Epstein-Barr virus and molecular mimicry in systemic lupus erythematosus. Autoimmunity

Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma, OK 73104, USA.
Autoimmunity (Impact Factor: 2.71). 03/2006; 39(1):63-70. DOI: 10.1080/08916930500484849
Source: PubMed


Systemic lupus erythematosus (SLE or lupus) is a complex disease with a multifactoral etiology, with genetic, hormonal, and environmental influences. Molecular mimicry as a result of viral infection may contribute to the development of lupus. The pattern of autoantibody development in lupus is consistent with initiation through molecular mimicry, as the initial autoantigenic epitopes that have been observed are limited and cross-reactive with viral proteins. Autoantibody specificity may then later diversify to other autoantigens through B-cell epitope spreading. Epstein-Barr virus (EBV) is an excellent candidate to be involved in molecular mimicry in lupus. EBV infection has been associated with lupus through serological and DNA studies. Infection with EBV results in the production of the viral protein Epstein-Barr virus nuclear antigen-1 (EBNA-1), antibodies against which cross-react with lupus-associated autoantigens, including Ro, Sm B/B', and Sm D1, in lupus patients. The immune response against EBV, and EBNA-1 in particular, differs among lupus patients and healthy controls, with controls maintaining a limited humoral response and failing to produce long-standing cross-reactive antibodies. We hypothesize that the humoral immune response to EBNA-1 in susceptible individuals leads to the generation of cross-reactive antibodies. Through the process of epitope spreading, these cross-reactive antibodies target additional, non-cross reactive autoepitopes, spread to additional autoantigens, and become pathogenic, leading eventually to clinical lupus. This paper reviews some of the current literature supporting roles for EBV exposure and epitope spreading in SLE.

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    • "Immunization with the PPPGRRP sequence from EBNA-1 lead to development of cross-reactive antibodies that recognized both epitopes, as well as further epitope spreading leading to autoimmunity against Sm and nRNP complexes. Also, 5 out of the 6 rabbits immunized developed SLE like symptoms over the course of the experiment indicating that the mechanism of molecular mimicry involving EBNA-1 can lead to development of systemic lupus erythematosus-like disease [25]. Clinical evidence shows similar results with respect to the spreading of epitopes in SLE. "
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    ABSTRACT: While a variety of factors act to trigger or initiate autoimmune diseases, the process of epitope spreading is an important contributor in their development. Epitope spreading is a diversification of the epitopes recognized by the immune system. This process happens to both T and B cells, with this review focusing on B cells. Such spreading can progress among multiple epitopes on a single antigen, or from one antigenic molecule to another. Systemic lupus erythematosus, multiple sclerosis, pemphigus, bullous pemphigoid and other autoimmune diseases, are all influenced by intermolecular and intramolecular B cell epitope spreading. Endocytic processing, antigen presentation, and somatic hypermutation act as molecular mechanisms that assist in driving epitope spreading and broadening the immune response in autoimmune diseases. The purpose of this review is to summarize our current understanding of B cell epitope spreading with regard to autoimmunity, how it contributes during the progression of various autoimmune diseases, and treatment options available. Copyright © 2014 Elsevier B.V. All rights reserved.
    Full-text · Article · Nov 2014 · Immunology Letters
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    • "TLR7 is specialized in recognizing single-stranded RNA (ssRNA) originating from viruses [34], but it has been postulated that self-RNA becomes a target, when self-tolerance is breached [36]. This break of tolerance has been demonstrated upon EBV infection, inducing anti-Ro and Sm antibodies [37], [38]. In autoimmune diseases, autoantibodies directed against RNA-binding self-antigens (anti-Ro/SSA and La/SSB), consequently deliver aberrantly exposed extracellular RNA to the endosomal compartment of B cells and pDCs (via the B cell receptor or Fc receptors) and subsequently trigger TLR7 signalling [39]. "
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    ABSTRACT: To investigate the potential synergy of IL-7-driven T cell-dependent and TLR7-mediated B cell activation and to assess the additive effects of monocyte/macrophages in this respect. Isolated CD19 B cells and CD4 T cells from healthy donors were co-cultured with TLR7 agonist (TLR7A, Gardiquimod), IL-7, or their combination with or without CD14 monocytes/macrophages (T/B/mono; 1 : 1 : 0,1). Proliferation was measured using 3H-thymidine incorporation and Ki67 expression. Activation marker (CD19, HLA-DR, CD25) expression was measured by FACS analysis. Immunoglobulins were measured by ELISA and release of cytokines was measured by Luminex assay. TLR7-induced B cell activation was not associated with T cell activation. IL-7-induced T cell activation alone and together with TLR7A synergistically increased numbers of both proliferating (Ki67+) B cells and T cells, which was further increased in the presence of monocytes/macrophages. This was associated by up regulation of activation markers on B cells and T cells. Additive or synergistic induction of production of immunoglobulins by TLR7 and IL-7 was associated by synergistic induction of T cell cytokines (IFNγ, IL-17A, IL-22), which was only evident in the presence of monocytes/macrophages. IL-7-induced CD4 T cell activation and TLR7-induced B cell activation synergistically induce T helper cell cytokine and B cell immunoglobulin production, which is critically dependent on monocytes/macrophages. Our results indicate that previously described increased expression of IL-7 and TLR7 together with increased numbers of macrophages at sites of inflammation in autoimmune diseases like RA and pSS significantly contributes to enhanced lymphocyte activation.
    Full-text · Article · Apr 2014 · PLoS ONE
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