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Immunobiology Sep 2023The complement system is an essential component of the innate immune response and plays a vital role in host defense and inflammation. Dysregulation of the complement...
The complement system is an essential component of the innate immune response and plays a vital role in host defense and inflammation. Dysregulation of the complement system, particularly involving the anaphylatoxin C5a and its receptors (C5aR1 and C5aR2), has been linked to several autoimmune diseases, indicating the potential for targeted therapies. C5aR1 and C5aR2 are seven-transmembrane receptors with distinct signaling mechanisms that play both partially overlapping and opposing roles in immunity. Both receptors are expressed on a broad spectrum of immune and non-immune cells and are involved in cellular functions and physiological processes during homeostasis and inflammation. Dysregulated C5a-mediated inflammation contributes to autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, epidermolysis bullosa acquisita, antiphospholipid syndrome, and others. Therefore, targeting C5a or its receptors may yield therapeutic innovations in these autoimmune diseases by reducing the recruitment and activation of immune cells that lead to tissue inflammation and injury, thereby exacerbating the autoimmune response. Clinical trials focused on the inhibition of C5 cleavage or the C5a/C5aR1-axis using small molecules or monoclonal antibodies hold promise for bringing novel treatments for autoimmune diseases into practice. However, given the heterogeneous nature of (systemic) autoimmune diseases, there are still several challenges, such as patient selection, optimal dosing, and treatment duration, that require further investigation and development to realize the full therapeutic potential of C5a receptor inhibition, ideally in the context of a personalized medicine approach. Here, we aim to provide a brief overview of the current knowledge on the function of C5a receptors, the involvement of C5a receptors in autoimmune disorders, the molecular mechanisms underlying C5a receptor-mediated autoimmunity, and the potential for targeted therapies to modulate their activity.
Topics: Humans; Autoimmunity; Receptor, Anaphylatoxin C5a; Autoimmune Diseases; Arthritis, Rheumatoid; Inflammation
PubMed: 37598588
DOI: 10.1016/j.imbio.2023.152413 -
Autoimmunity Reviews Dec 2020Autoimmune rheumatic diseases (ARDs) are chronic conditions with a striking female predominance, frequently affecting women of childbearing age. Sex hormones and gender... (Review)
Review
Autoimmune rheumatic diseases (ARDs) are chronic conditions with a striking female predominance, frequently affecting women of childbearing age. Sex hormones and gender dimorphism of immune response are major determinants in the multifactorial pathogenesis of ARDs, with significant implications throughout reproductive life. Particularly, pregnancy represents a challenging condition in the context of autoimmunity, baring profound hormonal and immunologic changes, which are responsible for the bi-directional interaction between ARDs outcome and pregnancy course. In the latest years epigenetics has proven to be an important player in ARDs pathogenesis, finely modulating major immune functions and variably tuning the significant gender effects in autoimmunity. Additionally, epigenetics is a recognised influencer of the physiological dynamic modifications occurring during pregnancy. Still, there is currently little evidence on the pregnancy-related epigenetic modulation of immune response in ARDs patients. This review aims to overview the current knowledge of the role of epigenetics in the context of autoimmunity, as well as during physiologic and pathologic pregnancy, discussing under-regarded aspects in the interplay between ARDs and pregnancy pathology. The outline of a new ongoing European project will be presented.
Topics: Autoimmune Diseases; Autoimmunity; Epigenesis, Genetic; Epigenomics; Female; Humans; Pregnancy; Pregnancy Complications; Rheumatic Diseases
PubMed: 33115633
DOI: 10.1016/j.autrev.2020.102685 -
Cell Research Feb 2023Autoimmunity and autoinflammation arise from aberrant immunological and inflammatory responses toward self-components, contributing to various autoimmune diseases and... (Review)
Review
Autoimmunity and autoinflammation arise from aberrant immunological and inflammatory responses toward self-components, contributing to various autoimmune diseases and autoinflammatory diseases. RNA-binding proteins (RBPs) are essential for immune cell development and function, mainly via exerting post-transcriptional regulation of RNA metabolism and function. Functional dysregulation of RBPs and abnormities in RNA metabolism are closely associated with multiple autoimmune or autoinflammatory disorders. Distinct RBPs play critical roles in aberrant autoreactive inflammatory responses via orchestrating a complex regulatory network consisting of DNAs, RNAs and proteins within immune cells. In-depth characterizations of RBP-RNA interactomes during autoimmunity and autoinflammation will lead to a better understanding of autoimmune pathogenesis and facilitate the development of effective therapeutic strategies. In this review, we summarize and discuss the functions of RBP-RNA interactions in controlling aberrant autoimmune inflammation and their potential as biomarkers and therapeutic targets.
