HLA Allele Frequencies in Pediatric and Adolescent Multiple Sclerosis Patients

Early-onset (pediatric and adolescent) multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disorder of the central nervous system, which accounts for 3–5% of all MS cases. The major histocompatibility complex (MHC) with its polymorphisms has been the genetic locus with the most robust association with adult MS, since its first discovery in the 1970s. Nowadays, human leukocyte antigen (HLA) typing studies and genome-wide association studies (GWAS) have tried to provide insight into the genetics of early-onset MS and their role in disease diagnosis, prognosis, and therapeutic decision-making. Fundamental genetic similarities have emerged, supporting the assumption that MS shares similar genetic variants and biological processes in all age groups. In this chapter, we considered it useful to collect all the available data concerning the HLA distribution in early-onset MS, given the absence of a review paper with such an approach. We additionally aimed toward the summarization of the association of the HLA frequencies in early-onset MS and the main acquired demyelinating disorders that are considered in differential diagnosis of early-onset MS, like ADEM, NMO/NMOSD, and anti-MOG encephalopathy, for further understanding and current or future research in this promising field

HLA-DPB1*03 as Risk Allele and HLA-DPB1*04 as Protective Allele for Both Early- and Adult-Onset Multiple Sclerosis in a Hellenic Cohort

Background: Human Leucocyte Antigens (HLA) represent the genetic loci most strongly linked to Multiple Sclerosis (MS). Apart from HLA-DR and HLA–DQ, HLA-DP alleles have been previously studied regarding their role in MS pathogenesis, but to a much lesser extent. Our objective was to investigate the risk/resistance influence of HLA-DPB1 alleles in Hellenic patients with early- and adult-onset MS (EOMS/AOMS), and possible associations with the HLA-DRB1*15:01 risk allele. Methods: One hundred MS-patients (28 EOMS, 72 AOMS) fulfilling the McDonald-2010 criteria were enrolled. HLA genotyping was performed with standard low-resolution Sequence-Specific Oligonucleotide techniques. Demographics, clinical and laboratory data were statistically processed using well-defined parametric and nonparametric methods and the SPSSv22.0 software. Results: No significant HLA-DPB1 differences were found between EOMS and AOMS patients for 23 distinct HLA-DPB1 and 12 HLA-DRB1 alleles. The HLA-DPB1*03 allele frequency was found to be significantly increased, and the HLA-DPB1*02 allele frequency significantly decreased, in AOMS patients compared to controls. The HLA-DPB1*04 allele was to be found significantly decreased in AOMS and EOMS patients compared to controls. Conclusions: Our study supports the previously reported risk susceptibility role of the HLA-DPB1*03 allele in AOMS among Caucasians. Additionally, we report for the first time a protective role of the HLA-DPB1*04 allele among Hellenic patients with both EOMS and AOMS

Anti-Myelin Oligodendrocyte Glycoprotein and Human Leukocyte Antigens as Markers in Pediatric and Adolescent Multiple Sclerosis: on Diagnosis, Clinical Phenotypes, and Therapeutic Responses

Early-onset (pediatric and adolescent) multiple sclerosis (MS) is a well-established demyelinating disease that accounts for approximately 3-5% of all MS cases. Thus, identifying potential biomarkers that can reflect the pathogenic mechanisms, disease course and prognosis, and therapeutic response in such patients is of paramount importance. Myelin oligodendrocyte glycoprotein (MOG) has been regarded as a putative autoantigen and autoantibody target in patients with demyelinating diseases for almost three decades. However, recent studies have suggested that antibodies against MOG represent a distinct clinical entity of dominantly humoral profile, with a range of clinical phenotypes closely related to the age of onset, specific patterns of disease course, and responses to treatment. Furthermore, the major histocompatibility complex (MHC)—which has been regarded as the “gold standard” for attributing genetic burden in adult MS since the early 1970s—has also emerged as the primary genetic locus in early-onset MS, particularly with regard to the human leukocyte antigen (HLA) alleles DRB1⁎1501 and DRB1⁎0401. Recent studies have investigated the potential interactions among HLA, MOG, and environmental factors, demonstrating that early-onset MS is characterized by genetic, immunogenetic, immunological, and familial trait correlations. In this paper, we review recent evidence regarding HLA-genotyping and MOG antibodies—the two most important candidate biomarkers for early-onset MS—as well as their potential application in the diagnosis and treatment of MS

Anti-Myelin Oligodendrocyte Glycoprotein and Human Leukocyte Antigens as Markers in Pediatric and Adolescent Multiple Sclerosis: on Diagnosis, Clinical Phenotypes, and Therapeutic Responses

