New insights into the pathogenesis of systemic lupus erythematosus

Although the etiology of systemic lupus erythematosus is unknown, recent studies have shed light on the pathoge-netic pathways that lead to tissue damage. The immune system in systemic lupus erythematosus is characterized by a complex interplay between overactive B cells, abnormally activated T cells, and antigen-presenting cells. This leads to the production of an array of inflammatory cytokines, diverse autoantibodies, and immune complexes that in turn activate effector cells and the complement system leading to the clinical manifestations of the disease.     

B cell receptor signaling in human systemic lupus erythematosus

PURPOSE OF REVIEW: The purpose of this review is to inform the scientific community of the most recent findings surrounding B cell receptor signaling function in human systemic lupus erythematosus and how altered B cell signaling may explain the characteristic hyperactivity of B cells in active disease and contribute to its pathogenesis. RECENT FINDINGS: B cell receptor signaling is abnormal in patients with active systemic lupus erythematosus as demonstrated by increased calcium flux and global B cell hyperactivity. Altered signaling has been explained by a variety of factors such as defective FcgammaRIIB signaling, decreased expression of the protein tyrosine kinase Lyn, and increased serum levels of B lymphocyte stimulator. SUMMARY: The studies reviewed suggest that B cells from systemic lupus erythematosus patients display molecular signaling defects that most likely contribute to pathogenesis of the disease and explain the characteristic hyperactivity of B cells in active disease.     

Pathogenic anti-nucleosome antibodies

There is increasing evidence that in systemic lupus erythematosus, nucleosomes, the basic chromatin component, represent both a driving immunogen and a major in vivo target for antibodies. Either a disturbed apoptosis or a reduced clearance of apoptotic cells by phagocytes may lead to an increased exposure of apoptotic nucleosomes to the immune system. These nucleosomes, which have been cleaved and modified during the process of apoptosis, escape normal clearance and encompass epitopes that normally are not encountered by the immune system. This may then lead to tolerance breaking and autoimmunity by the activation of nucleosome-specific autoreactive T cells (that help B cells) and subsequently to the production of anti-nucleosome, anti-histone and anti-DNA autoantibodies. Some anti-nucleosome antibody subsets are pathogenic and are involved in the nephritogenic process in systemic lupus erythematosus. Accordingly, several studies reported: (i) increased plasma circulating nucleosomes that positively correlated with an active disease, (ii) nucleosomes in typical glomerular deposits as well as in the basement membrane of non-lesional skin of systemic lupus erythematosus patients and (iii) a close correlation between nephritis and the presence of anti-nucleosome antibodies. Recent studies reported anti-nucleosome antibodies also in primary anti-phospholipid syndrome and particularly in patients with associated lupus-like disease.     

Engagement of complement receptor 2 on the surface of B cells from patients with systemic lupus erythematosus contributes to the increased responsiveness to antigen stimulation

B cells from patients with systemic lupus erythematosus (SLE) display increased responses following cross-linking of the surface antigen receptor. We explored the possibility that the increased responses are at least partially due to simultaneous cross-linking of the complement receptor 2 (CR2). To this end, we stimulated fresh B cells from SLE patients with an anti-IgD antibody conjugated to the Epstein-Barr virus gp350 protein, which binds to CR2, and recorded the free intracytoplasmic calcium response during the first 10 min. Despite the fact that SLE B cells were found to express half as many surface CR2 as normal B cells, both peak responses and the percentage of responding cells were significantly increased in the former. These observations suggest that regulatory molecules such as CR2 are involved in the increased B cell responses in SLE patients. We propose that certain immune complexes that circulate in the sera of SLE patients that have anti-surface immunoglobulin specificities and are decorated with natural ligands of CR2, such as C3d, elicit and promote B cell overactivity.     

