Materiały źródłowe

• #1 The Pathogenesis of Systemic Lupus Erythematosus – An Update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3508331/

  Systemic lupus erythematosus (SLE, lupus) is characterized by a global loss of self-tolerance with activation of autoreactive T and B cells leading to production of pathogenic autoantibodies and tissue injury. […] Aberrant innate immune responses play a significant role in the pathogenesis of SLE, contributing both to tissue injury via release of inflammatory cytokines as well as to aberrant activation of autoreactive T and B cells, with the latter leading to pathogenic autoantibody production and resultant end-organ injury. […] Self-antigen dependent activation of autoreactive B cells and CD4 T cells in secondary lymphoid organs, leads to production of pathogenic autoantibodies that, along with inflammatory cytokines, promotes tissue injury in lupus. […] Genetic predisposition is a requisite for aberrant immune system activation, in the setting of environmental and stochastic events.

• #2 Systemic Lupus Erythematosus – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK535405/

  Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multisystem involvement and is associated with significant morbidity and mortality. Genetic, immunological, endocrine, 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. […] Despite recent advances in technology and understanding of the pathological basis and risk factors for SLE, the exact pathogenesis is still not well known. […] The pathogenesis of SLE is complex, and the understanding of SLE pathogenesis is constantly evolving. A break in the tolerance in genetically susceptible individuals on exposure to environmental factors leads to the activation of autoimmunity. Cell damage caused by infectious and other environmental factors exposes the immune system to self-antigens leading to activation of T and B cells, which become self-sustained by a chronic self-aimed immune response. Cytokine release, complement activation, and autoantibody production lead to organ damage.

• #3 Systemic lupus erythematosus: Epidemiology and pathogenesis – UpToDate

  https://www.uptodate.com/contents/systemic-lupus-erythematosus-epidemiology-and-pathogenesis

  Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease that can have a wide array of disease manifestations, including constitutional symptoms, rashes, arthritis, hematologic abnormalities, and nephritis. […] While the underlying disease pathogenesis is incompletely understood, it involves the development of one or more autoantibodies with the subsequent production of immune complexes and may be related to a variety of genetic, hormonal, and environmental factors. […] As researchers learn more about the various abnormalities in genetic and biologic pathways that cause SLE, it is possible that specific disease variants or subtypes may emerge.

• #4

  https://link.springer.com/article/10.1186/s43556-024-00217-8

  Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by dysregulated immune responses and autoantibody production, which affects multiple organs and varies in clinical presentation and disease severity. […] The development of SLE is intricate, encompassing dysregulation within the immune system, a collapse of immunological tolerance, genetic susceptibilities to the disease, and a variety of environmental factors that can act as triggers. […] A deeper understanding of the pathogenesis of SLE and the exploration of new targeted treatment strategies are essential to advance the treatment of this complex autoimmune disease. […] The onset of SLE is intricately linked to the interplay between immune dysregulation, genetic predisposition, the collapse of immune tolerance, and a series of environmental triggers.

• #5 Cellular and molecular pathogenesis of systemic lupus erythematosus: lessons from animal models | Arthritis Research & Therapy | Full Text

  https://arthritis-research.biomedcentral.com/articles/10.1186/ar3465

  Systemic lupus erythematosus (SLE) is a complex disease characterized by the appearance of autoantibodies against nuclear antigens and the involvement of multiple organ systems, including the kidneys. […] Aberrations in the innate as well as adaptive arms of the immune system both play an important role in the genesis and progression of lupus. […] The cellular and molecular mechanisms that contribute to the pathogenesis of lupus are discussed in the following sections and are illustrated in Figure 1. […] The presence of high titers of autoantibodies against nuclear antigens is the hallmark of SLE. […] Although these studies warrant independent confirmation, they support the notion that apoptotic cells could harbor the immunogens responsible for antinuclear antibody formation. […] These data support the hypothesis that the inefficient clearance of apoptotic bodies could be one factor leading to the development of SLE.

• #6 Systemic Lupus Erythematosus – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK535405/

  Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multisystem involvement and is associated with significant morbidity and mortality. Genetic, immunological, endocrine, 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. […] Despite recent advances in technology and understanding of the pathological basis and risk factors for SLE, the exact pathogenesis is still not well known. […] The pathogenesis of SLE is complex, and the understanding of SLE pathogenesis is constantly evolving. A break in the tolerance in genetically susceptible individuals on exposure to environmental factors leads to the activation of autoimmunity. Cell damage caused by infectious and other environmental factors exposes the immune system to self-antigens leading to activation of T and B cells, which become self-sustained by a chronic self-aimed immune response. Cytokine release, complement activation, and autoantibody production lead to organ damage.

• #7

  https://link.springer.com/article/10.1186/s43556-024-00217-8

  These complex interactions ultimately result in the production of pathogenic autoantibodies. […] These lupus-associated autoantibodies collaborate with adaptive and innate immune responses, facilitating the accumulation of immune complexes in various tissues and organs. […] This process triggers acute and chronic inflammation, ultimately leading to damage to the affected organs. […] A pivotal factor in the pathogenesis of SLE is the immune responses dysregulation, which encompasses both innate and adaptive immune systems. […] Evidence suggests that the innate immune systems dysfunction, which includes reduced neutrophil phagocytic capacity and increased oxidative stress, is accompanied by a buildup of dendritic cells (DCs) at inflammatory locations, and defects or mutations in the complement system, are linked to SLE.

• #8 Systemic Lupus Erythematosus – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK535405/

  Both innate and adaptive immune systems play a role in the pathogenesis of SLE. The innate immune system activation is either Toll-like receptor (TLR) dependent or independent. The cell membrane-bound TLRs (TLR 2, 4, 6) are activated on exposure to the extracellular DNA and RNA from dying cells, which leads to downstream activation of the interferon regulatory family (IRF-3), NF-B, and MAP-kinases, which serve as transcription factors for the production of proinflammatory mediators such as IFN-b. […] T-lymphocytes and B-lymphocytes play a significant role in the pathogenesis of SLE. Apoptotic and damaged cell-derived antigens are presented to T-cells by antigen-presenting cells. T-cells in SLE display a distorted gene expression leading to the production of several cytokines. These T-cells produce less IL-2, which leads to altered regulatory T-cell production. Increased IL-6, IL-10, IL-12, and IL-23 increase mononuclear cell production while increased IL-17 and IL-21 lead to increased T-cell production. Increased Interferon leads to defective T-cell production. T-cells lead to the activation of autoreactive B-cells by CD40L and cytokine production, leading to autoantibody production, a hallmark of SLE.

• #9 Systemic Lupus Erythematosus Pathogenesis | Encyclopedia MDPI

  https://encyclopedia.pub/entry/42764

  Systemic lupus erythematosus (SLE) is a genetically predisposed, female-predominant disease, characterized by multiple organ damage, that in its most severe forms can be life-threatening. The pathogenesis of SLE is complex and involves cells of both innate and adaptive immunity. The distinguishing feature of SLE is the production of autoantibodies, with the formation of immune complexes that precipitate at the vascular level, causing organ damage. […] A key role in the generation of these autoantibodies is played by toll-like receptors (TLRs). Abnormal engagement of TLRs TLR7 and TLR9 subtypes in SLE, has been shown to effectively promote the production of autoantibodies against double-stranded DNA (dsDNA) and RNA-associated autoantigens, respectively. […] Self-reactive T cells play a key role in the genesis of SLE. T-helper 1 (Th1) cells play a central role in the pathogenesis of SLE, by promoting oxidative stress related to IFNγ production.

