Impressive progress has been made over the last several years toward understanding how almost every aspect of the immune system contributes to the expression of systemic autoimmunity. In parallel, studies have shed light on the mechanisms that contribute to organ inflammation and damage. New approaches that address the complicated interaction between genetic variants, epigenetic processes, sex and the environment promise to enlighten the multitude of pathways that lead to what is clinically defined as systemic lupus erythematosus. It is expected that each patient owns a unique ‘interactome’, which will dictate specific treatment.
It took almost 100 years to realize that lupus erythematosus, which was initially thought to be a skin entity, is a systemic disease that spares no organ and that an aberrant autoimmune response is involved in its pathogenesis. The involvement of vital organs and tissues such as the brain, blood and the kidney in most patients, the vast majority of whom are women of childbearing age, impels efforts to develop diagnostic tools and effective therapeutics. The prevalence ranges from 20 to 150 cases per 100,000 people and appears to be increasing as the disease is recognized more readily and survival rates improve. In the United States, people of African, Hispanic or Asian ancestry, as compared to those of other racial or ethnic groups, tend to have an increased prevalence of systemic lupus erythematosus (SLE) and greater involvement of vital organs. The 10-year survival rate has increased significantly over the last 50 years to more than 70%, mostly because of greater awareness of the disease, the extensive and wiser use of immunosuppressive drugs and a more efficient treatment of infections, the major cause of death1,2,3.
Although low levels of autoreactivity and autoimmunity are necessary for lymphocyte selection and, in general, for the regulation of the immune system, in certain individuals, autoimmunity advances through multiple pathways (reviewed in ref. 4) and leads to organ inflammation and damage. The diverse mechanisms do not contribute equally to the expression of disease in all patients with SLE, as will be discussed below. It appears that the clinical heterogeneity of the disease is matched by the multiple pathogenic processes, which justifies the call for the development of personalized medicine (Fig. 1).
Genes and genetics
Over the past two decades, extensive genome-wide association studies and meta-analyses have identified close to 150 new SLE risk loci across multiple ancestries5,6. Extensive use of exome sequencing has revealed an increasing number of monogenic cases of SLE, listed in ref. 7. Interestingly, several of the risk loci span multiple autoimmune diseases8,9, stipulating disease commonality. Functional studies of shared loci may eventually help reclassify autoimmune diseases according to shared pathways, along with clinical characteristics. Detailed lists of gene variants have been published, and a limited number is listed in Table 1, along with evidence supporting involvement in disease pathogenesis. Several variants have been linked genetically, some with supporting biology, to pathogenic mechanisms and specific clinical manifestations, pointing strongly to the heterogeneity of the disease. Several genes linked to the immune response are regulated through long-distance chromatin interactions10,11. Studies addressing long-distance interactions between gene variants in SLE are still missing, but, with the advent of new technologies, such studies will emerge.
Better understanding of the epigenome is needed to understand how it supplements the genetic contribution to the disease. Decreased DNA methylation of certain genes in SLE T cells has been recognized and has been attributed to poor function of the CpG remethylating enzyme DNMT1. For example, hypomethylation of TNFSF5, located on the X chromosome, results in increased CD40-ligand (CD40L) expression in T cells from women, and hypomethylation of Il10 increases interleukin (IL)-10 production. Yet methylation of genes in SLE is more complicated and does not follow a unidirectional pattern. For example, the CD8 locus is methylated in T cells from patients with SLE, resulting in the generation of CD3+CD4−CD8– T cells, whereas the Il2 locus is hypermethylated, resulting in low production of IL-2 (reviewed in ref. 12). Delivery of a demethylating agent specifically to either CD4+ or CD8+ cells in lupus-prone mice suppresses disease expression by enhancing the expression of FoxP3 and sustaining the expression of CD813.
In SLE T cells, the cyclic AMP response element modifier (CREMα) binds to various regulatory elements within the CD8 cluster and recruits histone modifiers, including DNMT3a and the histone methyltransferase G9a, causing stable silencing of CD8A and CD8B14. A similar process takes place in the Il2 locus, resulting in decreased IL-2 production15. In contrast, STAT3 recruitment to Il10 regulatory regions mediates the recruitment of histone acetyltransferase p300, resulting in enhanced gene expression16.
