Browsing by Subject "Multiple Sclerosis"
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Item Autoregulatory CD8 T-Cells Modulate CNS Autoimmune Disease by Targeting Encephalitogenic CD4 T-Cells(2013-01-16) Ortega, Sterling Bolivar; Karandikar, Nitin J.Multiple Sclerosis (MS) is a disease, which presents with neurological dysfunction and is believed to have an immunological etiology. Lesions in the central nervous system (CNS) are characterized by an inflammatory cellular infiltration and demyelination of neuronal axons. It is believed that myelin sheath-targeting CD4 T-cells are important mediators of this disease. While it is known that CD8 T-cells are present, oligoclonally expanded and are the predominant T-cell population in the MS CNS lesion, their antigen specificity and function remains to be elucidated. Using a murine model of MS, experimental autoimmune encephalomyelitis (EAE), we are currently evaluating the role of these poorly studied myelin antigen-specific CD8 T-cells in the context of this autoimmune disease. We have observed that myelin oligodendrocyte glycoprotein peptide (MOG₃₅₋₅₅)-specific CD8 T-cells do not mediate EAE, but in fact are capable of suppressing both de novo and established clinical disease. Corroborating these data, CD8-/- C57BL/6 mice are now shown to exhibit a more severe EAE. However, the characterization, mechanism of action and cellular targets of these autoreactive regulatory CD8 T-cells are still unknown. Initial observations revealed that disease ameliorating CD8 T-cells are not unique to MOG₃₅₋₅₅-induced EAE, as proteolipid protein peptide (PLP₁₇₈₋₁₉₁)-induced EAE in B6 and SJL mice strains were capable of generating disease ameliorating CNS antigen-specific CD8 T-cells. Autoreactive regulatory (autoregulatory) CD8 T-cells exhibit a central memory phenotype (CCR7+CD62L+CD44-) and produce IFN-γ and perforin. Disease suppression by these cells is dependent on recognition of cognate antigen in vivo within the context of MHC Class Ia. These cells do not traffic to the CNS upon transfer into naïve mice; however, they gain CNS access following induction of CNS inflammation, suggesting both a peripheral immune compartment and CNS mechanism of action. Interestingly, autoregulatory CD8 T-cell-mediated suppression is IFN-γ and perforin-dependent and can be augmented by IL-12 in vitro modulation. Next, we asked whether autoregulatory CD8 T-cells could directly target encephalitogenic myelin-specific CD4 T-cells. We now report that treatment with myelinspecific CD8 T-cells results in significantly attenuated adoptive (CD4 T-cell mediated) EAE. Moreover, increased disease severity in CD8-/- mice correlated with an increase in autoreactivity and inflammatory cytokine production by myelin-specific CD4 T-cells. This is reversible upon adoptive transfer of MOG₃₅₋₅₅-specific CD8 T-cells. Targeting of encephalitogenic CD4 T-cells by myelin-specific CD8 T-cells is sufficient, as induction of wildtype adoptive EAE in KᵇDᵇ-/- recipient mice could be suppressed. In vivo proliferation assays revealed a global suppression/cytotoxicity of MOG-specific CD4 T-cells. These studies define the immune regulatory function of autoreactive CD8 T-cells in EAE. Our results demonstrate that autoregulatory CD8 T-cells have an important disease ameliorating role in EAE, which is a disease of perturbed immune regulation. Understanding this arm of the adaptive immune system offers a promising strategy for immunotherapeutic intervention of MS.Item B Cell Modulation of T Cell Responses in Multiple Sclerosis(2010-01-12) Harp, Christopher Todd; Monson, Nancy L.Until recently, a definitive role for B cells in the pathogenesis of the autoimmune neurological disorder multiple sclerosis (MS), had not been widely accepted, and remains poorly understood. B cells have multiple functions in the immune system and can both positively and negatively modulate immune responses through the production of antibody, cytokine secretion, and/or antigen presentation. Several studies indirectly suggest that B cell-T cell cooperation may be paramount in MS disease pathogenesis, although this interaction has not been well studied in MS. Therefore, the focus of my thesis project was to test the hypothesis that B cells could be efficient neuro-antigen presenting cells in the context of MS. My work has demonstrated that the cerebrospinal fluid (CSF) B cell population in MS shows characteristics of both auto-reactivity and antigen driven selection in a germinal center reaction. These findings suggest that neuro-antigen driven selection had occurred in the periphery and prompted investigation of B cells as neuro-antigen presenting cells. Examination of CD40 ligand (CD40L) and interleukin-4 (IL-4) activated peripheral B cells demonstrated for the first time that B cells could efficiently elicit myelin basic protein (MBP) specific CD8+ and CD4+ T cell proliferation from resting T cells in vitro through a mechanism that was partially dependent on presentation through HLA-DR. Further inquiry into the antigen presentation capacity of specific subpopulations of resting B cells revealed that memory B cells from MS patients (but not healthy donors (HDs)) were significantly better neuro-antigen specific presenting cells than their na?ve counter parts. This data indicated that a specific peripheral immune response had been generated in response to neuro-antigens in RRMS patients but not HDs. Taken together, these data provide a model where antigen experienced peripheral B cells from MS patients (but not HDs) provide important T cell support through antigen presentation and add to our understanding of the role of B cells in the pathogenesis of this autoimmune disease of the CNS.Item Bandura's Social Cognitive Concepts and Physical Activity of People with Multiple Sclerosis: A Hierarchical Regression Analysis(2013-12-30) Gaylord, Kathryn Lee; Chiu, Chung-Yi; Froehlich-Grobe, Katherine; Rose, LindseyBACKGROUND: Social Cognitive Theory (SCT), developed by Alfred Bandura, is a theory often employed for health promotion. This theory focuses on a set of determinants, examining how each operates, and translating information about the determinants into health practices. The combination and interaction of the primary determinants of SCT (perceived self-efficacy, outcome expectations, goals, and