Distinct roles of myeloid and plasmacytoid dendritic cells in systemic lupus erythematosus

Dendritic cells (DCs) constitute a heterogeneous population of professional antigen presenting cells which are the initiators and key regulators for both immunity and tolerance induction. The significance and impact of DC biology in contemporary immunology and medical research is heightened by the award of the 2011 Nobel Prize for Medicine and Physiology to Ralf Steinman for his discovery and subsequent work on the role of DC in adaptive immunity. As a central regulator of immune responses, DCs also play a pivotal role in the pathogenesis of chronic inflammatory autoimmune conditions such as systemic lupus erythematosus (SLE). In this review, we will focus on the respective role of the two major subsets of blood DC, namely myeloid (m)-DC and plasmacytoid (p)-DC, in SLE immunopathogenesis. Accumulating evidence has highlighted pDCs as the culprit for SLE pathogenesis, mainly through type-I interferon production. Latest findings in the field also decipher the mechanisms by which pDCs interact with neutrophils and platelets and contribute to SLE development. The recent surge of interest in studying microRNA regulation in SLE pathogenesis will also be discussed.     

Blood dendritic cells and DC-poietins in systemic lupus erythematosus

Dendritic cells (DCs) control immunity and tolerance. Hence, we surmised that systemic lupus erythematosus (SLE), a systemic autoimmune disease with autoreactive T and B cells, might be due to alterations in DC homeostasis. Taken together, our results demonstrate profound alterations of DCs and DC-poietins homeostasis in SLE. Elevated levels of interferon- (IFN) in serum of SLE patients coexist with decreased numbers of cells producing IFN-, i.e., plasmacytoid dendritic cells (PDCs). Decreased numbers of circulating DCs correlate with increased levels of soluble tumor necrosis factor (TNF) receptors, thus suggesting the potential role of TNF pathway in the observed DC alterations. Finally, increased FMS-like tyrosine kinase 3-ligand (FLT3-L) and its correlation with soluble TNF receptors suggest a physiologic response to compensate low DC numbers. Although IFN- remains at the center of immunologic aberrations in SLE, it remains to be determined whether increased shedding of soluble TNF receptors could also be ascribed to IFN-.     

Prolactin, dendritic cells, and systemic lupus erythematosus

Dendritic cells (DC) play a central role in the induction of autoimmunity in T and B cells. DC express a high level of the major histocompatibility complex that interact with the receptors on T cells. Immature DC present antigens efficiently. Prolactin (PRL) participates in DC maturation. Systemic lupus erythematosus (SLE) is characterized by a loss of tolerance to self-antigens and persistent production of autoantibodies. Serum from SLE patients induces normal monocytes to differentiate into DC in correlation with disease activity depending on the actions of interferon-alpha, immune complexes, PRL, etc. High serum PRL levels have been found in a subset of SLE patients associated with active disease and organ involvement. It is possible that PRL interacts with DC, skewing its function from antigen presentation to a proinflammatory phenotype with high interferon-alpha production. Therefore, SLE is characterized by deficiency of DC functions and abnormal PRL secretion. The relationships between PRL and DC may have a role in the pathogenesis of SLE.     

CD4+CXCR3+ T cells and plasmacytoid dendritic cells drive accelerated atherosclerosis associated with systemic lupus erythematosus

Cardiovascular disease due to accelerated atherosclerosis is the leading cause of death in patients with systemic lupus erythematosus (SLE). Noteworthy, accelerated atherosclerosis in SLE patients appears to be independant of classical Framingham risk factors. This suggests that aggravated atherosclerosis in SLE patients may be a result of increased inflammation and altered immune responses. However, the mechanisms that mediate the acceleration of atherosclerosis in SLE remain elusive. Based on experimental data which includes both humans (SLE patients and control subjects) and rodents (ApoE−/− mice), we herein propose a multi-step model in which the immune dysfunction associated with SLE (i.e. high level of IFN-α production by TLR 9-stimulated pDCs) is associated with, first, an increased frequency of circulating pro inflammatory CD4+CXCR3+ T cells; second, an increased production of CXCR3 ligands by endothelial cells; third, an increased recruitment of pro-inflammatory CD4+CXCR3+ T cells into the arterial wall, and fourth, the development of atherosclerosis. In showing how SLE may promote accelerated atherosclerosis, our model also points to hypotheses for potential interventions, such as pDCs-targeted therapy, that might be studied in the future.     