A large number of microRNAs are suspected to control at least one-third of human mRNA stability and translation, and, reasonably, they have been studied in SLE. A limited list is presented in Table 2. MicroRNA serum concentrations may serve as disease biomarkers17, and the development of antagomirs, used to silence endogenous micoRNAs, may help to control the disease.
The contribution of epigenetic modifications to the expression of the disease complements the genetic susceptibility. Better understanding of the biochemical processes involved should offer unique opportunities to develop new therapeutics, and in a personalized manner.
Approximately a third of monozygotic twins are clinically concordant for SLE, which signifies the importance of environmental factors in the expression of the disease. The environment, including ultraviolet (UV) light, and cross-reactivity between self-antigens and molecules defined by viruses and other pathogens is important in the pathogenesis of SLE. Microbes, including innocuous commensal organisms that colonize the gut, skin, nasal cavities and the vagina, may trigger and sustain autoimmune inflammation in genetically susceptible hosts. Microbiota have been amply shown to shape the immune response, including the development of T helper type 1 (TH1), TH2 and regulatory T (Treg) cells and have been implicated in several autoimmune diseases18.
Cross-reactivity between bacterial species and autoantigens has been long claimed to contribute to the expression of disease in susceptible individuals. The bacterium Propionibacterium propionicum, which encodes an ortholog of the RNA-binding protein Ro60, was found in cutaneous lesions of patients with subcutaneous lupus erythematosus and was shown to stimulate memory T cells from patients with SLE19, suggesting a direct involvement of pathogens in T cell proliferation and the production of autoantibodies.
Segmented filamentous bacteria induce intestinal IL-17-producing TH17 cells20, and gut microbiota drive autoimmune arthritis by promoting the generation of follicular helper T (TFH) cells21. Microbiota apparently use Toll-like receptor (TLR) signaling because TNFAIP3 (A20)-deficient mice, which develop autoimmunity, fail to do so when MyD88 (a central TLR signaling molecule) is genetically deleted, or the mice are treated with antibiotics22. Microbiota translocate from the gut to the mesenteric lymph nodes, spleen23 and the liver and induce TH17 and TFH cells as well as innate immune pathways, including the plasmacytoid dendritic cell (pDC)–type I interferon (IFNα/β) axis. Interestingly, certain microbiota can be found in the liver of patients with SLE or autoimmune hepatitis24. Microbiota contribute to disease expression through a number of mechanisms, including molecular mimicry, engagement of the innate immune response and the propagation of proinflammatory TH17 cells. Accordingly, better understanding of the role of microbiota in the expression of SLE should reveal simple approaches for controlling autoimmunity though dietary changes or changing the distribution of microbiota in the gut and elsewhere.
Despite the fact that more than 90% of the people affected with SLE are women, we still do not have a clear understanding of the causative mechanisms. It is well known that people with XXX (Klinefelter syndrome) are prone to SLE and that epigenetic changes in certain pathogenic genes (for example, TNFSF5, encoding CD40L) contribute to disease expression. Also, six SLE susceptibility loci map to the X chromosome, four of which (TLR7, TMEM187, IRAK1 (MyD88-interacting kinase) and the IFN-α-inducible CXorf21) can escape X-chromosome inactivation25.
Estrogen alters the thresholds for B cell apoptosis and activation, and estrogen receptor α contributes to T cell–mediated autoimmune inflammation by promoting T cell activation, and it also promotes lupus in NZB × NZW F1 mice. At the molecular level, estrogen upregulates CREMα expression, which is known to control the expression of Il2 and Il17 (reviewed in ref. 26). Gene expression analysis revealed a female-biased autoimmunity-related network driven by the transcription factor VGLL3 that is linked with autoimmune diseases, including SLE, Sjogren’s syndrome and scleroderma27. While we still do not understand why women represent the vast majority of people with SLE, new evidence points to distinct molecular processes and the probable activation of X-chromosome-defined genes that are genetically linked to SLE.
