Medicine and Health Sciences | Open Access Articles

A Common Mechanism Links Epstein‐Barr Virus Infections And Autoimmune Diseases, Luwen Zhang

Nebraska Center for Virology: Faculty Publications

Epstein‐Barr virus (EBV) infection is associated with a variety of the autoimmune diseases. There is apparently no unified model for the role of EBV in autoimmune diseases. In this article, the development of autoimmune diseases is proposed as a simple two‐step process: specific autoimmune initiators may cause irreversible changes to genetic materials that increase autoimmune risks, and autoimmune promoters promote autoimmune disease formation once cells are susceptible to autoimmunity. EBV has several types of latencies including type III latency with higher proliferation potential. EBV could serve as autoimmune initiators for some autoimmune diseases. At the same time, EBV may play …

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Epstein Barr Virus-Immortalizedｂlymphocytes Exacerbate Experimental Autoimmune Encephalomyelitis In Xenograft Mice, Pascal Polepole, Alison Bartenslager, Yutong Liu, Thomas M. Petro, Samodha C. Fernando, Luwen Zhang

Nebraska Center for Virology: Faculty Publications

Multiple sclerosis (MS) is the most common autoimmune disorder affecting the central nervous system. Epstein-Barr virus (EBV) is a causative agent for infectious mononucleosis (IM) that is associated with MS pathogenesis. However, the exact mechanism by which EBV, specifically in IM, increases the risk for MS remains unknown. EBV immortalizes primary B lymphocytes in vitro and causes excessive B lymphocyte proliferation in IM in vivo. In asymptomatic carriers, EBV-infected B lymphocytes still proliferate to certain degrees, the process of which is tightly controlled by the host immune systems. Experimental autoimmune encephalomyelitis (EAE) mimics key features of MS in humans …

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Epstein Barr Virus-Immortalizedｂlymphocytes Exacerbate Experimental Autoimmune Encephalomyelitis In Xenograft Mice, Pascal Polepole, Alison Bartenslager, Yutong Liu, Thomas M. Petro, Samodha C. Fernando, Luwen Zhang

Nebraska Center for Virology: Faculty Publications

Multiple sclerosis (MS) is the most common autoimmune disorder affecting the central nervous system. Epstein-Barr virus (EBV) is a causative agent for infectious mononucleosis (IM) that is associated with MS pathogenesis. However, the exact mechanism by which EBV, specifically in IM, increases the risk for MS remains unknown. EBV immortalizes primary B lymphocytes in vitro and causes excessive B lymphocyte proliferation in IM in vivo. In asymptomatic carriers, EBV-infected B lymphocytes still proliferate to certain degrees, the process of which is tightly controlled by the host immune systems. Experimental autoimmune encephalomyelitis (EAE) mimics key features of MS in humans and …

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Whose Preferences Matter? A Patient-Centered Approach For Eliciting Treatment Goals, Nananda F. Col, Andrew J. Solomon, Vicky Springman, Calvin P. Garbin, Carolina Ionete, Lori Pbert, Enrique Alvarez, Brenda Tierman, Ashli Hopson, Christen Kutz, Idanis Berrios Morales, Carolyn Griffin, Glenn Phillips, Long H. Ngo

Department of Psychology: Faculty Publications

Background. Patients facing a high-stakes clinical decision are often confronted with an overwhelming array of options. High-quality decisions about treatment should reflect patients’ preferences as well as their clinical characteristics. Preference-assessment instruments typically focus on pre-selected clinical outcomes and attributes chosen by the investigator. Objective. We sought to develop a patient-centered approach to elicit and compare the treatment goals of patients with multiple sclerosis (MS) and healthcare providers (HCPs). Methods. We conducted five nominal group technique (NGT) meetings to elicit and prioritize treatment goals from patients and HCPs. Five to nine participants in each group responded silently to one question …

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A Urinary Metabolic Signature For Multiple Sclerosis And Neuromyelitis Optica, Teklab Gebregiworgis, Helle H. Nielsen, Chandirasegara Massilamany, Arunakumar Gangaplara, Jay Reddy, Zsolt Illes, Robert Powers

Jay Reddy Publications

Urine is a metabolite-rich biofluid that reflects the body’s effort to maintain chemical and osmotic homeostasis. Clinical diagnosis routinely relies on urine samples because the collection process is easy and noninvasive. Despite these advantages, urine is an under-investigated source of biomarkers for multiple sclerosis (MS). Nuclear magnetic resonance spectroscopy (NMR) has become a common approach for analyzing urinary metabolites for disease diagnosis and biomarker discovery. For illustration of the potential of urinary metabolites for diagnosing and treating MS patients, and for differentiating between MS and other illnesses, 38 urine samples were collected from healthy controls, MS patients, and neuromyelitis optica-spectrum …

