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What do mouse models teach us about human SLE?

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by extensive immunopathological aberrations and peripheral organ damage. Over the past 50 years, murine models have provided valuable insights in elucidating the mechanisms underlying lupus pathogenesis, identifying potential therapeutic targets, as well as examining the efficacy of potential treatment approaches. Commonly used murine lupus models The earliest murine lupus models comprise of various inbred strains, which develop…

Epigenetics

Introduction The pathophysiology of the systemic autoimmune/inflammatory disease systemic lupus erythematosus (SLE) is not completely understood. In rare cases, SLE or lupus-like disorders are conferred by disease-causing mutations in single genes, which include complement genes involved in the proximal classical activation pathway ( C1 , C2 , and C4 ). In “classical” SLE, a strong genetic component is evident by a 25- to 30-fold increased risk…

Metabolic control of lupus pathogenesis: central role for activation of the mechanistic target of rapamycin

Introduction The pathogenesis of systemic lupus erythematosus (SLE) is attributed to immune cell malfunction that results in the production of antinuclear autoantibodies (ANA). Current therapies mainly rely on cytotoxic agents. B-cell blockades have limited clinical efficacy. , Selective depletion of T cells (e.g., CD4 + cells) blocks lupus, however, such therapy creates a state of severe immunodeficiency similar to that caused by HIV. Although other cell…

MicroRNA in systemic lupus erythematosus

Introduction MicroRNAs (miRNAs) have been found as endogenous small noncoding RNAs that fine-tune cellular gene expression and regulate physiological functions. miRNAs are involved in controlling immune cell development and regulating innate and adaptive immunity in both physiological and pathological conditions. Abnormal miRNA expression has been documented in systemic lupus erythematosus (SLE). Functional studies illustrate various mechanisms for dysregulated miRNAs in the pathogenesis of SLE. Studies on…

Immune complexes in systemic lupus erythematosus

Introduction Immune complexes (ICs) are products of immune reactions that are formed by binding between antigen and antibody through non-covalent interactions. ICs play important roles in the clearance of pathogens. However, the production of autoantibodies and formation of ICs against autoantigens induce tissue injuries. Systemic lupus erythematosus (SLE) is an autoimmune disease, in which nucleic acid-containing IC deposition causes inflammation and tissue damage in multiple organs…

Antihistone and antispliceosome antibodies

Autoantibodies directed against intracellular targets are characteristic features of systemic lupus erythematosus (SLE) and other systemic autoimmune rheumatic diseases (SARD). Studies have provided strong evidence that autoantibodies are produced by antigen-driven responses, revealing the identity of antigens involved in breaking B cell tolerance and the pathogenic mechanisms of the disease. Some of these autoantibodies serve as disease-specific biomarkers and are directed against intracellular macromolecular complexes or…

Anti-DNA antibodies

Introduction Elevated anti-double-stranded (ds) DNA antibody titers are diagnostic and prognostic markers of systemic lupus erythematosus (SLE), and their presence is well documented to correlate with lupus nephritis. These antibodies are often deposited in the glomeruli and can be eluted from the kidneys of SLE patients and lupus mice. Moreover, passively transferring anti-dsDNA antibodies into mice can induce proteinuria. The observation that a subset of anti-dsDNA…

Origin of autoantibodies

Production of antinuclear antibodies (ANA) is a consistent manifestation of SLE (frequency ∼100%) and often the earliest. This is not due to a global loss of tolerance, as the antigenic targets are highly restricted. Indeed, autoantibodies against chromatin/DNA, U1 small nuclear ribonucleoproteins (snRNPs, recognized by anti-Sm and RNP antibodies), small cytoplasmic “Y” RNAs associated with Ro60, and other antigens (La, ribosomal P, RNA helicase A, and…

Microbiota influences on systemic lupus erythematosus and Sjögren’s syndrome

Introduction Mounting evidence suggests that microbes, including innocuous commensal organisms that colonize all humans, may trigger and sustain autoimmune inflammation in genetically susceptible hosts. Commensal microbial triggers have been implicated in a range of autoimmune diseases, including systemic lupus erythematosus (SLE), primary Sjögren’s syndrome (pSS), rheumatoid arthritis, multiple sclerosis, uveitis, ankylosing spondylitis, and type I diabetes mellitus. A better understanding of microbe-immune interactions in autoimmunity may…