Innate immune cell disturbances
Genetic and epigenetic factors contribute directly to alter cells of both the innate and adaptive immune responses. It is probable that certain immune aberrations may elicit others. Studies in mice and humans are still limited because of the reductionist approaches that are needed to understand the contribution of each abnormality to the expression of the disease. It will require artificial intelligence approaches to understand the sequence of events in any given patient. Such knowledge will be necessary for the application of precision treatment protocols.
Neutrophils in patients with SLE display an increased capacity to form neutrophil extracellular traps (NETosis) that harbor autoantigens, including chromatin, dsDNA and granular proteins. In patients with SLE, NETs are poorly cleared and stimulate pDCs to produce type I IFN through TLR9 stimulation28. Endothelin-1 and hypoxia-inducible factor-1α appear to mediate the expression of the stress-response protein REDD1, which drives the formation of NETs in SLE. NETs are decorated with tissue factor and IL-17 and are abundant in discoid skin lesions and in the kidneys of patients with SLE29. Further, splenic neutrophils localized in the perimarginal zone can induce immunoglobulin (Ig) class switching, somatic hypermutation and antibody production by activating marginal zone B cells. Interestingly, patients who are neutropenic have fewer and less mutated marginal zone B cells and less preimmune Ig specific for T-independent antigens, suggesting neutrophils generate an additonal level of innate immunity in the antibacterial defense30.
DCs link innate and adaptive immune responses and have been identified in the expression of SLE, as their uncontrolled activation may drive autoimmunity31. Although the numbers are decreased in the periphery, they are found activated in the inflamed tissues, producing inflammatory cytokines and helping T and B cells. Immune complexes containing RNA induce OX40-ligand expression by conventional SLE DCs. Subsequently, they drive the differentiation of naive and memory CD4+ T cells into TFH cells, which are able to help B cells32 and impair Treg function33. Conventional DCs in SLE instruct the differentiation of IgG and IgA plasmablasts and contribute to the formation of ectopic lymphoid structures34.
pDCs are distinguished from conventional DCs by morphology and cell surface markers and are similarly low in the periphery, probably because they lodge inflamed areas. Triggered by TLR7/9 agonists, they produce IFN type I35 to contribute to disease expression, and duplication of TLR7 promotes disease36. Specific depletion of pDCs in mice reduces disease manifestations such as autoantibody production, glomerulonephritis and expression of IFN-inducible genes37. At the clinical level, targeting of pDCs with a BDCA2 antibody ameliorates skin disease in patients with SLE38, while chronic triggering of pDCs through TLR7 and TLR9 renders pDCs resistant to inhibition of the NF-κB pathway and leads to steroid resistance39.
Marginal zone macrophages surrounding the splenic follicles are crucial for the efficient clearance of apoptotic cells and for the induction of tolerance to autoantigens. Phagocytosis of apoptotic cells by splenic marginal zone macrophages requires the megakaryoblastic leukemia 1 transcriptional coactivator–mediated mechanosensing pathway40. The production of type I IFN by macrophages in response to TLR7 engagement is enabled by the TREML4 receptor expressed on myeloid cells, and macrophages from Treml4–/– mice are hyporesponsive to TLR7 agonists, while TREML4-deficient MRL-lpr lupus-prone mice display decreased autoimmunity and nephritis41. It should also be noted that IFN type I and tumor necrosis factor (TNF) cooperate to promote an inflammatory signature in monocytes, and such cooperation also occurs in monocytes from patients with SLE42.
Type I IFN, which affects multiple components of the immune system, has been demonstrated to contribute to the pathogenesis of adult and pediatric SLE43 and to reflect disease activity (reviewed in detail in ref. 44). Yet type I IFN alone may not be sufficient to cause disease expression45 and, in some murine strains, may even be beneficial46.
Proper processing of apoptotic material involves the activation of the transcription factor aryl hydrocarbon receptor (AhR) following engagement of TLR9, which leads to a series of events that suppress inflammation, including the production of IL-10. Deletion of AhR in myeloid cells causes autoimmunity, and its transcription signature correlates with disease activity in mice and humans47. This observation may explain why TLR9 has a protective effect against autoimmunity.