Early-onset (pediatric and adolescent) multiple sclerosis (MS) is a well-established demyelinating disease that accounts for approximately 3-5% of all MS cases. Thus, identifying potential biomarkers that can reflect the pathogenic mechanisms, disease course and prognosis, and therapeutic response in such patients is of paramount importance. Myelin oligodendrocyte glycoprotein (MOG) has been regarded as a putative autoantigen and autoantibody target in patientswith demyelinating diseases for almost three decades. However, recent studies have suggested that antibodies against MOG represent a distinct clinical entity of dominantly humoral profile, with a range of clinical phenotypes closely related to the age of onset, specific patterns of disease course, and responses to treatment. Furthermore, the major histocompatibility complex (MHC)-which has been regarded as the “gold standard” for attributing genetic burden in adult MS since the early 1970s-has also emerged as the primary genetic locus in early-onsetMS, particularly with regard to the human leukocyte antigen (HLA) alleles DRB1*1501 and DRB1*0401. Recent studies have investigated the potential interactions among HLA, MOG, and environmental factors, demonstrating that early-onset MS is characterized by genetic, immunogenetic, immunological, and familial trait correlations. In this paper, we review recent evidence regarding HLA-genotyping and MOG antibodies-the two most important candidate biomarkers for early-onset MS-as well as their potential application in the diagnosis and treatment of MS

Biomarkers in Multiple Sclerosis: An Up-to-Date Overview

During the last decades, the effort of establishing satisfactory biomarkers for multiple sclerosis has been proven to be very difficult, due to the clinical and pathophysiological complexities of the disease. Recent knowledge acquired in the domains of genomics-immunogenetics and neuroimmunology, as well as the evolution in neuroimaging, has provided a whole new list of biomarkers. This variety, though, leads inevitably to confusion in the effort of decision making concerning strategic and individualized therapeutics. In this paper, our primary goal is to provide the reader with a list of the most important characteristics that a biomarker must possess in order to be considered as reliable. Additionally, up-to-date biomarkers are further divided into three subgroups, genetic-immunogenetic, laboratorial, and imaging. The most important representatives of each category are presented in the text and for the first time in a summarizing workable table, in a critical way, estimating their diagnostic potential and their efficacy to correlate with phenotypical expression, neuroinflammation, neurodegeneration, disability, and therapeutical response. Special attention is given to the “gold standards” of each category, like HLA-DRB1* polymorphisms, oligoclonal bands, vitamin D, and conventional and nonconventional imaging techniques. Moreover, not adequately established but quite promising, recently characterized biomarkers, like TOB-1 polymorphisms, are further discussed

Apoptosis of Oligodendrocytes and Post-Translational Modifications of Myelin Basic Protein in Multiple Sclerosis: Possible Role for the Early Stages of Multiple Sclerosis

Recent studies outline apoptosis of oligodendrocytes (OLDs) as an early event prior to the formation of the demyelinated plaque and post-translational modifications (PTMs) of myelin basic protein as characteristic processes of normal-appearing white matter in multiple sclerosis (MS). We reviewed reports using the following keywords: apoptosis, PTMs, autoimmunity and multiple sclerosis in all possible combinations. Introductory basic scientific information is included for the non-experts. Given the standard and ongoing studies, we raise the hypothesis that, at least in some cases, defective apoptosis of OLDs, early in the course of the disease, and post-translationally modified molecules lead to the activation of immune responses and eventually to autoimmunity. Autoimmune reactions and epitope spreading that take place in the course of the disease might obscure the initial events and leave most investigators blind to etiopathogenesis. Our paper outlines the need for studies at the very early stages of the disease, as well as sequential ones, in order to give us a valuable hint about the clarification of the cause(s) of the different clinical subtypes of MS. Copyright (C) 2010 S. Karger AG, Base

Aggressive Herpes Zoster in Young Patients With Multiple Sclerosis Under Dimethyl Fumarate: Significance of CD8

Dimethyl fumarate (DMF), approved for relapsing-remitting multiple sclerosis (RRMS), exerts immune-mediated mechanisms crucial for T-cell survival and migration, preferentially reducing CD8+ T cells.1 Although baseline absolute lymphocyte count (ALC) is considered the most critical predictor of developing lymphopenia,2 it was recently concluded that lymphocyte subset monitoring is not required for safety vigilance because T-cell subset reduction does not increase risks for serious infections.3 We present 2 young patients with RRMS, under DMF treatment, negative for HIV and SARSCoV-2 (by RT-PCR in nasal swab) and with normal follow-up white blood cell (WBC)/ALC counts, who developed severe herpes zoster (HZ) infection with normal ALC but low CD8+ and high CD56bright natural killer (NK) cells, and discuss the potential significance of T-cell immunophenotyping in HZ manifestation