Iron-(Fe3+) dependent reactivation of telomerase drives colorectal cancers.

Over-consumption of iron-rich red meat and hereditary or genetic iron overload are associated with increased risk of colorectal carcinogenesis, yet the mechanistic basis of how metal-mediated signaling leads to oncogenesis remains enigmatic. Using fresh colorectal cancer (CRC) samples we identify Pirin, an iron sensor, that overcomes a rate-limiting step in oncogenesis, by re-activating the dormant human-reverse-transcriptase (hTERT) subunit of telomerase holoenzyme in an iron-(Fe3+)-dependent-manner and thereby drives CRCs. Chemical genetic screens combined with isothermal-dose response fingerprinting and mass-spectrometry identified a small molecule SP2509, that specifically inhibits Pirin-mediated hTERT reactivation in CRCs by competing with iron-(Fe3+) binding. Our findings, first to document how metal ions reactivate telomerase, provide a molecular mechanism for the well-known association between red meat, and increased incidence of CRCs. Small molecules like SP2509 represent a novel modality to target telomerase that acts as driver of 90% human cancers and is yet to be targeted in clinic.

The role of temporality in adolescent refugees' sense of well-being.

Adolescent refugees confront a complex interplay of trauma arising from forced displacement, resettlement, and the challenges of transitioning from childhood to adulthood. Using photovoice methodology, this study engaged 14 Iraqi and Syrian adolescent refugees now residing in the United States with the aim to illuminate their well-being experiences. Our findings show that temporal continuities and discontinuities in adolescent refugees' lives contributed to their sense of well-being by helping satisfy their basic psychological needs for autonomy, competence, relatedness, and safety. Temporal continuities involved drawing upon past resources and formulating future career aspirations based on present experiences. Temporal discontinuities encompassed contrasting past and present and processing adversities endured. This study underscores that, beyond current circumstances, the interpretation of life experiences over extended timeframes influences the well-being of adolescent refugees.

The MOG antibody non-P42 epitope is predictive of a relapsing course in MOG antibody-associated disease.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) IgG seropositivity is a prerequisite for MOG antibody-associated disease (MOGAD) diagnosis. While a significant proportion of patients experience a relapsing disease, there is currently no biomarker predictive of disease course. We aim to determine whether MOG-IgG epitopes can predict a relapsing course in MOGAD patients. METHODS: MOG-IgG-seropositive confirmed adult MOGAD patients were included (n=202). Serum MOG-IgG and epitope binding were determined by validated flow cytometry live cell-based assays. Associations between epitopes, disease course, clinical phenotype, Expanded Disability Status Scale and Visual Functional System Score at onset and last review were evaluated. RESULTS: Of 202 MOGAD patients, 150 (74%) patients had MOG-IgG that recognised the immunodominant proline42 (P42) epitope and 115 (57%) recognised histidine103/serine104 (H103/S104). Fifty-two (26%) patients had non-P42 MOG-IgG and showed an increased risk of a relapsing course (HR 1.7; 95% CI 1.15 to 2.60, p=0.009). Relapse-freedom was shorter in patients with non-P42 MOG-IgG (p=0.0079). Non-P42 MOG-IgG epitope status remained unchanged from onset throughout the disease course and was a strong predictor of a relapsing course in patients with unilateral optic neuritis (HR 2.7, 95% CI 1.06 to 6.98, p=0.038), with high specificity (95%, 95% CI 77% to 100%) and positive predictive value (85%, 95% CI 45% to 98%). CONCLUSIONS: Non-P42 MOG-IgG predicts a relapsing course in a significant subgroup of MOGAD patients. Patients with unilateral optic neuritis, the most frequent MOGAD phenotype, can reliably be tested at onset, regardless of age and sex. Early detection and specialised management in these patients could minimise disability and improve long-term outcomes.

Loss of zebrafish pkd1l1 causes biliary defects that have implications for biliary atresia splenic malformation.

