scholarly journals Nonbilayer Phospholipid Arrangements Are Toll-Like Receptor-2/6 and TLR-4 Agonists and Trigger Inflammation in a Mouse Model Resembling Human Lupus

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Carlos Wong-Baeza ◽  
Alonso Tescucano ◽  
Horacio Astudillo ◽  
Albany Reséndiz ◽  
Carla Landa ◽  
...  
Keyword(s):  
B Cells ◽  
Lupus Erythematosus ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Autoantibody Production ◽  
Immune System Activation ◽  
Expression Of Genes ◽  
Nuclear Antigens ◽  
Proinflammatory Gene ◽  
Toll Like Receptor 2

Systemic lupus erythematosus is characterized by dysregulated activation of T and B cells and autoantibodies to nuclear antigens and, in some cases, lipid antigens. Liposomes with nonbilayer phospholipid arrangements induce a disease resembling human lupus in mice, including IgM and IgG antibodies against nonbilayer phospholipid arrangements. As the effect of these liposomes on the innate immune response is unknown and innate immune system activation is necessary for efficient antibody formation, we evaluated the effect of these liposomes on Toll-like receptor (TLR) signaling, cytokine production, proinflammatory gene expression, and T, NKT, dendritic, and B cells. Liposomes induce TLR-4- and, to a lesser extent, TLR-2/TLR-6-dependent signaling in TLR-expressing human embryonic kidney (HEK) cells and bone marrow-derived macrophages. Mice with the lupus-like disease had increased serum concentrations of proinflammatory cytokines, C3a and C5a; they also had more TLR-4-expressing splenocytes, a higher expression of genes associated with TRIF-dependent TLR-4-signaling and complement activation, and a lower expression of apoptosis-related genes, compared to healthy mice. The percentage of NKT and the percentage and activation of dendritic and B2 cells were also increased. Thus, TLR-4 and TLR-2/TLR-6 activation by nonbilayer phospholipid arrangements triggers an inflammatory response that could contribute to autoantibody production and the generation of a lupus-like disease in mice.

scholarly journals Anti-TLR7 Antibody Protects Against Lupus Nephritis in NZBWF1 Mice by Targeting B Cells and Patrolling Monocytes

2021 ◽  
Vol 12 ◽  
Author(s):  
Yusuke Murakami ◽  
Ryutaro Fukui ◽  
Reika Tanaka ◽  
Yuji Motoi ◽  
Atsuo Kanno ◽  
...  
Keyword(s):  
B Cells ◽  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Organ Damage ◽  
Multiple Organ ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Cellular Mechanisms ◽  
Autoantibody Production ◽  
Patrolling Monocytes

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and multiple organ damage. Toll-like receptor 7 (TLR7), an innate immune RNA sensor expressed in monocytes/macrophages, dendritic cells (DCs), and B cells, promotes disease progression. However, little is known about the cellular mechanisms through which TLR7 drives lupus nephritis. Here, we show that the anti-mouse TLR7 mAb, but not anti-TLR9 mAb, protected lupus-prone NZBWF1 mice from nephritis. The anti-TLR7 mAb reduced IgG deposition in glomeruli by inhibiting the production of autoantibodies to the RNA-associated antigens. We found a disease-associated increase in Ly6Clow patrolling monocytes that expressed high levels of TLR7 and had upregulated expression of lupus-associated IL-10, CD115, CD31, and TNFSF15 in NZBWF1 mice. Anti-TLR7 mAb abolished this lupus-associated increase in patrolling monocytes in the circulation, spleen, and glomeruli. These results suggested that TLR7 drives autoantibody production and lupus-associated monocytosis in NZBWF1 mice and, that anti-TLR7 mAb is a promising therapeutic tool targeting B cells and monocytes/macrophages.

scholarly journals Influence of dietary zinc on growth, zinc bioaccumulation and expression of genes involved in antioxidant and innate immune in juvenile mud crabs (Scylla paramamosain)

