Potential for Antigen-Specific Tolerizing Immunotherapy in Systematic Lupus Erythematosus

Systematic Lupus Erythematosus ◽

Curative Therapy

Systemic lupus erythematosus (SLE) is a chronic complex systemic autoimmune disease characterized by multiple autoantibodies and clinical manifestations, with the potential to affect nearly every organ. SLE treatments, including corticosteroids and immunosuppressive drugs, have greatly increased survival rates, but there is no curative therapy and SLE management is limited by drug complications and toxicities. There is an obvious clinical need for safe, effective SLE treatments. A promising treatment avenue is to restore immunological tolerance to reduce inflammatory clinical manifestations of SLE. Indeed, recent clinical trials of low-dose IL-2 supplementation in SLE patients showed that in vivo expansion of regulatory T cells (Treg cells) is associated with dramatic but transient improvement in SLE disease markers and clinical manifestations. However, the Treg cells that expanded were short-lived and unstable. Alternatively, antigen-specific tolerance (ASIT) approaches that establish long-lived immunological tolerance could be deployed in the context of SLE. In this review, we discuss the potential benefits and challenges of nanoparticle ASIT approaches to induce prolonged immunological tolerance in SLE.

Protection against Autoimmune Diabetes by Silkworm-Produced GFP-Tagged CTB-Insulin Fusion Protein

Clinical and Developmental Immunology ◽

10.1155/2011/831704 ◽

2011 ◽

Vol 2011 ◽

pp. 1-14 ◽

Cited By ~ 5

Author(s):

Qiaohong Meng ◽

Wenfeng Wang ◽

Xiaowen Shi ◽

Yongfeng Jin ◽

Yaozhou Zhang

Keyword(s):

Fusion Protein ◽

Oral Administration ◽

Fluorescent Protein ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Treg Cells ◽

Immunological Tolerance ◽

Protein Vaccine ◽

Green Fluorescent

In animals, oral administration of the cholera toxin B (CTB) subunit conjugated to the autoantigen insulin enhances the specific immune-unresponsive state. This is called oral tolerance and is capable of suppressing autoimmune type 1 diabetes (T1D). However, the process by which the CTB-insulin (CTB-INS) protein works as a therapy for T1Din vivoremains unclear. Here, we successfully expressed a green fluorescent protein- (GFP-) tagged CTB-Ins (CTB-Ins-GFP) fusion protein in silkworms in a pentameric form that retained the native ability to activate the mechanism. Oral administration of the CTB-Ins-GFP protein induced special tolerance, delayed the development of diabetic symptoms, and suppressed T1D onset in nonobese diabetic (NOD) mice. Moreover, it increased the numbers of CD4+CD25+Foxp3+T regulatory (Treg) cells in peripheral lymph tissues and affected the biological activity of spleen cells. This study demonstrated that the CTB-Ins-GFP protein produced in silkworms acted as an oral protein vaccine, inducing immunological tolerance involving CD4+CD25+Foxp3+Treg cells in treating T1D.

Drug-Induced Gingival Overgrowth in an 8-Year-Old Girl: A Case Report

Avicenna Journal of Dental Research ◽

10.34172/ajdr.2021.21 ◽

2021 ◽

Vol 13 (3) ◽

pp. 109-112

Author(s):

Parviz Torkzaban ◽

Amir Talaie

Keyword(s):

Case Report ◽

Autoimmune Disease ◽

Lupus Erythematosus ◽

Immunological Tolerance ◽

Channel Blockers ◽

Systemic Lupus ◽

Drug Induced ◽

Gingival Overgrowth

Systemic lupus erythematosus is a systemic autoimmune disease that involves multi organs. Genetic, endocrine, immunological, and environmental factors influence the loss of immunological tolerance against self-antigens leading to the formation of pathogenic autoantibodies that cause tissue damage through multiple mechanisms. The gingival overgrowth can be caused by three factors: noninflammatory, hyperplastic reaction to the medication; chronic inflammatory hyperplasia; or a combined enlargement due to chronic inflammation and drug-induced hyperplasia. Drug-Induced Gingival Overgrowth is associated with the use of three major classes of drugs, namely anticonvulsants, calcium channel blockers, and immunosuppressants. Due to recent indications for these drugs, their use continues to grow.

