% (follow-up1) and 101% (follow-up2). Ig subclasses were reduced by −70–89% (p < 0.0001) post-TPE with subsequent complete (IgM/IgA) and incomplete (IgG) recovery throughout the follow-ups. Mean IL-6 and CRP concentrations increased by a factor of 3–4 at post-TPE (p > 0.05) while PCT remained unaffected. We found no alterations in B- and T-cell populations. No adverse events related to TPE occurred. TPE induced a profound but transient reduction in circulating antibodies, while the investigated soluble immune components were not washed out. Future studies should explore the effects of TPE on particular cytokines and assess inflammatory lymphocyte lineages to illuminate the mode of action of TPE beyond autoantibody removal. Full article

(This article belongs to the Special Issue Autoimmunity in the Nervous Systems: Multiple Sclerosis and Beyond 2.0)

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13 pages, 1024 KiB

Open AccessArticle

Gene- and Gender-Related Decrease in Serum BDNF Levels in Alzheimer’s Disease

by Daniela Piancatelli, Anna Aureli, Pierluigi Sebastiani, Alessia Colanardi, Tiziana Del Beato, Lorenza Del Cane, Patrizia Sucapane, Carmine Marini and Silvia Di Loreto

Int. J. Mol. Sci. 2022, 23(23), 14599; https://doi.org/10.3390/ijms232314599 - 23 Nov 2022

Cited by 7 | Viewed by 2227

Abstract

Brain-derived neurotrophic factor (BDNF) has a protective role in Alzheimer’s disease (AD). Oxidative stress and inflammatory cytokines are potentially implicated in AD risk. In this study, BDNF was detected in serum of AD and mild cognitive impairment (MCI) patients and investigated in association with gene polymorphisms of BDNF (Val66Met and C270T), of some oxidative stress-related genes (FOXO3A, SIRT3, GLO1, and SOD2), and of interleukin-1 family genes (IL-1α, IL-1β, and IL-38). The APOE status and mini-mental state examination (MMSE) score were also evaluated. Serum BDNF was significantly lower in AD (p = 0.029), especially when comparing the female subsets (p = 0.005). Patients with BDNFVal/Val homozygous also had significantly lower circulating BDNF compared with controls (p = 0.010). Moreover, lower BDNF was associated with the presence of the T mutant allele of IL-1α(rs1800587) in AD (p = 0.040). These results were even more significant in the female subsets (BDNFVal/Val, p = 0.001; IL-1α, p = 0.013; males: ns). In conclusion, reduced serum levels of BDNF were found in AD; polymorphisms of the IL-1α and BDNF genes appear to be involved in changes in serum BDNF, particularly in female patients, while no effects of other gene variants affecting oxidative stress have been found. These findings add another step in identifying gender-related susceptibility to AD. Full article

(This article belongs to the Special Issue Autoimmunity in the Nervous Systems: Multiple Sclerosis and Beyond 2.0)

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13 pages, 1891 KiB

Open AccessArticle

PI3-Kinase p110α Deficiency Modulates T Cell Homeostasis and Function and Attenuates Experimental Allergic Encephalitis in Mature Mice

by José M. Rojo, María Montes-Casado, Laura Aragoneses-Fenoll, Gloria Ojeda, Umberto Dianzani and Pilar Portolés

Int. J. Mol. Sci. 2021, 22(16), 8698; https://doi.org/10.3390/ijms22168698 - 13 Aug 2021

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Abstract

Class I phosphoinositide 3-kinases (PI3K) are involved in the development of normal and autoimmune responses, including Experimental Autoimmune Encephalomyelitis (EAE), a mouse model for human multiple sclerosis (MS). Here, the role of the ubiquitously expressed class IA PI3K p110α catalytic subunits in EAE has been analyzed using a model of Cre/flox mediated T cell specific deletion of p110α catalytic chain (p110αΔT). Comparison of two month-old (young) and six month-old (mature) p110αΔT mice and their wild type (WT) counterparts indicated loss of spleen CD4⁺ T cells that increased with age, indicating a role of p110α in their homeostasis. In contrast, CD4⁺ T regulatory (Treg) cells were enhanced in mature p110αΔT mice when compared to WT mice. Since Myelin Oligodendrocyte Glycoprotein (MOG) peptide-induced EAE is dependent on, or mediated by CD4⁺ T cells and CD4⁺ T cell-derived cytokines and controlled by Treg cells, development of EAE in young and mature WT or p110αΔT mice was analyzed. EAE clinical symptoms and disease scores in six month p110αΔT mice were significantly lower than those of mature WT, or young WT and p110αΔT mice. Furthermore, ex vivo antigen activation of lymph node cells from MOG immunized mature p110αΔT mice induced significantly lower levels of IFN-γ and IL-17A than young p110αΔT or young and mature WT mice. Other cytokines including IL-2, IL-10 or TNF-α showed no significant differences between p110αΔT and WT mature mice. Our data show a lower incidence of MOG-induced EAE in mature p110αΔT mice linked to altered T cell homeostasis and lower secretion of inflammatory cytokines. Full article