Platelets are activated in patients and mice with SLE through a number of mechanisms, including the action of immune complexes and contact with injured endothelial cells, and they display a type I IFN signature48. Once activated, platelets express and release CD40L and modulate adaptive immunity by activating antigen-presenting cells, including DCs. Platelets interact with pDCs in patients to increase the secretion of type I IFN by triggering TLR9 and TLR749. Understanding of the contribution of platelets may reveal adjuvant tools for the treatment of SLE.
Autoreactive IgE causes basophils to home to lymph nodes, promote TH2 cell differentiation and enhance the production of self-reactive antibodies that cause lupus-like nephritis in mice lacking the protein tyrosine kinase Lyn. Patients with SLE with elevated concentrations of self-reactive IgEs and activated basophils have increased disease activity and active lupus nephritis50.
Studies in mice have shown, in a definitive manner, the roles of neutrophils, basophils, pDCs, TLR activation and IFN type I production in the expression of SLE. Several of these contribute directly to organ damage, whereas others instruct, directly or indirectly, the aberrations of the adaptive immune response. The diversity of the involved pathways underlines the wide clinical spectrum of the disease, and it is quite possible that each cellular element contributes to the expression of disease, to varying degrees.
Lymphocyte disturbances in SLE
B cells in SLE have been reviewed extensively51,52,53. Loss of B cell tolerance at distinct check points has explained the production of autoantibodies. B cell antigen receptor (BCR)–sequencing studies in children with SLE suggested that defects at distinct checkpoints in early B cell development accounted for autoantibody production54. Although autoimmunity results from the failure of tolerance checkpoints, there is evidence that it may arise from the expansion of existing autoreactive cells55.
Age-associated B cells (which include IgD–CD27– and CD21lo B cells) have been detected in human autoimmune disorders, including SLE. Their expansion is controlled by the transcription factor IRF5, variants of which are linked to SLE, through IL-21 expression and unique landscape remodeling56. In mice, age-associated B cells are expanded in the absence of GTPase regulatory proteins (DEF6 and SWAP70), and DEF6 variants have been identified as conferring increased susceptibility to SLE57.
The SLE molecular signature in B cells appears to become established during the resting naive phase and is dominated by the enrichment of accessible chromatin motifs for the transcription factors AP-1 and EGR58, which is facilitated by, probably among other factors, IFN-γ59. B cells that lack IgD and CD27 are known to be expanded in patients with SLE and to produce autoantibodies. These cells are hyperresponsive to TLR7 agonists and IL-21, lack the TLR regulator TRAF560 and have features of freshly activated naive B cells61.
Although allergic reactions are not more frequent in people with SLE as compared to normal subjects, IgE antibodies specific for dsDNA are present in the sera of patients with SLE. These IgE antibodies bind to the high-affinity FcγRI receptor for IgE, can activate pDCs and transfer DNA to TLR9 in phagosomes. This activation results in the secretion of substantial amounts of IFN-α62.
T cells are key players in promoting the autoimmune response by providing help to B cells and by activating antigen-presenting cells through cytokine release and direct cellular contact. Additionally, they infiltrate tissues and promote local inflammation. Autoreactive CD4+ T cells are presumed to respond to nucleosomal antigens and, in particular, to peptides derived from histones63. An interesting T cell subset of unknown pathogenic importance was recorded in patients with SLE and multiple sclerosis (CXCR3+CD38+CD39+PD-1+HLA-DR+CD161+KLRG1−CD28+OX40+), which differs from TFH cells and was first recognized in the gut of patients with celiac disease by virtue of binding gluten64.
TFH cells promote B cell function and evolve from CD4+ T cells in the presence of IL-6, IL-21 and inducible T cell costimulator (ICOS)65. ICOS deficiency protects MRL-lpr mice from disease66. A CD4+ cell subset that resembles TFH cells is expanded in the peripheral blood of patients with active SLE65. The ATP-gated ionotropic P2X7 receptor restricts the expansion of aberrant TFH cells, but TFH cells from patients with SLE are resistant to P2X7-mediated inhibition of cytokine-driven expansion, pointing to a signaling defect67. CXCR5–CXCR3+PD-1+ helper T cells, different from TFH cells, are present in the periphery and in kidney tissues of people with SLE, and provide help to B cells by producing IL-10 and succinate68.
