Toll-like receptor expression in lupus peripheral blood mononuclear cells (original) (raw)
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Mediators of Inflammation, 2014
Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown aetiology. The results of experimental studies point to the involvement of innate immunity receptors-toll-like receptors (TLR)-in the pathogenesis of the disease. The aim of the study was to assess the expression of TLR3, 7, and 9 in the population of peripheral blood mononuclear cells (PBMC) and in B lymphocytes (CD19 + ), T lymphocytes (CD4 + and CD8 + ) using flow cytometry. The study group included 35 patients with SLE and 15 healthy controls. The patient group presented a significantly higher percentage of TLR3-and TLR9-positive cells among all PBMCs and their subpopulations (CD3 + , CD4 + , CD8 + , and CD19 + lymphocytes) as well as TLR7 in CD19 + B-lymphocytes, compared to the control group. There was no correlation between the expression of all studied TLRs and the disease activity according to the SLAM scale, and the degree of organ damage according to the SLICC/ACR Damage Index. However, a correlation was observed between the percentage of various TLR-positive cells and some clinical (joint lesions) and laboratory (lymphopenia, hypogammaglobulinemia, anaemia, and higher ESR) features and menopause in women. The results of the study suggest that TLR3, 7, and 9 play a role in the pathogenesis of SLE and have an impact on organ involvement in SLE.
Clinical & Experimental Immunology, 2010
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease associated with aberrant activation of T and B lymphocytes for the production of inflammatory cytokines and autoreactive antibodies. Animal studies of SLE have indicated that Toll-like receptors (TLR) are important in the pathogenesis of murine lupus. In the present clinical study, differential protein expressions of TLR-1-9 of monocytes and different lymphocyte subsets from patients with SLE and normal control subjects were determined by flow cytometry. Results showed that the expression of intracellular TLRs (TLR-3, -8, -9) and extracellular TLRs (TLR-1, -2, -4, -5, -6) were elevated in monocytes, CD4 + T lymphocytes, CD8 + T lymphocytes and B lymphocytes of SLE patients compared to control subjects (all P < 0·001). Moreover, cell surface expression of TLR-4 on CD4 + T lymphocytes and CD8 + T lymphocytes, and TLR-6 on B lymphocytes, were correlated positively with SLE disease activity index (SLEDAI) (TLR-4 on CD4 + T lymphocytes and CD8 + T lymphocytes: r = 0·536, P = 0·04; r = 0·713, P = 0·003; TLR-6 in B lymphocytes: r = 0·572, P = 0·026). In concordance with the above results, there is an observable increased relative induction (%) of inflammatory cytokine interleukin (IL)-1b, IL-6, IL-10 and IL-12, chemokines CCL2, CXCL8, CCL5 and CXCL10 from peripheral blood mononuclear cells (PBMC) upon differential stimulation by PolyIC (TLR-3 ligand), lipopolysaccharide (TLR-4 ligand), peptidoglycan (TLR-2 ligand), flagellin (TLR-5 ligand), R837 (TLR-7 ligand) and CpG DNA (TLR-9 ligand) in SLE patients compared to controls. These results suggest that the innate immune response for extracellular pathogens and selforiginated DNA plays immunopathological roles via TLR activation in SLE.
Arthritis & Rheumatism, 2006
Toll-like receptors (TLRs) are patternassociated receptors in innate immunity that may be involved in the recognition of self antigens and the production of pathogenic autoantibodies. This study was undertaken to examine the expression and function of various TLRs in subpopulations of peripheral blood mononuclear cells (PBMCs) of patients with systemic lupus erythematosus (SLE). Methods. The expression of TLRs in PBMCs from 50 SLE patients with active disease (SLE Disease Activity Index [SLEDAI] score >8; n ؍ 26) or inactive disease (SLEDAI score <8; n ؍ 24) and 20 healthy controls was studied by flow cytometry. TLR expression was assessed on various subpopulations of PBMCs (TLR-2 and TLR-4 by membrane staining; TLR-3 and TLR-9 by intracellular staining). TLR function was accessed by stimulating PBMCs with specific ligands. Results. The proportion of B cells and monocytes expressing TLR-9 was higher among patients with active SLE (mean ؎ SD 49.5 ؎ 24.4% and 30.7 ؎ 24.1%, respectively) than among patients with inactive disease (22.8 ؎ 19.6% and 14.3 ؎ 8.4%, respectively; P ؍ 0.02 and P ؍ 0.03). Among B cells, the proportion of plasma cells and memory B cells expressing TLR-9 was increased in patients with active SLE. Increased percentages of TLR-9-expressing B cells correlated with the presence of anti-double-stranded DNA antibodies (P ؍ 0.007). Treatment with serum from patients with active disease increased the percentage of TLR-9-expressing plasma cells in serum from healthy controls. Enhanced induction of HLA-DR after TLR-9 stimulation was documented in B cells from patients with active disease. Conclusion. In patients with active SLE, the proportion of peripheral blood memory B cells and plasma cells expressing TLR-9 is increased. Endogenous nucleic acids released during apoptotic cell death may stimulate B cells via TLR-9 and contribute to SLE pathogenesis. Toll-like receptors (TLRs) have recently emerged as key components of the innate immune system that activate multiple pathways of inflammation and coordinate systemic defense against pathogens. At least 11 TLRs have been identified in mammals, with each one of them recognizing unique molecular patterns associated with different classes of pathogens. Of interest, TLR-2 and TLR-4 also recognize a number of self proteins, predominantly members of the heat-shock protein and fibronectin families, while TLR-3 and TLR-9 are capable of recognizing nucleic acids (RNA and DNA, respectively) that may not always be unique to microorganisms (1). Normally, there is a constant interplay between the innate and adaptive immune systems, which leads to protective immune responses against pathogens and contributes effectively to self-nonself discrimination. However, inappropriate activation of TLR pathways
Journal of Inflammation, 2015
Background: Systemic Lupus Erythematosus (SLE) is an auto-immune disease whose complex pathogenesis remains unraveled. Here we aim to explore the inflammatory ability of SLE patients' sera upon peripheral blood (PB) monocyte subsets and myeloid dendritic cells (mDCs) obtained from healthy donors. Methods: In this study we included 11 SLE patients with active disease (ASLE), 11 with inactive disease (ISLE) and 10 healthy controls (HC). PB from healthy donors was stimulated with patients' sera, toll-like receptor (TLR) 4 ligandlipopolysaccharide or both. The intracellular production of TNF-α was evaluated in classical, non-classical monocytes and mDCs, using flow cytometry. TNF-α mRNA expression was assessed in all these purified cells, after sera treatment.
