Pathogenesis of Human Systemic Lupus Erythematosus: A Cellular Perspective
TL;DR: Novel observations have provided an improved understanding of the contribution of tissue-specific factors and associated damage, T and B lymphocytes, as well as innate immune cell subsets and their corresponding abnormalities.
About: This article is published in Trends in Molecular Medicine.The article was published on 2017-07-01 and is currently open access. It has received 288 citations till now. The article focuses on the topics: Immune dysregulation & Autoimmunity.
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TL;DR: The role of sex hormones particularly estrogen, in the adaptive immune response, in health, and autoimmune disease with an emphasis on systemic lupus erythematosus is focused on.
Abstract: Women have stronger immune responses to infections and vaccination than men. Paradoxically, the stronger immune response comes at a steep price, which is the high incidence of autoimmune diseases in women. The reasons why women have stronger immunity and higher incidence of autoimmunity are not clear. Besides gender, sex hormones contribute to the development and activity of the immune system, accounting for differences in gender-related immune responses. Both innate and adaptive immune systems bear receptors for sex hormones and respond to hormonal cues. This review focuses on the role of sex hormones particularly estrogen, in the adaptive immune response, in health, and autoimmune disease with an emphasis on systemic lupus erythematosus.
303 citations
Cites background from "Pathogenesis of Human Systemic Lupu..."
...SLE is a prototypical chronic systemic autoimmune disease afflicting women in the childbearing years and can affect any organ in the body (10, 11)....
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TL;DR: Tsokos reviews how the genetic, epigenetic and microbial environments influence innate and adaptive immune cells to drive immunopathology and organ damage in systemic lupus erythematosus.
Abstract: Impressive progress has been made over the last several years toward understanding how almost every aspect of the immune system contributes to the expression of systemic autoimmunity. In parallel, studies have shed light on the mechanisms that contribute to organ inflammation and damage. New approaches that address the complicated interaction between genetic variants, epigenetic processes, sex and the environment promise to enlighten the multitude of pathways that lead to what is clinically defined as systemic lupus erythematosus. It is expected that each patient owns a unique 'interactome', which will dictate specific treatment.
250 citations
TL;DR: A review of the current knowledge about the differentiation of Th17 cells and the role of the IL-17/IL-23 axis in the pathogenesis of IMIDs aims to review the association of these IMIDs with periodontitis and briefly discusses the therapeutic potential of agents that modulate the IL
Abstract: Innate immunity represents the semi-specific first line of defense and provides the initial host response to tissue injury, trauma, and pathogens. Innate immunity activates the adaptive immunity, and both act highly regulated together to establish and maintain tissue homeostasis. Any dysregulation of this interaction can result in chronic inflammation and autoimmunity and is thought to be a major underlying cause in the initiation and progression of highly prevalent immune-mediated inflammatory diseases (IMIDs) such as psoriasis, rheumatoid arthritis, inflammatory bowel diseases among others, and periodontitis. Th1 and Th2 cells of the adaptive immune system are the major players in the pathogenesis of IMIDs. In addition, Th17 cells, their key cytokine IL-17, and IL-23 seem to play pivotal roles. This review aims to provide an overview of the current knowledge about the differentiation of Th17 cells and the role of the IL-17/IL-23 axis in the pathogenesis of IMIDs. Moreover, it aims to review the association of these IMIDs with periodontitis and briefly discusses the therapeutic potential of agents that modulate the IL-17/IL-23 axis.
243 citations
TL;DR: The current progress in modulating Treg cells in autoimmune disorders, transplantation and cancer is described to promote antitumour immunity and regression.
Abstract: Regulatory T (Treg) cells suppress inflammation and regulate immune system activity. In patients with systemic or organ-specific autoimmune diseases or those receiving transplanted organs, Treg cells are compromised. Approaches to strengthen Treg cell function, either by expanding them ex vivo and reinfusing them or by increasing the number or capacity of existing Treg cells, have entered clinical trials. Unlike the situation in autoimmunity, in patients with cancer, Treg cells limit the antitumour immune response and promote angiogenesis and tumour growth. Their immunosuppressive function may, in part, explain the failure of many immunotherapies in cancer. Strategies to reduce the function and/or number of Treg cells specifically in tumour sites are being investigated to promote antitumour immunity and regression. Here, we describe the current progress in modulating Treg cells in autoimmune disorders, transplantation and cancer.
