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| | | Year : 2009 | Volume : 20 | Issue : 5 | Page : 731-736 | | | Systemic lupus erythematosus conundrums | | | E Nigel Wardle
London NW1 8JS, United Kingdom
Click here for correspondence address and email | Date of Web Publication | 2-Sep-2009 | | |      | |  Abstract | | | Although the pathogenesis of systemic lupus erythematosus (SLE) might now seem very complicated, various aspects are coming together to make a coherent story. Firstly, there is a loss of tolerance by the T and B lymphocytes, so accounting for the formation of autoantibodies that characterize this autoimmune disease. Failure of methylation of vital genes could underlie this aspect. Secondly, as much emphasized in recent years, poor clearance of apoptotic cells on account of defective phagocyte receptors and complement deficiencies involves stimulation of Toll like Receptors (TLRs) 7 and 9 on plasmacytoid dendritic cells (pDCs) and results in release of type I interferon alpha (IFNa). Thirdly, the familiar Th-1 lymphocytes produce interleukins 12 and 18 and interferon gamma (IFNy)), along with chemokines, but now Th-17 lymphocytes are recognized to play an important role. How to cite this article:
Wardle E N. Systemic lupus erythematosus conundrums. Saudi J Kidney Dis Transpl 2009;20:731-6 |
| Introduction | |  |
Although the pathogenesis of SLE might now seem very complicated, various aspects are coming together to make a coherent story. There is a loss of tolerance by the T and B lymphocytes, poor clearance of apoptotic cells on account of defective phagocyte receptors and complement deficiencies, and the familiar Th-1 lymphocytes produce interleukins and chemokines. However, now Th-17 lymphocytes are recognized to play an important role.
| Apoptotic Cell Debris leading to B cell production of Autoantibodies | | |
The schema in [Figure 1] shows the basic features of systemic lupus erythematosus (SLE). Additionally, there is a delayed clearance of dying or apoptotic cells in SLE, [1] and the amount of apoptotic debris is increased for several possible reasons: (i) there is accelerated apoptosis of leucocytes, (ii) there is a deficiency of natural opsonins such as some complement components, [2] (iii) there is dysfunction of macrophages including a deficiency of macrophage scavenger receptors, [3],[4] (iv) and there are T cell derived autoantibodies. [5] On the surfaces of apoptotic cells there are blebs in which DNA and chromatin nucleosomal material is found. Persons predisposed to SLE form anti-nucleosomal and antidsDNA autoantibodies by their B lymphocytes. [6] That occurs because debris of apoptotic cells is cleared (in part) by attaching to Toll-like Receptors 9 and 7 in the auto-phagosomes of the B lymphocytes. [7] At the same time, when such antigens stimulate the B-cell receptors (BCRs) there is engagement with TLRs 7 and 9 expressed within macrophages, in plasmacytoid dendritic cells (pDCs), and in auto-phagosomes of B lymphocytes. [8] The activation of TLRs 7/9 by autoantibodies to self-nucleotides then creates more autoreactive B cells and antibodies. Quite recently, it was recognized that over expression of TLR7 in transgenic mice predisposes to lupus nephritis, [9] whilst lack of the TLR7 gene ameliorates disease progression in lupus prone mice. AntidsDNA autoantibodies in patients with lupus form immune complexes that deposit on the kidney glomerular basement membrane (GBM) [Figure 1] and [Figure 2].There is an alternative view that antidsDNA or anti nucleosomal antibodies can crossreact with proteins within the kidneys and accordingly exert a pathogenic effect on glomerular cells. Furthermore, cytokine interleukin 10, an anti-inflammatory cytokine, helps the expansion of the self-reactive B-cell clones. [10],[11]
| Lupus DNA in Apoptotic Debris is Hypo-Methylated | | |
There is increased attention to "epigenetics", the study of chromatin mechanisms in the regulation of gene expression, instead of genetic events determined directly by the DNA sequence. [12] The chromatin in cell nuclei consists of nucleosomes that comprise 8 core histones around which the DNA helix is wrapped. "Epigenetic mechanism" affects the structure of the chromatin and thereby the accessibility of genes in the DNA. [12]
DNA methylation down-regulates the expression of both Th-1 and Th-2 cytokines, however, hypo-methylation results in hypercytokinemia. Via epigenetic processes, environmental influences can affect gene expression in SLE. Methylation of the genes in the DNA usually results in normal silencing of gene transcription and involves modification of the cytosine residues of C-G dinucleotides, [13] which prevent binding of transcription factors. Furthermore, methyl CpG binding proteins such as MECP2, which recognize methylated DNA, recruit his tone deacetylases to render the chromatin inaccessible for transcription. In SLE, T cell DNA is hypo-methylated, which results in the relaxation of the chromatin with increased accessibility to the target sequences, and the cells become more easily activated. [14] When the nucleosomes in the apoptotic debris are hypomethylated, the DNA creates autoimmunity. For example, TLR 7 and 9 stimulation is activated by hypomethylated CpG DNA, [15] which is a strong stimulus to the production of type I interferon. [16]
