Autoimmunity plays a significant role in the pathogenesis of demyelination. Multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are now recognised as separate disease entities under the amalgam of human central nervous system demyelinating disorders. While these disorders share inherent similarities, investigations into their distinct clinical presentations and lesion pathologies have aided in differential diagnoses and understanding of disease pathogenesis. An interplay of various genetic and environmental factors contributes to each disease, many of which implicate an autoimmune response. The pivotal role of the adaptive immune system has been highlighted by the diagnostic autoantibodies in NMOSD and MOGAD, and the presence of autoreactive lymphocytes in MS lesions. While a number of autoantigens have been proposed in MS, recent emphasis on the contribution of B cells has shed new light on the well-established understanding of T cell involvement in pathogenesis. This review aims to synthesise the clinical characteristics and pathological findings, discuss existing and emerging hypotheses regarding the aetiology of demyelination and evaluate recent pathogenicity studies involving T cells, B cells, and autoantibodies and their implications in human demyelination.
Background: Myelin oligodendrocyte glycoprotein antibodies (MOG Ab) are essential in the diagnosis of MOG Ab-associated disease (MOGAD). Live cell-based assays (CBAs) are the gold standard for MOG Ab detection with improved sensitivity and specificity over fixed CBAs. A number of testing centers have used flow cytometry for its high throughput and quantitative utility. Presently, there is increasing demand to translate these research-based methods into an accredited routine diagnostic setting. Methods: A flow cytometry live CBA was used to detect MOG Ab in patients with demyelination. Serostatuses were compared between a research-based assay and a streamlined diagnostic assay. Inter-laboratory validation of the streamlined assay was performed in an accredited diagnostic laboratory. Further streamlining was performed by introducing a borderline serostatus range and reducing the number of controls used to determine the positivity threshold.Results: High serostatus agreement (98%-100%) was observed between streamlined and research-based assays.Intra-and inter-assay imprecision was improved in the streamlined assay (mean intra-and inter-assay CV ¼ 7.3% and 27.8%, respectively) compared to the research-based assay (mean intra-and inter-assay CV ¼ 11.8% and 33.6%, respectively). Borderline positive and clear positive serostatuses were associated with confirmed
Although a more efficient adaptive humoral immune response has been proposed to underlie the usually favorable outcome of pediatric COVID-19, the breadth of viral and vaccine cross-reactivity toward the ever-mutating Spike protein among variants of concern (VOCs) has not yet been compared between children and adults. We assessed antibodies to conformational Spike in COVID-19-naïve children and adults vaccinated by BNT162b2 and ChAdOx1, and naturally infected with SARS-CoV-2 Early Clade, Delta, and Omicron. Sera were analyzed against Spike including naturally occurring VOCs Alpha, Beta, Gamma, Delta, and Omicron BA.1, BA.2, BA.5, BQ.1.1, BA2.75.2, and XBB.1, and variants of interest Epsilon, Kappa, Eta, D.2, and artificial mutant Spikes. There was no notable difference between breadth and longevity of antibody against VOCs in children and adults. Vaccinated individuals displayed similar immunoreactivity profiles across variants compared with naturally infected individuals. Delta-infected patients had an enhanced cross-reactivity toward Delta and earlier VOCs compared to patients infected by Early Clade SARS-CoV-2. Although Omicron BA.1, BA.2, BA.5, BQ.1.1, BA2.75.2, and XBB.1 antibody titers were generated after Omicron infection, cross-reactive binding against Omicron subvariants was reduced across all infection, immunization, and age groups. Some mutations, such as 498R and 501Y, epistatically combined to enhance cross-reactive binding, but could not fully compensate for antibody-evasive mutations within the Omicron subvariants tested. Our results reveal important molecular features central to the generation of high antibody titers and broad immunoreactivity that should be considered in future vaccine design and global serosurveillance in the context of limited vaccine boosters available to the pediatric population.
A more efficient and effective adaptive humoral immune response has been proposed as the basis of the usually favourable outcome of paediatric COVID-19. The breadth of virus and vaccine immunogenicity towards the ever-mutating Spike protein amongst variants of concern (VOC) have not yet been compared between children and adults. We utilized molecular cloning and sensitive antibody detection against conformational Spike by flow cytometry to assess Spike antibodies and delineate the immunogenic region in immune naïve children and adults vaccinated by BNT162b2 and ChAdOx1, and naturally infected with Early Clade, Delta, and Omicron variants. Patient sera were analysed against SARS-CoV-2 Spike antigens including naturally occurring VOCs Alpha, Beta, Gamma, Delta, Omicron BA.1, BA.2, and BA.5 variants of interest Epsilon, Kappa, Eta, D.2, and artificial Spike mutants. There was no notable difference between breadth and longevity of antibody responses generated against VOCs in children and adults. Vaccinated individuals displayed similar immunoreactivity profiles across variants to naturally infected individuals. Delta-infected patients had an enhanced immunogenicity toward Delta and some VOCs compared to patients infected by Early Clade SARS-CoV-2. Although Omicron BA.1, BA.2, and BA.5 antibody levels were increased after Omicron infection in both children and adults, immunogenicity against Omicron subvariants was reduced. This decrease was observed across VOC infection, immunization, and age groups. Selected epistatically combined mutations led to an increase of immunogenicity in artificial Spikes, but were unable to compensate overall within Omicron. Our results reveal important molecular features central to the generation of high antibody titers and broad immunoreactivity that should be considered in future vaccine design and global serosurveillance.
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