211 citations
TL;DR: A better understanding of the molecular defects including signaling events and gene regulation underlying the dysfunctional T cells in SLE is necessary to pave the path for better management, therapy, and perhaps prevention of this complex disease.
Abstract: Systemic lupus erythematosus (SLE) is a chronic multi-organ debilitating autoimmune disease, which mainly afflicts women in the reproductive years. A complex interaction of genetics, environmental factors and hormones result in the breakdown of immune tolerance to "self" leading to damage and destruction of multiple organs, such as the skin, joints, kidneys, heart and brain. Both innate and adaptive immune systems are critically involved in the misguided immune response against self-antigens. Dendritic cells, neutrophils, and innate lymphoid cells are important in initiating antigen presentation and propagating inflammation at lymphoid and peripheral tissue sites. Autoantibodies produced by B lymphocytes and immune complex deposition in vital organs contribute to tissue damage. T lymphocytes are increasingly being recognized as key contributors to disease pathogenesis. CD4 T follicular helper cells enable autoantibody production, inflammatory Th17 subsets promote inflammation, while defects in regulatory T cells lead to unchecked immune responses. A better understanding of the molecular defects including signaling events and gene regulation underlying the dysfunctional T cells in SLE is necessary to pave the path for better management, therapy, and perhaps prevention of this complex disease. In this review, we focus on the aberrations in T cell signaling in SLE and highlight therapeutic advances in this field.
139 citations
References
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TL;DR: The 1971 preliminary criteria for the classification of systemic lupus erythematosus (SLE) were revised and updated to incorporate new immunologic knowledge and improve disease classification and showed gains in sensitivity and specificity.
Abstract: The 1971 preliminary criteria for the classification of systemic lupus erythematosus (SLE) were revised and updated to incorporate new immunologic knowledge and improve disease classification. The 1982 revised criteria include fluorescence antinuclear antibody and antibody to native DNA and Sm antigen. Some criteria involving the same organ systems were aggregated into single criteria. Raynaud's phenomenon and alopecia were not included in the 1982 revised criteria because of low sensitivity and specificity. The new criteria were 96% sensitive and 96% specific when tested with SLE and control patient data gathered from 18 participating clinics. When compared with the 1971 criteria, the 1982 revised criteria showed gains in sensitivity and specificity.
14,272 citations
"Pathogenesis of Human Systemic Lupu..." refers background in this paper
...1Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA 2Department of Rheumatology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA 3Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan *Correspondence: vmoulton@bidmc.harvard.edu (V.R. Moulton) and gtsokos@bidmc.harvard.edu (G.C. Tsokos)....
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...Currently, the diagnosis, which is frequently difficult and delayed, is based on established criteria by the American College of Rheumatology [2] and the treatment is still limited to the use of general immunosuppressive drugs....
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...Although the American College of Rheumatology criteria are used to diagnose the disease, it is abundantly clear that SLE is not a single disease/pathology....
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TL;DR: It is described that, upon activation, neutrophils release granule proteins and chromatin that together form extracellular fibers that bind Gram-positive and -negative bacteria, which degrade virulence factors and kill bacteria.
Abstract: Neutrophils engulf and kill bacteria when their antimicrobial granules fuse with the phagosome. Here, we describe that, upon activation, neutrophils release granule proteins and chromatin that together form extracellular fibers that bind Gram-positive and -negative bacteria. These neutrophil extracellular traps (NETs) degrade virulence factors and kill bacteria. NETs are abundant in vivo in experimental dysentery and spontaneous human appendicitis, two examples of acute inflammation. NETs appear to be a form of innate response that binds microorganisms, prevents them from spreading, and ensures a high local concentration of antimicrobial agents to degrade virulence factors and kill bacteria.
7,554 citations
Book•
01 Jun 1976TL;DR: Contributions are gathered from physicians and researchers from North America, South America, Europe, and Asia that highlight several important and/or novel aspects of the molecular pathogenesis, clinical organ involvement, and experimental therapies in this prototypical systemic autoimmune disease.