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Identification Of A Second Mimicry Epitope From Acanthamoeba Castellanii That Induces Cns Autoimmunity By Generating Cross-Reactive T Cells For Mbp 89–101 In Sjl Mice, Chandirasegaran Massilamany, Oluwatoyin A. Asojo, Arunakumar Gangaplara, David J. Steffen, Jay Reddy

Jay Reddy Publications

We had previously reported that Acanthamoeba castellanii (ACA) contains a mimicry epitope for proteolipid protein 139–151 capable of inducing central nervous system (CNS) autoimmunity in SJL/J mice. We now present evidence that ACA also contains a mimicry epitope for myelin basic protein (MBP) 89–101, a derivative from amoebic nicotinamide adenine dinucleotide dehydrogenase subunit 2 (NAD). The epitope, NAD 108–120, contains a discontinuous stretch of six amino acids in the core region (VVFFKNIILIGFL) sharing 46% identity with MBP 89–101 (VHFFKNIVTPRTP; identical residues are underlined). SJL mice immunized with NAD 108–120 develop encephalomyelitis similar to the disease induced by the cognate peptide. …

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Identification Of A Second Mimicry Epitope From Acanthamoeba Castellanii That Induces Cns Autoimmunity By Generating Cross-Reactive T Cells For Mbp 89–101 In Sjl Mice, Chandirasegaran Massilamany, Oluwatoyin A. Asojo, Arunakumar Gangaplara, David J. Steffen, Jay Reddy

Jay Reddy Publications

We had previously reported that Acanthamoeba castellanii (ACA) contains a mimicry epitope for proteolipid protein 139–151 capable of inducing central nervous system (CNS) autoimmunity in SJL/J mice. We now present evidence that ACA also contains a mimicry epitope for myelin basic protein (MBP) 89–101, a derivative from amoebic nicotinamide adenine dinucleotide dehydrogenase subunit 2 (NAD). The epitope, NAD 108–120, contains a discontinuous stretch of six amino acids in the core region (VVFFKNIILIGFL) sharing 46% identity with MBP 89–101 (VHFFKNIVTPRTP; identical residues are underlined). SJL mice immunized with NAD 108–120 develop encephalomyelitis similar to the disease induced by the cognate peptide. …

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Gender Differences In Cns Autoimmunity Induced By Mimicry Epitope For Plp 139–151 In Sjl Mice, Chandirasegara Massilamany, Sivasubramani Thulasingam, David Steffen, Jay Reddy

Jay Reddy Publications

Development of multiple sclerosis (MS) is more prevalent in females than in males, but the underlying mechanisms are not clear. Microbial infections have been suspected as triggers of MS and it is not known whether gender differences in reactivity to environmental antigens contribute to the disease pathogenesis. We demonstrated that ACA 83–95, a mimicry epitope from Acanthamoeba castellanii for proteolipid protein (PLP) 139–151, induces clinical signs of encephalomyelitis in both male and female SJL mice. Conversely ACA 83–95-induced effector cells from males fail to induce disease in female mice. Although we found no gender differences in the frequencies of antigen-specific …

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Fibroblast Growth Factor 1 (Fgfr1) Modulation Regulates Repair Capacity Of Oligodendrocyte Progenitor Cells Following Chronic Demyelination, Yong-Xing Zhou, Ravinder Pannu, Tuan Q. Le, Regina C. Armstrong

Uniformed Services University of the Health Sciences

The adult mammalian brain contains multiple populations of endogenous progenitor cell types. However, following CNS trauma or disease, the regenerative capacity of progenitor populations is typically insufficient and may actually be limited by non-permissive or inhibitory signals in the damaged parenchyma. Remyelination is the most effective and simplest regenerative process in the adult CNS yet is still insufficient following repeated or chronic demyelination. Our previous in vitro studies demonstrated that fibroblast growth factor receptor 1 (FGFR1) signaling inhibited oligodendrocyte progenitor (OP) differentiation into mature oligodendrocytes. Therefore, we questioned whether FGFR1 signaling may inhibit the capacity of OP cells to generate …