Biliary atresia is a fibroinflammatory neonatal disease with no effective therapies. A subset of cases (10-20%) is associated with laterality defects - labeled biliary atresia splenic malformation (BASM) syndrome. Recently, whole-exome sequencing of patients with BASM identified deleterious variants in PKD1L1. PKD1L1 is involved in left-right axis determination; however, its role in cholangiocytes is unknown. We generated the pkd1l1hsc117 allele using CRISPR/Cas9 mutagenesis in zebrafish to determine the role of Pkd1l1 in biliary development and function. Wild-type and mutant larvae were assessed for laterality defects, biliary function and biliary tree architecture at 5 days post fertilization. pkd1l1hsc117 mutant larvae exhibited early left-right patterning defects. The gallbladder was positioned on the left in 47% of mutants compared to 4% of wild-type larvae. Accumulation of PED6 in the gallbladder, an indicator of hepatobiliary function, was significantly reduced in pkd1l1hsc117 mutants (46%) compared to wild-type larvae (4%). pkd1l1hsc117 larvae exhibited fewer biliary epithelial cells and reduced density of the intrahepatic biliary network compared to those in wild-type larvae. These data highlight the essential role of pkd1l1 in normal development and function of the zebrafish biliary system, supporting a role for this gene as a cause of BASM.

Infection and Vaccine Induced Spike Antibody Responses Against SARS-CoV-2 Variants of Concern in COVID-19-Naïve Children and Adults.

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.

The SETPACE Trial: Stroke Survivors Impressions of the Education and Teaching Provided Regarding Physical Activity and Patient Confidence Regarding Exercise.

OBJECTIVE: The aim of the study is to investigate the association between patient self-efficacy, impression of exercise education, and physical activity among stroke survivors. We hypothesized that low self-efficacy and/or poor impressions of exercise education after stroke would be associated with reduced exercise participation. DESIGN: This is a cross-sectional investigation of patients' poststroke with physical activity as the primary outcome variable. Physical activity was measured with the Physical Activity Scale for Individuals with Physical Disabilities. Self-efficacy was measured with the Self-Efficacy for Exercise questionnaire. Impression of exercise education measured by the Exercise Impression Questionnaire. RESULTS: There was a low but significant correlation between Self-Efficacy for Exercise questionnaire and Physical Activity Scale for Individuals with Physical Disabilities ( r (66) = 0.272, P = 0.012). There was an insignificant correlation between Exercise Impression Questionnaire and Physical Activity Scale for Individuals with Physical Disabilities ( r (66) = 0.174, P = 0.078). There was a low but significant correlation between age and Physical Activity Scale for Individuals with Physical Disabilities ( r (66) = -0.269, P = 0.013). There was no correlation between sex and Physical Activity Scale for Individuals with Physical Disabilities ( r (66) = 0.051, P = 0.339). Age, sex, Exercise Impression Questionnaire, and Self-Efficacy for Exercise questionnaire predict 17.1% of Physical Activity Scale for Individuals with Physical Disabilities variance ( R2 = 0.171). CONCLUSION: Self-efficacy was the strongest predictor of physical activity participation. There was a lack of association between the impressions of exercise education and physical activity. Addressing patient confidence to complete exercise has the potential to improve exercise participation in patients after stroke.

Finding strength in adversity: Exploring the process of posttraumatic growth among multicultural individuals.

OBJECTIVES: We explore the process of posttraumatic growth for multicultural individuals after experiences of cumulative multicultural identity-relevant adversity. METHOD: We conducted an exploratory sequential mixed methods study with two parts. Study 1 utilized Photovoice methodology and individual interviews (N = 27; 13 women, 14 men) with multicultural individuals living in a Midwestern college town. In Study 2, we tested the relationships between themes revealed by our qualitative analysis in Study 1 in a sample of multicultural individuals living across the U.S. (N = 526; 40.1% men, 59.9% women) using a conditional process analysis. RESULTS: Findings from Study 1 indicate that participants appreciated environments that valued diversity, and this helped participants positively frame their cumulative adversities. Participants also described how the struggle with these adversities fostered psychological wellbeing outcomes of personal growth and positive relations with others. Results from Study 2 indicate that appreciation of diversity mediates and positive framing moderates the relationship between discrimination and personal growth, thus supporting and building on the findings in Study 1. CONCLUSIONS: Together, these studies highlight the significance of including cumulative adversity in the posttraumatic growth process for multicultural individuals, while identifying appreciation of diversity and positive framing as potential postadversarial growth mechanisms. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Implicit theories of opportunity: When opportunity fails to knock, keep waiting, or start cultivating?