2020 ◽  
Vol 124 (7) ◽  
pp. 681-692
Author(s):  
Jiaxiang Luo ◽  
Tingting Zhu ◽  
Min Jin ◽  
Xin Cheng ◽  
Ye Yuan ◽  
...  
Keyword(s):  
Innate Immune ◽  
Scylla Paramamosain ◽  
Toll Like Receptor ◽  
Expression Of Genes ◽  
Total Antioxidant ◽  
Percentage Weight ◽  
Toll Like Receptor 2 ◽  
Lower Expression ◽  
Total Superoxide Dismutase ◽  
Mud Crabs

AbstractThe aim of the present study was to investigate the effects of dietary Zn level on growth performance, Zn bioaccumulation, antioxidant capacity and innate immunity in juvenile mud crabs (Scylla paramamosain). Six semi-purified diets were formulated to contain dietary Zn levels of 44·5, 56·9, 68·5, 97·3, 155·6 or 254·7 mg/kg. Dietary Zn level significantly influenced percentage weight gain (PWG), with the highest observed in crabs fed the diet containing 97·3 mg/kg Zn. Tissue Zn concentrations significantly increased as dietary Zn levels increased from 44·5 to 254·7 mg/kg. Retention of Zn in hepatopancreas increased with dietary Zn levels up to 68·5 mg/kg and then significantly decreased. Moreover, inadequate dietary Zn (44·5 and 56·9 mg/kg) reduced antioxidation markers including total superoxide dismutase (SOD) and Cu/Zn SOD activities and total antioxidant level. Crabs fed the diet with 44·5 mg/kg Zn also showed significantly lower expression of genes involved in antioxidant status, such as Cu/Zn SOD, glutathione peroxidase, catalase and thioredoxin than those fed diets containing 68·5 and 97·3 mg/kg Zn. The highest activities of phenoloxidase and alkaline phosphatase were recorded in crabs fed the diets containing 68·5 and 97·3 mg/kg Zn. Expression levels of prophenoloxidase and toll-like receptor 2 were higher in crabs fed the 97·3 mg/kg Zn diet compared with crabs fed the other diets. Based on PWG alone, the optimal dietary Zn level was estimated to be 82·9 mg/kg, with 68·5 to 97·3 mg/kg recommended for maintaining optimal Zn bioaccumulation, oxidation resistance and innate immune response of juvenile mud crabs.

scholarly journals Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus

2005 ◽  
Vol 202 (2) ◽  
pp. 321-331 ◽  
Author(s):  
Sean R. Christensen ◽  
Michael Kashgarian ◽  
Lena Alexopoulou ◽  
Richard A. Flavell ◽  
Shizuo Akira ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Lupus Erythematosus ◽  
Critical Role ◽  
Systemic Autoimmune Disease ◽  
Toll Like Receptor ◽  
Autoantibody Production ◽  
Nuclear Antigens ◽  
Deficient Mice

Systemic autoimmune disease in humans and mice is characterized by loss of immunologic tolerance to a restricted set of self-nuclear antigens. Autoantigens, such as double-stranded (ds) DNA and the RNA-containing Smith antigen (Sm), may be selectively targeted in systemic lupus erythematosus because of their ability to activate a putative common receptor. Toll-like receptor 9 (TLR9), a receptor for CpG DNA, has been implicated in the activation of autoreactive B cells in vitro, but its role in promoting autoantibody production and disease in vivo has not been determined. We show that in TLR9-deficient lupus-prone mice, the generation of anti-dsDNA and antichromatin autoantibodies is specifically inhibited. Other autoantibodies, such as anti-Sm, are maintained and even increased in TLR9-deficient mice. In contrast, ablation of TLR3, a receptor for dsRNA, did not inhibit the formation of autoantibodies to either RNA- or DNA-containing antigens. Surprisingly, we found that despite the lack of anti-dsDNA autoantibodies in TLR9-deficient mice, there was no effect on the development of clinical autoimmune disease or nephritis. These results demonstrate a specific requirement for TLR9 in autoantibody formation in vivo and indicate a critical role for innate immune activation in autoimmunity.