New targeted therapies for treatment of thrombosis in antiphospholipid syndrome

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399407000506 ◽

2007 ◽

Vol 9 (30) ◽

pp. 1-15 ◽

Cited By ~ 23

Author(s):

Silvia S. Pierangeli ◽

Mariano E. Vega-Ostertag ◽

Emilio B. González

Keyword(s):

Antiphospholipid Syndrome ◽

Targeted Therapies ◽

Lupus Erythematosus ◽

Pregnancy Loss ◽

Cell Activation ◽

Clinical Manifestations ◽

Target Cells ◽

Endothelial Cell Activation ◽

In Vivo Models

Antiphospholipid (aPL) antibodies (Abs) are associated with thrombosis and pregnancy loss in antiphospholipid syndrome (APS), a disorder initially characterised in patients with systemic lupus erythematosus (SLE) but now known to occur in the absence of other autoimmune disease. There is strong evidence that aPL Abs are pathogenic in vivo, from studies of animal models of thrombosis, endothelial cell activation and pregnancy loss. In recent years, progress has been made in characterising the molecular basis of this pathogenicity, which includes direct effects on platelets, endothelial cells and monocytes as well as activation of complement. This review summarises the clinical manifestations of APS and current modalities of treatment, and explains recent advances in understanding the molecular events triggered by aPL Abs on target cells in coagulation pathways as well as effects of aPL Abs on complement activation. Based on this information and on additional scientific evidence using in vitro and in vivo models, new potential targeted therapies for treatment and/or prevention of thrombosis in APS are proposed and discussed.

Biologics in the Treatment of Lupus Erythematosus: A Critical Literature Review

BioMed Research International ◽

10.1155/2019/8142368 ◽

2019 ◽

Vol 2019 ◽

pp. 1-17 ◽

Cited By ~ 12

Author(s):

Dominik Samotij ◽

Adam Reich

Keyword(s):

Clinical Trials ◽

Lupus Erythematosus ◽

Unmet Need ◽

Clinical Manifestations ◽

Immunosuppressive Drugs ◽

Multiple Organ ◽

Biologic Agents ◽

Drug Induced ◽

Treatment Regimes ◽

Organ Systems

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease affecting multiple organ systems that runs an unpredictable course and may present with a wide variety of clinical manifestations. Advances in treatment over the last decades, such as use of corticosteroids and conventional immunosuppressive drugs, have improved life expectancy of SLE sufferers. Unfortunately, in many cases effective management of SLE is still related to severe drug-induced toxicity and contributes to organ function deterioration and infective complications, particularly among patients with refractory disease and/or lupus nephritis. Consequently, there is an unmet need for drugs with a better efficacy and safety profile. A range of different biologic agents have been proposed and subjected to clinical trials, particularly dedicated to this subset of patients whose disease is inadequately controlled by conventional treatment regimes. Unfortunately, most of these trials have given unsatisfactory results, with belimumab being the only targeted therapy approved for the treatment of SLE so far. Despite these pitfalls, several novel biologic agents targeting B cells, T cells, or cytokines are constantly being evaluated in clinical trials. It seems that they may enhance the therapeutic efficacy when combined with standard therapies. These efforts raise the hope that novel drugs for patients with refractory SLE may be available in the near future. This article reviews the current biological therapies being tested in the treatment of SLE.

Current Paradigms of Tolerogenic Dendritic Cells and Clinical Implications for Systemic Lupus Erythematosus

Cells ◽

10.3390/cells8101291 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1291 ◽

Cited By ~ 2

Author(s):

Ritprajak ◽

Kaewraemruaen ◽

Hirankarn

Keyword(s):

Dendritic Cells ◽

Autoimmune Diseases ◽

Lupus Erythematosus ◽

Ex Vivo ◽

Immunosuppressive Drugs ◽

Clinical Implications ◽

Systemic Lupus ◽

Tolerogenic Dendritic Cells

Tolerogenic dendritic cells (tolDCs) are central players in the initiation and maintenance of immune tolerance and subsequent prevention of autoimmunity. Recent advances in treatment of autoimmune diseases including systemic lupus erythematosus (SLE) have focused on inducing specific tolerance to avoid long-term use of immunosuppressive drugs. Therefore, DC-targeted therapies to either suppress DC immunogenicity or to promote DC tolerogenicity are of high interest. This review describes details of the typical characteristics of in vivo and ex vivo tolDC, which will help to select a protocol that can generate tolDC with high functional quality for clinical treatment of autoimmune disease in individual patients. In addition, we discuss the recent studies uncovering metabolic pathways and their interrelation intertwined with DC tolerogenicity. This review also highlights the clinical implications of tolDC-based therapy for SLE treatment, examines the current clinical therapeutics in patients with SLE, which can generate tolDC in vivo, and further discusses on possibility and limitation on each strategy. This synthesis provides new perspectives on development of novel therapeutic approaches for SLE and other autoimmune diseases.

Aberrant Non-Coding RNA Expression in Patients with Systemic Lupus Erythematosus: Consequences for Immune Dysfunctions and Tissue Damage

Biomolecules ◽

10.3390/biom10121641 ◽

2020 ◽

Vol 10 (12) ◽

pp. 1641

Author(s):

Chang-Youh Tsai ◽

Chieh-Yu Shen ◽

Chih-Wei Liu ◽

Song-Chou Hsieh ◽

Hsien-Tzung Liao ◽

...