perceived facilitators and barriers) not only determine, but also influence the health behaviors individuals engage in. Through the use of this theory, determinants to change and adoption of a new behavior can be assessed, and individual treatment plans may be developed to effectively focus on the most influential targets for behavioral change. Multiple Sclerosis, a chronic and debilitating health problem estimated to affect hundreds of thousands of individuals in the United States, often leads to individual suffering and an overall decreased quality of life. Currently, there is no cure for MS, so symptom management and a decrease in debility remain a critical area of focus for health professionals working with MS patients. While there is no cure for this disorder, physical activity has been shown to alleviate multiple symptoms of MS such as mobility impairment, fatigue, pain, and depression, which then improves the quality of one’s life. Furthermore, there is strong empirical evidence to support the use of SCT as an efficacious treatment approach for employing health promotion practices. The purpose of this study is to extend previous findings by examining how various SCT concepts relate to physical health, mental health, stage of change for exercise, and action planning and coping planning for exercise. Additionally, the present study examines how disability affects self-efficacy thereby impacting physical activity. SUBJECTS: A total of 214 individuals (185 females [86%] and 29 males [14%] with self-reported MS recruited from the National Multiple Sclerosis Society and a neurology clinic of a university teaching hospital in the Midwest participated in the current study. The average age among participants was 46.97 years (SD = 9.92). Around 36% of participants were retired due to MS, and approximately 72% of participants reported being treated for secondary health problems (e.g., overweight, high blood pressure, and diabetes). METHOD: Participant demographic data were gathered from self-reports and include age, gender, ethnicity, marital status, years since onset of MS, secondary health issues, education level, vocational status, occupation, area of residence, current and past rehabilitation services received, source of income, total income, access to physical exercise in community, and changes in health practice since onset of MS. SCT concepts were assessed using the following measures: Action Self-Efficacy Scale-Physical Exercise (ASES-PE), Outcome Expectancy Scale-Physical Exercise (OES-PE), Health/Safety Risk Perceptions Scale (HRPS), Health/Safety Expected Benefits Scale (HEBS), Barriers to Health Promoting Activities for Disabled Persons Scale (BHADP), the Action Planning and Coping planning Scale-Physical Exercise (APCPS-PE), the Physical Activity Stages of Change Instrument (PASC). Participant disability and health were assessed using the following measures: Minimal Record of Disability (MRD) and the MOS Short form Health Survey (SF-12v2). The present study used a hierarchical regression analysis to examine associations between various domains and a set of social cognitive concepts (self-efficacy, knowledge of health and risk benefits, and outcome expectancy). RESULTS: There were several significant findings when examining the four domains of action planning and coping planning, stage of change, physical health, and mental health. Results indicated action planning and coping planning was predicted by action self-efficacy (R2 = 45%, ß = .45, p < .001), outcome expectancy (R2 = 45%, ß = .20, p < .01), risk perception (R2 = 45%, ß = .14, p < .05), and perceived barriers (R2 = 16%, ß = -.14, p < .05). Results indicated that stage of change was predicted by action planning and coping planning (R2 = 28%, ß = .26, p < .01). When “physical health” was the outcome variable, it was predicted by age (R2 = 8%, ß = -.20, p < .01), severity of disability (R2 = 14%, ß = -.28, p < .01), action self-efficacy (R2 = 22%, ß = -.16, p < .05), and outcome expectancy (R2 = 22%, ß = .27, p < .01). Lastly, when “mental health” was the outcome variable, it was predicted by age (R2 = 6%, ß = .18, p < .05), perceived barriers (R2 = 11%, ß = -.23, p < .01), outcome expectancy (R2 = 18%, ß = -.25, p < .01), and action self-efficacy (R2 = 18%, ß = .22, p < .05). DISCUSSION: The research findings support the applicability of Bandura’s Social Cognitive Theory as a model for exercise or physical activity for people with MS. This study found unique relationships between physical health and action self-efficacy, and mental health and outcome expectancy (with both relationships having a negative correlation). The current study includes a unique subset of the MS population who are well-educated, affluent, and report greater access to services and who expressed the negative correlate between action self-efficacy and physical health. The aforementioned factors are supposed to support physical health. However, the current group has high action self-efficacy to exercise, and given that they likely have good knowledge about exercise benefits to MS and good environmental support to engage in exercise, their motivation has likely surpassed, and is greater than, their experienced physical health, such as suffering pain and fatigue, which decreases physical health. Furthermore, it may be that the participants in the current study have good knowledge about how physical activity benefits their MS symptoms and progress management; consequently, they have high intention to push themselves to engage in exercise even though they may have experienced pain and fatigue, both of which have affected physical health significantly. Additionally, considering that high outcome expectations of a behavior may lead to stress and anxiety, such stress may decrease mental health, particularly if the positive effects of an activity (such as exercise) are not experienced as soon as and as much as expected. Examining the social cognitive, physical health, and mental health domains provides a well-rounded and empirical basis for employing health promotion efforts in clinical work with persons with MS. Rehabilitation professionals may help persons with MS implement physical activity through the use of SCT, which may improve their mobility impairment, pain, fatigue, and depression. The present study’s findings