• #10 Systemic lupus erythematosus: updated insights on the pathogenesis, diagnosis, prevention and therapeutics | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-025-02168-0

  Type I IFNs are generated in response to, primarily, the activation of nucleic acid-binding pattern recognition receptors such as the endosomal TLR3/4/7/9, the cytosolic sensor cyclic guanosine monophosphate-adenosine monophosphate (cGMP-AMP) synthase (cGAS), and the ribonucleic acid (RNA)-sensor retinoic acid-inducible gene (RIG) I like receptors (RLRs)-mitochondreal antiviral signaling protein (MAVS). […] The pathogenesis of SLE is associated with the failure of removing self-reactive clones of T and B cells. […] The complement system has been implicated in diverse biological processes in mammals including, e.g., modulation of the immune tolerance, and autoimmune diseases. […] The complement cascade is activated to initiate the proteolytic cleavage of complement proteins into fragments that relay signals to neighboring cells and leukocytes by being deposited onto the targets or released into the extracellular fluid.

• #11 Pathogenesis of systemic lupus erythematosus: risks, mechanisms and therapeutic targets | Annals of the Rheumatic Diseases

  https://ard.bmj.com/content/82/8/999

  A broad view of the pathogenesis of SLE. As SLE is an immune-mediated disease, research and identification of therapeutic targets have focused on elucidation of the relevant immune cells and mediators and the alterations in immune function that contribute to autoimmunity and inflammation in SLE. […] The complement locus, in the MHC class III region, is of particular interest in view of the important role of the classical pathway in clearing potentially pathogenic immune complexes. […] Recent detailed analyses of the MHC in patients with SLE and healthy subjects provide important insights regarding mechanisms of immune dysfunction in those bearing risk alleles. […] The identified human leucocyte antigen (HLA) risk haplotype is HLA-DRB1*03:01HLA-DQA1*05:01HLA-DQB1*02:01 (DR3) in those of EA descent and HLA-DRB1*15:03HLA-DQA1*01:02HLA-DQB1*06:02 (DR2) in the AAs, similar to observations in other studies.

• #12 Lupus – Wikipedia

  https://en.wikipedia.org/wiki/Lupus

  T cells, which regulate B-cell responses and infiltrate target tissues, have defects in signaling, adhesion, co-stimulation, gene transcription, and alternative splicing. […] The cytokines B-lymphocyte stimulator (BLyS), also known as B-cell activating factor (BAFF), interleukin 6, interleukin 17, interleukin 18, type I interferons, and tumor necrosis factor (TNF) are involved in the inflammatory process and are potential therapeutic targets. […] SLE is associated with low C3 levels in the complement system. […] Impaired clearance of dying cells is a potential pathway for the development of this systemic autoimmune disease. […] SLE is associated with defects in apoptotic clearance, and the damaging effects caused by apoptotic debris. […] Autoimmunity possibly results from the extended exposure to nuclear and intracellular autoantigens derived from late apoptotic and secondary necrotic cells.

• #13 Systemic Lupus Erythematosus – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK535405/

  Both innate and adaptive immune systems play a role in the pathogenesis of SLE. The innate immune system activation is either Toll-like receptor (TLR) dependent or independent. The cell membrane-bound TLRs (TLR 2, 4, 6) are activated on exposure to the extracellular DNA and RNA from dying cells, which leads to downstream activation of the interferon regulatory family (IRF-3), NF-B, and MAP-kinases, which serve as transcription factors for the production of proinflammatory mediators such as IFN-b. […] T-lymphocytes and B-lymphocytes play a significant role in the pathogenesis of SLE. Apoptotic and damaged cell-derived antigens are presented to T-cells by antigen-presenting cells. T-cells in SLE display a distorted gene expression leading to the production of several cytokines. These T-cells produce less IL-2, which leads to altered regulatory T-cell production. Increased IL-6, IL-10, IL-12, and IL-23 increase mononuclear cell production while increased IL-17 and IL-21 lead to increased T-cell production. Increased Interferon leads to defective T-cell production. T-cells lead to the activation of autoreactive B-cells by CD40L and cytokine production, leading to autoantibody production, a hallmark of SLE.

• #14 Lupus – Wikipedia

  https://en.wikipedia.org/wiki/Lupus

  T cells, which regulate B-cell responses and infiltrate target tissues, have defects in signaling, adhesion, co-stimulation, gene transcription, and alternative splicing. […] The cytokines B-lymphocyte stimulator (BLyS), also known as B-cell activating factor (BAFF), interleukin 6, interleukin 17, interleukin 18, type I interferons, and tumor necrosis factor (TNF) are involved in the inflammatory process and are potential therapeutic targets. […] SLE is associated with low C3 levels in the complement system. […] Impaired clearance of dying cells is a potential pathway for the development of this systemic autoimmune disease. […] SLE is associated with defects in apoptotic clearance, and the damaging effects caused by apoptotic debris. […] Autoimmunity possibly results from the extended exposure to nuclear and intracellular autoantigens derived from late apoptotic and secondary necrotic cells.

• #15 Systemic Lupus Erythematosus – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK535405/

  Both innate and adaptive immune systems play a role in the pathogenesis of SLE. The innate immune system activation is either Toll-like receptor (TLR) dependent or independent. The cell membrane-bound TLRs (TLR 2, 4, 6) are activated on exposure to the extracellular DNA and RNA from dying cells, which leads to downstream activation of the interferon regulatory family (IRF-3), NF-B, and MAP-kinases, which serve as transcription factors for the production of proinflammatory mediators such as IFN-b. […] T-lymphocytes and B-lymphocytes play a significant role in the pathogenesis of SLE. Apoptotic and damaged cell-derived antigens are presented to T-cells by antigen-presenting cells. T-cells in SLE display a distorted gene expression leading to the production of several cytokines. These T-cells produce less IL-2, which leads to altered regulatory T-cell production. Increased IL-6, IL-10, IL-12, and IL-23 increase mononuclear cell production while increased IL-17 and IL-21 lead to increased T-cell production. Increased Interferon leads to defective T-cell production. T-cells lead to the activation of autoreactive B-cells by CD40L and cytokine production, leading to autoantibody production, a hallmark of SLE.

• #16 Systemic Lupus Erythematosus – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK535405/

  Further, the autoreactive B-cells in SLE, stimulated by self-antigens, are not readily eliminated due to a deficiency of the process involved in the functional neutralization of autoreactive B cells. The B-cells can also serve as antigen-presenting cells and activate T-cells by presenting internalized soluble antigens to T-cells. This creates a loop where both B and T cells activate each other, leading to more autoimmunity.

• #17 Cellular and molecular pathogenesis of systemic lupus erythematosus: lessons from animal models | Arthritis Research & Therapy | Full Text

  https://arthritis-research.biomedcentral.com/articles/10.1186/ar3465

  Systemic lupus erythematosus (SLE) is a complex disease characterized by the appearance of autoantibodies against nuclear antigens and the involvement of multiple organ systems, including the kidneys. […] Aberrations in the innate as well as adaptive arms of the immune system both play an important role in the genesis and progression of lupus. […] The cellular and molecular mechanisms that contribute to the pathogenesis of lupus are discussed in the following sections and are illustrated in Figure 1. […] The presence of high titers of autoantibodies against nuclear antigens is the hallmark of SLE. […] Although these studies warrant independent confirmation, they support the notion that apoptotic cells could harbor the immunogens responsible for antinuclear antibody formation. […] These data support the hypothesis that the inefficient clearance of apoptotic bodies could be one factor leading to the development of SLE.