Sex and systemic lupus erythematosus: the role of the sex hormones estrogen and prolactin on the regulation of autoreactive B cells

PURPOSE OF REVIEW: For many decades, it has been speculated that sex hormones play a role in systemic lupus erythematosus. Recent data accumulated during the past few years provide striking evidence that hormonal modulation of B cells can have a profound impact on the survival, maturation and repertoire selection of autoreactive B cells and begin to explain the sex bias associated with the condition. RECENT FINDINGS: While there are still insufficient clinical data to define a role for estrogen or prolactin in human systemic lupus erythematosus, recent studies of anti-DNA antibody transgenic mice clearly demonstrate that an elevation in either estrogen or prolactin breaks tolerance of high affinity DNA-reactive B cells and induces a lupus phenotype. B cells with the same antigenic specificities are rescued by either estrogen or prolactin, but estrogen promotes the survival and activation of the T independent marginal zone B cell subset, while prolactin promotes the survival and activation of the T dependent follicular B cell subset. SUMMARY: Elevations in the levels of estrogen or prolactin can promote the survival and activation of high affinity autoreactive B cells. These hormones engage different B cell pathways to interfere with B cell tolerance. The identification of systemic lupus erythematosus patients with either an estrogen-responsive or prolactin-responsive disease will further the development of therapeutics that can specifically modulate hormonal responses.     

Antibodies in systemic autoimmune diseases. Special mention to systemic lupus erythematosus

Autoantibodies are the expression of humoral response to self-antigens and they may be diagnostic of autoimmune diseases. Studies in systemic lupus erythematosus (SLE) have shown that autoantibodies react with macromolecular structures such as the nucleosome or the spliceosome. These self-antigens are complexes of protein-DNA or protein-RNA like those recognized by anti-dsDNA or anti-RNPs (U1, Sm, Ro, La) antibodies respectively. Recent knowledge on innate immunity has shed more light on the pathological role of these autoantibodies. The antigen-antibody complexes formed as the result of an increase of sel-antigens in the blood as a consequence of an increase in apoptosis, attach to dendritic FcγII or B cell receptors. Through the attachment to the receptor, the macrocomplex is internalized within the cell and recognized in the endosomic membranes by receptors of the innate immune system named TLR (Toll-like receptor). There are at least 13 TLRs localized either in the cellular or the endosomic membranes. Of the latter group, TLR-7 is specific for ssRNA, and TLR-9 is specific for CpG DNA. The reaction of the immunocomplexes with the receptor triggers a kinase cascade that leads to IFNα production. The IFNα is a molecule of the innate and adaptative immune system responsible for the immune deregulation and pathological signs in the SLE. It plays an important role in antigen presentation to the autoreactive quiescent autoreactive T cells and in increasing the life span of dendritic and B cells. In addition, the increase in self-antigens released by greater apoptosis enhances the production of autoantibodies and their effect on the increase of IFNα production.     

Epstein-Barr virus and systemic lupus erythematosus

PURPOSE OF REVIEW: Systemic lupus erythematosus is a complex human disease likely influenced by a compilation of necessary, but not individually sufficient, features. Although many genetic and environmental factors are associated, this review will focus on the evolving evidence for key Epstein-Barr virus specific roles. RECENT FINDINGS: Recent studies have shown additional molecular mimicry mechanisms between early events in lupus autoimmunity and specific Epstein-Barr virus responses. In addition, several recent papers have demonstrated increased Epstein-Barr viral load, increased numbers of latently infected peripheral B cells, impaired functional T cell responses, and association of the presence of Epstein-Barr virus DNA in systemic lupus erythematosus patients compared with controls. Additional work has continued to show association of various aspects of Epstein-Barr virus serology with systemic lupus erythematosus and a recent paper outlines differences in the pediatric systemic lupus erythematosus humoral immune response to Epstein-Barr virus nuclear antigen-1 compared with matched controls. SUMMARY: This review will briefly outline the recent advances that show serologic, DNA, gene expression, viral load, T cell responses, humoral fine specificity, and molecular mimicry evidence for differences between systemic lupus erythematosus patients and controls and the impact that these findings have on understanding the role of Epstein-Barr virus in systemic lupus.     

Gene therapy in systemic lupus erythematosus

Preclinical studies have provided proof of concept for the feasibility and efficacy of gene therapy in human systemic lupus erythematosus (SLE). Successful efforts include gene constructs that alter the expression of cytokines or limit the cognate interaction of immune cells. Other efforts may include gene modified cell transfer such as autologous B cells transfected with tolerogenic constructs or T cells in which specific molecular aberrations have been corrected.     