Infections in early systemic lupus erythematosus pathogenesis

Introduction Patients with systemic lupus erythematosus (SLE) may experience arthritis, serositis, renal involvement, and a wide range of other clinical manifestations with the potential to affect nearly any organ system. These pathologies are driven by chronic inflammation and the presence of autoantibodies, which arise through complex interactions between genetic predisposition, hormonal influences, and environmental exposures. For example, infections commonly lead to transient, low-level production of autoantibodies…

Apoptosis, autophagy, and necrosis

Two and a half millennia ago Hippocrates used the word “apoptosis” to describe the gangrene resulting from treatment of fractures with bandages. Interestingly, he was describing a pathological form of tissue (cell) death. In 1972 Kerr reused the word “apoptosis” with a different connotation, to describe a physiological form of cell demise with profound biological and pathological implications. Indeed today, 4 decades later, this form of…

Fcγ receptors in autoimmunity and end-organ damage

Introduction Antibodies are potent inducers of inflammation. A consistent feature of systemic lupus erythematosus (SLE) is the presence of autoantibodies and complement-fixing immune complexes (ICs) resulting in inflammatory lesions in multiple organ systems. Fc receptors, the receptors for IgG antibodies, are a group of transmembrane glycoproteins which contribute to host defense against pathogens but, not surprisingly, can also inflict significant tissue damage when antibodies are directed…

The role of interferons in systemic lupus erythematosus

Introduction The interferon (IFN) system consists of three different families of proteins (i.e., type I, type II and type III IFNs), and their cell surface receptor complexes. IFNs constitute an essential part of our innate and adaptive immune system, as they have evolved to protect the body from viral infections and other pathogens. The initial observation that patients with systemic lupus erythematosus (SLE) have increased serum…

RNA/DNA sensing in SLE—Toll-like receptors and beyond

Introduction In recent years it has become increasingly clear that aberrant response to nucleic acids (be they endogenous or exogenous) in systemic lupus erythematosus (SLE) patients plays a large role in triggering and sustaining the disruption of immune responses in a genetically predisposed individual. Nucleic acids are recognized by both membrane-bound Toll-like receptors (TLRs) and intracellular RNA and DNA sensors. In predisposed individuals, dysregulation of nucleic…

Cytokines

Cytokines in SLE Cytokines produced by the cells of the innate immune system important in SLE pathogenesis include interferon alpha (IFN-α), interleukin (IL)-1, IL-6, tumor necrosis factor (TNF), IL-10, B cell activating factor (BAFF), and a proliferation inducing ligand (APRIL). Cytokines produced by the adaptive immune system include those produced by the CD4 T helper (Th) cells and are IL-2, Th1 cytokines (IFN-γ), Th2 cytokines (IL-4, IL-5,…

The role of dendritic cells in systemic lupus erythematosus

Following the discovery of dendritic cells (DCs) in mice by Ralph Steinman in 1973, the early nineties saw the description of different culture conditions, allowing the generation of large numbers of DC, and energized the study of DCs in both health and disease. Because DCs are the primary line of defense against pathogens that invade the body, they form a critical interface between innate and adaptive…

Neutrophils in systemic lupus erythematosus

Introduction Neutrophils are the most abundant immune-competent cells in the peripheral blood, and represent up to ∼70% of total white blood cells. They play an important role in innate immune responses and are often at the first line of defense against infections. Neutrophils are capable of phagocytosis and produce reactive oxygen species to kill invading microorganisms. They are short lived (half-life ∼7 hours in the circulation, though…

B cells in SLE

Introduction B cells play a central role in the pathogenesis of systemic lupus erythematosus (SLE), including the unique capacity of plasma cells as ultimately differentiated autoreactive B cells to produce autoantibodies. These antibodies reacting against self-antigens participate in the induction and maintenance of tissue damage and represent hallmarks of SLE, which is characterized by the largest variety of specificities, with 180 autoantibodies so far described. The…

T cells

Patients with systemic lupus erythematosus (SLE) develop a chronic autoimmune response against ubiquitous, mostly intranuclear, self-antigens. This response, manifested by the presence of autoantibodies, represents the source of immune complexes and activated T cells that eventually gain access to target organs causing inflammation and damage. T cells are key players in this process. They promote the autoimmune response by providing help to B cells and activating…

Clinical aspects of the complement system in systemic lupus erythematosus

Introduction General comments The complement system is a double-edged sword in lupus ( Fig. 14.1 ). On the one hand, in its absence, a systemic autoimmune disease develops. Thus a complete deficiency of C1q, C1r, C1s, C4, or C2, all early components of the classical pathway (CP), represents a single protein deficiency state that causes lupus. Over 80% of patients with a total C1q or C4 deficiency…