Keyword(s):

Lupus Erythematosus ◽

Tissue Damage ◽

Immune Modulation ◽

Clinical Manifestations ◽

Circular Rnas ◽

Contributing Factors ◽

Systemic Lupus ◽

Non Coding Rnas

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease with heterogeneous clinical manifestations. A diverse innate and adaptive immune dysregulation is involved in the immunopathogenesis of SLE. The dysregulation of immune-related cells may derive from the intricate interactions among genetic, epigenetic, environmental, and immunological factors. Of these contributing factors, non-coding RNAs (ncRNAs), including microRNAs (miRNAs, miRs), and long non-coding RNAs (lncRNAs) play critical roles in the post-transcriptional mRNA expression of cytokines, chemokines, and growth factors, which are essential for immune modulation. In the present review, we emphasize the roles of ncRNA expression in the immune-related cells and cell-free plasma, urine, and tissues contributing to the immunopathogenesis and tissue damage in SLE. In addition, the circular RNAs (circRNA) and their post-translational regulation of protein synthesis in SLE are also briefly described. We wish these critical reviews would be useful in the search for biomarkers/biosignatures and novel therapeutic strategies for SLE patients in the future.

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

Journal of Experimental Medicine ◽

10.1084/jem.20050338 ◽

2005 ◽

Vol 202 (2) ◽

pp. 321-331 ◽

Cited By ~ 380

Author(s):

Sean R. Christensen ◽

Michael Kashgarian ◽

Lena Alexopoulou ◽

Richard A. Flavell ◽

Shizuo Akira ◽

...

Keyword(s):

Autoimmune Disease ◽

Lupus Erythematosus ◽

Critical Role ◽

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.

Autoantigen TRIM21/Ro52 as a Possible Target for Treatment of Systemic Lupus Erythematosus

International Journal of Rheumatology ◽

10.1155/2012/718237 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 31

Author(s):

Ryusuke Yoshimi ◽

Yoshiaki Ishigatsubo ◽

Keiko Ozato

Keyword(s):

Autoimmune Disease ◽

Lupus Erythematosus ◽

Immunosuppressive Drugs ◽

Type I ◽

Systemic Lupus ◽

Molecular Features ◽

Attractive Therapeutic Target ◽

Autoimmune Processes

Systemic lupus erythematosus (SLE) is a chronic, systemic, and autoimmune disease, whose etiology is still unknown. Although there has been progress in the treatment of SLE through the use of glucocorticoid and immunosuppressive drugs, these drugs have limited efficacy and pose significant risks of toxicity. Moreover, prognosis of patients with SLE has remained difficult to assess. TRIM21/Ro52/SS-A1, a 52-kDa protein, is an autoantigen recognized by antibodies in sera of patients with SLE and Sjögren's syndrome (SS), another systemic autoimmune disease, and anti-TRIM21 antibodies have been used as a diagnostic marker for decades. TRIM21 belongs to the tripartite motif-containing (TRIM) super family, which has been found to play important roles in innate and acquired immunity. Recently, TRIM21 has been shown to be involved in both physiological immune responses and pathological autoimmune processes. For example, TRIM21 ubiquitylates proteins of the interferon-regulatory factor (IRF) family and regulates type I interferon and proinflammatory cytokines. In this paper, we summarize molecular features of TRIM21 revealed so far and discuss its potential as an attractive therapeutic target for SLE.

Immunosuppressive drugs on inducing Ag-specific CD4+CD25+Foxp3+ Treg cells during immune response in vivo

Transplant Immunology ◽

10.1016/j.trim.2012.05.001 ◽

2012 ◽

Vol 27 (1) ◽

pp. 30-38 ◽

Cited By ~ 29

Author(s):

Tingting Wu ◽

Lianjun Zhang ◽

Kerui Xu ◽

Chenming Sun ◽

Tong Lei ◽

...

Keyword(s):

Immune Response ◽

Treg Cells ◽

Immunosuppressive Drugs

Lupic Outbreak and Covid-19 Pneumonia-Case Report

International Journal of Clinical Case Reports and Reviews ◽

10.31579/2690-4861/152 ◽

2021 ◽

Vol 7 (5) ◽

pp. 01-06

Author(s):

Tamayo Luis

Keyword(s):

Case Report ◽

Autoimmune Disease ◽

Respiratory Infection ◽

Lupus Erythematosus ◽

Immunosuppressive Drugs ◽

Systematic Lupus Erythematosus ◽

Population Groups ◽

Therapeutic Challenge ◽

Pneumonia Case ◽

Lupus Flare

Coronavirus disease 2019 (COVID-19) is a respiratory infection that can cause mild symptoms or even death, to patients who suffer from it. It affects all population groups without distinction. Systematic Lupus Erythematosus (SLE) is a chronic and fluctuating autoimmune disease. One of the goals of the treatment is to avoid flare-ups and thereby reduce mortality. Their innate alterations in immunity, added to the use of immunosuppressive drugs to control the disease and prevent outbreaks makes them more vulnerable to develop severe symptoms in SARS-CoV-2 infection. We present the case of a patient with SLE infected by SARS-CoV-2 with a lupus flare during hospitalization, entailing a diagnostic and therapeutic challenge.