Epstein-Barr Virus in Systemic Lupus Erythematosus, Rheumatoid Arthritis and Multiple Sclerosis—Association and Causation

Lossius, Andreas; Johansen, Jorunn N.; Torkildsen, Øivind; Vartdal, Frode; Holmøy, Trygve

doi:10.3390/v4123701

Cited by 116 publications

(101 citation statements)

References 219 publications

(272 reference statements)

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“…(Jones and Straus 1987;Miller et al 1987). In general, individuals with aberrant (elevated) levels of EA(D) antibodies, are considered to (temporally) lack proper immunological control over endogenous latent EBV, resulting in increased viral reactivation and replication and re-expression of immunogenic early antigens, as observed in "stress" and "fatigue" cohort studies (Glaser et al 2005;Lerner et al 2012), but which are also observed in patients with certain autoimmune disorders, such as SLE and RA (Ballandraud et al 2004;Lossius et al 2012), and nasopharyngeal carcinoma (Paramita et al 2007). …”

Section: Ebv Humoral Immune Responses As Defined By Classic Serology mentioning

confidence: 99%

Epstein-Barr Virus-Specific Humoral Immune Responses in Health and Disease

Middeldorp

2015

Current Topics in Microbiology and Immunology

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Epstein-Barr virus (EBV) is widely distributed in the world and associated with a still increasing number of acute, chronic, malignant and autoimmune disease syndromes. Humoral immune responses to EBV have been studied for diagnostic, pathogenic and protective (vaccine) purposes. These studies use a range of methodologies, from cell-based immunofluorescence testing to antibody-diversity analysis using immunoblot and epitope analysis using recombinant or synthetic peptide-scanning. First, the individual EBV antigen complexes (VCA , MA, EA(D), EA(R) and EBNA) are defined at cellular and molecular levels, providing a historic overview. The characteristic antibody responses to these complexes in health and disease are described, and differences are highlighted by clinical examples. Options for EBV vaccination are briefly addressed. For a selected number of immunodominant proteins, in particular EBNA1, the interaction with human antibodies is further detailed at the epitope level, revealing interesting insights for structure, function and immunological aspects, not considered previously. Humoral immune responses against EBV-encoded tumour antigens LMP1, LMP2 and BARF1 are addressed, which provide novel options for targeted immunotherapy. Finally, some considerations on EBV-linked autoimmune diseases are given, and mechanisms of antigen mimicry are briefly discussed. Further analysis of humoral immune responses against EBV in health and disease in carefully selected patient cohorts will open new options for understanding pathogenesis of individual EBV-linked diseases and developing targeted diagnostic and therapeutic approaches.

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Section: Ebv Humoral Immune Responses As Defined By Classic Serology mentioning

confidence: 99%

Epstein-Barr Virus-Specific Humoral Immune Responses in Health and Disease

Middeldorp

2015

Current Topics in Microbiology and Immunology

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“…It is also relevant to highlight that EBV-reactive CD8 + T cells are enriched in or near the diseased organs of patients with rheumatoid arthritis (44,45) and MS (46), including a high proportion of T cells specific for BZLF1 (47). This could reflect a local immune response against EBV in the diseased organs, or nonspecific homing of virus-specific T cells to inflamed sites (48).…”

Section: Discussionmentioning

confidence: 99%

T Cell Cross-Reactivity between a Highly Immunogenic EBV Epitope and a Self-Peptide Naturally Presented by HLA-B*18:01+ Cells

Hibbert

Croft

Smith

et al. 2015

The Journal of Immunology

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T cell cross-reactivity underpins the molecular mimicry hypothesis in which microbial peptides sharing structural features with host peptides stimulate T cells that cross-react with self-peptides, thereby initiating and/or perpetuating autoimmune disease. EBV represents a potentially important factor in the pathogenesis of several T cell–mediated autoimmune disorders, with molecular mimicry a likely mechanism. In this study, we describe a human self-peptide (DELEIKAY) that is a homolog of a highly immunogenic EBV T cell epitope (SELEIKRY) presented by HLA-B*18:01. This self-peptide was shown to bind stably to HLA-B*18:01, and peptide elution/mass spectrometric studies showed it is naturally presented by this HLA molecule on the surface of human cells. A significant proportion of CD8+ T cells raised from some healthy individuals against this EBV epitope cross-reacted with the self-peptide. A diverse array of TCRs was expressed by the cross-reactive T cells, with variable functional avidity for the self-peptide, including some T cells that appeared to avoid autoreactivity by a narrow margin, with only 10-fold more of the self-peptide required for equivalent activation as compared with the EBV peptide. Structural studies revealed that the self-peptide–HLA-B*18:01 complex is a structural mimic of the EBV peptide–HLA-B*18:01 complex, and that the strong antiviral T cell response is primarily dependent on the alanine/arginine mismatch at position 7. To our knowledge, this is the first report confirming the natural presentation of a self-peptide cross-recognized in the context of self-HLA by EBV-reactive CD8+ T cells. These results illustrate how aberrant immune responses and immunopathological diseases could be generated by EBV infection.

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“…Til tross for at gjennomgått Epstein-Barrvirusinfeksjon er meget vanlig i den generelle voksne befolkningen (90 -95 %), er dette viruset sterkt assosiert med utvikling av multippel sklerose (18). Tilnaermet alle voksne pasienter med sykdommen har gjennomgått en slik virusinfeksjon, og en prospektiv studie viste at dette skjer før debut av symptomer på multippel sklerose (19).…”

Section: Epstein-barr-virusunclassified

“…To forhold tyder på at ungdomsårene er den viktigste sårbarhetsperioden for EpsteinBarr-viruseksponering: I områder hvor primaer infeksjon skjer tidlig, er forekomsten av multippel sklerose lav, og infeksiøs mononukleose, som skyldes primaer Epstein-Barrvirusinfeksjon i ungdomsårene, dobler risikoen for multippel sklerose (18).…”

Section: Epstein-barr-virusunclassified

“…Mulige mekanismer for Epstein-Barrvirusinfeksjon ved multippel sklerose inkluderer immunologisk kryssreaksjon, at viruset beskytter autoreaktive B-celler mot apoptose samt aktivering av autoreaktive T-celler ved overskytende immunreaksjoner mot EpsteinBarr-virus (18). I tråd med en immunologisk mekanisme ser det ut til at T-celler rettet mot viruset akkumuleres i spinalvaesken hos personer med multippel sklerose (21).…”

Section: Epstein-barr-virusunclassified

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