We live in a time of disappearing professions, pandemic-related upheaval, and growing social inequality. While recognizing that good opportunities are unequally distributed in society (an injustice that requires rectification), can beliefs about the nature and workings of opportunities help people see the door to their goals as more open than closed, and can these beliefs influence the likelihood of goal attainment? Seven studies (N = 1,031) examined people's beliefs about whether or not opportunities can be changed (growth vs. fixed theory of opportunity). In Studies 1a-4, participants responded to scenarios about competent people (or themselves) with challenging, long-term aspirations. When opportunities were available, both theories predicted high expectations for success and a preference for active strategies to pursue the goal, like being persistent. By contrast, when opportunities seemed unavailable, a stronger fixed theory predicted lower expectations for success and a preference for passive strategies, like simply waiting. We also established the implicit theories' causal role and demonstrated processes explaining how a growth theory leads to higher anticipated success. The final two studies examined unemployed people. In Study 5, those with a stronger growth theory chose to engage more in a task about cultivating new opportunities for employment. Study 6 showed that those with a stronger growth theory were more likely to report securing employment 5 months later, even when controlling for motivation-relevant variables, education, and socioeconomic status. They also engaged in more active job-search strategies. These studies offer a novel perspective on when, how, and why people initiate and maintain goal pursuit. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Tracking the clonal dynamics of SARS-CoV-2-specific T cells in children and adults with mild/asymptomatic COVID-19.

Children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop less severe coronavirus disease 2019 (COVID-19) than adults. The mechanisms for the age-specific differences and the implications for infection-induced immunity are beginning to be uncovered. We show by longitudinal multimodal analysis that SARS-CoV-2 leaves a small footprint in the circulating T cell compartment in children with mild/asymptomatic COVID-19 compared to adult household contacts with the same disease severity who had more evidence of systemic T cell interferon activation, cytotoxicity and exhaustion. Children harbored diverse polyclonal SARS-CoV-2-specific naïve T cells whereas adults harbored clonally expanded SARS-CoV-2-specific memory T cells. A novel population of naïve interferon-activated T cells is expanded in acute COVID-19 and is recruited into the memory compartment during convalescence in adults but not children. This was associated with the development of robust CD4+ memory T cell responses in adults but not children. These data suggest that rapid clearance of SARS-CoV-2 in children may compromise their cellular immunity and ability to resist reinfection.

Single-cell and bulk transcriptome sequencing identifies two epithelial tumor cell states and refines the consensus molecular classification of colorectal cancer.

The consensus molecular subtype (CMS) classification of colorectal cancer is based on bulk transcriptomics. The underlying epithelial cell diversity remains unclear. We analyzed 373,058 single-cell transcriptomes from 63 patients, focusing on 49,155 epithelial cells. We identified a pervasive genetic and transcriptomic dichotomy of malignant cells, based on distinct gene expression, DNA copy number and gene regulatory network. We recapitulated these subtypes in bulk transcriptomes from 3,614 patients. The two intrinsic subtypes, iCMS2 and iCMS3, refine CMS. iCMS3 comprises microsatellite unstable (MSI-H) cancers and one-third of microsatellite-stable (MSS) tumors. iCMS3 MSS cancers are transcriptomically more similar to MSI-H cancers than to other MSS cancers. CMS4 cancers had either iCMS2 or iCMS3 epithelium; the latter had the worst prognosis. We defined the intrinsic epithelial axis of colorectal cancer and propose a refined 'IMF' classification with five subtypes, combining intrinsic epithelial subtype (I), microsatellite instability status (M) and fibrosis (F).

