Pathogenesis of Human Systemic Lupus Erythematosus: A Cellular Perspective

Recent work has identified patterns of altered gene expression denoting molecular pathways operating in groups of SLE patients. Studies have identified local, organ-specific factors enabling or ameliorating SLE tissue damage, thereby dissociating autoimmunity and end-organ damage. Novel subsets of adaptive immune effectors, and the contributions of innate immune cells including platelets and neutrophils, are being increasingly recognized in lupus pathogenesis. Studies have revealed metabolic cellular aberrations, which underwrite cell and organ injury, as important contributors to lupus disease. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organs. A complex interaction of genetics, environment, and hormones leads to immune dysregulation and breakdown of tolerance to self-antigens, resulting in autoantibody production, inflammation, and destruction of end-organs. Emerging evidence on the role of these factors has increased our knowledge of this complex disease, guiding therapeutic strategies and identifying putative biomarkers. Recent findings include the characterization of genetic/epigenetic factors linked to SLE, as well as cellular effectors. Novel observations have provided an improved understanding of the contribution of tissue-specific factors and associated damage, T and B lymphocytes, as well as innate immune cell subsets and their corresponding abnormalities. The intricate web of involved factors and pathways dictates the adoption of tailored therapeutic approaches to conquer this disease. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organs. A complex interaction of genetics, environment, and hormones leads to immune dysregulation and breakdown of tolerance to self-antigens, resulting in autoantibody production, inflammation, and destruction of end-organs. Emerging evidence on the role of these factors has increased our knowledge of this complex disease, guiding therapeutic strategies and identifying putative biomarkers. Recent findings include the characterization of genetic/epigenetic factors linked to SLE, as well as cellular effectors. Novel observations have provided an improved understanding of the contribution of tissue-specific factors and associated damage, T and B lymphocytes, as well as innate immune cell subsets and their corresponding abnormalities. The intricate web of involved factors and pathways dictates the adoption of tailored therapeutic approaches to conquer this disease. a major species of anti-apoptotic cell antibodies in SLE serum; associated with disease activity. antibodies reacting with double-stranded (ds)DNA; these are highly diagnostic of SLE and are implicated in the pathogenesis of lupus nephritis. antibodies against phospholipids that are found in all living cells and cell membranes. an intracellular degradation process in which a cell digests itself. homozygous mice for three NZB/W-derived lupus susceptibility gene loci (Sle1, Sle2, Sle3) on the C57BL/6J background; animals develop systemic autoimmunity with fatal glomerulonephritis; model for SLE. mice harboring a blood dendritic cell antigen 2 (BDCA2)–diphtheria toxin receptor (DTR) fusion transgene; this enables efficient plasmacytoid dendritic cell (pDC) depletion in vivo after a single dose of diphtheria toxin. serine/threonine kinase implicated in T cell transcriptional regulation. by releasing cytokines, Th cells can help to suppress or regulate immune responses; they are essential for B cell antibody class-switching, the activation and growth of cytotoxic T cells, and for maximizing the bactericidal activity of phagocytes. a subunit of CD3 complex of the T cell receptor; helps to activate cytotoxic CD8+ and CD4+ helper T cells and is downregulated in many chronic inflammatory diseases. the first subcomponent of the C1 complex in the classical pathway of complement activation. a series of small proteins and protein fragments (>30) that lead to the stimulation of phagocytes to clear foreign and damaged material, proxy inflammation to attract additional phagocytes, and activate the cell-killing membrane attack complex. The complement system includes serum and serosal proteins, as well as cell membrane receptors. a reduction in the number of cells (blood); often observed in SLE patients. class IV disease, the most severe and most common subtype of lupus nephritis. More than 50% of glomeruli are involved. Lesions can be segmental or global, and active or chronic, with endocapillary or extracapillary proliferative lesions. catalyze the addition of a methyl group to DNA; they might contribute to aberrant epigenetic regulation in SLE. IgD−CD27− cells; these are age-related or autoimmune disease-associated. antigen-experienced CD4+ T cells found outside B cell follicles of secondary lymphoid organs such as lymph nodes, spleens, and Peyer's patches; eTfh cells are identified by constitutive expression of CXCR4. a crucial component of Fc receptors expressed on many inflammatory cells. Fc receptors are essential for the initiation or maintenance of immune responses. examination of a genome-wide set of genetic variants, in different individuals within a population, that are potentially associated with a given trait. mature B cells reside in germinal centers within lymphoid organs, central factories for the generation of affinity-matured B cells specialized in producing refined antibodies. enzymes that catalyze