Quantitation of IgM- and IgG-secreting B cells in the peripheral blood of patients with systemic lupus erythematosus.

An enzyme-linked immunospot assay was used to quantitate the number of autoantibody-secreting B cells in the peripheral blood of 67 patients with systemic lupus erythematosus. These patients had 1.5-4-fold more lymphocytes secreting IgG and IgM per million peripheral blood lymphocytes than did normal controls. There was a concomitant increase in the number of B cells secreting antibodies reactive with a diverse panel of foreign and self antigens (including actin, myosin, tri-nitrophenylated keyhole limpet hemocyanin, ovalbumin, and retroviral gp160). By comparison, the number of B cells producing anti-DNA antibodies was increased disproportionately. The magnitude of this anti-DNA response correlated significantly with disease activity. Thus, B cell activation in human systemic lupus erythematosus had characteristics of both generalized (polyclonal) B cell activation and (auto)antigen-specific immune stimulation.     

The innate immune system in SLE: type I interferons and dendritic cells

Patients with systemic lupus erythematosus (SLE) have an increased expression of type I interferon (IFN) regulated genes because of a continuous production of IFN-alpha. The cellular and molecular background to this IFN-alpha production has started to be elucidated during the last years, as well as the consequences for the innate and adaptive immune systems. Plasmacytoid dendritic cells (pDC) activated by immune complexes containing nucleic acids secrete type I IFN in SLE. Type I IFN causes differentiation of monocytes to myeloid-derived dendritic cell (mDC) and activation of autoreactive T and B cells. A new therapeutic option in patients with SLE is, therefore, inhibition of IFN-alpha, and recent data from a phase I clinical trial suggests that administration of neutralizing monoclonal antibodies against anti-IFN-alpha can ameliorate disease activity.     

Complement and systemic lupus erythematosus

PURPOSE OF REVIEW: It is well recognized that the complement system plays multiple roles in systemic lupus erythematosus. Activation of the classical pathway by immune complexes leads to the generation of inflammatory mediators, thus promoting tissue injury. Complement activation also plays an important role in the maintenance of tolerance to self-antigens. This review discusses recent insights in the role of complement in the pathogenesis of systemic lupus erythematosus. RECENT FINDINGS: The antiphospholipid syndrome is a major feature of systemic lupus erythematosus. New findings have clearly demonstrated that the prothrombotic effects seen in a mouse model of this syndrome depend on complement activation, whereas the protective effects of heparin are due to its anticomplementary effects rather than its anticoagulant action. Secondly, a potential mechanism explaining the association of anti-C1q autoantibodies with lupus glomerulonephritis has been elucidated in a mouse model system. SUMMARY: New findings have helped to reinforce the role of complement in the etiology and tissue damage of systemic lupus erythematosus. These findings point to more precise, mechanism-based therapies for autoimmune and inflammatory disease.     

The central role of dendritic cells and interferon-alpha in SLE

PURPOSE OF REVIEW: Until recently, systemic lupus erythematosus has been viewed mainly as a B-cell disease resulting from altered T cell-B cell interactions. The recognition of the fundamental role of dendritic cells in the control of tolerance and immunity led to the hypothesis that systemic lupus erythematosus may be driven through unabated dendritic cell activation. This review summarizes the recently uncovered role of dendritic cell subsets and one of their products, interferon-alpha, in the pathophysiology of systemic lupus erythematosus. RECENT FINDINGS: CD14+ monocytes isolated from the blood of patients with systemic lupus erythematosus, but not those from healthy individuals, act as dendritic cells. Their activation is driven by circulating interferon-alpha that may come from one of the dendritic cell subsets (ie, plasmacytoid dendritic cells that infiltrate systemic lupus erythematosus skin lesions). Although only a fraction of patients with active systemic lupus erythematosus show circulating interferon-alpha, blood mononuclear cells from all of them display an interferon-alpha signature. SUMMARY: The disease model that the authors propose places interferon-alpha at the center of the immunologic abnormalities observed in systemic lupus erythematosus, and poses interferon-alpha and/or interferon-alpha-producing cells as novel targets for therapy in this disease. The authors surmise that type I interferon antagonists will bring systemic lupus erythematosus patients the relief that tumor necrosis factor antagonists brought to patients with rheumatoid arthritis.     