Altered dendritic cells with tolerizing phenotype in patients with systemic lupus erythematosus

Earlier we showed the generation of tolerizing human monocyte-derived DC following interaction with iC3b-opsonized apoptotic cells. In this study we examine the generation of DC with our previously described tolerogenic phenotype in patients with the systemic autoimmune disease systemic lupus erythematosus (SLE). Monocyte-derived DC were generated in 71 SLE patients, characterized, and then tested for clearance of iC3b-opsonized 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanineperchlorate-stained apoptotic cells using flow cytometry, and for autologous T-cell activation using autologous mixed lymphocyte reaction (AMLR), at the same time as controls. Compared with healthy, age- and gender-matched controls, SLE patients showed upregulation of MHC class II, with a mean expression of 130.5%+/-36.8% (p < 0.007); CD86 in immature DC from SLE patients, generated in autologous human or control plasma, were also upregulated, with mean expression 106.6%+/-18.0% (p < 0.03). A significant (> 20%) reduction in iC3b-apoptotic cell uptake, together with increased autologous mixed lymphocyte reaction, was seen in 75% of SLE patients. Mean 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanineperchlorate-stained apoptotic cell acquisition was 70.0%+/-24% (p < 0.0001) compared with healthy controls. Altered generation of a tolerizing DC phenotype was seen in at least one third of SLE patients following interaction with iC3b-opsonized apoptotic cells. These results suggest that a substantial portion of SLE patients fail to generate DC with a tolerizing phenotype.     

Circulating immune complexes in systemic lupus erythematosus.

Sera from twenty-one patients with systemic lupus erythematosus (SLE) were analysed for the presence of circulating soluble immune complexes by a sensitive and quantitative radioimmunoassay employing radioiodinated human Clq (Clq-deviation test). In twenty-five normal individuals the percentage of Clq inhibition was 2-64 +/- 4-45%. Eleven of the SLE patients had significantly elevated values, and the mean value for the group was 20-38 +/- 20-64%. The seven patients with renal disease had somewhat higher levels (24-14 +/- 18-70%) than those without kidney involvement (19-00 +/- 21-84%), and elevated levels of antibodies to native DNA also were associated with high levels of percentage of Clq inhibition. Both intermediate (7S-19S) and large (greater than 19S) complexes were present in the sera, and digestions with DNase and RNase indicated that antibodies to DNA and RNA accounted for only some of them. Serial studies in individual patients demonstrated the assocation of circulating complexes with, and often preceding, falling complement levels during disease activation.     

Contribution of dendritic cells to the autoimmune pathology of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a heterogeneous disease in which excessive inflammation, autoantibodies and complement activation lead to multisystem tissue damage. The contribution of the individual genetic composition has been extensively studied, and several susceptibility genes related to immune pathways that participate in SLE pathogenesis have been identified. It has been proposed that SLE takes place when susceptibility factors interact with environmental stimuli leading to a deregulated immune response. Experimental evidence suggests that such events are related to the failure of T-cell and B-cell suppression mediated by defects in cell signalling, immune tolerance and apoptotic mechanism promoting autoimmunity. In addition, it has been reported that dendritic cells (DCs) from SLE patients, which are crucial in the modulation of peripheral tolerance to self-antigens, show an increased ratio of activating/inhibitory receptors on their surfaces. This phenotype and an augmented expression of co-stimulatory molecules is thought to be critical for disease pathogenesis. Accordingly, tolerogenic DCs can be a potential strategy for developing antigen-specific therapies to reduce detrimental inflammation without causing systemic immunosuppression. In this review article we discuss the most relevant data relative to the contribution of DCs to the triggering of SLE.     

Phenotype and function of dendritic cells of patients with systemic lupus erythematosus

Dendritic cells (DC) regulate the activation and differentiation of T cells. They are activated by signals of inflammation and tissue damage, and thus could play a role in the amplification and perpetuation of autoimmune diseases such as systemic lupus erythematosus (SLE). Here we analyzed the phenotype of circulating DC from patients with SLE and studied their differentiation from monocytes. Peripheral blood DC exhibited increased levels of activation in patients with SLE. Although their in vitro differentiation process occurred normally, their responses to activation stimuli (LPS, TNF-α plus PGE(2), anti-CD40) were abnormal when compared to DC differentiated from healthy monocytes. When incubated in the presence of IL-10, DC from patients with SLE were able to induce tolerance to allogeneic antigens in a normal manner. Our results suggest that DC from patients with SLE are abnormal, in part due to the effect of abundant pro-inflammatory signals, but also because of intrinsic cellular defects that alter their responses to activation stimuli.     