• #18

  https://link.springer.com/article/10.1186/s43556-024-00217-8

  Additionally, the compromised function of adaptive immunity, such as augmented B cell activity, failure in the clearance of autoreactive B cells, and the overactivation of T cells, can lead to an upsurge in autoantibody production. […] Studies have indicated that elevated levels of type I interferons (IFNs) are detectable in SLE and are associated with the severity of the disease. […] In SLE, pathogenesis is driven by the abnormal activation of both adaptive and innate immune cells. […] This activation leads to an overproduction of autoantibodies by B cells, which then form immune complexes. […] These complexes accumulate in tissues, initiating an inflammatory response. […] The collapse of immune tolerance plays a pivotal role in the development of autoimmune conditions; however, the precise mechanisms driving this breakdown remain to be fully elucidated.

• #19 Systemic lupus erythematosus: updated insights on the pathogenesis, diagnosis, prevention and therapeutics | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-025-02168-0

  SLE is caused by an autoimmune reaction involving both the innate and adaptive immune systems, where an abnormal immune response is directed to nucleic acid-containing cellular particles. […] Complexities regarding SLE therapeutics render it essential and urgent to identify the mechanisms-of-action and pivotal signaling axis driving SLE pathogenesis. […] Following the introduction of some basic knowledge of SLE including the history and epidemiology, this review characterized three key determinants of SLE pathogenesis by their mechanisms-of-action, i.e., over-activated immune response, skewed cytokine microenvironment homeostasis, impaired debris clearance machinery. […] SLE is characteristic of increased presentation of autoantibodies such as ANA, anti-Sm, anti-double-stranded DNA (anti-dsDNA) antibody, antiphospholipid (aPL) antibodies, and anti-2-glycoprotein (a2GPI) antibodies, which even occur years prior to the clinical onset of SLE.

• #20 Cellular and molecular pathogenesis of systemic lupus erythematosus: lessons from animal models | Arthritis Research & Therapy | Full Text

  https://arthritis-research.biomedcentral.com/articles/10.1186/ar3465

  The important role of the complement system and FcR in the process of clearing apoptotic materials has also been recently documented. […] Autoantibodies are major contributors to end organ damage as illustrated by the glomerulonephritis associated with antinuclear and anti-glomerular antibodies, congenital heart block associated with anti-Ro antibody, and thrombosis associated with anti-cardiolipin antibodies. […] This study convincingly showed that B cells may contribute to the development of lupus in ways that are independent of autoantibodies. […] Recent studies have implicated a class of immune system receptors called Toll-like receptors (TLRs) in the synergistic activation of B cells by BCR and TLR signaling. […] The role of neutrophils in murine lupus, unlike that in human lupus, is poorly studied.

• #21 The Pathogenesis, Molecular Mechanisms, and Therapeutic Potential of the Interferon Pathway in Systemic Lupus Erythematosus and Other Autoimmune Diseases

  https://www.mdpi.com/1422-0067/22/20/11286

  The Pathogenesis, Molecular Mechanisms, and Therapeutic Potential of the Interferon Pathway in Systemic Lupus Erythematosus and Other Autoimmune Diseases […] Therapeutic success in treating patients with systemic lupus erythematosus (SLE) is limited by the multivariate disease etiology, multi-organ presentation, systemic involvement, and complex immunopathogenesis. […] Dysregulated type I interferon signaling is detectable in many patients with SLE and other autoimmune diseases, and the extent of this dysregulation is associated with disease severity, making type I interferons therapeutically tangible targets. […] While the transient induction of type I interferon genes in response to viral stimuli is key for host immunity, chronic or dysregulated activation of the type I interferon pathway can contribute to the development of systemic lupus erythematosus (SLE). […] This chronic type I interferon production stimulates the innate and adaptive immune systems in response to a self-derived trigger, enhancing the original stimulus and contributing to the loss of immune tolerance that is characteristic of autoimmunity. […] A build-up of autoimmune complexes can induce systemic and localized inflammation. […] While the cellular source of chronic type I interferon production in SLE and other autoimmune diseases is incompletely understood, the predominant source in SLE is likely the plasmacytoid dendritic cell (pDC). […] Over the past 40 years, progressive research has contributed to our understanding of the role of interferons in the immunopathogenesis of SLE and other autoimmune diseases. […] A role for type I interferons in autoimmunity was first proposed in 1979, when Hooks et al. identified elevated levels of interferon in the serum of patients with SLE, rheumatoid arthritis, systemic sclerosis (SSc), and Sjögren’s syndrome. […] Following initial observations in the 1970s of elevated interferon proteins in patients with autoimmune disease, the next line of evidence for a role of interferons came from observational studies and case reports beginning in 1985. […] While measurement of interferon chemokines and reports of unwanted side effects of IFN-α therapy were fundamental in establishing a role for type I interferons in patients with SLE, there are practical challenges associated with quantifying IFN-α protein, which is often present at very low concentrations. […] Recently, single-cell analyses have been utilized to investigate the cellular source of the elevated type I interferon gene signature detected in serum and tissue of patients with SLE or LN. […] Within the past 13 years, genome-wide association and pathway-centered sequencing studies have identified many polymorphisms in interferon pathway genes that predispose an individual to developing SLE. […] Decades of profiling gene and protein expression have confirmed the molecular heterogeneity of SLE, and recent studies have attempted to contextualize interferon upregulation within broader immune dysregulation. […] A wealth of literature supports an association between the presence/extent of type I interferon signaling dysregulation and lupus disease activity. […] Together, multiple lines of evidence support the fundamental role of interferons in autoimmunity and mediating response to standard therapies and highlight the therapeutic potential of targeting the type I interferon pathway in autoimmune diseases. […] The role of type I interferons in autoimmunity highlights the therapeutic potential of targeting the type I interferon pathway in autoimmune diseases. […] Anifrolumab disrupts the type I interferon auto-amplification loop that can trigger the loss of immune tolerance and autoimmunity, as it blocks type I interferon signaling in pDCs and suppresses the induction of type I interferons following immune complex stimulation. […] The type I interferon pathway plays a major role in the etiology of SLE and many other autoimmune diseases.

• #22 Lupus – Advancing the science behind SLE

  https://www.astrazeneca.com/our-therapy-areas/respiratory-and-immunology/lupus.html

  In people living with SLE, their immune system dysfunctions and inappropriately attacks healthy tissue within the body. SLE disease activity involves B, T and dendritic cells, as well as inflammatory cytokines such as type 1 interferons (IFN-1), IL-6 and B-cell activating factor. Cytokines are molecules that act as immune signallers, regulating processes along immune pathways that coordinate the overall immune response. Normally, these cells come together to act as a defence network that protects us from infection. In SLE, this dysfunction results in the immune system attacking tissues in the body. This can lead to inflammation, and in some cases permanent tissue damage, which can be widespread, affecting the skin, joints, heart, lung kidneys, blood cells and brain. Up to 60-80% of adults with SLE have an elevated IFN-1 gene signature, which can be associated with increased disease severity. […] The biological mechanism behind SLE. Dysregulation in the innate immune system and adaptive immune responses results in chronic autoimmune conditions and disease progression.

• #23 Systemic lupus erythematosus: updated insights on the pathogenesis, diagnosis, prevention and therapeutics | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-025-02168-0

  Type I IFNs are generated in response to, primarily, the activation of nucleic acid-binding pattern recognition receptors such as the endosomal TLR3/4/7/9, the cytosolic sensor cyclic guanosine monophosphate-adenosine monophosphate (cGMP-AMP) synthase (cGAS), and the ribonucleic acid (RNA)-sensor retinoic acid-inducible gene (RIG) I like receptors (RLRs)-mitochondreal antiviral signaling protein (MAVS). […] The pathogenesis of SLE is associated with the failure of removing self-reactive clones of T and B cells. […] The complement system has been implicated in diverse biological processes in mammals including, e.g., modulation of the immune tolerance, and autoimmune diseases. […] The complement cascade is activated to initiate the proteolytic cleavage of complement proteins into fragments that relay signals to neighboring cells and leukocytes by being deposited onto the targets or released into the extracellular fluid.

