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The Role of Autoimmunity in Multiple Sclerosis

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

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 7963

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Dr. Paola Sarchielli

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Azienda Ospedaliera di Perugia, Università degli Studi di Perugia, Perugia, Italy
Interests: immunology; endocrinology; pathology; neuroscience

Special Issue Information

Dear Colleagues,

Multiple sclerosis (MS) is a chronic autoimmune, inflammatory and neurodegenerative disease affecting the central nervous system (CNS). MS is characterized by immune dysregulation, resulting in the infiltration of the CNS by immune cells, which are responsible for demyelination, axonal damage, and neurodegeneration. Although MS is classically believed to be a T-cell-mediated disease, the role of B cells and autoantibodies is considered increasingly crucial in MS pathogenesis. NK and NK T cells are also regarded as relevant cell subsets involved in the autoimmune mechanisms of MS.

Among the factors that have been associated with MS autoimmunity are genetic susceptibility, epigenetic mechanisms, and environmental factors such as infections and microbiota.

The most recent research has focused on the search for potential biomarkers of the disease, including immunological markers, and on the relationship between neuroinflammation and neurodegeneration in MS.

This Special Issue, “The Role of Autoimmunity in Multiple Sclerosis”, welcomes original research and review articles in the field. Specific topics can include not only the principal players of autoimmunity in MS but also genetic and epigenetic factors influencing autoimmunity in MS, as well as novel potential therapeutic strategies targeting autoimmune mechanisms of MS.

Dr. Paola Sarchielli
Guest Editor

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Published Papers (4 papers)

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Research

16 pages, 2255 KiB

Open AccessArticle

Dynamics of Inflammatory and Neurodegenerative Biomarkers after Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis

by Josefine Ruder, Gianna Dinner, Aleksandra Maceski, Ernesto Berenjeno-Correa, Antonia Maria Müller, Ilijas Jelcic, Jens Kuhle and Roland Martin

Int. J. Mol. Sci. 2022, 23(18), 10946; https://doi.org/10.3390/ijms231810946 - 19 Sep 2022

Cited by 6 | Viewed by 2457

Abstract

Autologous hematopoietic stem cell transplantation (aHSCT) is a highly efficient treatment of multiple sclerosis (MS), and hence it likely normalizes pathological and/or enhances beneficial processes in MS. The disease pathomechanisms include neuroinflammation, glial cell activation and neuronal damage. We studied biomarkers that in part reflect these, like markers for neuroinflammation (C-X-C motif chemokine ligand (CXCL) 9, CXCL10, CXCL13, and chitinase 3-like 1 (CHI3L1)), glial perturbations (glial fibrillary acidic protein (GFAP) and in part CHI3L1), and neurodegeneration (neurofilament light chain (NfL)) by enzyme-linked immunosorbent assays (ELISA) and single-molecule array assay (SIMOA) in the serum and cerebrospinal fluid (CSF) of 32 MS patients that underwent aHSCT. We sampled before and at 1, 3, 6, 12, 24 and 36 months after aHSCT for serum, as well as before and 24 months after aHSCT for CSF. We found a strong increase of serum CXCL10, NfL and GFAP one month after the transplantation, which normalized one and two years post-aHSCT. CXCL10 was particularly increased in patients that experienced reactivation of cytomegalovirus (CMV) infection, but not those with Epstein-Barr virus (EBV) reactivation. Furthermore, patients with CMV reactivation showed increased Th1 phenotype in effector memory CD4+ T cells. Changes of the other serum markers were more subtle with a trend for an increase in serum CXCL9 early post-aHSCT. In CSF, GFAP levels were increased 24 months after aHSCT, which may indicate sustained astroglia activation 24 months post-aHSCT. Other CSF markers remained largely stable. We conclude that MS-related biomarkers indicate neurotoxicity early after aHSCT that normalizes after one year while astrocyte activation appears increased beyond that, and increased serum CXCL10 likely does not reflect inflammation within the central nervous system (CNS) but rather occurs in the context of CMV reactivation or other infections post-aHSCT. Full article

(This article belongs to the Special Issue The Role of Autoimmunity in Multiple Sclerosis)

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13 pages, 1630 KiB

Open AccessArticle

Impact of Multiple Sclerosis Risk Polymorphism rs7665090 on MANBA Activity, Lysosomal Endocytosis, and Lymphocyte Activation

by Adela González-Jiménez, Pilar López-Cotarelo, Teresa Agudo-Jiménez, Ignacio Casanova, Carlos López de Silanes, Ángeles Martín-Requero, Fuencisla Matesanz, Elena Urcelay and Laura Espino-Paisán

Int. J. Mol. Sci. 2022, 23(15), 8116; https://doi.org/10.3390/ijms23158116 - 23 Jul 2022