The role myeloid dendritic cells play in the pathogenesis of systemic lupus erythematosus

Dendritic cells (DC) play a pivotal role in the development of immune responses and the maintenance of peripheral tolerance. They continuously patrol tissues and sample antigens in search for the presence of inflammatory or pathogen-derived signals; they mature in accordance to signs prevalent in their environment and, by doing so, acquire certain features that will allow them to convey a precise message--either productive or regulatory--to the T cells they will encounter within regional lymph nodes. Evidence suggests that DC are involved in the pathogenesis of SLE. Their capacity to induce an antinuclear-oriented autoimmune response has been proven in animal models. Further, their maturation process is abnormal and their cytokine secretion and T cell stimulation is biased in patients with SLE. Lupus, however, is a problematic environment for their study and characterization. Sera from SLE patients contain several factors capable of inducing phenotypic and functional changes in DC. Thus, the abnormalities that have been reported may represent DC-intrinsic defects, a skewed phenotype due to an abnormal milieu, or a combination of both. In this review we discuss the available information in an attempt to reconcile these issues.     

雷公藤内酯醇对系统性红斑狼疮患者DC细胞功能及成熟的影响

目的 通过体外实验研究雷公藤内酯醇(triptolide)对系统性红斑狼疮(systemic lupus erythematosus,SLE)患者树突状细胞(dendritic cell,DC)功能及成熟的影响,为进一步阐明雷公藤内酯醇的免疫学活性提供依据.方法 从SLE患者外周血分离单个核细胞,流式细胞仪分选DC,加入0、5、10、30μg/L的雷公藤内酯醇共孵育,24h后收集上清液,ELISA检测IFN-α、IL-6、TNF-α量,5d后收集细胞,流式细胞仪检测DC表型CD11c、CD80、CD86阳性率,光镜观察DC的形态,扫描电镜观察DC的超微结构.结果 雷公藤内酯醇显著减低活动期与非活动期SLE患者IFN-α、IL-6、TNF-α量,并呈雷公藤内酯醇浓度依赖性(P＜0.05);雷公藤内酯醇可抑制SLE患者DC的分化和成熟,并呈雷公藤内酯醇浓度依赖性(P＜0.05).结论 雷公藤内酯醇能够减弱SLE患者DC的功能,并抑制其分化和成熟.     

Regulatory T cells in systemic lupus erythematosus

Systemic lupus erythematosus (SLE), an autoimmune disease, develops when immunologic self‐tolerance fails. Treg cells are a subset of CD4⁺ T cells that maintain self‐tolerance by suppressing autoreactive lymphocytes. Defects in Treg cells are therefore considered to be an aspect of SLE pathogenesis. Nevertheless, reports on the numbers and function of Treg cells in SLE are contradictory and the definitive role of Treg cells in SLE remains unclear. In this review, we summarize findings from murine models and ex vivo experiments, which provide insights into the mechanisms that result in the breakdown of tolerance. We also include recent findings about Treg‐cell subsets and their markers in human SLE. The identification of unique markers to identify bona fide Treg cells, as well as therapies to reconstitute the balance between Treg cells and autoreactive T cells in SLE, are the future challenges for SLE research.     

Dysfunctional B cells in systemic lupus erythematosus

The classical view of B cells in the biology of autoimmune responses to infectious and self-antigens (Ag) that they promote immunity primarily by producing antibodies (Ab) is far from being complete. Indeed, studies over the last decade suggest that B cells have extraordinarily diverse functions within the immune system other than Ab production, which could contribute to autoimmunity. They normally play a role in the development of lymphoid architecture, regulating dentritic cells (DC) and T cell subsets function through cytokine production, and in activation of T cells. Receptor editing is also important in B cells which aids in immunity to infection and, possibly, prevention of autoimmunity. Both abnormalities in the distribution of B cells subsets and clinical benefit response to B cell depletion in autoimmune diseases, including systemic lupus erythematosus (SLE), highlight their pivotal function. Transgenic (Tg) animal models have shown that sensitivity of B cells to B cell Ag receptor (BCR) cross-linking is correlated to autoimmunity. Indeed, negative signaling by CD5 and other molecules, such as CD22, in maintaining tolerance through recruitment of src-homology two domain-containing protein tyrosine phosphatase-1 (SHP-1) has also been documented. In fact, we have now reached a newer area whereby B cells returned as an important contributor to autoimmune disorders.     