Topics: Humans; Autoimmunity; RNA; Autoimmune Diseases; Gene Expression Regulation; Inflammation
PubMed: 36599968
DOI: 10.1038/s41422-022-00752-5 -
Autophagy Feb 2021IRGM is a genetic risk factor for several autoimmune diseases. However, the mechanism of IRGM-mediated protection in autoimmunity remains undetermined. The abnormal... (Review)
Review
IRGM is a genetic risk factor for several autoimmune diseases. However, the mechanism of IRGM-mediated protection in autoimmunity remains undetermined. The abnormal activation of type I interferon (IFN) response is one of the significant factors in the pathogenesis of several autoimmune diseases. In our recent study, we showed that IRGM is a master suppressor of the interferon response. We found that the depletion of IRGM results in constitutively activated CGAS-STING1, DDX58/RIG-I-MAVS, and TLR3-TICAM1/TRIF signaling pathways resulting in upregulation of almost all IFN-responsive genes. Mechanistically, IRGM utilizes a two-pronged mechanism to suppress the interferon response. First, it mediates SQSTM1/p62-dependent selective macroautophagy/autophagy of nucleic acid sensor proteins, including CGAS, DDX58/RIG-I, and TLR3. Second, it facilitates the removal of defective mitochondria by mitophagy and avoids a buildup of mito-ROS and mito-damage/danger-associated molecular patterns (DAMPs). Thus, IRGM deficiency results in increased nucleic acid sensors and DAMPs engaging a vicious cycle of aberrant activation of IFN response that is known to occur in systemic autoimmune-like conditions.
Topics: Autoimmune Diseases; Autoimmunity; Autophagy; GTP-Binding Proteins; Humans; Mitochondria; Signal Transduction
PubMed: 32813580
DOI: 10.1080/15548627.2020.1810920 -
Journal of Autoimmunity May 2023Immune aging is a complex process rendering the host susceptible to cancer, infection, and insufficient tissue repair. Many autoimmune diseases preferentially occur... (Review)
Review
Immune aging is a complex process rendering the host susceptible to cancer, infection, and insufficient tissue repair. Many autoimmune diseases preferentially occur during the second half of life, counterintuitive to the concept of excess adaptive immunity driving immune-mediated tissue damage. T cells are particularly susceptible to aging-imposed changes, as they are under extreme proliferative pressure to fulfill the demands of clonal expansion and of homeostatic T cell repopulation. T cells in older adults have a footprint of genetic and epigenetic changes, lack mitochondrial fitness, and fail to maintain proteostasis, diverging them from host protection to host injury. Here, we review recent progress in understanding how the human T-cell system ages and the evidence detailing how T cell aging contributes to autoimmune conditions. T cell aging is now recognized as a risk determinant in two prototypic autoimmune syndromes; rheumatoid arthritis and giant cell arteritis. The emerging concept adds susceptibility to autoimmune and autoinflammatory disease to the spectrum of aging-imposed adaptations and opens new opportunities for immunomodulatory therapy by restoring the functional intactness of aging T cells.
Topics: Humans; Aged; Autoimmunity; T-Lymphocytes; Autoimmune Diseases; Aging; Cellular Senescence; Risk Factors
PubMed: 36357240
DOI: 10.1016/j.jaut.2022.102947 -
Current Opinion in Immunology Apr 2023
Topics: Humans; Autoimmunity; Autoimmune Diseases
PubMed: 36841191
DOI: 10.1016/j.coi.2023.102287 -
Journal of Clinical Immunology Apr 2024Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by its large heterogeneity in terms of clinical presentation and severity. The... (Review)
Review
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by its large heterogeneity in terms of clinical presentation and severity. The pathophysiology of SLE involves an aberrant autoimmune response against various tissues, an excess of apoptotic bodies, and an overproduction of type-I interferon. The genetic contribution to the disease is supported by studies of monozygotic twins, familial clustering, and genome-wide association studies (GWAS) that have identified numerous risk loci. In the early 70s, complement deficiencies led to the description of familial forms of SLE caused by a single gene defect. High-throughput sequencing has recently identified an increasing number of monogenic defects associated with lupus, shaping the concept of monogenic lupus and enhancing our insights into immune tolerance mechanisms. Monogenic lupus (moSLE) should be suspected in patients with either early-onset lupus or syndromic lupus, in male, or in familial cases of lupus. This review discusses the genetic basis of monogenic SLE and proposes its classification based on disrupted pathways. These pathways include defects in the clearance of apoptotic cells or immune complexes, interferonopathies, JAK-STATopathies, TLRopathies, and T and B cell dysregulations.