CD8+ T cell cytotoxic responses are decreased in SLE and contribute to increased rates of infection7. A CD8+CD38+ T cell population is expanded in the peripheral blood of patients with SLE. CD8+CD38+ T cells display decreased production of granzymes and perforin and reduced cytotoxic capacity, and patients with SLE, for whom this population is expanded, experience infections more frequently. CD38, a marker of T cell exhaustion, is an ectonucleotidase that degrades NAD and, through the histone methyltransferase EZH2, suppresses the expression of cytotoxicity-related molecules69. Specific inhibitors of CD38-mediated NAD degradation ameliorate age-related metabolic dysfunction and may be of use in restoring CD8+ T cell cytotoxic activity in people with SLE70. Although exhaustion, defined by the levels of expression of molecules, has been argued to be desirable in autoimmunity71, it is important to understand the metabolic processes involved in further detail.
Treg cells are characterized by constitutive expression of the transcription factor FoxP3 and high expression of the high-avidity IL-2 receptor α chain (CD25); in humans, some activated T effector (Teff) cells also transiently express this molecule. The number of Treg cells is reduced during the early phases of the disease, whereas the CD45RA−FoxP3lo non-Treg cell population is increased in active SLE72. The realization that Treg cells have higher affinity receptors for IL-2 and, therefore, stronger IL-2 receptor (IL-2R)–mediated signaling than Teff cells, suggested that administration of IL-2 at a lower dose than that used for Teff cells should promote Treg cell expansion and function. Administration of low-dose IL-2 to lupus-prone mice expanded the population of Treg cells and shrank the pool of CD3+CD4–CD8– IL-17-producing T cells73, which are known to contribute to the development of lupus nephritis74. Low-dose IL-2 administered to people with SLE has been reported75 to produce clinical benefit. A caveat to the apparent success of low-dose IL-2 is evidence that the IL-2–IL-2R–p-STAT5 signaling pathway in SLE T cells is compromised76. IL-2 has the potential to reverse several pathogenic processes involved in the development of SLE, including poor Treg cell function, increased IL-17 production, increased TFH cell activity and the expansion of the population of CD4–CD8– T cells77. The demonstration that Treg cells contribute to tissue repair78 and the possibility that Treg cells are limited in the kidneys of patients with lupus nephritis79 encourage the consideration of approaches that enrich Treg cells in the kidneys or other tissues.
The phenotype and function of T cells isolated from patients with SLE has been extensively studied in the search for clues to explain the pathogenesis of the disease and in an attempt to identify molecules that can serve as biomarkers and/or therapeutic targets80. These studies have revealed that, in the context of SLE, T cell function is severely compromised as a result of a large number of signaling aberrations that distort gene expression profiles and skew the cellular immune response toward a proinflammatory type (reviewed in refs. 80,81). In brief, CD3-mediated T cell signaling is abnormal in people with SLE, and this is followed by aberrant expression of kinases, phosphatases, transcription factors, chemokine receptors and adhesion molecules and the production of chemokines and proinflammatory cytokines (Fig. 2).
Metabolic abnormalities have been recognized in people with SLE and in lupus-prone mice and have been linked to abnormal T cell function. SLE T cells display increased oxidative stress, as indicated by the depletion of glutathione (via NADPH loss), metabolic checkpoint kinase complex mTORC1, glycolysis and glutaminolysis. Inhibition of increased mTORC1, glycolysis or glutaminolysis mitigates disease in lupus-prone mice (reviewed in ref. 82).
The kidney is involved in more than half of patients with SLE and contributes significantly to morbidity. The contribution of autoantibodies with a number of reactivities and of immune complexes in the expression of kidney inflammation has been reviewed extensively over the years. Their role in instigating injury is considered to be mediated through the activation of the complement system, which accounts for the inflammatory response83. Podocytes express increased amounts of the serine/threonine kinase CaMK4, which, through a distinct series of biochemical events, causes injury, and cell-targeted inhibition of CaMK4 in podocytes averts the deposition of immune complexes and nephritis84. These findings signify the importance of resident cells in the initiation and propagation of kidney inflammation.