• #24

  https://link.springer.com/article/10.1186/s43556-024-00217-8

  Additionally, the compromised function of adaptive immunity, such as augmented B cell activity, failure in the clearance of autoreactive B cells, and the overactivation of T cells, can lead to an upsurge in autoantibody production. […] Studies have indicated that elevated levels of type I interferons (IFNs) are detectable in SLE and are associated with the severity of the disease. […] In SLE, pathogenesis is driven by the abnormal activation of both adaptive and innate immune cells. […] This activation leads to an overproduction of autoantibodies by B cells, which then form immune complexes. […] These complexes accumulate in tissues, initiating an inflammatory response. […] The collapse of immune tolerance plays a pivotal role in the development of autoimmune conditions; however, the precise mechanisms driving this breakdown remain to be fully elucidated.

• #25 Lupus – Wikipedia

  https://en.wikipedia.org/wiki/Lupus

  T cells, which regulate B-cell responses and infiltrate target tissues, have defects in signaling, adhesion, co-stimulation, gene transcription, and alternative splicing. […] The cytokines B-lymphocyte stimulator (BLyS), also known as B-cell activating factor (BAFF), interleukin 6, interleukin 17, interleukin 18, type I interferons, and tumor necrosis factor (TNF) are involved in the inflammatory process and are potential therapeutic targets. […] SLE is associated with low C3 levels in the complement system. […] Impaired clearance of dying cells is a potential pathway for the development of this systemic autoimmune disease. […] SLE is associated with defects in apoptotic clearance, and the damaging effects caused by apoptotic debris. […] Autoimmunity possibly results from the extended exposure to nuclear and intracellular autoantigens derived from late apoptotic and secondary necrotic cells.

• #26 Pathogenesis of systemic lupus erythematosus: risks, mechanisms and therapeutic targets | Annals of the Rheumatic Diseases

  https://ard.bmj.com/content/82/8/999

  Research elucidating the pathogenesis of systemic lupus erythematosus (SLE) has defined two critical families of mediators, type I interferon (IFN-I) and autoantibodies targeting nucleic acids and nucleic acid-binding proteins, as fundamental contributors to the disease. […] When innate and adaptive immune system cells are engaged and collaborate in the autoimmune response, clinical SLE can develop. […] The goal of these studies is to understand disease mechanisms, identify therapeutic targets and stimulate development of therapeutics that can achieve improved outcomes for patients. […] The diversity of clinical manifestations and the multiple molecular pathways implicated in patients diagnosed with SLE have raised the possibility that lupus represents many diseases rather than variable presentations of one disease.

• #27 The Pathogenesis of Systemic Lupus Erythematosus – An Update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3508331/

  The combined T and B cell abnormalities in SLE result in production of pathogenic autoantibodies. […] The kidney is a primary site of tissue injury in murine and human lupus. Nephritis results from glomerular deposition of immune complexes of autoantibodies and autoantigens, with engagement of FcRs on immune cells along with complement fixation. […] As autoantibodies are critical for the pathogenesis of SLE and resultant tissue injury, B cell depletion is an attractive therapeutic option in disease. […] The pathogenic mechanisms that lead to the clinical lupus phenotype are becoming clear, with genetic predisposition in the setting of environmental and/or stochastic triggers leading to innate immune system activation associated with pathological T-B cell collaboration and subsequent inflammation and tissue injury.

• #28 Lupus – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/lupus/symptoms-causes/syc-20365789

  Lupus is a disease that occurs when your body’s immune system attacks your own tissues and organs (autoimmune disease). Inflammation caused by lupus can affect many different body systems including your joints, skin, kidneys, blood cells, brain, heart and lungs. […] As an autoimmune disease, lupus occurs when your immune system attacks healthy tissue in your body. It’s likely that lupus results from a combination of your genetics and your environment. […] It appears that people with an inherited predisposition for lupus may develop the disease when they come into contact with something in the environment that can trigger lupus. The cause of lupus in most cases, however, is unknown. Some potential triggers include: […] Lupus can cause serious kidney damage, and kidney failure is one of the leading causes of death among people with lupus.

• #29 Lupus – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/lupus/symptoms-causes/syc-20365789

  If your brain is affected by lupus, you may experience headaches, dizziness, behavior changes, vision problems, and even strokes or seizures. Many people with lupus experience memory problems and may have difficulty expressing their thoughts. […] Lupus may lead to blood problems, including a reduced number of healthy red blood cells (anemia) and an increased risk of bleeding or blood clotting. It can also cause inflammation of the blood vessels. […] Having lupus increases your chances of developing an inflammation of the chest cavity lining, which can make breathing painful. Bleeding into lungs and pneumonia also are possible. […] Lupus can cause inflammation of your heart muscle, your arteries or heart membrane. The risk of cardiovascular disease and heart attacks increases greatly as well. […] Having lupus appears to increase your risk of cancer; however, the risk is small. […] A review of advances in the understanding of lupus nephritis pathogenesis as a basis for emerging therapies.

• #30 The Pathogenesis of Systemic Lupus Erythematosus – An Update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3508331/

  Systemic lupus erythematosus (SLE, lupus) is characterized by a global loss of self-tolerance with activation of autoreactive T and B cells leading to production of pathogenic autoantibodies and tissue injury. […] Aberrant innate immune responses play a significant role in the pathogenesis of SLE, contributing both to tissue injury via release of inflammatory cytokines as well as to aberrant activation of autoreactive T and B cells, with the latter leading to pathogenic autoantibody production and resultant end-organ injury. […] Self-antigen dependent activation of autoreactive B cells and CD4 T cells in secondary lymphoid organs, leads to production of pathogenic autoantibodies that, along with inflammatory cytokines, promotes tissue injury in lupus. […] Genetic predisposition is a requisite for aberrant immune system activation, in the setting of environmental and stochastic events.

• #31

  https://link.springer.com/article/10.1186/s43556-024-00217-8

  A combination of epigenetic changes and genetic susceptibility contributes to the failure of immunological tolerance, leading to autoimmunity. […] The origins and mechanisms behind autoimmune diseases are exceedingly intricate. […] The genetic predisposition to lupus in humans is firmly established, as evidenced by the markedly higher disease concordance rates among monozygotic twins compared to dizygotic twins. […] The major histocompatibility complex (MHC) genes, as well as components of the complement system such as C2 and C4, and tumor necrosis factor (TNF) genes, are located on chromosome 6. […] Polymorphisms within these genes have been shown to confer susceptibility to SLE. […] In SLE, the buildup of immune complexes and autoantibodies can trigger inflammation and damage in specific organs. […] The pathogenesis of SLE is complex and involves immune dysregulation, genetic predisposition, environmental factors and immune complexes and tissue injury.

• #32

  https://link.springer.com/article/10.1186/s43556-024-00217-8

  A combination of epigenetic changes and genetic susceptibility contributes to the failure of immunological tolerance, leading to autoimmunity. […] The origins and mechanisms behind autoimmune diseases are exceedingly intricate. […] The genetic predisposition to lupus in humans is firmly established, as evidenced by the markedly higher disease concordance rates among monozygotic twins compared to dizygotic twins. […] The major histocompatibility complex (MHC) genes, as well as components of the complement system such as C2 and C4, and tumor necrosis factor (TNF) genes, are located on chromosome 6. […] Polymorphisms within these genes have been shown to confer susceptibility to SLE. […] In SLE, the buildup of immune complexes and autoantibodies can trigger inflammation and damage in specific organs. […] The pathogenesis of SLE is complex and involves immune dysregulation, genetic predisposition, environmental factors and immune complexes and tissue injury.