enable clinicians and rehabilitation professionals to better create and customize treatment to best meet individual patients’ needs and improve their overall quality of life.Item Biomarker Discovery in Autoimmune Diseases: A Proteomics Approach(2009-01-14) Tan, Chiang "Niclas"; Kodadek, Thomas J.Proteins constitute the functional machinery of cells and are prime candidates for disease marker discovery. Mass spectrometry-based proteomics biomarker discovery holds the ability to interrogate a constellation of proteins simultaneously in a high-throughput manner to uncover a panel of markers that are specific to the presence of a disease. However, the rate of introduction of novel biomarkers with clinical currency has declined in the past few years due to challenges faced by both the discovery and validation stages. Surface retentate chemistry-mass spectrometry is a powerful platform that allows on-chip simplification of complex biological samples to better match the current dynamic range of mass spectrometers. Initial reports on differential protein profiling using this approach produced profiles with high sensitivities and specificities for disease classification. As with any maturing technology, issues that were overlooked during its introduction are now the main barriers to its clinical utility. The improved workflow described here aims to address some of these pending issues. Specifically, the experimental design incorporated knowledge of the disease pathway into sample selection, elected sample sources that are rich in diagnostic markers, and adopted biological and technical replicates to minimize variance. To ensure reproducibility, complete automation of the process from sample preparation to data acquisition was incorporated along with the adoption of a high performance mass spectrometer with minimal mass drift. A robust data analysis approach was implemented to overcome the issue of overfitting and to effectively trim down the list of candidate biomarkers to the selected few with true discriminatory power to facilitate downstream validation. As a demonstration of the robustness and utility of the workflow, profiling studies were performed on two autoimmune diseases. Protein profiles with high mass peak fidelity were obtained with high discriminatory power. Selective differential peaks were further investigated and confirmed to display differential levels in clinical samples. Validation in a larger sample set should determine the diagnostic potential of these markers for clinical application. Finally, a high-throughput study is reported showing that peptoids are, in general, a relatively more cell permeable class of molecules than peptides, rendering them ideal for drug development to target disease biomarkers.Item Clinical Diagnostic Potential and Characterization of Distinctly Hypermutated Antibodies in Multiple Sclerosis Patients(2016-08-12) Rounds, William Harold Alexander; Cowell, Lindsay G.; Monson, Nancy L.; Wakeland, Edward K.; Patrie, Steven M.; Ward, E. SallyMultiple sclerosis (MS) diagnosis primarily revolves around the use of brain lesion detection by MRI and the elimination of other possible neurological disorder diagnoses through clinical testing and history. For many patients first experiencing clinical symptoms that could be MS-related, this presents a challenge since diagnostic certainty based on clinical presentation and testing does not always reach a consensus among doctors who evaluate them. With a growing body of evidence for B cell involvement and dysregulation in MS, our group investigated and identified a potential biomarker in the cerebrospinal fluid of patients with MS based on B cell antibody sequencing. This work first identified a distinct mutation pattern in the antibody sequences of CSF-derived B cells, termed the antibody gene signature (AGS), that could be used to identify patients with MS or patients who would convert to MS subsequent to their first onset of clinically detectable symptoms. This thesis project outlines the transition from AGS testing in a laboratory setting to its use and implementation as an additional clinical diagnostic tool for MS (MSPrecise®) using next generation sequencing (NGS). One of its main goals is to thoroughly evaluate the performance of MSPrecise® using the far greater throughput which NGS allows for. Over the course of the project, NGS technology and accuracy optimization methods have advanced significantly. As our laboratory is the first to ever utilize NGS for somatic hypermutation evaluation, we focused strongly on the evaluation of challenges and features associated with NGS use for immune repertoire diversity and somatic hypermutation profiling of clinical samples. In this context, this project also highlights observations on sequence library preparation and post-sequencing data filtering that affect all immune repertoire research that uses these rapidly developing sequencing platforms.Item CNS-Specific, Autoreactive CD8+ T Cells Have a Regulatory Role in Autoimmune Demyelination(2010-05-14) York, Nathan Ronald; Karandikar, Nitin J.Multiple Sclerosis (MS) is an inflammatory disorder characterized by the destruction of myelin sheaths, which encase neurons of the central nervous system. A great deal of our current knowledge about the immune pathogenesis of MS derives from work in its murine model, experimental autoimmune encephalomyelitis (EAE), which can be induced by inoculation with a specific neuroantigen or by adoptive transfer of CNS-specific activated T cells. The vast majority of studies in MS and EAE have focused on the role of CD4+ T cells in this disease, with the underlying assumption that MS, like EAE, is a CD4+ Th1-mediated autoimmune disease. However, several reports have implicated both CD4+ and CD8+ T cells in the pathogenesis and regulation of these diseases. In this study, we show the presence of antigen-specific, autoreactive CD8+ T cells in several models of EAE. Furthermore, through series of adoptive transfer studies, we show that these cells play a regulatory role in the pathogenesis of autoimmune demyelination. Using novel in vivo killing assays, we show that these cells retain their killing capacity and that they target both activated APC and CD4+ T cells that have been loaded with the specific antigen. These cells are also shown to produce cytokines that may be involved in disease regulation. We also show that these cells modify antigen-presenting capacity of APC. In conclusion, our studies provide strong evidence that antigen-specific CD8+ T cells are involved in regulatory processes in the context of autoimmune demyelinationItem Disease Exacerbation in Multiple Sclerosis Patients is Characterized by Loss of Terminally Differentiated CD8+ T Regulatory Cells(2014-02-04) Cunnusamy, Khrishen; Baughman, Ethan J.; Franco, Jorge; Ortega, Sterling B.; Greenberg, Benjamin M.; Frohman, Elliot M.; Karandikar, Nitin J.Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) that afflicts more than 400,000 people in the US. Although the etiology of the disease is unknown, pathogenic T cells are thought to underlie MS immune pathology. In contrast to the current paradigm, we recently showed that MS patients harbor CNS-specific CD8+ T regulatory cells (CD8 Tregs) that are deficient during disease relapse. In the current study, we demonstrate that the neuroantigen-specific CD8 Tregs were cytolytic and eliminated pathogenic CD4+ T cells. Sorting of CD8+ T cells using an array of surface cellular markers revealed that the CD8 Tregs were terminally differentiated (CD27-, CD45RO-). The CD8 Treg-mediated suppression was perforin, granzyme B, and interferon-γ-dependent. Interestingly, we found that MS patients with acute disease exacerbation displayed a significant loss (averaging 25%) in the terminally differentiated CD8+ T cells, with a concurrent loss in perforin and granzyme B expression. In order to restore the regulatory potential of impaired CD8 Tregs during exacerbation, we pre-treated exacerbation-derived bulk CD8+ T cells with the cytokine IL-12 and significantly increased the suppressive capability of the cells by ~48% through upregulation of granzyme B and perforin. Our studies uncover the immune suppressive mechanism of neuroantigen-specific CD8 Tregs, and may contribute to the design of clinically relevant immune therapies for MS patients.Item Dysregulated B Cells in Relapsing Remitting Multiple Sclerosis and Their Impact on T-Cell Function(2015-03-10) Ireland, Sara Jean; Monson, Nancy L.; Farrar, J. David; Davis, Laurie; van Oers, Nicolai S. C.; Kasper, LloydRelapsing-remitting multiple sclerosis (MS) is an autoimmune mediated inflammatory demyelinating disorder of the central nervous system. The role of B cells in the pathoetiology of MS is substantiated by cell depletion therapies but is not well understood. We hypothesized that B cells from MS patients would secrete more pro-inflammatory cytokines and support T cell responses to self-antigens and that the therapeutic agent glatiramer acetate (GA) could modulate these aspects of B cell function. To test this hypothesis we interrogated the ability of memory and naive B cells from healthy donors (HD), MS patients, and GA-treated MS patients (GA-MS) to proliferate and secrete cytokines in vitro. We identified a remarkable loss of IL-10 secretion by B cells from MS patients, but a marked increase in the production of IL-6, particularly from naïve B cells. We also found that memory B cells from MS patients exhibited hyperactive proliferation compared to healthy donors and naïve B cells from MS patients. GA had no measurable impact on any of the B cell functions we tested; however, B cells from GA-treated MS patients had a restored ability to produce IL-10, greatly enhanced immunoglobulin production, altered proliferation capacity and a transient diminishment of IL-6 production for patients on therapy for less than 32 months. To address whether memory or naïve B cells from MS patients supported neuro-antigen specific T cell responses, we co-cultured B and T cells in the absence or presence of foreign or neuro-antigens. We found that memory and naïve B cells from MS patients support more CD4+ T cell proliferation and TH1 and TH17 responses to neuro-antigens despite a similar frequency of neuroantigen specific T cells. Together, these data reveal that B cells from MS patients exhibit dysregulated proliferation and cytokine secretion that can be modulated by GA. Furthermore B cells from MS patients support neuroantigen-specific T cell proliferation and pro-inflammatory cytokine production in response to self neuro-antigens.Item Evidence of B Cell Dysregulation in Early Multiple Sclerosis Patients(2017-04-04) Rivas, Jacqueline Ruth; Satterthwaite, Anne B.; Monson, Nancy L.; Stowe, Ann; Cowell, Lindsay G.; Greenberg, Benjamin M.Plasmablasts are a highly differentiated, antibody secreting B cell subset whose prevalence correlates with disease activity in Multiple Sclerosis (MS). For many patients experiencing partial transverse myelitis symptoms, plasmablasts are elevated in the blood and cerebrospinal fluid (CSF) at the first clinical presentation of disease. Plasmablasts are a transient subset, representing the portion of B cells currently participating in an antibody-mediated immune response. However, it has not been investigated whether these cells have the potential to participate in the autoimmune response through the expression of autoreactive receptors. In these studies, we found genetic evidence of B cell dysregulation in early MS patients, likely from a loss of peripheral tolerance, and the development of affinity maturated, autoreactive plasmablasts. Plasmablasts from these early MS patients over-utilize immunoglobulin heavy chain V-region subgroup 4 (VH4) genes, exhibit excess light chain receptor editing, and have increased mutation accumulation in IgG utilizing VH4+ cells. Many highly mutated antibodies utilizing VH4 gene segments from both CSF B cells and peripheral plasmablasts recognize neurons and glial cells. Certain peripheral cells are polyreactive, while those in the CSF are typically specific for central nervous system antigens. Other V gene families have the potential for autoreactivity as well, although the strongest binding was observed in VH4+ antibodies. The peripheral plasmablast response is directed toward cytoplasmic neuronal antigens, and this autoreactivity is detectable in the serum IgG antibody pool. Interestingly, certain mutations in six key codons along the VH4 domain correlate with polyreactivity, neuron reactivity, or glial cell reactivity. Previous work identified that the prevalence of mutations at these codons in CSF B