IL-6 Modulates CD5 Expression in B Cells from Patients with Lupus by Regulating DNA Methylation

Research Unit EA2216 Immunology and Pathology, IFR148 ScInBioS, Université de Brest, Brest, France.
The Journal of Immunology (Impact Factor: 4.92). 06/2009; 182(9):5623-32. DOI: 10.4049/jimmunol.0802412
Source: PubMed


B lymphocytes from patients with systemic lupus erythematosus (SLE) are characterized by reduced expression levels of membrane CD5. Recent studies from our laboratory have revealed that the level of membrane CD5 is determined by the relative level of two alternative CD5 isoforms; CD5-E1A, which is expressed on the membrane, and CD5-E1B, which is retained in the cytoplasm. Using bisulfite sequencing and methylation-sensitive endonuclease assays we show that the promoter for the alternative CD5-E1B isoform is demethylated in B cells from patients with SLE but not in healthy controls. We go on to show that differential methylation is more pronounced following BCR engagement. As a result of this demethylation, CD5-E1B mRNA is transcribed at the expense of CD5-E1A mRNA transcription. We provide further evidence that production of high IL-6 levels by SLE B cells abrogates the ability of SLE B cells to induce DNA methyl transferase (DNMT1) and then to methylate DNA, an effect that is reversed in the presence of a blocking Ab to the IL-6 receptor. The pattern of demethylation of CpG islands in the CD5-E1B promoter in SLE B cells is similar to those in B cells from healthy controls stimulated in the presence of IL-6, or treated with the methylation inhibitor PD98059. The study reveals that engagement of the BCR with constitutive IL-6 down-regulates the level of membrane CD5, which negatively regulates BCR signaling, in SLE B cells. This altered signaling could, in turn, promote the activation and expansion of autoreactive B cells in SLE patients.

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    • "At the same time, Brookes et al. (1992) mentioned that the human T cell lymphotropic virus (HTLV) related endogenous sequence, HRES1, was overexpressed in the epithelium of labial salivary glands obtained from patients with primary SS (pSS). HRES1 regulation by DNA methylation was recently provided (Garaud et al., 2009; Fali et al., 2013) Later, the HERV- K113, and HRV-5 retroviral elements were found overexpressed in pSS patients (Murovska et al., 2000; Moyes et al., 2005). More recently, using a RT-PCR approach we have observed that at least one HERV-E element was detected when testing labial salivary glands from SS patients (Le Dantec et al., 2012). "
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    ABSTRACT: Sjögren's syndrome (SS) is a chronic autoimmune epithelitis that combines exocrine gland dysfunctions and lymphocytic infiltrations. While the pathogenesis of SS remains unclear, its etiology is multifunctional and includes a combination of genetic predispositions, environmental factors, and epigenetic factors. Recently, interest has grown in the involvement of epigenetics in autoimmune diseases. Epigenetics is defined as changes in gene expression, that are inheritable and that do not entail changes in the DNA sequence. In SS, several epigenetic mechanisms are defective including DNA demethylation that predominates in epithelial cells, an abnormal expression of microRNAs, and abnormal chromatin positioning-associated with autoantibody production. Last but not least, epigenetic modifications are reversible as observed in minor salivary glands from SS patients after B cell depletion using rituximab. Thus epigenetic findings in SS open new perspectives for therapeutic approaches as well as the possible identification of new biomarkers.
    Frontiers in Genetics 04/2014; 5:71. DOI:10.3389/fgene.2014.00071
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    • "On the other hand, B cells expressing high levels of CD5-E1B, induced probably by external stimuli, would more likely to be activated. To support these results, in B lymphocytes from SLE patients, the levels of CD5-E1B are higher, indicating a more activating B cell [85]. These high levels of CD5-E1B traduces in reduced expression of membrane CD5. "
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    ABSTRACT: B lymphocytes are the effectors of humoral immunity, providing defense against pathogens through different functions including antibody production. B cells constitute approximately 15% of peripheral blood leukocytes and arise from hemopoietic stem cells in the bone marrow. It is here that their antigen receptors (surface immunoglobulin) are assembled. In the context of autoimmune diseases defined by B and/or T cell autoreactive that upon activation lead to chronic tissue inflammation and often irreversible structural and functional damage, B lymphocytes play an essential role by not only producing autoantibodies but also functioning as antigen-presenting cells (APC) and as a source of cytokines. In this paper, we describe B lymphocyte functions in autoimmunity and autoimmune diseases with a special focus on their abnormalities in systemic lupus erythematosus.
    09/2013; 2013(22):827254. DOI:10.1155/2013/827254
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    • "It is thought that hypomethylation may alter synovial fibroblasts, which triggers RA development [85-86]. Altered methylation has been explored in B cells [87] and T cells [88] while changes in the pattern of DNA methylation have been found to associate with twin discordance in SLE [89]. Murine models have clearly demonstrated reduced methylation levels in the thymus of lupus-prone mice compared to non-prone mice [90]. "
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    ABSTRACT: Autoimmune rheumatic diseases, such as RA and SLE, are caused by genetic, hormonal and environmental factors. Human Endogenous Retroviruses (HERVs) may be triggers of autoimmune rheumatic disease. HERVs are fossil viruses that began to be integrated into the human genome some 30-40 million years ago and now make up 8% of the genome. Evidence suggests HERVs may cause RA and SLE, among other rheumatic diseases. The key mechanisms by which HERVS are postulated to cause disease include molecular mimicry and immune dysregulation. Identification of HERVs in RA and SLE could lead to novel treatments for these chronic conditions. This review summarises the evidence for HERVs as contributors to autoimmune rheumatic disease and the clinical implications and mechanisms of pathogenesis are discussed.
    The Open Rheumatology Journal 03/2013; 7:13-21. DOI:10.2174/1874312901307010013
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