Abstract: In sharp distinction to organ-specific autoimmune diseases such as thyroiditis, diabetes, or myasthenia gravis, systemic lupus erythematosus (SLE) is a constellation of signs and symptoms classified as one nosologic entity. Indeed, it is the diversity of presentation, accumulation of manifestations over time, and undulating disease course that challenge the most astute of clinicians. With rare exception, the unifying laboratory abnormality is the presence of circulating antinuclear antibodies (ANA). Acknowledging the complexity of this disease, its broad differential diagnosis, and the need to develop better and more specific therapies, the American College of Rheumatology (ACR) has designated 11 diagnostic criteria (presented in Table 15A-1) (1,2). These criteria reflect the major clinical features of the disease (mucocutaneous, articular, serosal, renal, neurologic) and incorporate the associated laboratory findings (hematologic and immunologic). The presence of four or more criteria is required for diagnosis. They need not necessarily present simultaneously: a single criterion such as arthritis or thrombocytopenia may recur over months or years before the diagnosis can be confirmed by the appearance of additional features. While there is incomplete agreement among rheumatologists as to whether these criteria need to be strictly applied in a practice setting, or reserved only for formal academic studies, they do facilitate a methodologic approach to evaluate a patient.
3,541 citations
TL;DR: Global gene expression profiling of peripheral blood mononuclear cells is used to identify distinct patterns of gene expression that distinguish most SLE patients from healthy controls, and identify a subgroup of patients who may benefit from therapies targeting the IFN pathway.
Abstract: Systemic lupus erythematosus (SLE) is a complex, inflammatory autoimmune disease that affects multiple organ systems. We used global gene expression profiling of peripheral blood mononuclear cells to identify distinct patterns of gene expression that distinguish most SLE patients from healthy controls. Strikingly, about half of the patients studied showed dysregulated expression of genes in the IFN pathway. Furthermore, this IFN gene expression “signature” served as a marker for more severe disease involving the kidneys, hematopoetic cells, and/or the central nervous system. These results provide insights into the genetic pathways underlying SLE, and identify a subgroup of patients who may benefit from therapies targeting the IFN pathway.
2,075 citations
"Pathogenesis of Human Systemic Lupu..." refers background in this paper
...pDCs produce large amounts of type I IFN, and this IFN-a/b ‘signature’ is often observed in SLE patients [18]....
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...Transcriptomics refers to the analysis of gene expression at a global level, and microarrays have helped to explore aberrantly regulated genes in peripheral blood mononuclear cells (PBMCs) taken from SLE patients relative to healthy controls [18,19]....
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TL;DR: Microarray analysis of blood cells reveals that immature granulocytes may be involved in SLE pathogenesis, and the IFN signature confirms the central role of this cytokine in Sle, using oligonucleotide microarrays.
Abstract: Systemic lupus erythematosus (SLE) is a prototype systemic autoimmune disease characterized by flares of high morbidity. Using oligonucleotide microarrays, we now show that active SLE can be distinguished by a remarkably homogeneous gene expression pattern with overexpression of granulopoiesis-related and interferon (IFN)-induced genes. Using the most stringent statistical analysis (Bonferroni correction), 15 genes were found highly up-regulated in SLE patients, 14 of which are targets of IFN and one, defensin DEFA-3, a major product of immature granulocytes. A more liberal correction (Benjamini and Hochberg correction) yielded 18 additional genes, 12 of which are IFN-regulated and 4 granulocyte-specific. Indeed immature neutrophils were identified in a large fraction of SLE patients white blood cells. High dose glucocorticoids, a standard treatment of disease flares, shuts down the interferon signature, further supporting the role of this cytokine in SLE. The expression of 10 genes correlated with disease activity according to the SLEDAI. The most striking correlation (P < 0.001, r = 0.55) was found with the formyl peptide receptor-like 1 protein that mediates chemotactic activities of defensins. Therefore, while the IFN signature confirms the central role of this cytokine in SLE, microarray analysis of blood cells reveals that immature granulocytes may be involved in SLE pathogenesis.
1,873 citations
"Pathogenesis of Human Systemic Lupu..." refers background in this paper
...These defects play vital roles in the pathogenesis of SLE, including ineffective apoptotic debris clearance [96], self-antigen presentation [92], and inflammatory cytokine production [19,94,97] (Figure 3)....
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...Transcriptomics refers to the analysis of gene expression at a global level, and microarrays have helped to explore aberrantly regulated genes in peripheral blood mononuclear cells (PBMCs) taken from SLE patients relative to healthy controls [18,19]....
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