What makes us complete: Hybrid multicultural identity and its social contextual origins.

Our research explores the experience of holding a Hybrid Multicultural Identity (a superordinate cultural identity; HMI) and the social contextual experiences hybrid multiculturals describe as influential to the development of an HMI. We conducted a Photovoice study with 10 hybrid multiculturals (age 18-32; 6 women and 4 men) living in a college town in the Midwestern US. The participants valued HMI for the psychological advantages they attributed to this identity. We also found the participants described three broad categories of their social environment that were key to the development of HMI: cultural composition in living environments, perceptions of macro-level marginalization, and culturally related interpersonal experiences. Our research documents (1) the lived experience of being a hybrid multicultural (2) the importance of cultural mixing for HMI development, and (3) how people with HMI describe primarily negative perceptions of the social environment as instrumental to the development of HMI.

Validation of a Flow Cytometry Live Cell-Based Assay to Detect Myelin Oligodendrocyte Glycoprotein Antibodies for Clinical Diagnostics.

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 = 7.3% and 27.8%, respectively) compared to the research-based assay (mean intra- and inter-assay CV = 11.8% and 33.6%, respectively). Borderline positive and clear positive serostatuses were associated with confirmed phenotypes typical of MOGAD. Compared to using 24 controls, robust serostatus classification was observed when using 13 controls without compromising analytical performance (93%-98.5% agreement). CONCLUSIONS: Flow cytometry live CBAs show robust utility in determining MOG Ab serostatus. Streamlining and standardizing use of this assay for diagnostics would improve the accuracy and reliability of routine testing to aid diagnosis and treatment of patients with demyelination.

SARS-CoV-2 neutralizing antibodies: Longevity, breadth, and evasion by emerging viral variants.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) antibody neutralization response and its evasion by emerging viral variants and variant of concern (VOC) are unknown, but critical to understand reinfection risk and breakthrough infection following vaccination. Antibody immunoreactivity against SARS-CoV-2 antigens and Spike variants, inhibition of Spike-driven virus-cell fusion, and infectious SARS-CoV-2 neutralization were characterized in 807 serial samples from 233 reverse transcription polymerase chain reaction (RT-PCR)-confirmed Coronavirus Disease 2019 (COVID-19) individuals with detailed demographics and followed up to 7 months. A broad and sustained polyantigenic immunoreactivity against SARS-CoV-2 Spike, Membrane, and Nucleocapsid proteins, along with high viral neutralization, was associated with COVID-19 severity. A subgroup of "high responders" maintained high neutralizing responses over time, representing ideal convalescent plasma donors. Antibodies generated against SARS-CoV-2 during the first COVID-19 wave had reduced immunoreactivity and neutralization potency to emerging Spike variants and VOC. Accurate monitoring of SARS-CoV-2 antibody responses would be essential for selection of optimal responders and vaccine monitoring and design.

DUSP16 promotes cancer chemoresistance through regulation of mitochondria-mediated cell death.

Drug resistance is a major obstacle to the treatment of most human tumors. In this study, we find that dual-specificity phosphatase 16 (DUSP16) regulates resistance to chemotherapy in nasopharyngeal carcinoma, colorectal cancer, gastric and breast cancer. Cancer cells expressing higher DUSP16 are intrinsically more resistant to chemotherapy-induced cell death than cells with lower DUSP16 expression. Overexpression of DUSP16 in cancer cells leads to increased resistance to cell death upon chemotherapy treatment. In contrast, knockdown of DUSP16 in cancer cells increases their sensitivity to treatment. Mechanistically, DUSP16 inhibits JNK and p38 activation, thereby reducing BAX accumulation in mitochondria to reduce apoptosis. Analysis of patient survival in head & neck cancer and breast cancer patient cohorts supports DUSP16 as a marker for sensitivity to chemotherapy and therapeutic outcome. This study therefore identifies DUSP16 as a prognostic marker for the efficacy of chemotherapy, and as a therapeutic target for overcoming chemoresistance in cancer.