Anticytokine therapy in systemic lupus erythematosus

Systemic lupus erythematosus is a prototype of heterogeneous autoimmune disease. There have been few newly approved therapeutic agents in lupus treatment for many reasons. Several animal studies and human data have shown that many potential cytokines are related to the pathogenesis and disease activity of systemic lupus erythematosus. Cytokines are produced by many immune cell types and have variable functions in the immune system. Following the success of biological agents in the treatment of inflammatory arthritis, inflammatory bowel disease, and psoriasis, biological targeting to specific cytokines or receptor molecules is now promising in the treatment of systemic lupus erythematosus. In addition to B-cell deleting modalities, clinical trials targeting potential cytokines associated with disease pathogenesis are underway at various clinical stages. Among potential cytokines, targeting agents against B-cell activating factor and interferon-alpha are in the most advanced stage, and belimumab (anti-B-cell activating factor antibody) could be the first biological agent approved in the treatment of systemic lupus erythematosus. Anti-tumor necrosis factor was tried with some success, but with a potential risk of infection in a small number of patients. In this review, we discuss the rationale for anticytokine therapies and review agents currently in clinical trials, and those that could be developed in the near future for systemic lupus erythematosus. We present the results mostly from published trials and data from http://clinicaltrials.gov/ct2/     

Endothelial dysfunction in rheumatic autoimmune diseases

Rheumatic autoimmune diseases have been associated with accelerated atherosclerosis and various types of vasculopathies. Atherosclerosis is an inflammatory condition which starts as a "response to injury" favoring endothelial dysfunction which is associated with increased expression of adhesion molecules, pro-inflammatory cytokines, pro-thrombotic factors, oxidative stress upregulation and abnormal vascular tone modulation. Endothelial dysfunction in rheumatic autoimmune diseases involves innate immune responses, including macrophages and dendritic cells expression of scavenger and toll-like receptors for modified or native LDL as well as neutrophil and complement activation, and dysregulation of adaptive immune responses, including proliferation of autoreactive T-helper-1 lymphocytes and defective function of dendritic and regulatory T cells. Specific differences for endothelial function among different disorders include: a) increased amounts of pro-atherogenic hormones, decreased amounts of anti-atherogenic hormones and increased insulin resistance in rheumatoid arthritis; b) autoantibodies production in systemic lupus erythematosus and antiphospholipid syndrome; c) smooth muscle cells proliferation, destruction of internal elastic lamina, fibrosis and coagulation and fibrinolytic system dysfunction in systemic sclerosis. Several self-antigens (i.e. high density lipoproteins, heat shock proteins, β2-glycoprotein1) and self-molecules modified by oxidative events (i.e. low density lipoproteins and oxidized hemoglobin) have been identified as targets of autoimmune responses. Endothelial dysfunction leads to accelerated atherosclerosis in rheumatoid arthritis, systemic lupus erythematosus and spondyloarthropaties whereas obliterative vasculopathy is associated with systemic sclerosis. In this paper, we will briefly review the most relevant information upon endothelial dysfunction and inflammatory mechanisms in atherosclerosis and we will summarize the similarities and differences in vascular disease patterns underlying different rheumatic autoimmune diseases.     