(This article belongs to the Special Issue Autoimmunity in the Nervous Systems: Multiple Sclerosis and Beyond)

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14 pages, 3007 KiB

Open AccessArticle

Pertussis Toxin Inhibits Encephalitogenic T-Cell Infiltration and Promotes a B-Cell-Driven Disease during Th17-EAE

by Zahra Maria, Emma Turner, Agnieshka Agasing, Gaurav Kumar and Robert C. Axtell

Int. J. Mol. Sci. 2021, 22(6), 2924; https://doi.org/10.3390/ijms22062924 - 13 Mar 2021

Cited by 5 | Viewed by 3658

Abstract

Pertussis toxin (PTX) is a required co-adjuvant for experimental autoimmune encephalomyelitis (EAE) induced by immunization with myelin antigen. However, PTX’s effects on EAE induced by the transfer of myelin-specific T helper cells is not known. Therefore, we investigated how PTX affects the Th17 transfer EAE model (Th17-EAE). We found that PTX significantly reduced Th17-EAE by inhibiting chemokine-receptor-dependent trafficking of Th17 cells. Strikingly, PTX also promoted the accumulation of B cells in the CNS, suggesting that PTX alters the disease toward a B-cell-dependent pathology. To determine the role of B cells, we compared the effects of PTX on Th17-EAE in wild-type (WT) and B-cell-deficient (µMT) mice. Without PTX treatment, disease severity was equivalent between WT and µMT mice. In contrast, with PTX treatment, the µMT mice had significantly less disease and a reduction in pathogenic Th17 cells in the CNS compared to the WT mice. In conclusion, this study shows that PTX inhibits the migration of pathogenic Th17 cells, while promoting the accumulation of pathogenic B cells in the CNS during Th17-EAE. These data provide useful methodological information for adoptive-transfer Th17-EAE and, furthermore, describe another important experimental system to study the pathogenic mechanisms of B cells in multiple sclerosis. Full article

(This article belongs to the Special Issue Autoimmunity in the Nervous Systems: Multiple Sclerosis and Beyond)

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16 pages, 2063 KiB

Open AccessArticle

Rapid Expansion of Virus-Specific CD4⁺ T Cell Types in the CNS of Susceptible Mice Infected with Theiler’s Virus

by Hyun Seok Kang, Wanqiu Hou and Byung S. Kim

Int. J. Mol. Sci. 2020, 21(20), 7719; https://doi.org/10.3390/ijms21207719 - 19 Oct 2020

Cited by 4 | Viewed by 2269

Abstract

The infection of susceptible mice with Theiler’s murine encephalomyelitis virus (TMEV) induces a T cell-mediated demyelinating disease. This system has been studied as a relevant infection model for multiple sclerosis (MS). Therefore, defining the type of T cell responses and their functions is critically important for understanding the relevant pathogenic mechanisms. In this study, we adoptively transferred naive VP2-specific TCR-Tg CD4⁺ T cells into syngeneic susceptible SJL mice and monitored the development of the disease and the activation and proliferation of CD4⁺ T cells during the early stages of viral infection. The preexisting VP2-specific naive CD4⁺ T cells promoted the pathogenesis of the disease in a dose-dependent manner. The transferred VP2-specific CD4⁺ T cells proliferated rapidly in the CNS starting at 2–3 dpi. High levels of FoxP3⁺CD4⁺ T cells were found in the CNS early in viral infection (3 dpi) and persisted throughout the infection. Activated VP2-specific FoxP3⁺CD4⁺ T cells inhibited the production of IFN-γ, but not IL-17, via the same VP2-specific CD4⁺ T cells without interfering in proliferation. Thus, the early presence of regulatory T cells in the CNS with viral infection may favor the induction of pathogenic Th17 cells over protective Th1 cells in susceptible mice, thereby establishing the pathogenesis of virus-induced demyelinating disease. Full article

(This article belongs to the Special Issue Autoimmunity in the Nervous Systems: Multiple Sclerosis and Beyond)

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Review

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20 pages, 1046 KiB

Open AccessReview

Sex and Gender Differences in Neurodegenerative Diseases: Challenges for Therapeutic Opportunities

by Annalisa Bianco, Ylenia Antonacci and Maria Liguori

Int. J. Mol. Sci. 2023, 24(7), 6354; https://doi.org/10.3390/ijms24076354 - 28 Mar 2023

