B cell epitope spreading: Mechanisms and contribution to autoimmune diseases

Cornaby, Caleb; Gibbons, Lauren; Mayhew, Vera; Sloan, Chad S.; Welling, Andrew; Poole, Brian

doi:10.1016/j.imlet.2014.11.001

Cited by 155 publications

(130 citation statements)

References 129 publications

(225 reference statements)

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“…General consensus seems exist for a role of EBV as inflammatory trigger, possibly through the release of EBER molecules into the circulation, providing general innate and adaptive activation signals (Iwakiri 2014) and EBNA1-DNA complexes as a rich source of antigen sequences that may induce cross-reactive antibodies, depending on the host MHC-II background (Yadav et al 2011). The release of complex and structured multi-epitope EBNA1-DNA complexes presented on APC during the cytokine-rich convalescent phase of mononucleosis together with innate signalling triggered by released EBER-protein/exosome complexes may trigger autoantibody formation by crossing the tolerance threshold and extending the restricted repertoire to include autoreactive clones, a phenomenon called epitope spreading (Füst 2013;Cornaby et al 2014). Evidence for such B-cell repertoire disturbance during mononucleosis has been presented and requires further analysis (Mockridge et al 2004).…”

Section: Autoimmunity and Antigen Mimicrymentioning

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: Autoimmunity and Antigen Mimicrymentioning

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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“…In addition, exogenous molecules could mimic endogenous ligands and cause aberrant receptor activation [58,60,61] Epitope spreading B and T cells can expand to include additional epitopes on a targeted protein and other similar epitopes on other endogenous material due to the proximity and overlap of these new epitopes with the initial immune provoking epitopes on an antigen. This has parallels with the molecular mimicry hypothesis [63,64] ASIA The Bautoimmune (or auto-inflammatory) syndrome induced by adjuvantsĥ ypothesis proposes that autoimmune diseases can result from agents to which persons are frequently exposed such as aluminum added to vaccines to enhance the immune reaction. The adjuvant could directly or indirectly provoke immune hyperactivity [66,71] Leaky gut syndrome…”

Section: Hypotheses Of Autoimmune Diseasesmentioning

confidence: 89%

A Review of Autoimmune Disease Hypotheses with Introduction of the “Nucleolus” Hypothesis

Brooks

2016

Clinic Rev Allerg Immunol

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Numerous hypotheses have been proposed in order to explain the complexity of autoimmune diseases. These hypotheses provide frameworks towards understanding the relations between triggers, autoantigen development, symptoms, and demographics. However, testing and refining these hypotheses are difficult tasks since autoimmune diseases have a potentially overwhelming number of variables due to the influence on autoimmune diseases from environmental factors, genetics, and epigenetics. Typically, the hypotheses are narrow in scope, for example, explaining the diseases in terms of genetics without defining detailed roles for environmental factors or epigenetics. Here, we present a brief review of the major hypotheses of autoimmune diseases including a new one related to the consequences of abnormal nucleolar interactions with chromatin, the "nucleolus" hypothesis which was originally termed the "inactive X chromosome and nucleolus nexus" hypothesis. Indeed, the dynamic nucleolus can expand as part of a cellular stress response and potentially engulf portions of chromatin, leading to disruption of the chromatin. The inactive X chromosome (a.k.a. the Barr body) is particularly vulnerable due to its close proximity to the nucleolus. In addition, the polyamines, present at high levels in the nucleolus, are also suspected of contributing to the development of autoantigens.

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“…Поскольку пос-ле дебюта РА «сероконверсия» АЦБ наблюдается редко [49], это свидетельствует о том, что гиперпродукция ан-тител является «причинным» фактором, а не следствием болезни и рассматривается как важное доказательство существования «преклинической» системной «аутоим-мунной» фазы РА. Характерными особенностями синте-за АЦБ при РА являются экспансия антигенного репер-туара (феномен расширения эпитопа -epitope spreading) [50] и нарастание авидности антител к аутоантигенным детерминантам модифицированных белков, которые до-стигают максимальной выраженности непосредственно перед развитием симптомов РА [51][52][53]. В развернутой стадии РА специфичность аутоантител существенно не меняется [54].…”

Section: роль ау тоантителunclassified

Problems of Rheumatoid Arthritis Immunopathology: Evolution of the Disease

Насонов¹

2017

rsp

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B cell epitope spreading: Mechanisms and contribution to autoimmune diseases

Cited by 155 publications

References 129 publications

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

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

A Review of Autoimmune Disease Hypotheses with Introduction of the “Nucleolus” Hypothesis

Problems of Rheumatoid Arthritis Immunopathology: Evolution of the Disease

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