Apoptosis in autoimmune diseases

Over the past decade, our understanding of apoptosis, or programmed cell death, has increased greatly, with the identification of some of the major components of the apoptotic program and the processes regulating their activation. Although apoptosis is an intrinsic process present in all cells, it can be regulated by extrinsic factors, including growth factors, cell surface receptors, cellular stress and hormones. Apoptotis plays an important role in autoimmune diseases. Normal thyrocytes could induce apoptosis of infiltrating activated T cells and protect against attack by such cells, i.e., the normal thyroid tissues act as an immune privileged site. In Hashimoto's thyroiditis (HT), Fas-mediated apoptosis of thyrocytes in a section of tissues is due to at least two separate mechanisms, the first by infiltrating activated T cells, and the other by FasL-positive thyrocytes in a suicidal or fratricidal fashion. A common feature of autoimmune diseases such as systemic lupus erythematosus (SLE) is the breakdown of tolerance of self antigens, a consequence of which is the production of autoantibodies reactive with multiple self proteins. Evidence is accumulating that modifications of autoantigens during apoptosis lead to the development of autoantibodies by bypassing the normal mechanisms of tolerance. Tissue homeostasis is maintained through a balance between cell proliferation and apoptotic cell death. Rheumatoid arthritis (RA) is characterized by pronounced hyperplasia of the synovial tissue, cell infiltration and periarticular osteoporosis. Enhanced Bcl-2 expression and NF-kappaB nuclear translocation of synovial cells are induced by inflammatory cytokines and/or growth factors. These synovial cells become resistant toward apoptosis triggered by various stimuli. The infiltrated cells which are defect in activation-induced cell death can cause autoimmunity by allowing the survival of autoreactive T and B cells. These data suggest that apoptosis might be implicated with the pathogenesis of autoimmunity, whereas the mechanisms might be distinct in each autoimmune disease.     

Genetic variation in toll-like receptor 9 and susceptibility to systemic lupus erythematosus

OBJECTIVE: Autoantibodies produced by differentiated B cells play an important role in the pathogenesis of systemic lupus erythematosus (SLE). The Toll-like receptor 9 (TLR-9) gene has recently emerged as an important costimulatory molecule for both B cells and dendritic cells that respond to chromatin immune complexes. Genetic variation affecting the function of TLR-9 may therefore increase or decrease the threshold of B cell or dendritic cell activation. This variability in activation threshold may, in turn, affect an individual's susceptibility to SLE. This study assessed the role of genetic variation within the TLR-9 gene in susceptibility to SLE. METHODS: We genotyped 362 SLE-affected subject/parent trios for 10 single-nucleotide polymorphisms (SNPs) covering a 68,742-bp genomic segment that contains the TLR-9 gene and approximately 60 kb of flanking sequence. We analyzed the data using the transmission disequilibrium test. RESULTS: There was no association of susceptibility to SLE with any of the 9 SNPs that generated usable data or the 8 haplotypes found at a frequency of >0.05 in this population. When analyzing the subset of 143 subjects with lupus nephritis, there was also no evidence of association between disease susceptibility and any SNP or haplotype. CONCLUSION: These results indicate that there is no evidence that common (frequency higher than 5%) alleles of the TLR-9 gene contribute significantly to the genetic risk involved in susceptibility to SLE or lupus nephritis.     

Altered signal transduction in SLE T cells

T cells from patients with systemic lupus erythematosus display numerous signalling abnormalities. The T cell receptor complex is rewired with the common FcRgamma chain replacing the CD3 zeta chain while the T cell surface membrane lipid rafts are aggregated. These two aberrations result in enhanced early signalling events and altered downstream signalling events. These are in turn responsible for an altered expression of cytokines such as interleukin-6 (IL-6), IL-10, IL-2, IFNy and CD40 ligand. While some of these abnormalities explain the enhanced ability of T cells to help B cells to produce autoantibodies, decreased IL-2 production results in enhanced susceptibility to infections, reduced activation-induced cell death and prolonged survival of autoreactive T cells, which promote help to autoreactive B cells.     

Enhanced CD3-mediated T lymphocyte proliferation in patients with systemic lupus erythematosus.

Nonfractionated peripheral blood lymphocytes from patients with systemic lupus erythematosus (SLE) showed enhanced proliferative responses when stimulated via the CD3 pathway. In contrast, proliferative responses induced by phytohemagglutinin were diminished in SLE patients. Levels of CD3-induced interleukin-2 production and interleukin-2 receptor expression were comparable with normal levels. Highly purified T cells also showed augmented CD3 responses, but only in the presence of phorbol myristate acetate or a combination of phorbol myristate acetate plus calcium ionophore A23187, and not with calcium ionophore alone. The data suggest integrity of the T cell receptor/CD3 pathway for T cell activation in patients with SLE, as examined in cultures stimulated with specific anti-CD3 monoclonal antibodies rather than with multivalent lectins. An increased response via the CD3 complex could contribute to the autoimmune activity in human SLE.