B cells and atherosclerosis in systemic lupus erythematosus

Introduction: Cardiovascular (CV) events, as a result of accelerated atherosclerosis, are an important cause of mortality in patients with Systemic lupus erythematosus (SLE). The etiology of SLE is multifactorial and still unclear; among other potential culprits, excessive B cell activation seems to play a crucial role. Accumulating evidence supports a contributory role of B cells in the pathogenesis of atherosclerosis as well.

Areas covered: This article focuses on the contribution of both B cells and autoantibodies in the pathogenesis of atherosclerosis in both general and lupus populations. Review of the published literature on experimental models has also been performed.

Expert opinion: Distinct B cell subsets seem to exhibit separate effects on the progression of atherosclerosis, with B2 B cells displaying a mainly atherogenic phenotype, while B1 B cells are mostly viewed as atheroprotective. Selective B2 inhibition by anti-B cell therapies seems a promising therapeutic strategy against atherosclerosis development in the setting of lupus.     

Complement-mediated solubilization of immune complexes in systemic lupus erythematosus.

The capacity of complement-mediated solubilization of immune complexes (complex releasing activity: CRA) was studied in 63 sera from eight systemic lupus erythematosus (SLE) patients. CRA in sera of active SLE (35 +/- 17.%) was significantly lower than that of inactive SLE (64.1 +/- 24.1%, P less than 0.001). In addition, 20 of 23 sera collected during active diseases demonstrated CRA values less than 50% of the control pooled serum. On the other hand, CRA of 29 of 40 sera from inactive disease exceeded the 50% level. CRA in SLE sera correlated with complement component levels and in particular with the CH50. Serial determination of CRA and of levels of circulating immune complexes (CIC), C4 and C3 in two active patients indicated that the correlation between CRA and the complement components was positive, while that between CRA and CIC was negative. These studies provide evidence that CRA may be useful for following the activity of SLE and that CRA reflects the levels of the complement components of both classical and alternative pathways. The possibility that CIC may be solubilized and opsonized by complement and cleared by the reticuloendothelial system was discussed.     

Cutaneous distribution of plasmacytoid dendritic cells in lupus erythematosus. Selective tropism at the site of epithelial apoptotic damage

Recent evidences suggest a significant role of Plasmacytoid dendritic cells (PDC) role in the pathogenesis of lupus erythematosus (LE) via production of type I IFN. Taking advantage on the availability of multiple reagents (CD123, BDCA2, and CD2ap) specifically recognizing PDC on fixed tissues, we investigated the occurrence of PDC in a cohort of 74 LE patients. The large majority of LE biopsies (67/74; 90.5%) showed cutaneous infiltration of PDC. PDC were more frequently observed (96.4 vs 72.2) and numerous in cutaneous LE compared to systemic LE (SLE) and correlated with the density of the inflammatory infiltrate (r=0.40; p<0.001). PDC reduction in SLE might be related to a broader tissue distribution of this cellular population, as indicated by their occurrence in kidneys in 11 out of 24 (45.8%) cases studied. The distribution of cutaneous PDC showed two distinct patterns. More commonly, PDC were observed within perivascular inflammatory nodules in the dermis, associated with CD208+ mature DC and T-bet+ cells [D-PDC]. A second component was observed along the dermal-epithelial junction [J-PDC], in association with cytotoxic T-cells in areas of severe epithelial damage. Notably, chemerin reactivity was observed in 64% of LE biopsies on endothelial cells and in the granular layer keratinocytes. Cutaneous PDC in LE strongly produced type I IFN, as indicated by the diffuse MxA expression, and the cytotoxic molecule granzyme B.This study confirms cutaneous PDC infiltration as hallmark of LE. The topographical segregation in D-PDC and J-PDC suggests a novel view of the role of these cells in skin autoimmunity.     