Topics: Humans; Male; Antigen-Antibody Complex; Autoimmunity; Genome-Wide Association Study; Lupus Erythematosus, Systemic; Phenotype; Female; Twin Studies as Topic
PubMed: 38619739
DOI: 10.1007/s10875-024-01696-8 -
Frontiers in Immunology 2022The complement system (CS) is an ancient and highly conserved part of the innate immune system with important functions in immune defense. The multiple fragments bind to... (Review)
Review
The complement system (CS) is an ancient and highly conserved part of the innate immune system with important functions in immune defense. The multiple fragments bind to specific receptors on innate and adaptive immune cells, the activation of which translates the initial humoral innate immune response (IR) into cellular innate and adaptive immunity. Dysregulation of the CS has been associated with the development of several autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ANCA-associated vasculitis, and autoimmune bullous dermatoses (AIBDs), where complement drives the inflammatory response in the effector phase. The role of the CS in autoimmunity is complex. On the one hand, complement deficiencies were identified as risk factors to develop autoimmune disorders. On the other hand, activation of complement can drive autoimmune responses. The anaphylatoxins C3a and C5a are potent mediators and regulators of inflammation during the effector phase of autoimmunity through engagement of specific anaphylatoxin receptors, i.e., C3aR, C5aR1, and C5aR2 either on or in immune cells. In addition to their role in innate IRs, anaphylatoxins regulate humoral and cellular adaptive IRs including B-cell and T-cell activation, differentiation, and survival. They regulate B- and T-lymphocyte responses either directly or indirectly through the activation of anaphylatoxin receptors dendritic cells that modulate lymphocyte function. Here, we will briefly review our current understanding of the complex roles of anaphylatoxins in the regulation of immunologic tolerance and the early events driving autoimmunity and the implications of such regulation for therapeutic approaches that target the CS.
Topics: Anaphylatoxins; Autoimmune Diseases; Autoimmunity; Complement System Proteins; Humans; T-Lymphocytes
PubMed: 35958588
DOI: 10.3389/fimmu.2022.958392 -
Autoimmunity May 2020Antimicrobial peptides (AMPs) were firstly discovered as cytotoxic substances that killed bacteria. Later they were described as biologically active peptides that are... (Review)
Review
Antimicrobial peptides (AMPs) were firstly discovered as cytotoxic substances that killed bacteria. Later they were described as biologically active peptides that are able not only to kill invaders but also to modulate host immunity. In particular, it is shown that human antimicrobial peptides are able to influence the activity of different innate and adaptive immunity components, thus, obviously, they also participate in autoimmune processes. In this review we discuss the nature of human AMPs and analyze their role in such autoimmune disorders like type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, Crohn's disease and sarcoidosis. These peptides were shown to have a "double-sided" influence on the autoimmune disease pathogenesis. Thus, described facts should be taken into account for the development of new pharmaceutical agents to cure patients with autoimmune disorders. These agents could derive from natural antimicrobial peptides that in some cases modulate immune response. For example, it was shown that human AMPs are able to modulate complement system dysregulation of which is known to be one of the most dangerous pathogenic factors during autoimmune processes.
Topics: Adaptive Immunity; Animals; Autoimmune Diseases; Autoimmunity; Humans; Immunity, Innate; Pore Forming Cytotoxic Proteins
PubMed: 31914804
DOI: 10.1080/08916934.2020.1711517 -
Wiener Medizinische Wochenschrift (1946) Feb 2024
Topics: Humans; Neurology; Autoimmunity
PubMed: 37921999
DOI: 10.1007/s10354-023-01023-7