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An Epitope From Acanthamoeba Castellanii That Cross-React With Proteolipid Protein 139-151-Reactive T Cells Induces Autoimmune Encephalomyelitis In Sjl Mice, Chandirasegaran Massilamany, David Steffan, Jay Reddy

Jay Reddy Publications

We report here that an epitope (aa, 83-95) derived from Acanthamoeba castellanii (ACA) induces clinical signs of experimental autoimmune encephalomyelitis (EAE) in SJL/J mice reminiscent of the disease induced with myelin proteolipid protein (PLP) 139-151. By using IA^s/tetramers, we demonstrate that both ACA 83-95 and PLP 139-151 generate antigen-specific cross-reactive CD4 T cells and the T cells secrete identical patterns of cytokines and induce EAE with a similar severity. These results may provide insights into the pathogenesis of multiple sclerosis and ACA-induced granulomatous encephalitis.

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Monoclonal Antibodies To Distinct Regions Of Human Myelin Proteolipid Protein Simultaneously Recognize Central Nervous System Myelin And Neurons Of Many Vertebrate Species, Edward A. Greenfield, Jay Reddy, Andrew Lees, Charissa A. Dyer, Omanand Koul, Khuong Nguyen, Shannon Bell, Nasim Kassam, Julian Hinojoza, Mary Jane Eaton, Marjorie B. Lees, Vijay K. Kuchroo, Raymond A. Sobel

Jay Reddy Publications

Myelin proteolipid protein (PLP), the major protein of mammalian CNS myelin, is a member of the proteolipid gene family (pgf). It is an evolutionarily conserved polytopic integral membrane protein and a potential autoantigen in multiple sclerosis (MS). To analyze antibody recognition of PLP epitopes in situ, monoclonal antibodies (mAbs) specific for different regions of human PLP (50–69, 100–123, 139–151, 178–191, 200–219, 264–276) were generated and used to immunostain CNS tissues of representative vertebrates. mAbs to each region recognized whole human PLP on Western blots; the anti-100–123 mAb did not recognize DM-20, the PLP isoform that lacks residues 116–150. All of …

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Peptide 15-Mers Of Defined Sequence That Substitute For Random Amino Acid Copolymers In Amelioration Of Experimental Autoimmune Encephalomyelitis, Joel N.H. Stern, Zsolt Illés, Jay Reddy, Derin B. Keskin, Masha Fridkis-Hareli, Vijay K. Kuchroo, Jack L. Strominger

Jay Reddy Publications

Myelin basic protein (MBP) is a major candidate autoantigen in multiple sclerosis (MS). Its immunodominant epitope, MBP 85–99, forms a complex with human leukocyte antigen (HLA)-DR2 with which multiple sclerosis is genetically associated. Copolymer 1 (Copaxone), a random amino acid copolymer [poly (Y,E,A,K)n] as well as two modiﬁed synthetic copolymers [poly (F,Y,A,K)n and poly (V,W,A,K)n] also form complexes with HLA-DR2 (DRA DRB1*1501) and compete with MBP 85–99 for binding. Moreover, two high-afﬁnity synthetic peptide 15-mers that could inhibit binding even more effectively were previously designed. Here, we show that further-modiﬁed peptide 15-mers inhibited even more strongly (in order J5 > J3 …

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Modified Amino Acid Copolymers Suppress Myelin Basic Protein 85–99-Induced Encephalomyelitis In Humanized Mice Through Different Effects On T Cells, Zsolt Illés, Joel N.H. Stern, Jay Reddy, Hanspeter Waldner, Marcin P. Mycko, Celia F. Brosnan, Stephan Ellmerich, Daniel M. Altmann, Laura Santambrogio, Jack L. Strominger, Vijay K. Kuchroo

Jay Reddy Publications

A humanized mouse bearing the HLA-DR2 (DRA/DRB1*1501) pro- tein associated with multiple sclerosis (MS) and the myelin basic protein (MBP) 85–99-speciﬁc HLA-DR2-restricted T cell receptor from an MS patient has been used to examine the effectiveness of modiﬁed amino acid copolymers poly(F,Y,A,K)n and poly- (V,W,A,K)n in therapy of MBP 85–99-induced experimental auto-immune encephalomyelitis (EAE) in comparison to Copolymer 1 [Copaxone, poly(Y,E,A,K)n]. The copolymers were designed to optimize binding to HLA-DR2. Vaccination, prevention, and treatment of MBP-induced EAE in the humanized mice with copolymers FYAK and VWAK ameliorated EAE more effectively than Copolymer 1, reduced the number of pathological lesions, and …