the removal of acetyl groups from histone proteins (epigenetic regulation). formed by the binding of an antibody to a soluble antigen. Their deposition in tissues (e.g., kidneys) causes damage and is a prominent feature of several autoimmune diseases. a CD28 superfamily costimulatory molecule that is expressed on activated T cells. proteins which regulate the transcription of interferons (IFNs) and are crucial for innate immunity. Dysregulation of IRF signaling might contribute to autoimmune diseases. interleukin produced by T cells, has essential roles in tolerance and immunity. produced by T helper cells; acts as a potent mediator of delayed-type immune reactions and inflammation. produced by activated T cells to regulate immune responses; strongly linked to inflammation and autoimmunity. mechanism by which B cell production of immunoglobulin is changed from one type to another. metabolite of the amino acid L-tryptophan. an autophagy-related process in which phagosomes become decorated with LC3 and are subsequently trafficked to the lysosome for degradation. subdomains of the plasma membrane containing high concentrations of cholesterol and glycosphingolipids. Signaling in these domains differs in T cells from patients with SLE and rheumatoid arthritis. low levels of lymphocytes in the blood. ubiquitous atypical serine/threonine kinase important for cellular processes including survival, growth, and proliferation. Aberrant mTOR signaling is involved in many diseases (including autoimmune). a small specialized macrophage subset residing in the marginal zone of the spleen; MZMs play a central role in the clearance of apoptotic cells to minimize the immunogenicity of autoantigens. constitute the glomerular mesangium and, with the mesangial matrix, form the vascular pole of the glomerulus. Their primary function is to remove trapped residues and aggregated protein from the basement membrane. mice homozygous for the lymphoproliferation spontaneous mutation (Faslpr) show systemic autoimmunity, massive lymphadenopathy associated with proliferation of aberrant T cells, arthritis, and immune complex-induced glomerulonephrosis; model for SLE. networks of extracellular fibers that are primarily composed of DNA from neutrophils, and may provide a source of autoantigens in autoimmune diseases. these mice develop an autoimmune disease resembling human SLE: high levels of antinuclear antibodies, hemolytic anemia, proteinuria, and progressive immune complex glomerulonephritis (more pronounced in females). a subtype predominantly found in germinal centers that contain many phagocytized, apoptotic cells. immature B cells that divide rapidly and secrete antibodies (but less than plasma cells). effector B cells that secrete large volumes of antibodies. cells in the renal Bowman’s capsule that wrap around the capillaries of the glomerulus. Their primary function is to filter blood and retain large molecules (e.g., albumin). inhibitory T cell-surface receptor implicated in mechanisms of self-tolerance. It is an immune checkpoint against autoimmunity. ubiquitously expressed; regulates cellular function by dephosphorylating molecules such as Akt, p53, c-Myc and β-catenin. Deregulation of PP2A in T cells has been implicated in autoimmunity. lymphoid-specific intracellular phosphatase that acts as negative regulator of T cell receptor signaling. Mutations in its coding gene may be associated with autoimmune disorders including SLE. quantitative study of chemical processes involving metabolites. proteins involved in cytoskeletal reorganization and control of cell adhesion and migration, apoptosis, proliferation, and differentiation. a family of signaling intermediates in the Janus kinase (JAK)/STAT signaling pathway which initiate gene transcription. Gain-of-function or loss-of-function mutations of different STATs can lead to immunodeficiency, infections, or multiorgan autoimmunity. a group of type I transmembrane receptors. SLAM members appear to play crucial roles in multiple autoimmune diseases. variations in a single nucleotide occurring at a specific position in the genome, where each variation is present to some appreciable degree within a population. cellular mechanism by which the immune system adapts to new foreign elements. It involves a programmed process of mutation affecting the variable regions of immunoglobulin genes. a B cell subtype that is formed within germinal centers following antigen encounter (switched immunoglobulin receptor). T cells that display the distinctive γδ T cell receptor (TCR) on their surface (most T cells bear αβ chain TCRs); mostly expressed in mucosal sites; considered as ‘first line of defense' or ‘bridge between innate and adaptive immunity. functional ectopic lymphoid structures formed inside non-lymphoid tissues, presumed to have immune functions. a CD4+ T cell subset that provides IL-21-mediated help to B cells (Tfh cells express BCL6). the ability of the immune system to recognize and tolerate the body's own proteins and organs, avoiding attacks against ‘self’. play key roles in innate immunity; sense danger/damage signals, recognizing structurally conserved molecular patterns derived from microbes (e.g., pattern-recognition receptors). Endogenous TLR ligands, particularly nucleic acids, may contribute to the modulation of aberrant adaptive immunity (e.g., SLE). immature B cells residing in peripheral lymphoid tissues; are capable of differentiating into mature B cells.