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Are Toll-Like Receptors and Decoy Receptors Involved in the Immunopathogenesis of Systemic Lupus Erythematosus and Lupus-Like Syndromes?
Giuliana Guggino,Anna Rita Giardina,Francesco Ciccia,Giovanni Triolo,Francesco Dieli,Guido Sireci
Clinical and Developmental Immunology , 2012, DOI: 10.1155/2012/135932
Abstract: In this paper we focus our attention on the role of two families of receptors, Toll-like receptors (TLR) and decoy receptors (DcR) involved in the generation of systemic lupus erythematosus (SLE) and lupus-like syndromes in human and mouse models. To date, these molecules were described in several autoimmune disorders such as rheumatoid arthritis, antiphospholipids syndrome, bowel inflammation, and SLE. Here, we summarize the findings of recent investigations on TLR and DcR and their role in the immunopathogenesis of the SLE.
Toll-like receptors and innate immune responses in systemic lupus erythematosus
Robert Lafyatis, Ann Marshak-Rothstein
Arthritis Research & Therapy , 2007, DOI: 10.1186/ar2321
Abstract: Pattern recognition receptors are the key to innate immune system recognition of microbes. The strength of these receptors in terms of their ability to respond to molecular motifs common to pathogens may also prove to be the weakness that results in autoimmunity, because they are potentially less discrete than the cognate immune system in distinguishing self from nonself. The most important pattern recognition receptor family of receptors involved in lupus, namely the Toll-like receptors (TLRs), can recognize a broad range of microbial components, including DNA and RNA. In this review we consider the implications of multiple studies showing how these receptors play key roles in autoimmunity in patients with systemic lupus erythematosus (SLE).Autoantibodies to DNA, RNA, and associated proteins represent a central puzzle in SLE pathogenesis. They are common targets of the autoimmune response, but the stimulus for their formation and their roles in pathogenesis have been obscure. Although exposed protein targets, such as β2-glycoprotein I and red blood cell or platelet surface proteins, can be readily implicated in pathogenesis, antibodies to nucleic acids also appear to contribute to pathology. Most notably, anti-DNA antibodies are associated with disease severity in lupus nephritis, deposit in renal tissues, crossreact with renal antigens, and can induce nephritis in mice. Anti-DNA antibodies can also crossreact with the anti-N-methyl-D-aspartate receptor and may cause cognitive dysfunction or depression in lupus patients [1,2]. Other common targets of antinuclear antibodies include proteins that bind to DNA and RNA [3]: histone proteins bind and package DNA, Sm proteins bind U RNAs and direct mRNA splicing, and Ro protein binds Y RNAs and recognizes misfolded RNAs.A common theme of autoantigens in SLE is their association in intermolecularly linked complexes associated with nucleic acids. Autoantibodies target multiple regions of autoantigens and have undergone affi
MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus  [PDF]
Yun Deng equal contributor,Jian Zhao equal contributor,Daisuke Sakurai,Kenneth M. Kaufman,Jeffrey C. Edberg,Robert P. Kimberly,Diane L. Kamen,Gary S. Gilkeson,Chaim O. Jacob,R. Hal Scofield,Carl D. Langefeld,Jennifer A. Kelly,Rosalind Ramsey-Goldman,Michelle A. Petri,John D. Reveille,Luis M. Vilá,Graciela S. Alarcón,Timothy J. Vyse,Bernardo A. Pons-Estel,on behalf of the Argentine Collaborative Group ?,Barry I. Freedman,Patrick M. Gaffney,Kathy Moser Sivils,Judith A. James,Peter K. Gregersen,Juan-Manuel Anaya,Timothy B. Niewold,Joan T. Merrill,Lindsey A. Criswell,Anne M. Stevens,Susan A. Boackle,Rita M. Cantor,Weiling Chen,Jeniffer M. Grossman,Bevra H. Hahn,John B. Harley,Marta E. Alarc?n-Riquelme,on behalf of the BIOLUPUS and GENLES networks ?,Elizabeth E. Brown,Betty P. Tsao
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003336