Regulatory T cells and systemic lupus erythematosus

CD4+CD25+ regulatory T cells (Treg) constitute an important mechanism of peripheral immune tolerance. Organ-specific autoimmune conditions, such as thyroiditis and insulin-dependent diabetes mellitus have been attributed to a breakdown of this tolerance mechanism. However, this T-cell subset has not been well studied in patients and mice with systemic lupus erythematosus (SLE; lupus). The information that has been gathered so far using new tools that discriminate Treg from activated T cells indicates that reduced numbers of Treg may exist in patients with lupus. In addition, potential defects in SLE Treg function have been documented in humans and mice. Our group has demonstrated equivalent proportions of thymic Treg in lupus prone and normal mice. We therefore propose that Treg function in SLE is the more important factor to address in future studies of murine lupus. Recent studies have shown that Toll-like receptor (TLR) ligation can result in an abrogation of Treg-mediated suppression; specifically ligation of TLR-2, -4, -8 and -9. We address this new information about TLRs and Treg and propose a model for Treg tolerance breakdown to nucleic acid-binding SLE autoantigens.     

Opsonization by anti-dsDNA antibodies of apoptotic cells in systemic lupus erythematosus

In order to asses the role of the soluble mediators of serum from patients with SLE in the apoptotic cell clearance, we measured the in vitro phagocytosis of apoptotic Jurkat cells by normal healthy donor macrophages in the presence of SLE patients' sera. A significant increase of the phagocytic index (NHD = 1.0 +/- 0.3; SLE = 1.9 +/- 0.6; p < 0.01) was to be observed in the presence of serum from patients with SLE. The increased phagocytic index correlated to the anti-dsDNA antibodies titers. We conclude that anti-dsDNA antibodies present in sera of patients with SLE favor the apoptotic cell phagocytosis by opsonization of the target cells. This may represent a deviation of the clearance process towards inflammation and a new pathologic feature of these autoantibodies in SLE.     

Phenotypic analysis of IL-10-treated, monocyte-derived dendritic cells in patients with systemic lupus erythematosus

Dendritic cells (DC) play a dual role in the immune response, participating in its induction, and the maintenance of immune tolerance. The aim of this work was to perform a quantitative and phenotypic analysis of DC generated in vitro in the presence of IL-10 in patients with systemic lupus erythematosus (SLE). Blood samples were obtained from 10 active and untreated patients with SLE and six controls. Monocyte-derived DC were generated in vitro in the presence or absence of IL-10, and a quantitative and phenotypic analysis was performed. We found that freshly isolated monocytes from SLE patients had an increased expression of CD11b. On the other hand, the efficiency of in vitro DC generation was diminished in blood samples from SLE patients for conventional DC, but not for IL-10-treated DC. A diminished expression of HLA-DR, CD9 and CD86 was observed in conventional DC from SLE patients compared with controls. In contrast, enhanced levels of HLA-DR, CD80, CD9 and CD151 tetraspanins, FN1 (a class II MHC-tetraspanin epitope), CD85j/ILT2 and CD69 were detected in IL-10-treated DC from SLE patients. Accordingly, the phenotypic profile of IL-10-treated DC was very different in SLE and controls. However, the synthesis of IL-10 and IL-12 was similar in IL-10-treated and conventional cells in both SLE patients and controls. Our findings on the aberrant phenotype of IL-10-treated DC in SLE and their normal efficiency of in vitro generation may be important for the design of future therapies of this condition based on the administration of DC to induce immune tolerance.     

Phenotypic and functional deficiencies of monocyte-derived dendritic cells in systemic lupus erythematosus (SLE) patients

Systemic lupus erythematosus (SLE) represents an autoimmune disease for which alterations of T cells, B cells as well as various antigen-presenting cell (APC) populations have been described. In order to better define APC-associated deficiencies, we analyzed morphologic, phenotypic and functional characteristics of in vitro-generated monocyte-derived dendritic cells (MoDC) from SLE patients as compared with healthy controls. Analysis of MoDC at different stages of maturation revealed substantial phenotypic and functional defects of MoDC from SLE patients as compared with healthy controls. In particular, we observed a significantly reduced up-regulation of MHC class II molecules on MoDC upon activation which correlated with disease activity scores and functional deficiencies in mixed lymphocyte reaction experiments. Our data imply a crucial role of APC in the immunological imbalance in SLE for foreign and self-antigen reactivity.