scholarly journals TLR9/MyD88 signaling is required for class switching to pathogenic IgG2a and 2b autoantibodies in SLE

2006 ◽  
Vol 203 (3) ◽  
pp. 553-561 ◽  
Author(s):  
Marc Ehlers ◽  
Hidehiro Fukuyama ◽  
Tracy L. McGaha ◽  
Alan Aderem ◽  
Jeffrey V. Ravetch
Keyword(s):  
B Cells ◽  
Lupus Erythematosus ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Class Switching ◽  
Systemic Lupus ◽  
Autoreactive B Cells ◽  
Loss Of Tolerance ◽  
Myd88 Signaling ◽  
Deficient Mice

Loss of tolerance in systemic lupus erythematosus (SLE) leads to the generation of autoantibodies, which accumulate in end-organs where they induce disease. Here we show that immunoglobulin (Ig)G2a and 2b autoantibodies are the pathogenic isotypes by recruiting FcγRIV expressing macrophages. Class switching, but not development, of IgM anti-self B cells to these pathogenic subclasses requires the innate immune receptor Toll-like receptor (TLR)9 and MyD88 signaling. In their absence, switching of autoreactive B cells to the IgG2a and 2b subclasses is blocked, resulting in reduced pathology and mortality. In contrast, switching of anti-self B cells to IgG1 is not perturbed and generation of nonautoreactive IgG2a and 2b antibodies is not impaired in TLR9-deficient mice. Thus, the TLR9 pathway is a potential target for therapeutic intervention in SLE.

scholarly journals An intrinsic B cell defect is required for the production of autoantibodies in the lpr model of murine systemic autoimmunity.

1991 ◽  
Vol 173 (6) ◽  
pp. 1441-1449 ◽  
Author(s):  
E S Sobel ◽  
T Katagiri ◽  
K Katagiri ◽  
S C Morris ◽  
P L Cohen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
B Cells ◽  
Lupus Erythematosus ◽  
Immunofluorescence Assay ◽  
Total Serum ◽  
Enzyme Linked Immunosorbent Assay ◽  
Cell Phenotype ◽  
Autoantibody Production ◽  
Systemic Autoimmunity

Mice homozygous for the gene lpr develop marked lymphadenopathy and a spectrum of autoantibodies closely resembling that of human systemic lupus erythematosus. The unusual T cell phenotype of the expanded lymphocyte population and the T-dependence of several antibodies in this strain have suggested that primary T cell abnormalities underlie the autoimmune syndrome. Using double chimeras, we now show that expression of the lpr gene in B cells is absolutely necessary for autoantibody production. Combinations of anti-Thy 1.2 + C' treated bone marrow from congenic strains of C57BL/6 mice, differing only at the immunoglobulin heavy chain (Igh) and lpr loci, were transferred into lethally irradiated B6/lpr mice. Double chimerism was documented by allotype-specific surface IgD and IgM immunofluorescence assay of peripheral blood and by allotype-specific enzyme-linked immunosorbent assay for total IgM in serum. Despite the presence of both +/+ and lpr B cells, IgM and IgG2a anti-chromatin as well as IgM anti-IgG were entirely the products of lpr B cells. Total serum IgG2a and IgG1 were also dominated by the lpr phenotype but not to the same extent. A similar experiment using B6/lpr-Igha recipients confirmed these findings. Additional experiments in which B6/lpr recipients were infused with ratios of donor bone marrow favoring B6.C20 +/+ over B6/lpr showed that even though +/+ B cells were overrepresented, autoantibodies were only of the lpr allotype. In addition, in the presence of lpr B cells, normal B cells showed little response to an exogenous, T cell-dependent antigen. The data thus indicate that lpr B cells manifest an intrinsic abnormality which is essential for autoantibody production in the lpr model.

scholarly journals Multiple Functions of B Cells in the Pathogenesis of Systemic Lupus Erythematosus