T cell migration to the kidney is important in the development of lupus-like nephritis85. MRL-lpr mice that lack TCRαβ do not develop lupus nephritis86. Although kidney-infiltrating cells were thought to be exhausted87, clonally expanded CD4+ and CD8+ T cells with memory effector cell markers are present in the kidneys of lupus nephritis. CD8+ T cells are present in all biopsy samples and were found to adhere to the Bowman’s capsule and to infiltrate the tubular epithelium88 and contribute to kidney damage. IL-17-producing T cells have been found within kidney cell infiltrates of patients with lupus nephritis74, and IL-17 is important for the development of lupus nephritis89. TFH cells are present in the kidneys in close association with B cells in people with lupus nephritis, suggesting that they may provide help to them90. Intrarenal B cells form germinal center–like structures produce antibodies to vimentin, which is a dominant target in human lupus tubulointerstitial nephritis91. Application of deep convolutional neural network methodology in specimens from patients with lupus nephritis enabled cell-distance mapping, which confirmed that DCs present antigen to CD4+ T cells92. Understanding the cellular architectures of in situ immunity in lupus nephritis should expand our understanding of the involved pathogenic processes.
Intrarenal macrophages have been considered important in the development of lupus nephritis (reviewed in ref. 93). Analyses of macrophage and DC infiltrates in murine lupus nephritis have shown considerable heterogeneity. Monocytes are located around glomeruli and adjacent to tubules and peritubular capillaries in the renal interstitium and derive from the expanded circulating Gr1lo monocyte population94. Brief ischemia accelerates the infiltration of Ly6Chi inflammatory macrophages into the kidneys of MRL-lpr mice95. DCs also infiltrate the kidneys in people with lupus nephritis, probably propagating local adaptive immune responses. Myeloid DC infiltration is associated with the accumulation of lymphoid aggregates in the kidneys94. The identification of anti-inflammatory monocytes in the kidneys of patients with lupus nephritis96 is especially important in considering prohealing rather than immunosuppressive therapeutic approaches. Lastly, CD43hiCD11c+F4/80loMHC-II– patrolling monocytes, which are known to orchestrate experimental kidney inflammation97, are present in the kidneys of patients with lupus nephritis and lupus-prone mice. Their function depends on TNFAIP3-interacting protein 1 (also referred to as ABIN1) and its absence promotes lupus nephritis in a TLR-dependent manner98.
Single-cell RNA sequencing of kidney and skin biopsy material from patients with lupus nephritis revealed type I IFN–response signatures in tubular cells and keratinocytes. Also, high IFN response and fibrotic signatures in tubular cells were associated with failure to respond to treatment99. Recent single-cell RNA sequencing of kidney samples from people with lupus nephritis revealed 21 subsets of disease-active leukocytes, including multiple populations of myeloid cells, T cells, natural killer cells and B cells, that demonstrated both pro-inflammatory responses and inflammation-resolving responses. Also, evidence of activated B cells and of progressive stages of monocyte differentiation were detected in the kidney. A clear IFN type I response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, implying they may have central roles in cell trafficking100. Similar studies that investigate resident kidney cells in parallel may reveal how the invasion of inflammatory cells alters the gene expression landscape and the function of kidney cells.
Nephritis can develop independently of systemic autoimmunity. Mice lacking ABIN1 develop glomerulonephritis and autoimmunity, both of which depend on TLR signaling, but ABIN1-deficient Rag1–/– and C3–/– mice develop glomerulonephritis without autoimmunity98. Similarly, B6.Nr4a1.Sle1.yaa mice, which have a duplication of the Tlr7 locus, lack patrolling monocytes and are prone to developing autoimmunity, do not develop glomerulonephritis but display ample evidence of systemic autoimmunity98. A lack of association between autoimmunity and kidney damage has been previously suggested by studies of congenic lupus-prone NZM2328 strains101. The notion that the two processes are independent explains why certain patients with lupus nephritis develop end-stage renal disease despite heavy treatment with immunosuppressive drugs, while many people with systemic autoimmunity never develop clinical renal disease.