Abstract: We previously reported that the G allele of rs3853839 at 3′untranslated region (UTR) of Toll-like receptor 7 (TLR7) was associated with elevated transcript expression and increased risk for systemic lupus erythematosus (SLE) in 9,274 Eastern Asians [P = 6.5×10?10, odds ratio (OR) (95%CI) = 1.27 (1.17–1.36)]. Here, we conducted trans-ancestral fine-mapping in 13,339 subjects including European Americans, African Americans, and Amerindian/Hispanics and confirmed rs3853839 as the only variant within the TLR7-TLR8 region exhibiting consistent and independent association with SLE (Pmeta = 7.5×10?11, OR = 1.24 [1.18–1.34]). The risk G allele was associated with significantly increased levels of TLR7 mRNA and protein in peripheral blood mononuclear cells (PBMCs) and elevated luciferase activity of reporter gene in transfected cells. TLR7 3′UTR sequence bearing the non-risk C allele of rs3853839 matches a predicted binding site of microRNA-3148 (miR-3148), suggesting that this microRNA may regulate TLR7 expression. Indeed, miR-3148 levels were inversely correlated with TLR7 transcript levels in PBMCs from SLE patients and controls (R2 = 0.255, P = 0.001). Overexpression of miR-3148 in HEK-293 cells led to significant dose-dependent decrease in luciferase activity for construct driven by TLR7 3′UTR segment bearing the C allele (P = 0.0003). Compared with the G-allele construct, the C-allele construct showed greater than two-fold reduction of luciferase activity in the presence of miR-3148. Reduced modulation by miR-3148 conferred slower degradation of the risk G-allele containing TLR7 transcripts, resulting in elevated levels of gene products. These data establish rs3853839 of TLR7 as a shared risk variant of SLE in 22,613 subjects of Asian, EA, AA, and Amerindian/Hispanic ancestries (Pmeta = 2.0×10?19, OR = 1.25 [1.20–1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148.
The Largely Normal Response to Toll-Like Receptor 7 and 9 Stimulation and the Enhanced Expression of SIGIRR by B Cells in Systemic Lupus Erythematosus  [PDF]
Yun-Yan Zhu, Yin Su, Zhan-Guo Li, Yu Zhang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044131
Abstract: Background Altered Toll-like receptor (TLR) signaling has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The present study was undertaken to characterize responses of B cells from SLE patients to TLR7 and TLR9 stimulation and to explore the potential role of single immunoglobulin interleukin-1 receptor related molecule (SIGIRR) in the regulation of TLR-mediated responses of SLE B cells. Methodology/Principal Findings Peripheral blood mononuclear cells (PBMC) were isolated from 64 patients with SLE and 37 healthy donors. CD19+ B cells purified using microbeads were cultured with TLR7 or TLR9 agonists. Cell proliferation was measured by thymine incorporation and the frequency of antibody-secreting cells was determined by ELISPOT assay. SIGIRR expression in PBMCs and B cells was analyzed using flow cytometry analysis. In contrast to the enhanced proliferation following B cell receptor (BCR) engagement, B cells from SLE patients exhibited a virtually normal proliferative response to TLR7 or TLR9 stimulation. Moreover, B cells from SLE patients and healthy donors were almost equally competent to differentiate into antibody-secreting cells upon TLR engagement except for a reduction in the generation of IgG-secreting cells by TLR9-stimulated lupus B cells. In line with these somehow unexpected observations, SLE B cells were found to express a significantly higher level of SIGIRR than normal B cells. Conclusions/Significance Despite the reported upregulation of TLR7 and TLR9 expression in B cell from SLE patients, their responses to TLR stimulation were largely normal. The increased expression of the negative regulator SIGIRR may be partly responsible for the “balance of terror”.
Lupus erythematosus profundus  [cached]
Aggarwal Kamal,Jain V,Dayal Surbhi
Indian Journal of Dermatology, Venereology and Leprology , 2002,
Abstract: A case of lupus erythematosus profundus, with associated mastitis, but without any lesions of discoid lupus erythematosus or systemic lupus erythematosus is being reported.
Systemic lupus erythematosus conundrums  [cached]
Wardle E
Saudi Journal of Kidney Diseases and Transplantation , 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 de-fective 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 inter-feron gamma (IFNy)), along with chemokines, but now Th-17 lymphocytes are recognized to play an important role.
