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 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 Sysyemic Lupus Erythematosus with Multiple Organ Damage

2020 ◽  
Vol 17 (5) ◽  
pp. 63-73
Author(s):  
Andreea Alexandra Nicola ◽  
Mădălina Dună ◽  
Ioana Miler ◽  
Nicoleta Petre ◽  
Denisa Predeţeanu
Keyword(s):  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Clinical Manifestations ◽  
Organ Damage ◽  
Multiple Organ ◽  
Alveolar Haemorrhage ◽  
Interdisciplinary Management ◽  
Childbearing Age ◽  
Pulmonary Infarction ◽  
Pulmonary Manifestations

Abstract Systemic lupus erythematosus (SLE) is a heterogeneous rheumatic disease with various clinical manifestations and a multifactorial pathogenesis. Although the etiology of SLE is unknown, certain risk factors have been identified as promoters of an imbalance in the immune system with antibody formation and tissue damage secondary to the deposition of immune complexes. Women of childbearing age are predominantly affected, regardless of ethnicity. SLE affects the kidneys in about 50% of patients, lupus nephritis (LN) being a major risk factor for overall morbidity and mortality. The lungs are commonly involved later in the course of the disease, pulmonary involvement in SLE being extremely varied. It includes along with pleuritis which is the most common manifestation, acute lupus pneumonitis, pulmonary vasculitis, pulmonary embolism, diffuse alveolar haemorrhage; opportunistic pulmonary infections or drug toxicity could be other pulmonary manifestations. We present the case of a young woman with SLE complicated with lupus nephritis class V and pulmonary infarction due to thromobosis of a pulmonary artery. It is a case of SLE with multiple organ damage and life-threatening complications that require interdisciplinary management and appropriate treatment.

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 Research Progress on Regulatory B Cells in Systemic Lupus Erythematosus

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Tao Wang ◽  
Yongjun Mei ◽  
Zhijun Li
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
Lupus Erythematosus ◽  
Transforming Growth Factor ◽  
Organ Damage ◽  
Multiple Organ ◽  
Research Progress ◽  
Regulatory B Cells ◽  
Systemic Lupus ◽  
B Cell Subsets

Systemic lupus erythematosus (SLE) is a chronic, systemic, autoimmune inflammatory disease characterized by the production of numerous autoantibodies and cytokines, as well as multiple organ damage. Specific B cell subsets negatively regulate immune responses and have been termed regulatory B cells (Bregs). Bregs are characterized by the production of the immunoregulatory cytokines interleukin (IL)-10, IL-35, and transforming growth factor (TGF)-β. Bregs suppress other immune cells through the secretion of these immunosuppressive cytokines and have thus been studied extensively for their potential role in the treatment of various autoimmune diseases. The progress of the research on Bregs and SLE in recent years is reviewed in this paper.

scholarly journals RNA sensing by conventional dendritic cells is central to the development of lupus nephritis

2015 ◽  
Vol 112 (45) ◽  
pp. E6195-E6204 ◽  
Author(s):  
Teja Celhar ◽  
Richard Hopkins ◽  
Susannah I. Thornhill ◽  
Raquel De Magalhaes ◽  
Sun-Hee Hwang ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Dendritic Cells ◽  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Moderate Increase ◽  
Rna Recognition ◽  
Toll Like Receptor ◽  
Systemic Lupus ◽  
Slow Progression ◽  
Inflammatory Milieu

Glomerulonephritis is a common and debilitating feature of systemic lupus erythematosus (SLE). The precise immune mechanisms that drive the progression from benign autoimmunity to glomerulonephritis are largely unknown. Previous investigations have shown that a moderate increase of the innate Toll-like receptor 7 (TLR7) is sufficient for the development of nephritis. In these systems normalization of B-cell TLR7 expression or temporal depletion of plasmacytoid dendritic cells (pDCs) slow progression; however, the critical cell that is responsible for driving full immunopathology remains unidentified. In this investigation we have shown that conventional DC expression of TLR7 is essential for severe autoimmunity in the Sle1Tg7 model of SLE. We show that a novel expanding CD11b+ conventional DC subpopulation dominates the infiltrating renal inflammatory milieu, localizing to the glomeruli. Moreover, exposure of human myeloid DCs to IFN-α or Flu increases TLR7 expression, suggesting they may have a role in self-RNA recognition pathways in clinical disease. To our knowledge, this study is the first to highlight the importance of conventional DC-TLR7 expression for kidney pathogenesis in a murine model of SLE.

scholarly journals Atypical hemolytic uremic syndrome secondary to lupus nephritis, responsive to eculizumab

2016 ◽  
Vol 8 (3) ◽  
Author(s):  
Alexander G. Raufi ◽  
Shruti Scott ◽  
Omar Darwish ◽  
Kevin Harley ◽  
Kanwarpal Kahlon ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Hemolytic Uremic Syndrome ◽  
Lupus Erythematosus ◽  
Multidisciplinary Approach ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Organ Damage ◽  
Atypical Hus ◽  
First Line Therapy ◽  
Autoimmune Attack ◽  
Uremic Syndrome

Among the spectrum of disease manifestations associated with systemic lupus erythematosus, lupus nephritis is particularly concerning due to the potential for renal failure. This autoimmune attack may not, however, be limited to the kidney and is increasingly being recognized as a trigger for atypical Hemolytic Uremic Syndrome (aHUS). Atypical HUS falls under the spectrum of the thrombotic microangiopathies (TMAs) – a group of disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end organ damage. Although plasma exchange is considered first-line therapy for thrombotic thrombocytopenic purpura – a TMA classically associated with autoimmune depletion of ADAMTS-13 – aHUS demonstrates less reliable responsiveness to this modality. Instead, use of the late complement inhibitor Eculizumab has emerged as an effective modality for the management of such patients. Diagnosis of aHUS, however, is largely clinically based, relying heavily upon a multidisciplinary approach. Herein we present the case of a patient with atypical HUS successfully treated with Eculizumab in the setting of Class IV-G (A) lupus nephritis and hypocomplementemia.

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.

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