Effects of the Positive Threshold and Data Analysis on Human MOG Antibody Detection by Live Flow Cytometry.

Human autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG Ab) have become a useful clinical biomarker for the diagnosis of a spectrum of inflammatory demyelinating disorders. Live cell-based assays that detect MOG Ab against conformational MOG are currently the gold standard. Flow cytometry, in which serum binding to MOG-expressing cells and control cells are quantitively evaluated, is a widely used observer-independent, precise, and reliable detection method. However, there is currently no consensus on data analysis; for example, seropositive thresholds have been reported using varying standard deviations above a control cohort. Herein, we used a large cohort of 482 sera including samples from patients with monophasic or relapsing demyelination phenotypes consistent with MOG antibody-associated demyelination and other neurological diseases, as well as healthy controls, and applied a series of published analyses involving a background subtraction (delta) or a division (ratio). Loss of seropositivity and reduced detection sensitivity were observed when MOG ratio analyses or when 10 standard deviation (SD) or an arbitrary number was used to establish the threshold. Background binding and MOG ratio value were negatively correlated, in which patients seronegative by MOG ratio had high non-specific binding, a characteristic of serum that must be acknowledged. Most MOG Ab serostatuses were similar across analyses when optimal thresholds obtained by ROC analyses were used, demonstrating the robust nature and high discriminatory power of flow cytometry cell-based assays. With increased demand to identify MOG Ab-positive patients, a consensus on analysis is vital to improve patient diagnosis and for cross-study comparisons to ultimately define MOG Ab-associated disorders.

The otic microbiota and mycobiota in a referral population of dogs in eastern USA with otitis externa.

BACKGROUND: Canine otitis externa (OE) is a common inflammatory disease that is frequently complicated by secondary bacterial and/or yeast infections. The otic microbial population is more complex than appreciated by cytological methods and aerobic culture alone. HYPOTHESIS/OBJECTIVES: Differences in bacterial and fungal populations of the external ear canal will correlate with specific cytological and culture-based definitions of bacterial and Malassezia otitis. ANIMALS: Forty client-owned dogs; 30 with OE and 10 with healthy ears. METHODS AND MATERIALS: Prospective study comparing cytological samples, aerobic bacterial cultures and culture-independent sequencing-based analyses of the external ear canal. Subjects with OE included 10 dogs with only cocci [≥25/high power field (HPF)] on cytological evaluation and culture of Staphylococcus spp.; 10 dogs with rods (≥25/HPF) and exclusive culture of Pseudomonas aeruginosa; 10 dogs with only yeast on cytological results morphologically compatible with Malassezia spp. (≥5/HPF). RESULTS: Staphylococcus was the most abundant taxa across all groups. Ears cytologically positive for cocci had decreased diversity, and all types of OE were associated with decreased fungal diversity compared to controls. CONCLUSIONS AND CLINICAL IMPORTANCE: Cytological and culture-based assessment of the ear canal is not predictive of the diverse microbiota of the ear canal in cases of Pseudomonas or Malassezia otitis. Less abundant bacterial taxa in cases of staphylococcal OE are worth scrutiny for future biological therapy.

Pro-inflammatory dopamine-2 receptor-specific T cells in paediatric movement and psychiatric disorders.