Bullous systemic lupus erythematosus  [cached]
Aswani V,Vaz B,Shah S,Malkani R
Indian Journal of Dermatology, Venereology and Leprology , 1993,
Abstract: Bullous systemic lupus erythematosus (BSLE) is a rare variant of systemic lupus erythematosus (SLE) which histologically resembles dermatitis herpetiformis (DH) and responds dramatically to dapsone. We report a case of bullous SLE.
Dysfunctional interferon-α production by peripheral plasmacytoid dendritic cells upon Toll-like receptor-9 stimulation in patients with systemic lupus erythematosus
Seung-Ki Kwok, June-Yong Lee, Se-Ho Park, Mi-La Cho, So-Youn Min, Sung-Hwan Park, Ho-Youn Kim, Young-Gyu Cho
Arthritis Research & Therapy , 2008, DOI: 10.1186/ar2382
Abstract: The concentrations of IFN-α were determined in serum and culture supernatant of peripheral blood mononuclear cells (PBMCs) from SLE patients and healthy controls after stimulation with CpG ODN2216 or SLE serum. The numbers of circulating pDCs were analyzed by fluoresence-activated cell sorting analysis. pDCs were treated with CpG ODN2216 and SLE serum repeatedly, and levels of produced IFN-α were measured. The expression of IFN-α signature genes and inhibitory molecules of TLR signaling were examined in PBMCs from SLE patients and healthy control individuals.Although there was no significant difference in serum concentration of IFN-α and number of circulating pDCs between SLE patients and healthy control individuals, the IFN-α producing capacity of PBMCs was significantly reduced in SLE patients. Interestingly, the degree which TLR9 ligand-induced IFN-α production in SLE PBMCs was inversely correlated with the SLE serum-induced production of IFN-α in healthy PMBCs. Because repeated stimulation pDCs with TLR9 ligands showed decreased level of IFN-α production, continuous TLR9 stimulation may lead to decreased production of IFN-α in SLE PBMCs. In addition, PBMCs isolated from SLE patients exhibited higher expression of IFN-α signature genes and inhibitory molecules of TLR signaling, indicating that these cells had already undergone IFN-α stimulation and had become desensitized to TLR signaling.We suggest that the persistent presence of endogenous IFN-α inducing factors induces TLR tolerance in pDCs of SLE patients, leading to impaired production of IFN-α.Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is characterized by generation of autoantibodies against nuclear DNA and/or nuclear proteins [1]. The precise pathogenesis of SLE remains unknown, but both genetic and environmental factors are involved [2]. Over the past two decades numerous studies have suggested that interferon (IFN)-α may play a pathogenic role in SLE. This view is derived fr
Toll-Like Receptor 2 or Toll-Like Receptor 4 Deficiency Does Not Modify Lupus in MRLlpr Mice  [PDF]
Simon J. Freeley, Angela Giorgini, Calogero Tulone, Reena J. Popat, Catherine Horsfield, Michael G. Robson
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074112
Abstract: Systemic lupus erythematosus is an autoimmune disease with a high morbidity and nephritis is a common manifestation. Previous studies in murine lupus models have suggest a role for Toll-like receptor 2 and 4. We examined the role of these molecules in MRL lpr mice which is one of the most established and robust murine models. We compared disease parameters in Toll-like receptor 2 or Toll-like receptor 4 deficient mice with their littermate controls. We found no difference in the severity of glomerulonephritis as assessed by histology, serum creatinine and albuminuria when Toll-like receptor 2 or Toll-like receptor 4 deficient MRLlpr mice were compared with Toll-like receptor sufficient controls. We also found similar levels of anti-dsDNA and anti-ssDNA antibodies. These results show that Toll-like receptor 2 and Toll-like receptor 4 do not play a significant role in MRLlpr mice, and therefore they may not be important in human lupus.
Lupus erythematosus panniculitis  [cached]
Khatri M,Shafi M
Indian Journal of Dermatology, Venereology and Leprology , 1994,
Abstract: An infant presented with thick erythematous plaques having central necrosis, situated over cheeks and wrists. On the basis of clinical features and histology, diagnosis of lupus erythematosus panniculitis (LEP) was made. Lesions responded well to systemic steroids. To our knowledge, cases of LEP in this age group have not been reported earlier.
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