• #33 Pathogenesis of systemic lupus erythematosus: risks, mechanisms and therapeutic targets | Annals of the Rheumatic Diseases

  https://ard.bmj.com/content/82/8/999

  A broad view of the pathogenesis of SLE. As SLE is an immune-mediated disease, research and identification of therapeutic targets have focused on elucidation of the relevant immune cells and mediators and the alterations in immune function that contribute to autoimmunity and inflammation in SLE. […] The complement locus, in the MHC class III region, is of particular interest in view of the important role of the classical pathway in clearing potentially pathogenic immune complexes. […] Recent detailed analyses of the MHC in patients with SLE and healthy subjects provide important insights regarding mechanisms of immune dysfunction in those bearing risk alleles. […] The identified human leucocyte antigen (HLA) risk haplotype is HLA-DRB1*03:01HLA-DQA1*05:01HLA-DQB1*02:01 (DR3) in those of EA descent and HLA-DRB1*15:03HLA-DQA1*01:02HLA-DQB1*06:02 (DR2) in the AAs, similar to observations in other studies.

• #34 Pathogenesis of systemic lupus erythematosus: risks, mechanisms and therapeutic targets | Annals of the Rheumatic Diseases

  https://ard.bmj.com/content/82/8/999

  While genetic risk and microbial or other environmental factors establish fertile ground for development of SLE, specific drivers of immune system activation are required to initiate production of IFN-I and self-antigen-specific autoantibodies. […] It is possible that either IFN-I pathway activation or development of lupus autoantibodies may serve as an initial event, likely influenced by the specific genetic risk factors at play. […] Among women with anti-Ro and/or anti-La autoantibodies, those with clinical manifestations of SLE or SS were significantly more likely to have increased serum levels of IFN-I, highlighting some common mechanisms between the two systemic autoimmune diseases. […] Neutrophils, particularly low-density granulocytes, and neutrophil products, including neutrophil extracellular traps (NETs), remain a potential source of stimulatory nucleic acid and innate immune system activation. […] The specific targets of the autoimmune response in SLE include intracellular and intranuclear particles that include nucleic acid and nucleic acid-binding proteins.

• #35 Pathogenesis of systemic lupus erythematosus: risks, mechanisms and therapeutic targets | Annals of the Rheumatic Diseases

  https://ard.bmj.com/content/82/8/999

  While genetic risk and microbial or other environmental factors establish fertile ground for development of SLE, specific drivers of immune system activation are required to initiate production of IFN-I and self-antigen-specific autoantibodies. […] It is possible that either IFN-I pathway activation or development of lupus autoantibodies may serve as an initial event, likely influenced by the specific genetic risk factors at play. […] Among women with anti-Ro and/or anti-La autoantibodies, those with clinical manifestations of SLE or SS were significantly more likely to have increased serum levels of IFN-I, highlighting some common mechanisms between the two systemic autoimmune diseases. […] Neutrophils, particularly low-density granulocytes, and neutrophil products, including neutrophil extracellular traps (NETs), remain a potential source of stimulatory nucleic acid and innate immune system activation. […] The specific targets of the autoimmune response in SLE include intracellular and intranuclear particles that include nucleic acid and nucleic acid-binding proteins.

• #36 Lupus – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/lupus/symptoms-causes/syc-20365789

  Lupus is a disease that occurs when your body’s immune system attacks your own tissues and organs (autoimmune disease). Inflammation caused by lupus can affect many different body systems including your joints, skin, kidneys, blood cells, brain, heart and lungs. […] As an autoimmune disease, lupus occurs when your immune system attacks healthy tissue in your body. It’s likely that lupus results from a combination of your genetics and your environment. […] It appears that people with an inherited predisposition for lupus may develop the disease when they come into contact with something in the environment that can trigger lupus. The cause of lupus in most cases, however, is unknown. Some potential triggers include: […] Lupus can cause serious kidney damage, and kidney failure is one of the leading causes of death among people with lupus.

• #37 Systemic Lupus Erythematosus – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK535405/

  Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multisystem involvement and is associated with significant morbidity and mortality. Genetic, immunological, endocrine, 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. […] Despite recent advances in technology and understanding of the pathological basis and risk factors for SLE, the exact pathogenesis is still not well known. […] The pathogenesis of SLE is complex, and the understanding of SLE pathogenesis is constantly evolving. A break in the tolerance in genetically susceptible individuals on exposure to environmental factors leads to the activation of autoimmunity. Cell damage caused by infectious and other environmental factors exposes the immune system to self-antigens leading to activation of T and B cells, which become self-sustained by a chronic self-aimed immune response. Cytokine release, complement activation, and autoantibody production lead to organ damage.

• #38 Pathogenesis of systemic lupus erythematosus: risks, mechanisms and therapeutic targets | Annals of the Rheumatic Diseases

  https://ard.bmj.com/content/82/8/999

  While genetic risk and microbial or other environmental factors establish fertile ground for development of SLE, specific drivers of immune system activation are required to initiate production of IFN-I and self-antigen-specific autoantibodies. […] It is possible that either IFN-I pathway activation or development of lupus autoantibodies may serve as an initial event, likely influenced by the specific genetic risk factors at play. […] Among women with anti-Ro and/or anti-La autoantibodies, those with clinical manifestations of SLE or SS were significantly more likely to have increased serum levels of IFN-I, highlighting some common mechanisms between the two systemic autoimmune diseases. […] Neutrophils, particularly low-density granulocytes, and neutrophil products, including neutrophil extracellular traps (NETs), remain a potential source of stimulatory nucleic acid and innate immune system activation. […] The specific targets of the autoimmune response in SLE include intracellular and intranuclear particles that include nucleic acid and nucleic acid-binding proteins.

• #39 Systemic Lupus Erythematosus Pathogenesis | Encyclopedia MDPI

  https://encyclopedia.pub/entry/42764

  It has been observed that in SLE, the neutrophil function is abnormal at several levels. First, neutrophils show reduced phagocytic capacity and the inability to remove apoptotic cells, which are a known source of normally hidden self-antigens. […] Lymphoid-origin plasmacytoid dendritic cells (pDCs) are characterized by the ability to produce high levels of type-I IFN, thus playing a key role in the pathogenesis of SLE. […] Mitochondria are organelles that provide the energy necessary for cell metabolism and survival, being the major source of adenosine triphosphate (ATP) synthesis. These ancestral structures can release high quantities of mitochondrial DNA (mtDNA) after destruction, following cell apoptosis. […] A deficiency of nucleases is responsible for lupus-like manifestations in mouse models. […] A recent finding on the pathogenesis of SLE that opened new lines of research for innovative drug development, was the recognition of a high type-I IFN signature in SLE patients.