There are a multitude of mechanisms that are involved in the expression of lupus nephritis, including immune complexes, complement, infiltrating proinflammatory T cells and antibody-producing B cells, and monocytes and the inherent processes of resident cells account for the majority of the clinical heterogeneity of lupus nephritis and for the variable response to drugs and biologics. Understanding the dominant operative mechanism in each patient is the only way to develop personalized medicine.
Central nervous system (CNS) SLE
The central nervous system is involved frequently in people and mice with SLE. The clinical manifestations are quite diverse, apparently reflecting numerous immune and local pathogenic processes102. So far, antibody-mediated neuronal injury, microglial cell activation and infiltrating T cells are involved in the expression of brain injury. Antibodies that recognize double-stranded DNA can cross-react with the NR2A and NR2B subunits of the N-methyl-D-aspartate receptor and cause neuronal death, primarily via increased neuronal calcium influx, which mimics glutamate excitotoxicity103. Transfer of these antibodies to normal mice104 or immunization with the NMDAR-derived DWEYS pentapeptide105 causes neuropsychiatric disease.
Within the brain, resident microglia are the predominant immune cells of the CNS and are potent cytokine producers. It appears that neuronal injury is followed by microglial activation, which involves the activation of the angiotensin-converting enzyme. Blockade of microglial activation with an angiotensin-converting enzyme inhibitor limits neuronal injury106, offering another treatment option.
Lymphocytes and other immune cells are probably important in the expression of CNS disease. Tertiary lymphoid structures are present in the choroid plexus of lupus-prone mice and people with SLE106, and lymphocytes apparently enter the brain parenchyma, but their nature and function have not been studied. The recent reports on the presence of T cells in the brains of people with autism107 and Alzheimer’s disease108 call for more attention on the role of T cells in brain tissue injury.
Four of the eleven American College of Rheumatology–established criteria for the classification of the disease involve skin manifestations that exposure to sun may elicit or worsen. UV light–induced skin inflammation depends on the production of the cytokine CSF-1 by keratinocytes, which in turn recruits and activates monocytes, which enhance apoptosis of keratinocytes109. Dying keratinocytes release autoantigens, including Ro60 (Ro antibodies have long been linked to cutaneous lupus), which may propagate the autoimmune response. Mice and humans deficient in the complement protein C1q are known to have a defect in the clearance of apoptotic material and have lupus-like skin manifestations110. C1q-coated apoptotic cells are engulfed by DCs, macrophages and endothelial cells through binding the receptor SCARF1 on the surface of these cells. SCARF1-deficient mice develop lupus-like disease111.
TH17 cells, which are present in skin biopsy material, may contribute to the inflammatory process112. pDCs have the unique capacity to rapidly produce huge amounts of IFN-α upon recognition of viral RNA and DNA through TLR7 and TLR9 or through other pathogen recognition receptors that are present in skin lesions113. The development of skin lesions depends on FasL expressed on infiltrating TH1 cells recognizing cognate antigen and on TLR7 in the absence of TLR9, revealing a complex regulation of skin inflammation in lupus. pDCs and IFN-α have been shown to be abundant in skin lesions114.
The importance of TNF in the expression of skin lesions has been shown in experiments in which lupus IgG was injected into the skin of various genetically modified mice. In brief, monocytes but not lymphocytes or Ig were required for the induction of skin inflammation (reviewed in ref. 115). Although TNF was required, only TNF receptor type I and not II trimerization was needed for the induction of inflammation. While blockade of IL-17 may have value in the treatment of patients with skin lupus, it is unclear whether TNF receptor trimerization inhibitors may have any value, particularly given that TNF blockade may lead to autoimmune manifestations.
Cardiovascular disease in SLE
Patients with SLE, and particularly those with oxidized LDL and β2-glycoprotein I, have a 2-fold increased risk for cardiovascular disease116. Multiple mechanisms have been found to contribute to the expression of vascular damage. Type I IFN has been shown to inhibit the production of endothelial nitric oxide synthase and to cause endothelial damage117. Low-density granulocytes damage the vasculature because of their increased propensity for NETosis and promote vascular leakage and endothelial-to-mesenchymal transition through the degradation of vascular endothelial cadherin118. CCR5+T-bet+FoxP3+ CD4+ effector T cells are present in atherosclerotic plaques119. Invariant natural killer T cells, however, were recently claimed to interact with monocytes and promote an atheroprotective effect120.