cells predicts conversion to MS, demonstrating their likely role in progression of disease. Plasmablasts may provide a useful biomarker of B cell activation in MS, or may be direct participants in autoimmunity. In either case, the study of plasmablasts provides insight to the development of the autoreactive B cell response in early MS patients.Item Implications of Dysregulated Antibody Hypermutation Patterns in Multiple Sclerosis Patients(2014-01-06) Ligocki, Ann Jolanta; Ward, E. Sally; Monson, Nancy L.; Vitetta, Ellen S.; Scheuermann, Richard H.; Diamond, Betty A.The potential role of B cells in contributing to the pathology of the human autoimmune neurological disease multiple sclerosis (MS) has recently become of significant interest. MS is a complex disorder of the central nervous system (CNS) with various presentation types, symptoms, and damage that involves many different components of the immune system. Historically, the role of B cells was considered minimal and overshadowed by the impact of T cells. The main effector function of a B cell is mediated by the downstream production of antibodies, that bind to their cognate antigens.. Thus, detailed investigation of antibody genomics reveals important information regarding the response of a B cell to its environment. We previously discovered a pattern of somatic hypermutation in the antibody genes expressed isolated from cerebrospinal fluid (CSF) B cells of patients with MS and those at high risk for developing MS. The focus of this thesis project was to further characterize this pattern of mutation termed the antibody gene signature (AGS) and determine the biological significance of this shared AGS among patients. Secondly, I aimed to discover differences in B cell subtypes and antibody genomics in the two of the most common initial presentations of clinically isolated syndrome (CIS) patients at high risk for converting to MS: optic neuritis (ONCIS) and transverse myelitis (TMCIS). Through my work in analyzing antibody genomics, I demonstrated that the AGS is present at the site of MS disease, within the CNS tissue. This provides support for the study of CSF B cells since it recapitulates what is present within the parenchyma. I also determined that both ONCIS and TMCIS patients are enriched for AGS positive B cells within the CSF. This exemplifies that regardless of initial presentation, patients at high risk for converting to MS share this AGS. Further characterization of TMCIS patients revealed that a subset harbor an expansion of plasmablasts in both the periphery and the CSF compared to ONCIS patients. Furthermore, in depth analyses of the peripheral plasmablasts uncovered altered genomic selective pressures in the periphery. This differential expansion of plasmablasts may offer insight for future studies of the possible varied underlying biological processes between these two patient groups. I aimed to determine the biological significance of this shared genomic pattern of the AGS by examining the CNS targeting potential. Immunohistochemical experiments revealed that AGS-enriched antibodies from ONCIS, TMCIS, and MS patients target neurons and astrocytes within the gray matter. These novel findings provide future directions for elucidating the auto-antigen(s) responsible for eliciting the shared AGS. Furthermore, identifying the AGS-enriched antibody binding patterns could aid in identifying potential therapeutic targets to help reduce CNS damage in both CIS and MS patients.Item The MMPI-2 Restructured Clinical (RC) Scales and Personality Assessment in Multiple Sclerosis(2011-02-01) Rosvall, Traci; Lacritz, Laura H.Multiple sclerosis (MS) is a demyelinating central nervous system disease commonly accompanied by mood changes and cognitive deficits. The Minnesota Multiphasic Personality Inventory-2 (MMPI-2) is frequently used in MS but has been criticized for its inclusion of items referring to neurologic content. MS patients may accurately endorse physical symptoms, which may lead to multiple scale elevations due to the extensive item overlap across the MMPI-2 Clinical Scales. Many published studies have documented elevations on Scales 1, 2, 3, 7, and 8 in MS. In 2003, Tellegen et al. used factor analysis and a construct validity-guided approach to adapt the MMPI-2 and create a set of Restructured Clinical (RC) Scales that included 388 items. The RC scales have attracted significant attention, with evidence of improved psychometric properties, but also criticism about their conceptual foundations and applications. This study had three broad goals. The first was to compare psychometric properties in the RC and Clinical Scales in an MS sample. Secondly, profiles were examined to compare the association between somatic symptoms and the RC and Clinical Scales. Third, the relationship between cognitive dysfunction and the RC and Clinical Scales was investigated. Scores from the RC and Clinical Scales and several cognitive measures were examined from 84 patients in an outpatient neuropsychology clinic. Results showed higher item-total correlations and lower inter-scale correlations for the RC Scales compared to the Clinical Scales, although internal consistency coefficients were comparable or better for the Clinical Scales. Thus, internal consistency findings were mixed with regard to improvement for the RC Scales, while some evidence of higher discriminant validity was found. Somatic and cognitive symptoms were associated with higher Clinical Scale elevations compared to their RC counterparts, particularly on Scales 1, 2, 3, 7, and 8, which were clinically significant in this sample. Mean RC Scale scores were within normal limits with the exception of RC1 (Somatic Complaints), indicating less psychopathology in the sample than the Clinical Scales would suggest. Findings support the need for cautious interpretation of Clinical Scale profiles in MS and suggest that the RC Scales may be a useful measure with this population.Item Neuroantigen-Specific CD8+ Regulatory T-Cell Function Is Deficient During Acute Exacerbation of Multiple Sclerosis(2013-05-31) Baughman, Ethan James; Karandikar, Nitin J.; Street, Nancy E.; Thiele, Dwain L.; Forman, James; Greenberg, Benjamin M.Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). MS is thought to be T-cell-mediated, with prior research predominantly focusing on CD4+ T-cells. There is a high prevalence of CNS-specific CD8+ T-cell responses in MS patients and healthy subjects. However, the role of neuroantigen-specific CD8+ T-cells in MS is poorly understood, with the prevalent notion that these may represent pathogenic T-cells. We show here that healthy subjects and MS patients demonstrate similar magnitudes of CD8+ and CD4+ T-cell responses to various antigenic stimuli. Interestingly, CD8+ T-cells specific for CNS autoantigens, but not those specific for control foreign antigens, exhibit immune regulatory ability, suppressing proliferation of CD4+CD25- T-cells when stimulated by their cognate antigen. While CD8+ T-cell-mediated immune suppression is similar between healthy subjects and clinically quiescent treatment-naïve MS patients, it is significantly deficient during acute exacerbation of MS. Of note, the recovery of neuroantigen-specific CD8+ T-cell suppression correlates with disease recovery post-relapse. In healthy adult subjects, we observed that the CD62L- subset of CD8+ T cells harbored increased CNS- and Copaxone-specific suppressive ability, when compared to the CD62L+ subset and bulk CD8+ T cells, and that the CD28+ subset of CD8+ T cells harbored increased global suppressive ability, when compared to the CD28- subset. In contrast, we observed CD8+ T cells from neonates harbored increased global suppressive ability in the CD28- subset. The mechanism of neuroantigen-specific suppression by CD8+ T cells was dependent upon HLA class I, IFN gamma, with possible partial involvement by NKG2D, PD-1, and IL-10. These studies reveal a novel immune suppressor function for neuroantigen-specific CD8+ T-cells that is clinically relevant in the maintenance of peripheral tolerance and the intrinsic regulation of MS immune pathology.Item Neurocognitive and Psychosocial Profiles of Pediatric Multiple Sclerosis and Transverse Myelitis(2018-07-30) Tan, Alexander; Harder, Lana; Hughes, Jennifer L.; Hynan, Linda S.; Lacritz, Laura H.; Greenberg, Benjamin M.Research shows that youth with multiple sclerosis (MS) are at risk for neuropsychological deficits due to cerebral involvement, but establishing a clear profile remains difficult due to disease complexity. Emerging evidence also shows neuropsychological deficits and the possibility of brain-based involvement in youth with transverse myelitis (TM) despite absence of obvious cerebral pathology. The present objective is to further investigate neuropsychological sequelae associated with pediatric MS and TM by characterizing and comparing neurocognitive and psychosocial profiles using profile analysis, a method which has not been utilized to investigate neuropsychological functioning in pediatric demyelinating diseases. Sixty-two pediatric MS and 46 pediatric idiopathic TM participants were administered brief neuropsychological screening evaluations during routine clinical care. Separate profile analyses were conducted on performance-based neurocognitive and parent-rated psychosocial variables of interest. Results of the neurocognitive profile analysis revealed significantly (p < .05) poorer overall performance in MS, with measures of cognitive flexibility, visual-motor integration, and fine-motor speed and dexterity found to be significant (p < .05) contributors to combined profiles. However, no significant difference was found in profile patterns between MS and TM groups. Results of the psychosocial profile analysis revealed no significant difference in overall levels of psychosocial problems between groups, with no individual measures found to be significant contributors to combined profiles. However, a significant (p < .05) difference in profile patterns was found between MS and TM groups, characterized by increased elevations in working memory and attention difficulties in MS and physical and social quality of life difficulties in TM. These findings elucidate the neurocognitive and psychosocial sequelae of pediatric MS and TM. While it is established that pediatric patients with MS often present with wide-ranging neuropsychological deficits consistent with brain-based pathology, the present study shows that pediatric patients with TM are also considered to be at risk for neuropsychological difficulties, suggesting that disease mechanisms may impact brain function despite the lack of obvious cerebral involvement. Findings of the current study indicate neuropsychologists play an important role in assessment and treatment planning for these populations, and youth with TM may also benefit from interventions to address cognitive and psychosocial problems.Item [News](1985-04-23) Rutherford, SusanItem Predictors of Quality of Life in Multiple Sclerosis: Relationships Between Cognitive, Physical, and Subjective Measures of Disease Burden(2011-12-14) Noll, Kyle Richard; Lacritz, Laura H.The varied constellation of symptoms characteristic of multiple sclerosis (MS) are often functionally impairing, affecting the health-related quality of life (QoL) of many of those afflicted. However, it remains unclear to what extent subjective, cognitive, and physical measures differentially predict overall health-related QoL in MS, and which (combination of) factors are most useful when making clinical inferences regarding patient well-being. Stepwise linear regression analyses were used to investigate predictors of QoL in 55 consecutive MS patients, recruited as part of the Cognition and Demyelinating Disease project at the UTSW MS Clinic. Out of all cognitive, physical, and self-report predictors of overall health-related QoL, only the Modified Fatigue Impact Scale (MFIS) was significant, accounting for 31% of the variance in Overall scores on the MSQOL-54 (p < .001). Significant predictors of mental health-related QoL included the Quick Inventory of Depressive Symptoms (QIDS) and the Modified Fatigue Impact Scale (MFIS) (p < .001). The QIDS alone accounted for 64% of the variance in MSQOL-54 Mental Composite scores, which increased to 71% with the inclusion of the MFIS. Significant predictors of physical health-related QoL included the MFIS, Timed 25-Foot Walk (T25FW), and Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) (p < .001). The MFIS alone accounted for 72% of the variance in MSQOL-54 Physical Composite scores, which increased to 76% with the inclusion of the