• #40 A surprise mechanism uncovered in the development of lupus | Yale News

  https://news.yale.edu/2012/10/24/surprise-mechanism-uncovered-development-lupus

  In a study with a surprising outcome, scientists at Yale School of Medicine have discovered that an enzyme complex known for promoting natural resistance to bacteria and fungi unexpectedly inhibits the development of lupus. […] The Yale researchers focused on a key enzyme complex in this process known as NADPH oxidase, or Nox2, and evaluated its role in lupus pathogenesis. […] Contrary to expectations, the Nox2-deficient mice whose neutrophils failed to generate NETs not only still got lupus, but got a much worse form of the disease. Surprised by the finding, researchers realized that normal function of Nox2 inhibits the development of lupus, rather than promoting it. […] We now plan to explore the mechanism by which NADPH oxidase is exerting its effects. Doing so should provide additional insights into the cause of this disease. […] We suspect that without NADPH oxidase, neutrophils may die in a way that inflames the immune system, Shlomchik explains. This may help us develop therapies that promote NADPH oxidase function and thereby suppress disease.

• #41 Systemic Lupus Erythematosus Pathogenesis: Interferon and Beyond. | Gale and Ira Drukier Institute for Children’s Health

  https://drukierinstitute.weill.cornell.edu/publications/systemic-lupus-erythematosus-pathogenesis-interferon-and-beyond

  Autoreactive B cells and interferons are central players in systemic lupus erythematosus (SLE) pathogenesis. […] The partial success of drugs targeting these pathways, however, supports heterogeneity in upstream mechanisms contributing to disease pathogenesis. […] Among them, novel mutations in genes affecting intrinsic B cell activation or clearance of interferogenic nucleic acids have been described. […] Mitochondria have emerged as relevant inducers and/or amplifiers of SLE pathogenesis through a variety of mechanisms that include disruption of organelle integrity or compartmentalization, defective metabolism, and failure of quality control measures. […] These result in extra- or intracellular release of interferogenic nucleic acids as well as in innate and/or adaptive immune cell activation.

• #42 Systemic Lupus Erythematosus Pathogenesis | Encyclopedia MDPI

  https://encyclopedia.pub/entry/42764

  It has been observed that in SLE, the neutrophil function is abnormal at several levels. First, neutrophils show reduced phagocytic capacity and the inability to remove apoptotic cells, which are a known source of normally hidden self-antigens. […] Lymphoid-origin plasmacytoid dendritic cells (pDCs) are characterized by the ability to produce high levels of type-I IFN, thus playing a key role in the pathogenesis of SLE. […] Mitochondria are organelles that provide the energy necessary for cell metabolism and survival, being the major source of adenosine triphosphate (ATP) synthesis. These ancestral structures can release high quantities of mitochondrial DNA (mtDNA) after destruction, following cell apoptosis. […] A deficiency of nucleases is responsible for lupus-like manifestations in mouse models. […] A recent finding on the pathogenesis of SLE that opened new lines of research for innovative drug development, was the recognition of a high type-I IFN signature in SLE patients.

• #43 Mechanism of lupus pathogenesis unveiled | ScienceDaily

  https://www.sciencedaily.com/releases/2024/07/240701232818.htm

  A research team of Professor Yoontae Lee and Jiho Park, a PhD candidate, from the Department of Life Sciences at Pohang University of Science and Technology (POSTECH) recently discovered that a particular protein promotes the development of systemic lupus erythematosus (SLE). […] Previous research by Professor Yoontae Lee’s team suggested that ETV5, a specific transcription factor expressed in T cells, promotes the differentiation of T cells into TFH cells, potentially leading to SLE. […] As a result, autoimmune symptoms such as autoantibody concentrations, immune cell infiltration into body tissues, and renal glomerulonephritis, and the development of TFH cells were reduced in the ETV5-deficient SLE mouse model. The team discovered that ETV5 enhances the expression of its target protein, osteopontin (OPN) which in turn activates the AKT protein, leading to the differentiation into TFH cells.

• #44 Mechanism of lupus pathogenesis unveiled | ScienceDaily

  https://www.sciencedaily.com/releases/2024/07/240701232818.htm

  The researchers further confirmed that in human T cells, the differentiation into TFH cells is also regulated by the levels of ETV5 and OPN expression. Aligning with the findings from the animal models, ETV5 and OPN were expressed at higher levels in SLE patient models compared to the general population. Additionally, disease activity and blood autoantibody concentrations were generally proportional to the levels of ETV5 and OPN expression. […] Professor Yoontae Lee, who led the study, expressed his aspiration by saying, „We have identified a mechanism of SLE pathogenesis involving ETV5 and OPN in real-world experiments.”

• #45 LRRK2 is involved in the pathogenesis of system lupus erythematosus through promoting pathogenic antibody production | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-019-1786-6

  Our study demonstrates that LRRK2 expression is upregulated in B cells from SLE patients with strong correlations to disease severity. LRRK2 deficiency largely attenuates the pathogenic progress of lupus-like features in pristane-induced mice. This is probably achieved through affecting B cell terminal differentiation and subsequent immunoglobulin production. […] In this study, we found that LRRK2 expression was dramatically increased in B cells from SLE patients compared to that from healthy controls (HCs). Of note, LRRK2 expression in B cells was positively correlated with disease severity and the levels of serum IgG in SLE patients. Furthermore, we demonstrated that LRRK2 promoted B cell terminal differentiation, humoral immune response and consequently lupus-like syndrome in a pristane-induced mouse model, thus implicating LRRK2 as a novel target in SLE therapy.

• #46 What’s New in SLE: Pathogenesis & Novel Therapies – The Rheumatologist

  https://www.the-rheumatologist.org/article/whats-new-in-sle-pathogenesis-novel-therapies/

  In SLE, a positive feed-forward loop of adaptive and innate immune activation is comprised of two main signatures: the type I interferon (IFN) signature and the B cell/plasma cell/BLyS signature. […] The important point to take away here is that in about half of the patients with SLE who have anti-IFN antibodies, those antibodies are neutralizing and down-modulate the IFN signature, Dr. Drner said. […] Dr. Drner highlighted several potential new therapeutic targets in SLE. Antibodies directed against blood dendritic cell antigen 2 (BDCA2), a unique plasmacytoid dendritic cell (pDC)-specific receptor, inhibits but doesn’t deplete pDCs. It also reduces the production of type I IFN and other inflammatory mediators. […] Iberdomide shifts the transcriptional program. It reduces B-cell activation and autoantibody production, targets pDCs and reduces the type I IFN signature.

• #47 What’s New in SLE: Pathogenesis & Novel Therapies – The Rheumatologist

  https://www.the-rheumatologist.org/article/whats-new-in-sle-pathogenesis-novel-therapies/

  In SLE, a positive feed-forward loop of adaptive and innate immune activation is comprised of two main signatures: the type I interferon (IFN) signature and the B cell/plasma cell/BLyS signature. […] The important point to take away here is that in about half of the patients with SLE who have anti-IFN antibodies, those antibodies are neutralizing and down-modulate the IFN signature, Dr. Drner said. […] Dr. Drner highlighted several potential new therapeutic targets in SLE. Antibodies directed against blood dendritic cell antigen 2 (BDCA2), a unique plasmacytoid dendritic cell (pDC)-specific receptor, inhibits but doesn’t deplete pDCs. It also reduces the production of type I IFN and other inflammatory mediators. […] Iberdomide shifts the transcriptional program. It reduces B-cell activation and autoantibody production, targets pDCs and reduces the type I IFN signature.

