Expansion of toll-like receptor 9–expressing B cells in active systemic lupus erythematosus: Implications for the induction and maintenance of the autoimmune process (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 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.
Toll-like receptor expression in lupus peripheral blood mononuclear cells
The Journal of rheumatology, 2007
To investigate expression of members of the Toll-like receptor (TLR) family in peripheral blood mononuclear cells (PBMC) in patients with systemic lupus erythematosus (SLE). We analyzed PBMC from 14 patients with SLE and 15 healthy subjects. The surface expressions of TLR2 and TLR4 and intracellular expression of TLR9 on PBMC were analyzed by flow cytometry. Although TLR4 expressions on CD14+ monocytes were not significantly different between healthy subjects and patients with SLE, TLR2 expressions on monocytes were reduced in patients with SLE compared to healthy subjects. Intracellular TLR9 expression levels of CD19+ B lymphocytes were significantly elevated in patients with SLE. However, the TLR9 expression levels of plasmacytoid dendritic cells were not significantly different between these patients and healthy subjects. Our results show that human peripheral blood B cells express TLR9 and that its expression is increased in patients with SLE. This upregulated expression of TLR9...
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.
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.
Rheumatology, 2010
Objectives. Toll-like receptor 9 (TLR9), which recognizes hypomethylated DNA [cytosine-phosphate-guanine (CpG)], plays a role in the maintenance of serological memory and has been recently implicated in the pathogenesis of SLE. We previously reported that in vitro TLR9 triggers memory B-cell differentiation into antibody-producing cells, and that the MyD88-inhibitor ST2825 blocks TLR9-induced plasma cell (PC) generation. Here, we investigated whether memory B cells produce autoantibodies in SLE patients with active disease or in clinical remission, and whether ST2825 could inhibit PC generation in SLE patients.