T25FW, and 78% when the MSNQ was also added. These results suggested that measures of self-reported fatigue and depression were the best predictors of health-related QoL in the domains of overall, physical, and mental functioning. In light of these findings, screening for fatigue and mood dysregulation should be incorporated into routine clinical evaluations of MS patients. Results of ROC analyses revealed that the QIDS and MFIS were both significant discriminators of level of QoL (high vs. low) for each of the three MSQOL-54 summary measures (AUCs = .79 to .92). Examining rates of correct classification, specificity, and sensitivity, indicated that cut-scores of greater than nine on the QIDS and greater than 37 on the MFIS were optimal for discriminating between low and high QoL.Item Preferential Regulatory T-Cell Generation from Memory CD4+ T-Cells Is Deficient During Acute Exacerbation of Multiple Sclerosis(2014-06-11) Mohiuddin, Imran Hafiz; Niederkorn, Jerry Y.; Karakndikar, Nitin J.; Mohan, Chandra; Gruchalla, Rebecca S.Multiple sclerosis (MS) is an immune-mediated disease with reported defects in thymic T-cell output. Thymically-derived natural regulatory T-cells (nTregs) play a vital role in suppressing autoimmune responses. We have previously shown that, in humans, all activated T-cells attain transient FOXP3 expression that correlates with suppressive ability. In fact, peripheral generation of induced Tregs (iTregs) is likely the dominant source of regulatory cells in healthy adults and even more so in MS patients. Through the use of a sensitive flow-based suppression assay, we observed that memory and naïve CD4+CD25-FOXP3- T-cells both developed regulatory ability subsequent to a variety of activating stimuli. This suppressive ability was greater than that observed in nTregs and not explained by exhaustion of nutrients or competition for APCs. While blockade of activation using anti-IL-2, CTLA-4 Ig, anti-TGF-β, indomethacin or cyclosporin A did not affect iTreg generation, methotrexate preempted the induction of regulatory ability. Moreover, irradiation of iTregs also abrogated regulatory function. Interestingly, memory-derived CD25+ iTregs displayed significantly greater activation-induced FOXP3 induction compared to naïve counterparts, and exhibited significantly enhanced suppressive function per cell. Furthermore, the CD25- fraction of activated memory-derived iTregs also demonstrated regulatory function not observed in naïve counterparts. In particular, this induced regulatory population was present in both healthy controls and quiescent MS patients, but deficient during MS acute exacerbation. These studies suggest that iTreg development and function may vary dependent on precursor origin, and that clinical recovery from exacerbation to ix quiescence in MS is associated with a restoration of function in memory-derived CD4+CD25-FOXP3- Tregs.Item A Proposed Battery Used to Monitor Treatment Outcomes in Individuals with Multiple Sclerosis: A Case Study(2013-05-17) Riggs, Amanda Lynn; Gatchel, Robert J.; Chiu, Chung-Yi; Haggard, RobbieBACKGROUND: Multiple Sclerosis (MS) is a chronic disease of the central nervous system. As of now, there is no cure for MS, but different forms of treatment have been studied to ameliorate both physical and psychosocial symptoms. Numerous measures have been used within the MS population to monitor symptoms before, during, and after treatment. The aim of this present study was to ensure the usefulness of a battery of outcome measures that will assess MS-related symptoms before and after standard treatment. Another aim of the study was to assess treatment outcomes and determine the current success of each individualized treatment plan. SUBJECTS: All participants had a confirmed diagnosis of MS, were able to read and write in English, were 18 years of age and older, and able to walk, even briefly, with or without an assistive device. Participants were recruited through The University of Texas Southwestern Medical Center, Multiple Sclerosis Clinic. METHOD: Ten qualified MS patients were given a Six-minute walk test, two cognitive tests, and nine psychosocial measures as a baseline assessment. After six to eight weeks of Standard care, all participants were asked to return in order to complete all the measures again. It was hypothesized that the proposed battery of measures would prove to be useful in monitoring treatment outcomes in patients with MS. It was also hypothesized that individualized treatment would prove to be beneficial to each participant over the course of the study. RESULTS: This study did not provide any evidence that the individualized treatment was beneficial. Moreover, it did not provide any evidence that this particular battery was sensitive enough to truly monitor treatment outcomes. There was only one significant difference found between initial and follow-up assessment. The sum of ranks for the BORG was 0.00 (Z = -2.00, p = .046, r = -0.89) when comparing breathlessness scores. This indicates that individuals that returned for follow-up assessment experienced less breathlessness at follow-up assessment before and after the Six-minute Walk Test than before and after the Six-minute Walk test upon initial assessment. DISCUSSION: The period between assessments may not have been long enough to identify any changes in treatment or treatment outcomes. Due to the unpredictable nature of MS, it may be important for providers to assess individuals using a comprehensive, biopsychosocial battery on a case-by-case basis rather than a generalized pre-established time frame.Item The Role of Chronically Stimulated and Senescent T Cells in Autoimmunity(2006-09-25) Ratts, Robert Bruce; Racke, Michael K.Myelin-reactive T cells have been hypothesized to play a role in the pathogenesis of MS. If this is the case, these T cells would be expected to be repeatedly stimulated over the course of this disease because of the episodic breakdown of myelin membranes. Continuous stimulation of myelin-reactive T cells may also change the phenotype of these T cells. For example it may drive autoreactive T cells into senescence. Senescent T cells would be unable to divide but may still retain effector functions such as the ability to lyse target cells. The existence of senescent autoreactive T cells in MS patients could