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Constitutional symptoms and fatigue in systemic lupus erythematosus

Introduction Constitutional symptoms are very common in systemic lupus erythematosus (SLE) but are rather nonspecific; therefore, they are not taken into account in the classification criteria for SLE. Fatigue is the most common constitutional symptom associated with SLE, affecting up to 90% of patients. Other constitutional symptoms such as fever, anorexia, lymphadenopathy, and splenomegaly are less common. The presence of constitutional symptoms may reflect ongoing active…

Pathogenesis of tissue injury in the brain in patients with systemic lupus erythematosus

The brain and nervous system are important targets of immunological injury in people with systemic lupus erythematosus. The nature of this brain injury is complex and all levels of the neuroaxis can be affected, including the brain parenchyma, spinal cord, the cerebral vasculature, and the peripheral nervous system. Compared to other organ system, our mechanistic understanding of brain disease in lupus remains modest, and represents a…

The mechanism of skin damage

Introduction Lupus erythematosus (LE) comprises a broad spectrum of chronic inflammatory autoimmune disorders that display many diverse symptoms. Localized cutaneous LE (CLE) and severe systemic LE (SLE) represent the two ends of the spectrum of LE. The various cutaneous manifestations of LE are divided into LE-specific and LE-nonspecific skin disease based on histopathological findings. The underlying cause of lupus like lesion is unknown but it is…

Mechanisms of vascular damage in systemic lupus erythematosus

Epidemiology of vascular damage in systemic lupus erythematosus Accelerated atherosclerosis leading to cardiovascular (CV) events is a well-established cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). A bimodal mortality pattern in SLE was recognized in the 1970s, and these observations of enhanced mortality late in the course of SLE disease due primarily to CV disease (CVD) have been replicated in several other…

Mechanisms of renal damage in systemic lupus erythematosus

Introduction Renal involvement of systemic lupus erythematosus (SLE) was first reported by W. Osler in 1895. “Wire loop” glomeruli, the pathological lesions that are characteristic of lupus nephritis (LN) were described by Baehr et al in 1935. With the advent of immunofluorescence microscopy, Ig deposits in the kidneys of LN were recognized and complement deposition was demonstrated. Subsequently Ig was eluted from diseased kidney. The eluted Ig…

Genes and genetics of murine systemic lupus erythematosus

Introduction Systemic lupus erythematosus (SLE) is inherited as a multifactorial trait with genetic predisposition playing a major role. Consequently, there has been considerable interest in defining the genetics of this disease. Progress in this area has advanced tremendously over the past few years, resulting in the identification of more than 100 genes associated with lupus risk variants. This effort has been greatly facilitated by studies in…

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…