Chinese Medical Journal, 2012
Background Toll like receptor (TLR) 9 has been shown to play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE) in animal models. Its pathogenic role in human SLE, however, was poorly elucidated. This study was performed to investigate the role of TLR9 involved in the aberrant signaling pathway and its correlation with disease activity in SLE. Methods mRNA level of TLR9 and interferon (IFN) regulatory factor 5 (IRF5) in peripheral blood mononuclear cells (PBMCs) were determined by real-time polymerase chain reaction (PCR). IFN- expression was measured in the serum of the SLE patients by enzyme-linked immunosorbent assay (ELISA). Results TLR9 expression was significantly higher in SLE patients than that in health controls (P=0.011). SLE patients with positive anti-dsDNA antibody had significantly higher expression of TLR9 than that with negative anti-dsDNA antibody (P=0.001). TLR9 expression was positively correlated with fever (P=0.017), alopecia (P=0.046), safety of estrogens in lupus erythematosus national assessment SLE disease activity index (SELENA-SLEDAI) score (r s =0.385, P=0.003), and the level of IRF5 (r s =0.35, P=0.027) and IFN- (r s =0.627, P=0.001) in SLE patients. Conclusion TLR9 is associated with SLE disease activity and might be involved in the IFN- pathway of SLE.
Evaluation of PBMC Distribution and TLR9 Expression in Patients with Systemic Lupus Erythematosus
Iranian journal of allergy, asthma, and immunology, 2016
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease which results in damage to various organs. Some animal studies have revealed that activation of Toll-like receptors (TLRs) is important in the pathogenesis of SLE. In the present study, the percentage of different immune cell subsets in 35 SLE patients and 38 control subjects was analyzed by flow cytometry. We also assessed the expression of TLR9 in the population of peripheral blood mononuclear cells (PBMCs) including T lymphocytes (CD4+ and CD8+), B lymphocytes (CD19+), NK cells (CD56+) and monocytes (CD14+) in SLE patients and healthy controls. The results showed that the percentage of CD8+ T lymphocytes and CD14+ monocytes were significantly higher (p˂0.001) in the SLE patients than the healthy control subjects. Moreover, the percentage of CD56+ NK cells were significantly lower in the SLE patients than the healthy control subjects (p=0.001). The findings indicated that the expression of TLR9 was significantly hi...
Arthritis Research & Therapy, 2014
Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease associated with a break in self-tolerance reflected by a production of antinuclear autoantibodies. Since autoantibody production can be activated via nucleic acid Toll-like receptor 9 (TLR9), the respective pathway has been implicated in the development of SLE and pathogenic B cell responses. However, the response of B cells from SLE patients to TLR9 stimulation remains incompletely characterized. Methods: In the current study, the response of B cells from SLE patients and healthy donors upon TLR9 stimulation was analyzed in terms of proliferation and cytokine production and correlated with the lupus disease activity and anti-dsDNA titers. Results: B cells from SLE patients showed a reduced response to TLR9 agonist compared to B cells from healthy donors in terms of proliferation and activation. B cells from SLE patients with higher disease activity produced less interleukin (IL)-6, IL-10, vascular endothelial growth factor, and IL-1ra than B cells from healthy donors. Further analyses revealed an inverse correlation of cytokines produced by TLR9-stimulated B cells with lupus disease activity and anti-dsDNA titer, respectively. Conclusion: The capacity of B cells from lupus patients to produce cytokines upon TLR9 engagement becomes less efficient with increasing disease activity, suggesting that they either enter an exhausted state or become tolerant to TLR stimulation for cytokine production when disease worsens.
Role for toll-like receptors in autoimmune disease: The example of systemic lupus erythematosus
Joint Bone Spine, 2011
Systemic lupus erythematosus (SLE) is a multisystem disease characterized by an autoimmune response to nuclear antigens. Although the pathophysiology of SLE remains incompletely understood, many recent studies indicate a major role for innate immunity. The toll-like receptors (TLRs), which play a key role in innate responses to infections, are also involved in acute and chronic inflammatory processes induced by endogenous ligands. Numerous in vitro studies have established that TLR7 and TLR9 are involved in immune complex recognition. Activation of these receptors leads to activation of immune cells, most notably B cells and dendritic cells, and to the inappropriate production of many cytokines known to be directly involved in the pathogenesis of SLE. These data prompted studies in several murine models of SLE to assess the impact of inactivation or overexpression of genes encoding TLRs or molecules involved in TLR signaling pathways. The results confirmed the major role for TLR7 and suggested involvement of TLR4 in the induction of an aggressive autoimmune response. However, in vivo data suggest a protective effect of TLR9, thus contradicting the in vitro results. In humans, genetic studies have identified polymorphisms associated with increased susceptibility to SLE.