• #48 The Pathogenesis, Molecular Mechanisms, and Therapeutic Potential of the Interferon Pathway in Systemic Lupus Erythematosus and Other Autoimmune Diseases

  https://www.mdpi.com/1422-0067/22/20/11286

  The Pathogenesis, Molecular Mechanisms, and Therapeutic Potential of the Interferon Pathway in Systemic Lupus Erythematosus and Other Autoimmune Diseases […] Therapeutic success in treating patients with systemic lupus erythematosus (SLE) is limited by the multivariate disease etiology, multi-organ presentation, systemic involvement, and complex immunopathogenesis. […] Dysregulated type I interferon signaling is detectable in many patients with SLE and other autoimmune diseases, and the extent of this dysregulation is associated with disease severity, making type I interferons therapeutically tangible targets. […] While the transient induction of type I interferon genes in response to viral stimuli is key for host immunity, chronic or dysregulated activation of the type I interferon pathway can contribute to the development of systemic lupus erythematosus (SLE). […] This chronic type I interferon production stimulates the innate and adaptive immune systems in response to a self-derived trigger, enhancing the original stimulus and contributing to the loss of immune tolerance that is characteristic of autoimmunity. […] A build-up of autoimmune complexes can induce systemic and localized inflammation. […] While the cellular source of chronic type I interferon production in SLE and other autoimmune diseases is incompletely understood, the predominant source in SLE is likely the plasmacytoid dendritic cell (pDC). […] Over the past 40 years, progressive research has contributed to our understanding of the role of interferons in the immunopathogenesis of SLE and other autoimmune diseases. […] A role for type I interferons in autoimmunity was first proposed in 1979, when Hooks et al. identified elevated levels of interferon in the serum of patients with SLE, rheumatoid arthritis, systemic sclerosis (SSc), and Sjögren’s syndrome. […] Following initial observations in the 1970s of elevated interferon proteins in patients with autoimmune disease, the next line of evidence for a role of interferons came from observational studies and case reports beginning in 1985. […] While measurement of interferon chemokines and reports of unwanted side effects of IFN-α therapy were fundamental in establishing a role for type I interferons in patients with SLE, there are practical challenges associated with quantifying IFN-α protein, which is often present at very low concentrations. […] Recently, single-cell analyses have been utilized to investigate the cellular source of the elevated type I interferon gene signature detected in serum and tissue of patients with SLE or LN. […] Within the past 13 years, genome-wide association and pathway-centered sequencing studies have identified many polymorphisms in interferon pathway genes that predispose an individual to developing SLE. […] Decades of profiling gene and protein expression have confirmed the molecular heterogeneity of SLE, and recent studies have attempted to contextualize interferon upregulation within broader immune dysregulation. […] A wealth of literature supports an association between the presence/extent of type I interferon signaling dysregulation and lupus disease activity. […] Together, multiple lines of evidence support the fundamental role of interferons in autoimmunity and mediating response to standard therapies and highlight the therapeutic potential of targeting the type I interferon pathway in autoimmune diseases. […] The role of type I interferons in autoimmunity highlights the therapeutic potential of targeting the type I interferon pathway in autoimmune diseases. […] Anifrolumab disrupts the type I interferon auto-amplification loop that can trigger the loss of immune tolerance and autoimmunity, as it blocks type I interferon signaling in pDCs and suppresses the induction of type I interferons following immune complex stimulation. […] The type I interferon pathway plays a major role in the etiology of SLE and many other autoimmune diseases.

• #49 The Pathogenesis of Systemic Lupus Erythematosus – An Update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3508331/

  The combined T and B cell abnormalities in SLE result in production of pathogenic autoantibodies. […] The kidney is a primary site of tissue injury in murine and human lupus. Nephritis results from glomerular deposition of immune complexes of autoantibodies and autoantigens, with engagement of FcRs on immune cells along with complement fixation. […] As autoantibodies are critical for the pathogenesis of SLE and resultant tissue injury, B cell depletion is an attractive therapeutic option in disease. […] The pathogenic mechanisms that lead to the clinical lupus phenotype are becoming clear, with genetic predisposition in the setting of environmental and/or stochastic triggers leading to innate immune system activation associated with pathological T-B cell collaboration and subsequent inflammation and tissue injury.

• #50 Lupus Mechanism of Action | BENLYSTA (belimumab) for HCPs

  https://www.benlystahcp.com/lupus/mechanism-of-action/

  BENLYSTA is the only FDA-approved treatment designed to target BLyS/BAFF, an underlying cause of lupus and lupus nephritis. […] BENLYSTA (belimumab) is designed for lupus. BENLYSTA is the only biologic with a mechanism of action that selectively targets the B-lymphocyte stimulator protein, or BLyS, a known underlying cause of systemic lupus erythematosus, or SLE, with or without lupus nephritis. […] BENLYSTA selectively blocks the binding of soluble BLyS to its receptor on B cells. […] Although it does not bind to B cells directly, BENLYSTA inhibits the survival of autoreactive B cells and reduces the differentiation of B cells into immunoglobulin-producing plasma cells. […] In patients with lupus who were positive for anti-double-stranded DNA, treatment with BENLYSTA resulted in a 41% reduction in anti-double-stranded DNA antibody levels over 52 weeks.

• #51 Lupus Mechanism of Action | BENLYSTA (belimumab) for HCPs

  https://www.benlystahcp.com/lupus/mechanism-of-action/

  BENLYSTA is the only FDA-approved treatment designed to target BLyS/BAFF, an underlying cause of lupus and lupus nephritis. […] BENLYSTA (belimumab) is designed for lupus. BENLYSTA is the only biologic with a mechanism of action that selectively targets the B-lymphocyte stimulator protein, or BLyS, a known underlying cause of systemic lupus erythematosus, or SLE, with or without lupus nephritis. […] BENLYSTA selectively blocks the binding of soluble BLyS to its receptor on B cells. […] Although it does not bind to B cells directly, BENLYSTA inhibits the survival of autoreactive B cells and reduces the differentiation of B cells into immunoglobulin-producing plasma cells. […] In patients with lupus who were positive for anti-double-stranded DNA, treatment with BENLYSTA resulted in a 41% reduction in anti-double-stranded DNA antibody levels over 52 weeks.

• #52 Lupus Mechanism of Action | BENLYSTA (belimumab) for HCPs

  https://www.benlystahcp.com/lupus/mechanism-of-action/

  In patients with lupus nephritis, treatment with BENLYSTA led to a decrease in serum IgG as early as Week 4, and, subsequently, there was an increase in serum IgG levels, which was associated with decreased proteinuria. […] BLyS/BAFF is elevated in patients with lupus. […] BLyS/BAFF levels correlate with lupus disease activity and anti-dsDNA titers in many patients. […] At Week 52, adult patients with lupus on BENLYSTA showed reductions in IgG and anti-dsDNA antibodies. […] Adult patients with lupus on BENLYSTA experienced a 41% reduction in anti-dsDNA levels over 52 weeks. […] At Week 52, adult patients with lupus on BENLYSTA had significant reductions in B-cell subsets. […] BENLYSTA reduced autoantibodies and normalized low complement levels.

• #53 Immunosupressors in lupus nephritis | IJNRD

  https://www.dovepress.com/mechanism-of-action-and-efficacy-of-immunosupressors-in-lupus-nephriti-peer-reviewed-fulltext-article-IJNRD

  Approximately 70% of the patients with systemic lupus erythematosus will have clinical evidence of kidney damage during their evolution. […] Understanding the mechanism of action of immunosuppressants is essential for proper prescription. Steroids inhibit the DNA sequence that promotes the release of inflammatory cytokines. Phosphoramide mustard, metabolite of cyclophosphamide, cross-link with the DNA, causing the aggregation of an alkyl group, causing cell death. Mycophenolate inhibits inosine monophosphate dehydrogenase, prevents de novo synthesis of guanine, inducing cell arrest in S phase. Azathioprine blocks the synthesis of purines and induces apoptosis. Calcineurin inhibitors prevent the dephosphorylation of NFAT and reduce the production of interleukin 2. The mechanism of action of rituximab is related to complement-dependent cytotoxicity and the elimination of anti-CD20-labeled B cells.