OBJECTIVES: A dysregulated inflammatory response against the dopamine-2 receptor (D2R) has been implicated in movement and psychiatric disorders. D2R antibodies were previously reported in a subset of these patients; however, the role of T cells in these disorders remains unknown. Our objective was to identify and characterise pro-inflammatory D2R-specific T cells in movement and psychiatric disorders. METHODS: Blood from paediatric patients with movement and psychiatric disorders of suspected autoimmune and neurodevelopmental aetiology (n = 24) and controls (n = 16) was cultured in vitro with a human D2R peptide library, and D2R-specific T cells were identified by flow cytometric quantification of CD4+CD25+CD134+ T cells. Cytokine secretion was analysed using a cytometric bead array and ELISA. HLA genotypes were examined in D2R-specific T-cell-positive patients. D2R antibody seropositivity was determined using a flow cytometry live cell-based assay. RESULTS: Three immunodominant regions of D2R, amino acid (aa)121-131, aa171-181 and aa396-416, specifically activated CD4+ T cells in 8/24 patients. Peptides corresponding to these regions were predicted to bind with high affinity to the HLA of the eight positive patients and had also elicited the secretion of pro-inflammatory cytokines IL-2, IFN- γ, TNF, IL-6, IL-17A and IL-17F. All eight patients were seronegative for D2R antibodies. CONCLUSION: Autoreactive D2R-specific T cells and a pro-inflammatory Th1 and Th17 cytokine profile characterise a subset of paediatric patients with movement and psychiatric disorders, further underpinning the theory of immune dysregulation in these disorders. These findings offer new perspectives into the neuroinflammatory mechanisms of movement and psychiatric disorders and can influence patient diagnosis and treatment.

Roles affect individuals' preferences for organizations: A values perspective.

People are guided by the roles they assume in their everyday lives. Roles are cognitive schemas that are associated with specific goals and expectations that organize and guide individuals' perception and preferences. The social roles individuals assume affect their goals, which in turn affect their point of view and preferences. We propose and show that role schemas are malleable, allowing individuals to shift from one schema to another depending on the role they assume at the moment of judgment. Drawing on role theory and theories of espoused organizational values, we show that matching between the goals derived from a specific role and espoused organizational values influence the preferences of individuals toward an organization. An experiment with 476 working adults and students in three countries, found that individual assumed role (as a potential employee or an investor) and espoused organizational values (embeddedness-autonomy, egalitarianism-hierarchy, and mastery-harmony) affected individuals' preferences to invest or work in organizations. Our findings suggest that role-specific goals are important drivers of how individuals perceive organizations, and that individuals seek "fit" between organizational values and their role-specific goals. Finally, we discuss supplementary analyses testing the classical notion of value-based person-organization fit. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Characterization of the human myelin oligodendrocyte glycoprotein antibody response in demyelination.

Over recent years, human autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG Ab) have been associated with monophasic and relapsing central nervous system demyelination involving the optic nerves, spinal cord, and brain. While the clinical relevance of MOG Ab detection is becoming increasingly clear as therapeutic and prognostic differences from multiple sclerosis are acknowledged, an in-depth characterization of human MOG Ab is required to answer key challenges in patient diagnosis, treatment, and prognosis. Herein, we investigated the epitope, binding sensitivity, and affinity of MOG Ab in a cohort of 139 and 148 MOG antibody-seropositive children and adults (n = 287 patients at baseline, 130 longitudinal samples, and 22 cerebrospinal fluid samples). MOG extracellular domain was also immobilized to determine the affinity of MOG Ab. MOG Ab response was of immunoglobulin G1 isotype, and was of peripheral rather than intrathecal origin. High affinity MOG Ab were detected in 15% paediatric and 18% adult sera. More than 75% of paediatric and adult MOG Ab targeted a dominant extracellular antigenic region around Proline42. MOG Ab titers fluctuated over the progression of disease, but affinity and reactivity to Proline42 remained stable. Adults with a relapsing course intrinsically presented with a reduced immunoreactivity to Proline42 and had a more diverse MOG Ab response, a feature that may be harnessed for predicting relapse. Higher titers of MOG Ab were observed in more severe phenotypes and during active disease, supporting the pathogenic role of MOG Ab. Loss of MOG Ab seropositivity was observed upon conformational changes to MOG, and this greatly impacted the sensitivity of the detection of relapsing disorders, largely considered as more severe. Careful consideration of the binding characteristics of autoantigens should be taken into account when detecting disease-relevant autoantibodies.