Cited by 19 | Viewed by 4288

Abstract

The term “neurodegenerative diseases” (NDs) identifies a group of heterogeneous diseases characterized by progressive loss of selectively vulnerable populations of neurons, which progressively deteriorates over time, leading to neuronal dysfunction. Protein aggregation and neuronal loss have been considered the most characteristic hallmarks of NDs, but growing evidence confirms that significant dysregulation of innate immune pathways plays a crucial role as well. NDs vary from multiple sclerosis, in which the autoimmune inflammatory component is predominant, to more “classical” NDs, such as Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and spinal muscular atrophy. Of interest, many of the clinical differences reported in NDs seem to be closely linked to sex, which may be justified by the significant changes in immune mechanisms between affected females and males. In this review, we examined some of the most studied NDs by looking at their pathogenic and phenotypical features to highlight sex-related discrepancies, if any, with particular interest in the individuals’ responses to treatment. We believe that pointing out these differences in clinical practice may help achieve more successful precision and personalized care. Full article

(This article belongs to the Special Issue Autoimmunity in the Nervous Systems: Multiple Sclerosis and Beyond 2.0)

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16 pages, 1010 KiB

Open AccessReview

NKT and NKT-like Cells in Autoimmune Neuroinflammatory Diseases—Multiple Sclerosis, Myasthenia Gravis and Guillain-Barre Syndrome

by Michał K. Zarobkiewicz, Izabela Morawska, Adam Michalski, Jacek Roliński and Agnieszka Bojarska-Junak

Int. J. Mol. Sci. 2021, 22(17), 9520; https://doi.org/10.3390/ijms22179520 - 1 Sep 2021

Cited by 17 | Viewed by 5277

Abstract

NKT cells comprise three subsets—type I (invariant, iNKT), type II, and NKT-like cells, of which iNKT cells are the most studied subset. They are capable of rapid cytokine production after the initial stimulus, thus they may be important for polarisation of Th cells. Due to this, they may be an important cell subset in autoimmune diseases. In the current review, we are summarising results of NKT-oriented studies in major neurological autoimmune diseases—multiple sclerosis, myasthenia gravis, and Guillain-Barre syndrome and their corresponding animal models. Full article

(This article belongs to the Special Issue Autoimmunity in the Nervous Systems: Multiple Sclerosis and Beyond)

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16 pages, 512 KiB

Open AccessReview

Neurological Immunotoxicity from Cancer Treatment

by Sarah F. Wesley, Aya Haggiagi, Kiran T. Thakur and Philip L. De Jager

Int. J. Mol. Sci. 2021, 22(13), 6716; https://doi.org/10.3390/ijms22136716 - 23 Jun 2021

Cited by 13 | Viewed by 3647

Abstract

The emergence of immune-based treatments for cancer has led to a growing field dedicated to understanding and managing iatrogenic immunotoxicities that arise from these agents. Immune-related adverse events (irAEs) can develop as isolated events or as toxicities affecting multiple body systems. In particular, this review details the neurological irAEs from immune checkpoint inhibitors (ICI) and chimeric antigen receptor (CAR) T cell immunotherapies. The recognition and treatment of neurological irAEs has variable success, depending on the severity and nature of the neurological involvement. Understanding the involved mechanisms, predicting those at higher risk for irAEs, and establishing safety parameters for resuming cancer immunotherapies after irAEs are all important fields of ongoing research. Full article

(This article belongs to the Special Issue Autoimmunity in the Nervous Systems: Multiple Sclerosis and Beyond)

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11 pages, 522 KiB

Open AccessReview

A Case of Double Standard: Sex Differences in Multiple Sclerosis Risk Factors

by Benedetta Angeloni, Rachele Bigi, Gianmarco Bellucci, Rosella Mechelli, Chiara Ballerini, Carmela Romano, Emanuele Morena, Giulia Pellicciari, Roberta Reniè, Virginia Rinaldi, Maria Chiara Buscarinu, Silvia Romano, Giovanni Ristori and Marco Salvetti

Int. J. Mol. Sci. 2021, 22(7), 3696; https://doi.org/10.3390/ijms22073696 - 2 Apr 2021

Cited by 17 | Viewed by 3472

Abstract

Multiple sclerosis is a complex, multifactorial, dysimmune disease prevalent in women. Its etiopathogenesis is extremely intricate, since each risk factor behaves as a variable that is interconnected with others. In order to understand these interactions, sex must be considered as a determining element, either in a protective or pathological sense, and not as one of many variables. In particular, sex seems to highly influence immune response at chromosomal, epigenetic, and hormonal levels. Environmental and genetic risk factors cannot be considered without sex, since sex-based immunological differences deeply affect disease onset, course, and prognosis. Understanding the mechanisms underlying sex-based differences is necessary in order to develop a more effective and personalized therapeutic approach. Full article

(This article belongs to the Special Issue Autoimmunity in the Nervous Systems: Multiple Sclerosis and Beyond)

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