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Amelioration Of Proteolipid Protein 139–151-Induced Encephalomyelitis In Sjl Mice By Modified Amino Acid Copolymers And Their Mechanisms, Joel N.H. Stern, Zsolt Illés, Jay Reddy, Derin B. Keskin, Eric Sheu, Masha Fridkis-Hareli, Hiroyuki Nishimura, Celia F. Brosnan, Laura Santambrogio, Vijay K. Kuchroo, Jack L. Strominger

Jay Reddy Publications

Copolymer 1 [Cop1, glatiramer acetate, Copaxone, poly(Y,E,A,K)n] is widely used in the treatment of relapsing/remitting multiple sclerosis in which it reduces the frequency of relapses by ≈30%. In the present study, copolymers with modified amino acid compositions (based on the binding motif of myelin basic protein 85–99 to HLA-DR2) have been developed with the aim of suppressing multiple sclerosis more effectively. The enhanced efficacy of these copolymers in experimental autoimmune encephalomyelitis (EAE) induced in SJL/J mice with proteolipid protein 139–151 was demonstrated by using three protocols: (i) simultaneous administration of autoantigen and copolymer (termed prevention), (ii) …

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Full-Text Articles in Medicine and Health Sciences

A Common Mechanism Links Epstein‐Barr Virus Infections And Autoimmune Diseases, Luwen Zhang

Nebraska Center for Virology: Faculty Publications

Epstein Barr Virus-Immortalizedｂlymphocytes Exacerbate Experimental Autoimmune Encephalomyelitis In Xenograft Mice, Pascal Polepole, Alison Bartenslager, Yutong Liu, Thomas M. Petro, Samodha C. Fernando, Luwen Zhang

Nebraska Center for Virology: Faculty Publications

Epstein Barr Virus-Immortalizedｂlymphocytes Exacerbate Experimental Autoimmune Encephalomyelitis In Xenograft Mice, Pascal Polepole, Alison Bartenslager, Yutong Liu, Thomas M. Petro, Samodha C. Fernando, Luwen Zhang

Nebraska Center for Virology: Faculty Publications

Department of Psychology: Faculty Publications

A Urinary Metabolic Signature For Multiple Sclerosis And Neuromyelitis Optica, Teklab Gebregiworgis, Helle H. Nielsen, Chandirasegara Massilamany, Arunakumar Gangaplara, Jay Reddy, Zsolt Illes, Robert Powers

Jay Reddy Publications

Identification Of A Second Mimicry Epitope From Acanthamoeba Castellanii That Induces Cns Autoimmunity By Generating Cross-Reactive T Cells For Mbp 89–101 In Sjl Mice, Chandirasegaran Massilamany, Oluwatoyin A. Asojo, Arunakumar Gangaplara, David J. Steffen, Jay Reddy

Jay Reddy Publications

Identification Of A Second Mimicry Epitope From Acanthamoeba Castellanii That Induces Cns Autoimmunity By Generating Cross-Reactive T Cells For Mbp 89–101 In Sjl Mice, Chandirasegaran Massilamany, Oluwatoyin A. Asojo, Arunakumar Gangaplara, David J. Steffen, Jay Reddy

Jay Reddy Publications

Gender Differences In Cns Autoimmunity Induced By Mimicry Epitope For Plp 139–151 In Sjl Mice, Chandirasegara Massilamany, Sivasubramani Thulasingam, David Steffen, Jay Reddy

Jay Reddy Publications

Fibroblast Growth Factor 1 (Fgfr1) Modulation Regulates Repair Capacity Of Oligodendrocyte Progenitor Cells Following Chronic Demyelination, Yong-Xing Zhou, Ravinder Pannu, Tuan Q. Le, Regina C. Armstrong

Uniformed Services University of the Health Sciences

An Epitope From Acanthamoeba Castellanii That Cross-React With Proteolipid Protein 139-151-Reactive T Cells Induces Autoimmune Encephalomyelitis In Sjl Mice, Chandirasegaran Massilamany, David Steffan, Jay Reddy

Jay Reddy Publications

Jay Reddy Publications

Peptide 15-Mers Of Defined Sequence That Substitute For Random Amino Acid Copolymers In Amelioration Of Experimental Autoimmune Encephalomyelitis, Joel N.H. Stern, Zsolt Illés, Jay Reddy, Derin B. Keskin, Masha Fridkis-Hareli, Vijay K. Kuchroo, Jack L. Strominger

Jay Reddy Publications

Jay Reddy Publications

Jay Reddy Publications