Cited by 4 | Viewed by 1649

Abstract

Deficiencies in Mannosidase β (MANBA) are associated with neurological abnormalities and recurrent infections. The single nucleotide polymorphism located in the 3′UTR of MANBA, rs7665090, was found to be associated with multiple sclerosis (MS) susceptibility. We aimed to study the functional impact of this polymorphism in lymphocytes isolated from MS patients and healthy controls. A total of 152 MS patients and 112 controls were genotyped for rs7665090. MANBA mRNA expression was quantified through qPCR and MANBA enzymatic activity was analyzed. Upon phytohemagglutinin stimulation, immune activation was evaluated by flow cytometry detection of CD69, endocytic function, and metabolic rates with Seahorse XFp Analyzer, and results were stratified by variation in rs7665090. A significantly reduced gene expression (p < 0.0001) and enzymatic activity (p = 0.018) of MANBA were found in lymphocytes of MS patients compared to those of controls. The rs7665090*GG genotype led to a significant β-mannosidase enzymatic deficiency correlated with lysosomal dysfunction, as well as decreased metabolic activation in lymphocytes of MS patients compared to those of rs7665090*GG controls. In contrast, lymphocytes of MS patients and controls carrying the homozygous AA genotype behaved similarly. Our work provides new evidence highlighting the impact of the MS-risk variant, rs7665090, and the role of MANBA in the immunopathology of MS. Full article

(This article belongs to the Special Issue The Role of Autoimmunity in Multiple Sclerosis)

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21 pages, 3399 KiB

Open AccessArticle

Autoimmune Diseases: Enzymatic cross Recognition and Hydrolysis of H2B Histone, Myelin Basic Protein, and DNA by IgGs against These Antigens

by Georgy A. Nevinsky, Valentina N. Buneva and Pavel S. Dmitrienok

Int. J. Mol. Sci. 2022, 23(15), 8102; https://doi.org/10.3390/ijms23158102 - 22 Jul 2022

Cited by 1 | Viewed by 1495

Abstract

As shown in many studies, one of the earliest statistically significant indicators of the development of many autoimmune diseases (ADs) is the appearance in the blood of antibodies with catalytic activities (abzymes) hydrolyzing different autoantigens. Antibodies-abzymes having different enzymatic activities are a specific and essential feature of some ADs. Most abzymes are harmful to humans. Free histones in the blood are damage-associated proteins, and their administration to animals drives systemic inflammatory and toxic effects. Myelin basic protein (MBP) is the most critical component of the axon myelin-proteolipid sheath. Hydrolysis of MBP by abzymes leads to the disruption of nerve impulses. Here, we analyzed the possible pathways for the formation of unusual antibodies and abzymes that exhibit polyspecificity in recognition during complex formation with partially related antigens and possess the ability to catalyze several different reactions for the first time. Using IgGs of HIV-infected and multiple sclerosis patients against five individual histones (H1–H4), MBP, and DNA, it was first shown that abzymes against each of these antigens effectively recognize and hydrolyze all three antigens: histones, MBP, and DNA. The data obtained indicate that the formation of such polyspecific abzymes, whose single active center can recognize different substrates and catalyze several reactions, can occur in two main ways. They can be antibodies against DNA–protein complex hybrid antigenic determinants containing proteins and nucleic sequences. Their formation may also be associated with the previously described phenomenon of IgG extensive LH half-molecule (containing one L-light and one H-heavy chains) exchange leading to H₂L₂ molecules containing HL halves with variable fragments recognizing different antigens. Full article

(This article belongs to the Special Issue The Role of Autoimmunity in Multiple Sclerosis)

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11 pages, 1185 KiB

Open AccessArticle

Unraveling the Influence of HHEX Risk Polymorphism rs7923837 on Multiple Sclerosis Pathogenesis

by Adela González-Jiménez, Pilar López-Cotarelo, Teresa Agudo-Jiménez, Marisa Martínez-Ginés, Jose Manuel García-Domínguez, Elena Urcelay and Laura Espino-Paisán

Int. J. Mol. Sci. 2022, 23(14), 7956; https://doi.org/10.3390/ijms23147956 - 19 Jul 2022

Cited by 2 | Viewed by 1870

Abstract

One of the multiple sclerosis (MS) risk polymorphisms, rs7923837, maps near the HHEX (hematopoietically-expressed homeobox) gene. This variant has also been associated with type 2 diabetes susceptibility and with triglyceride levels, suggesting its metabolic involvement. HHEX plays a relevant role as a negative regulator of inflammatory genes in microglia. A reciprocal repression was reported between HHEX and BCL6, another putative risk factor in MS. The present study evidenced statistically significant lower HHEX mRNA levels in lymphocytes of MS patients compared to those of controls, showing a similar trend in MS patients to the already described eQTL effect in blood from healthy individuals. Even though no differences were found in protein expression according to HHEX genotypes, statistically significant divergent subcellular distributions of HHEX appeared in patients and controls. The epistatic interaction detected between BCL6 and HHEX MS-risk variants in healthy individuals was absent in patients, indicative of a perturbed reciprocal regulation in the latter. Lymphocytes from MS carriers of the homozygous mutant genotype exhibited a distinctive, more energetic profile, both in resting and activated conditions, and significantly increased glycolytic rates in resting conditions when compared to controls sharing the HHEX genotype. In contrast, significantly higher mitochondrial mass was evidenced in homozygous mutant controls. Full article

(This article belongs to the Special Issue The Role of Autoimmunity in Multiple Sclerosis)

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