| Interferon Alpha in SLE | | |
Plasmacytoid DCs (pDCs) are the principal source of type I interferon (IFNa), the main defence against virus infections. In SLE, pDCs release IFNa in response to apoptotic cells. [17] TLR7 and TLR9 stimulation by immune complexes is known to enhance IFNa production. [18]
It has been known for a long time that serum IFNa is elevated in SLE patients. [19] Recently, patients with neuropsychiatric SLE have been found to manifest abnormally high IFNa inducing activity in their CSFs. [20]
One should also note that IFNa causes dendritic cells to release BLys/BAFF, the B lymphocyte stimulating factor. [21] BLys helps the survival of B cells and their transition to plasma cells and promotes development of B1 type and B-marginal zone cells in the lymphoid organs. Moreover, estrogen sustains auto reactive B lymphocytes. [22] [Figure 3] shows how B lymphocytes eventually are activated and how auto antibodies feature in SLE. It has been demonstrated recently that when dendritic cells are primed by cytokines, which are activated in SLE, then lipopolysaccharide acting on TLR4 receptors of the DCs induces production of even more IFNα[23]
| The Relevance of T Lymphocyte sub-types to SLE | | |
As T-lymphocytes develop in the thymus, there is a developmental phase when double negative (DN) cells predominate followed by development of DP double positive CD4+CD8+ cells, and finally after selection of positive and negative cells give rise to the usual CD4+ (helper) or CD8+ (cytotoxic) lymphocytes. Strangely, double negative T cells were found to be expanded in the peripheral blood of patients with SLE. [24] Such cells produce interleukin 4 and they induce the formation of immunoglobulins and anti-DNA antibodies as efficiently as normal CD4+ helper T-cells. Such double negative Tcells have now been found in the renal biopsies of the patients with lupus nephritis, [25] and are labelled as Th17 cells, since they produce interleukin 17. [26]
[Figure 4] explains more about IL-17 and Th-17 cells, which are known now to feature in various auto-immune diseases, [27] even though their primary function is to combat extracellular bacteria and fungi on epithelial cell surfaces. These cells develop under the influence of TGFI3 and Il-6, but they can also develop under the influence of IL-21 and IL-23, which is akin to IL12. Their understanding is a complicated immunological topic; they are marked by CD161 and CCR6, and develop under the influence of Stat3 and the transcription factor RORãt. [28] Whenever Th-17 cells are in abundance, the T regulatory (Treg) cells are in abeyance. Some groups have claimed that Treg cells are diminished in SLE, as demonstrated in some SLE mouse models. [29] Evidence continues to suggest that regulatory (suppressor)T-cells are somehow inadequate in SLE. [30]
Th-1 lymphocytes manifest in SLE, [32] and Th2 lymphocytes in cases of membranous nephropathy. [33] A recent study by Morimoto et al [33] demonstrates how Th1 lymphocytes predominate in the glomeruli in biopsies of types III and IV lupus nephritis. These cells produce interleukin 18, IL-12, and IFNα (interferon gamma). [34] IL-18 often enhances IL-12 driven Th-1 mediated immune responses. Additionally, there is a good evidence for formation of chemokines MCP-1 and IP-10, which attract Th-1 cells. [34] Furthermore, TNFa receptors and their adapter proteins were prominent in biopsies of class III and IV lupus nephritis patients. [35]
IL-20 and IL-21 have also been connected to lupus nephritis. IL-20 and its receptors were found to be upregulated in mesangial cells of NZB/W mice, and in mesangial and inflammatory cells in biopsies of patients with lupus nephritis. [36] IL-20 induces reactive oxygen species (ROS) and iNOS and IL-6 in mesangial cells, and induces transcripts of the chemokines CCL2 (MCP-1), CCL5 (Rantes) and CXCL10 (IP-10). IL-21, which controls the fate of activated B cells, [37] tends to be elevated in the mouse models of SLE; it helps B-cells become plasma cells, and causes apoptosis of B-cells depending on circumstances. Th-17 cells turn out to be a rich source of Il-21, [38] which helps sustain Th-17 lymphocytes. [39] Accordingly, reducing IL-21 levels in SLE patients may have a gratifying results in controlling this disease.
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Correspondence Address:
E Nigel Wardle
London NW1 8JS
United Kingdom
PMID: 19736466
[Figure 1], [Figure 2], [Figure 3], [Figure 4] | |
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