2019 ◽  
Vol 20 (23) ◽  
pp. 6021 ◽  
Author(s):  
Kongyang Ma ◽  
Wenhan Du ◽  
Xiaohui Wang ◽  
Shiwen Yuan ◽  
Xiaoyan Cai ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Therapeutic Interventions ◽  
Systemic Lupus ◽  
Autoantibody Production ◽  
Regulatory B Cell ◽  
Functional Features ◽  
B Cell Subsets

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by excessive autoantibody production and multi-organ involvement. Although the etiology of SLE still remains unclear, recent studies have characterized several pathogenic B cell subsets and regulatory B cell subsets involved in the pathogenesis of SLE. Among pathogenic B cell subsets, age-associated B cells (ABCs) are a newly identified subset of autoreactive B cells with T-bet-dependent transcriptional programs and unique functional features in SLE. Accumulation of T-bet+ CD11c+ ABCs has been observed in SLE patients and lupus mouse models. In addition, innate-like B cells with the autoreactive B cell receptor (BCR) expression and long-lived plasma cells with persistent autoantibody production contribute to the development of SLE. Moreover, several regulatory B cell subsets with immune suppressive functions have been identified, while the impaired inhibitory effects of regulatory B cells have been indicated in SLE. Thus, further elucidation on the functional features of B cell subsets will provide new insights in understanding lupus pathogenesis and lead to novel therapeutic interventions in the treatment of SLE.

scholarly journals Copper-Induced Expression of a Transmissible Lipoprotein Intramolecular Transacylase Alters Lipoprotein Acylation and the Toll-Like Receptor 2 Response to Listeria monocytogenes

2019 ◽  
Vol 201 (13) ◽  
Author(s):  
Krista M. Armbruster ◽  
Gloria Komazin ◽  
Timothy C. Meredith
Keyword(s):  
Listeria Monocytogenes ◽  
Bacterial Species ◽  
Acyl Chain ◽  
Constitutive Expression ◽  
Innate Immune ◽  
Copper Resistance ◽  
Toll Like Receptor ◽  
General Role ◽  
Content Type ◽  
Toll Like Receptor 2

ABSTRACT Bacterial lipoproteins are globular proteins anchored to the extracytoplasmic surfaces of cell membranes through lipidation at a conserved N-terminal cysteine. Lipoproteins contribute to an array of important cellular functions for bacteria, as well as being a focal point for innate immune system recognition through binding to Toll-like receptor 2 (TLR2) heterodimer complexes. Although lipoproteins are conserved among nearly all classes of bacteria, the presence and type of α-amino-linked acyl chain are highly variable and even strain specific within a given bacterial species. The reason for lyso-lipoprotein formation and N-acylation variability in general is presently not fully understood. In Enterococcus faecalis, lipoproteins are anchored by an N-acyl-S-monoacyl-glyceryl cysteine (lyso form) moiety installed by a chromosomally encoded lipoprotein intramolecular transacylase (Lit). Here, we describe a mobile genetic element common to environmental isolates of Listeria monocytogenes and Enterococcus spp. encoding a functional Lit ortholog (Lit2) that is cotranscribed with several well-established copper resistance determinants. Expression of Lit2 is tightly regulated, and induction by copper converts lipoproteins from the diacylglycerol-modified form characteristic of L. monocytogenes type strains to the α-amino-modified lyso form observed in E. faecalis. Conversion to the lyso form through either copper addition to media or constitutive expression of lit2 decreases TLR2 recognition when using an activated NF-κB secreted embryonic alkaline phosphatase reporter assay. While lyso formation significantly diminishes TLR2 recognition, lyso-modified lipoprotein is still predominantly recognized by the TLR2/TLR6 heterodimer. IMPORTANCE The induction of lipoprotein N-terminal remodeling in response to environmental copper in Gram-positive bacteria suggests a more general role in bacterial cell envelope physiology. N-terminal modification by lyso formation, in particular, simultaneously modulates the TLR2 response in direct comparison to their diacylglycerol-modified precursors. Thus, use of copper as a frontline antimicrobial control agent and ensuing selection raises the potential of diminished innate immune sensing and enhanced bacterial virulence.

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