explain why therapies that limit the proliferation of T cells have had little effect on the course of MS, particularly later in the course of the disease. Human T cells adopt a CD28-CD57+ phenotype in chronic viral infections and this has been hypothesized to result from chronic stimulation, however this phenotype may also be due to direct viral effects on T cells. Here I make use of human MS patients before and after chronic in vivo administration of the antigen glatiramer acetate to test this hypothesis. Before the initiation of glatiramer acetate treatment, glatiramer acetate -specific CD8 T cells were either CD28-CD57- or CD28+CD57-. This response changed to a predominantly CD28-CD57+ response after one year of continuous stimulation. This phenotype was only observed after chronic stimulation and not in a recall response to mumps. These cells were shown to contain perforin, indicating they likely play a cytotoxic role in vivo. Furthermore CD28-CD57+ CD8 T cells displayed a reduced proliferative capacity indicating they may be senescent or pre-senecent. When myelin-reactive T cell responses were examined a CD28-CD57+ CD8 T cell response could be detected in MS patients but not in healthy controls. These T cells contained mRNA consitant with a cytotoxic role and the abilty to home to the cerebrospinal fluid of MS patients. This observation may explain why therapies that limit the proliferation of T cells have had little effect on the course of MS, particularly later in the course of the disease.Item The Role of Fatigue, Depression, and Other Clinical Factors in Determining Cognitive Status in Pediatric Multiple Sclerosis and Transverse Myelitis(2019-07-29) Hague, Cole David; Harder, Lana; Greenberg, Benjamin M.; Heppner, Celia; Wilkinson-Smith, Alison; Hynan, Linda S.Multiple sclerosis (MS) and transverse myelitis (TM) are immune-mediated demyelinating diseases of the central nervous system (CNS). MS is a chronic inflammatory disease that impacts both the brain and spinal cord; whereas, TM is a monophasic condition impacting only the spinal cord. Not surprisingly, cerebral involvement present in MS has precipitated research documenting deficits in cognition and problems related to fatigue and depression. Few studies have examined the prevalence of cognitive impairment or the role of fatigue and depression in cognitive functioning in pediatric patients with TM. Limited evidence suggests that both youth with MS and TM are at risk for adverse neuropsychological outcomes, less is known about underlying clinical factors that may influence cognitive functioning. Consequently, the objective of the present study was to explore the role of fatigue, depression, and disease-related clinical variables (physical functioning, age at onset, time since onset) in determining the cognitive status (i.e., impaired or not impaired) in youth with MS and TM. Sixty-seven pediatric MS and 53 pediatric idiopathic TM participants were administered a brief neuropsychological screening evaluation as part of routine clinical care. Analyses examining parent-proxy rating of fatigue and depression revealed no significant differences between MS and TM groups. Additionally, a logistic regression was conducted to evaluate the impact of a proposed linear combination of predictor variables in determining cognitive status (i.e., impaired or not impaired). Results revealed that none of the predictor variables were significant contributors to cognitive status. However, a stepwise logistic regression revealed that increased parent-proxy ratings of depression symptoms contributed to the likelihood that MS and TM participants were defined as cognitively impaired. Additionally, exploratory analyses revealed that youth with MS (42%) experience a significantly higher rate of cognitive impairment than youth with TM (21%). Analyses found that both youth with MS and TM were rated as having a greater number of fatigue symptoms than would be expected in healthy controls, though they were not more likely to be rated as having depression symptoms. Findings of the present study suggest that youth with MS and youth with TM should undergo routine screening of cognitive functioning, as well as fatigue and depression symptoms. Such routine screenings would not only assist with identification of problems, but also facilitate the creation and implementation of interventions to address them. Research would likely benefit from additional studies examining the influence of fatigue and depression symptoms on cognitive functioning in MS and TM, albeit with larger sample sizes and additional metrics for assessing cognition, fatigue, and depression symptoms.Item The Role of Therapy-Induced CD8+ T Cells in a Mouse Model of Multiple Sclerosis(2009-06-18) Mendoza, Jason Paul; Karandikar, Nitin J.Murine experimental autoimmune encephalomyelitis (EAE) is an induced, autoimmune, demyelinating disease model for human multiple sclerosis (MS). Glatiramer acetate (GA) is an approved immunomodulatory therapy for MS that was discovered through studies in EAE. It is thought that the main mode of action of GA is the induction of a Th1 to Th2 shift in CD4+ T cells. We have shown that, in human MS, GA therapy induces an upregulation of cytotoxic, suppressor CD8+ T cell responses, suggesting that these cells are integrally involved in mediating the immune effects of this drug. In this study, we show that GA induces robust CD8+ T cell responses even in mice. Whereas GA immunization ameliorates the clinical and histologic severity of EAE in wild type C57BL/6 mice, such protection is not observed in CD8(-/-) mice, indicating that CD8+ T cells are required in mediating the effects of GA. Moreover, adoptive transfer of CD8+ T cells from GA-immunized (but not OVA-immunized) mice results in amelioration of EAE in CD8(-/-) and wildtype mice, suggesting therapeutic potential for GA-specific CD8+ T cells. These cells appear to mediate their effects through a cytotoxic/suppressor mechanism, similar to our findings in human MS. In addition, GA treatment results in decreased myelin oligodendrocyte glycoprotein (MOG)-specific CD4+ T cell responses. In conclusion, our studies provide strong evidence that the in vivo induction of immune modulatory CD8+ T cells is an essential step in mediating therapeutic protection during autoimmune demyelination.