Whereas inflammation promotes atherosclerosis, it has been demonstrated that atherogenic hyperlipidemia promotes autoimmune TH17 cell responses in vivo121. An atherogenic environment induces the production of IL-27 by DCs in a TLR4-dependent manner, which in turn triggers the differentiation of CXCR3+ TFH cells, which are increased in mice66 and patients with SLE122, while inhibiting the differentiation of follicular regulatory T cells123.
Prospects and needs
Amazing progress has been made over the last few years due to increased funding from various sources and the recruitment of skilled researchers from various sections of immunology and other fields of medicine, including nephrology, dermatology and cardiology, and other areas of science, including advanced molecular biology and bioinformatics. As this Review briefly summarizes, every cellular, molecular and biochemical aspect of the immune system contributes somehow to the expression of the disease. In humans it is obviously difficult to assign the time of entry for each recorded abnormality in the pathogenesis of the disease and classify it as either primary or secondary. Lupus-prone mice and engineered mice, in which one suspected molecule is deleted, overexpressed or structurally altered, invariably demonstrate that each molecule is able and sufficient to cause autoimmunity, reflecting a ‘house of cards’ effect, rather than what actually happens in people with SLE. While the complete understanding of each pathway, be it cellular or molecular, is of enormous significance, more important is the need to master technology to identify which pathway is the driver in each individual person with SLE.
The list of failing clinical trials keeps expanding and has been regularly updated, but there has been no effort to change the approach to clinical trials in a radical manner1. It is unfortunate, although unavoidable, that we define the disease using diverse classification criteria. There is no doubt that each biologic helps some people with SLE, mostly because that pathway is central to the expression of the disease in the responding group of patients, but this is not sufficient. There are two solutions: administer to each patient with SLE multiple drugs/biologics in the hope that a greater number will experience clinical benefit, or identify the driving pathway in each patient and treat her accordingly. A corollary to the first approach is to administer biologics that correct multiple pathways.
The expanding use of whole-exome sequencing along with genome-wide association studies has increased the number of patients with monogenic lupus, which will most probably continue to increase. For these patients, besides treatment with drugs to control manifestations, there is the possibility, with advancing technologies, of talking about a cure. Although still early, it is important to identify patients in whom two or a few gene variants contribute to the expression of the disease (oligogenic patients). New technologies should be adapted by investigators in the field to study how individual single nucleotide polymorphisms (SNPs) interact with remote genes or their variants to enable autoimmune pathology124.
The expanding use of single-cell sequencing will help to identify previously unknown functional immune cell subsets that may be upstream in immune system dysregulation and could offer new targets for treatment. Single-cell sequencing of involved tissues may reveal more features of the invading immune cells and, more importantly, that local resident cells have both previously unrecognized functions100 and the ability to produce molecules that cause organ destruction.
It is unfathomable that, although practically all patients are women (9 or more in 10), we know very little of what lies behind this. The X chromosome packs numerous genes involved in the immune response, and it appears that improper inactivation may perturb the immune balance in favor of autoimmunity125. Are there master regulators encoded by genes of the X chromosome that commandeer all that has been reported for SLE? Do these genes need to be expressed in a homozygous fashion through unleashing the inactive allele? In the same line of thinking, the study of the epigenome is still nascent in SLE.
Studies of the involved organs, including skin, the kidney and the brain, have revealed local processes that are responsible for tissue damage. Without ignoring the role of the autoimmune response in instigating organ damage, it is possible that the local inflammatory processes proceed independently with little or no outside input. Better understanding of these processes should open new approaches to disease treatment.
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I thank my colleagues current and past who have helped me acquire a better understanding of this formidable disease known as lupus. I want to thank M. Tsokos for her support and feedback during the preparation of this report and N. Plummer for helping with the assembly of references. The work in my laboratory has been supported by the NIH.
The author declares no competing interests.
Editor recognition statement L. A. Dempsey was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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