• #54 Immunosupressors in lupus nephritis | IJNRD

  https://www.dovepress.com/mechanism-of-action-and-efficacy-of-immunosupressors-in-lupus-nephriti-peer-reviewed-fulltext-article-IJNRD

  In the following review, we aimed to briefly describe the mechanisms of action and the current usefulness of immunosuppressive therapies in proliferative LN. […] The cumulative dose, oral or intravenous, appears to determine the initial response to CYC treatment, although there may be increased toxicity with the enteral route. […] Mycophenolate mofetil (MMF), a fermentation product of Penicillium brevicompactum and related fungi, has an inhibitory effect on the nucleic acids synthesis, an effect known more than 50 years ago. It is a selective, reversible and non-competitive inhibitor of inosine monophosphate dehydrogenase (IMPDH), especially type II isoform which is expressed in activated B and T lymphocytes, limiting the de novo synthesis of guanine, preventing its incorporation into DNA, inducing cell arrest in phase S.

• #55 Immunosupressors in lupus nephritis | IJNRD

  https://www.dovepress.com/mechanism-of-action-and-efficacy-of-immunosupressors-in-lupus-nephriti-peer-reviewed-fulltext-article-IJNRD

  The dual utility of MMF in induction and maintenance therapy may be associated with down-regulation of plasmablasts and plasma cells, with reduced production of immunoglobulins M, A, G and light chains, predominant in the first weeks of initiating therapy, reflecting the modulation of the immune response on short and long-term; those cellular effects were not detected with CYC. […] Azathioprine, synthesized in 1957, is an imidazole derivative, a prodrug metabolized by a non-enzymatic process to mercaptopurine and via glutathione transferase to 6-thioinosinic acid. […] The advantage of this drug is its low cost, good tolerability and it is the recommended drug during pregnancy. […] Although cyclosporine A (CsA) and tacrolimus (TAC) differ in their molecular structure and intracellular binding characteristics, their immunosuppressive properties result from the inhibition of calcium-calmodulin-calcineurin interaction.

• #56 Immunosupressors in lupus nephritis | IJNRD

  https://www.dovepress.com/mechanism-of-action-and-efficacy-of-immunosupressors-in-lupus-nephriti-peer-reviewed-fulltext-article-IJNRD

  The efficacy of this drug has been corroborated in other studies, most in Asia. […] Voclosporin is a new generation calcineurin inhibitor, with a structure derived from cyclosporin A, its stereoisomer Z-ISA247 binds to cyclophilin A. […] The use of voclosporin in lupus nephritis was carried out in the AURA-LV trial, a multicenter, double-blind, placebo-controlled study to evaluate the usefulness of voclosporin plus the standard of care, MMF, or corticosteroids. […] Lupus nephritis remains one of the most serious complications of systemic lupus erythematosus, and its early detection is essential to provide the best available treatment. Currently, there are several management alternatives, both in the remission induction phase and in the maintenance phase. Mycophenolate mofetil remains the mainstay of treatment, but cyclophosphamide is a less expensive option and perhaps more effective in severe kidney injury.

• #57 Pathogenesis of systemic lupus erythematosus: risks, mechanisms and therapeutic targets | Annals of the Rheumatic Diseases

  https://ard.bmj.com/content/82/8/999

  Specific SNPs have pointed to molecular pathways, mechanisms and therapeutic targets that underlie disease pathogenesis. […] The current view of SLE risk favours common risk variants accounting for most of its heritability; however, rare mutations can have sufficiently severe impact to cause SLE. […] The mechanisms impacted by complement deficiency may be multiple, with impaired removal of cell debris, apoptotic material or nucleic acid-containing immune complexes most important and contributing to augmented activation of endosomal TLRs and production of IFN-I. […] Identification of genomic loci and mutations associated with a diagnosis of SLE point to mechanisms central to lupus pathogenesis. […] In addition, insights regarding allele-related differences with broad impact on immune system activation, particularly those encoded in the MHC, may suggest novel approaches to identifying those at risk of SLE as well as productive approaches to therapy.

• #58 Functional Genomics of Tfh Cell Metabolism and Lupus Pathogenesis – Lupus Research Alliance

  https://www.lupusresearch.org/for-researchers/funded-research/grant/functional-genomics-of-tfh-cell-metabolism-and-lupus-pathogenesis/

  Lupus is a systemic autoimmune disorder driven by overactive immune cells. An increase in the number of follicular helper T cells (Tfh) one of the immune cell types is associated with lupus disease activity, but how the Tfh cell increase leads to lupus progression has remained unclear. […] Dr. Chi plans to use his Distinguished Innovator Award to investigate if unique metabolic features of Tfh cells are linked to and dictate their destructive behavior in lupus. Dr. Chi will also identify presently unknown factors that are involved in Tfh cell metabolism and function, which make these cells contribute to the disease activity of lupus. […] Emerging studies highlight the central roles of metabolic reprogramming in coordinating effector T cell fate decisions including Tfh cells. […] The goal of our program is to investigate the interface between metabolism and immunity, and how studying immunometabolism reveals new biology and disease targets for lupus.

• #59 Significance and impact of dietary factors on systemic lupus erythematosus pathogenesis (Review)

  https://www.spandidos-publications.com/10.3892/etm.2018.6986

  Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology, although its mechanisms involve genetic, epigenetic and environmental risk factors. […] Considering that SLE pathogenesis is yet to be explored, recent studies aimed to investigate the impact of diet on the disease, in terms of triggering or altering the course of SLE (1,2). […] The outstanding role that food plays is sustained not only by its nutritional value, but also by its capacity to modify the structure and function of the gut microbiota. […] An adequate diet is also important to help fight the associated comorbidities in SLE which increase the cardiovascular risk: diabetes mellitus, metabolic syndrome, dyslipidemia and obesity (6). […] At the moment, information regarding the impact of diet on autoimmune diseases is yet insufficient. However, caloric restriction was proven to induce various benefits to the immune system, since this restriction also leads to changes in the gut microbiota (5).

• #60 Cellular and molecular pathogenesis of systemic lupus erythematosus: lessons from animal models | Arthritis Research & Therapy | Full Text

  https://arthritis-research.biomedcentral.com/articles/10.1186/ar3465

  Studies in mouse models have been pivotal in determining the role that dendritic cells (DCs) play in the pathogenesis of lupus. […] Immune complexes (ICs) purified from sera of patients with SLE were found to stimulate plasmacytoid DCs (pDCs) to produce IFN-. […] Together, these reciprocal events lead to a pathogenic cycle, in which both the innate and adaptive immune systems cooperate and feedback upon each other, eventually leading to high titers of autoantibodies. […] The challenge ahead is to better define the cellular and molecular players orchestrating lupus and to translate our improved understanding of lupus pathogenesis into better rationalized therapeutics targeting selected cells or molecules (or both) that facilitate lupus.

• #61 Systemic lupus erythematosus: Epidemiology and pathogenesis – UpToDate

  https://www.uptodate.com/contents/systemic-lupus-erythematosus-epidemiology-and-pathogenesis

  Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease that can have a wide array of disease manifestations, including constitutional symptoms, rashes, arthritis, hematologic abnormalities, and nephritis. […] While the underlying disease pathogenesis is incompletely understood, it involves the development of one or more autoantibodies with the subsequent production of immune complexes and may be related to a variety of genetic, hormonal, and environmental factors. […] As researchers learn more about the various abnormalities in genetic and biologic pathways that cause SLE, it is possible that specific disease variants or subtypes may emerge.

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