REVIEW ARTICLE https://doi.org/10.1038/s41590-020-0677-6 Autoimmunity and organ damage in systemic lupus erythematosus George C. Tsokos ✉ Impressive progress has been made over the last several years toward understanding how almost every aspect of the immune sys- tem 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, epigen- etic 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. t took almost 100 years to realize that lupus erythematosus, strongly to the heterogeneity of the disease. Several genes linked to which was initially thought to be a skin entity, is a systemic the immune response are regulated through long-distance chroma- Idisease that spares no organ and that an aberrant autoimmune tin interactions10,11. Studies addressing long-distance interactions response is involved in its pathogenesis. The involvement of vital between gene variants in SLE are still missing, but, with the advent organs and tissues such as the brain, blood and the kidney in most of new technologies, such studies will emerge. patients, the vast majority of whom are women of childbearing age, Better understanding of the epigenome is needed to under- impels efforts to develop diagnostic tools and effective therapeu- stand how it supplements the genetic contribution to the dis- tics. The prevalence ranges from 20 to 150 cases per 100,000 peo- ease. Decreased DNA methylation of certain genes in SLE T cells ple and appears to be increasing as the disease is recognized more has been recognized and has been attributed to poor function readily and survival rates improve. In the United States, people of of the CpG remethylating enzyme DNMT1. For example, hypo- African, Hispanic or Asian ancestry, as compared to those of other methylation of TNFSF5, located on the X chromosome, results racial or ethnic groups, tend to have an increased prevalence of in increased CD40-ligand (CD40L) expression in T cells from systemic lupus erythematosus (SLE) and greater involvement of women, and hypomethylation of Il10 increases interleukin (IL)-10 vital organs. The 10-year survival rate has increased significantly production. Yet methylation of genes in SLE is more complicated over the last 50 years to more than 70%, mostly because of greater and does not follow a unidirectional pattern. For example, the CD8 awareness of the disease, the extensive and wiser use of immuno- locus is methylated in T cells from patients with SLE, resulting in suppressive drugs and a more efficient treatment of infections, the the generation of CD3+CD4−CD8– T cells, whereas the Il2 locus major cause of death1–3. is hypermethylated, resulting in low production of IL-2 (reviewed Although low levels of autoreactivity and autoimmunity are nec- in ref. 12). Delivery of a demethylating agent specifically to either essary for lymphocyte selection and, in general, for the regulation of CD4+ or CD8+ cells in lupus-prone mice suppresses disease expres- the immune system, in certain individuals, autoimmunity advances sion by enhancing the expression of FoxP3 and sustaining the through multiple pathways (reviewed in ref. 4) and leads to organ expression of CD813. inflammation and damage. The diverse mechanisms do not contrib- In SLE T cells, the cyclic AMP response element modi- ute equally to the expression of disease in all patients with SLE, as will fier (CREMα) binds to various regulatory elements within the be discussed below. It appears that the clinical heterogeneity of the CD8 cluster and recruits histone modifiers, including DNMT3a disease is matched by the multiple pathogenic processes, which justi- and the histone methyltransferase G9a, causing stable silencing fies the call for the development of personalized medicine (Fig. 1). of CD8A and CD8B14. A similar process takes place in the Il2 locus, resulting in decreased IL-2 production15. In con- Genes and genetics trast, STAT3 recruitment to Il10 regulatory regions mediates Over the past two decades, extensive genome-wide association the recruitment of histone acetyltransferase p300, resulting in studies and meta-analyses have identified close to 150 new SLE risk enhanced gene expression16. loci across multiple ancestries5,6. Extensive use of exome sequencing A large number of microRNAs are suspected to control at least has revealed an increasing number of monogenic cases of SLE, listed one-third of human mRNA stability and translation, and, reason- in ref. 7. Interestingly, several of the risk loci span multiple auto- ably, they have been studied in SLE. A limited list is presented in immune diseases8,9, stipulating disease commonality. Functional Table 2. MicroRNA serum concentrations may serve as disease studies of shared loci may eventually help reclassify autoimmune biomarkers17, and the development of antagomirs, used to silence diseases according to shared pathways, along with clinical charac- endogenous micoRNAs, may help to control the disease. teristics. Detailed lists of gene variants have been published, and a The contribution of epigenetic modifications to the expres- limited number is listed in Table 1, along with evidence support- sion of the disease complements the genetic susceptibility. Better ing involvement in disease pathogenesis. Several variants have understanding of the biochemical processes involved should been linked genetically, some with supporting biology, to patho- offer unique opportunities to develop new therapeutics, and in a genic mechanisms and specific clinical manifestations, pointing personalized manner. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA. ✉e-mail: [email protected] NatURE IMMUNOLOGY | VOL 21 | JUNE 2020 | 605–614 | www.nature.com/natureimmunology 605 REVIEW ARTICLE NATURE IMMUNOLOGY Genes Environment Hormones which encodes an ortholog of the RNA-binding protein Ro60, was Genetics Microbiome Sex found in cutaneous lesions of patients with subcutaneous lupus Nets 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. Neutrophils Apoptotic cells CD4 IL-2↓ Segmented filamentous bacteria induce intestinal C1qFcR 20 IL-17-producing TH17 cells , and gut microbiota drive autoim- CD8+ cDC Clearance mune arthritis by promoting the generation of follicular helper T 21 TLRs ↓ IL-17 (TFH) cells . Microbiota apparently use Toll-like receptor (TLR) IL-10 CD4– CD8– signaling because TNFAIP3 (A20)-deficient mice, which develop pDC autoimmunity, fail to do so when MyD88 (a central TLR signaling IFN-α TLRs IC molecule) is genetically deleted, or the mice are treated with antibi- B cells Plasma cell otics22. Microbiota translocate from the gut to the mesenteric lymph IgE 23 MZ macrophages nodes, spleen and the liver and induce TH17 and TFH cells as well Macrophages Basophil as innate immune pathways, including the plasmacytoid dendritic cell (pDC)–type I interferon (IFNα/β) axis. Interestingly, certain Platelets IRGs Organs microbiota can be found in the liver of patients with SLE or auto- immune hepatitis24. Microbiota contribute to disease expression through a number of mechanisms, including molecular mimicry, Fig. 1 | The pathogenetic landscape of SLE. Genetic, environmental and engagement of the innate immune response and the propagation of hormonal factors act on various elements of the innate and adaptive proinflammatory TH17 cells. Accordingly, better understanding of immune responses. Gene copy variants (for example, C4 and FCR) and the role of microbiota in the expression of SLE should reveal simple SNPs influence the expression of many genes involved in the immune approaches for controlling autoimmunity though dietary changes response as well as in the control of organ damage (for example, APOL1 or changing the distribution of microbiota in the gut and elsewhere. and KLK). Environmental factors, including UV light, drugs and products of the microbiome, alter T and B cell responses and the functions of Sex innate cells by stimulating TLRs. Hormones and genes defined by the X Despite the fact that more than 90% of the people affected with SLE chromosome contribute to disease expression by altering the function of are women, we still do not have a clear understanding of the caus- lymphocytes and of cells of the innate immune response. The involved ative mechanisms. It is well known that people with XXX (Klinefelter factors lead eventually to loss of tolerance of B and T cells to autoantigens, syndrome) are prone to SLE and that epigenetic changes in certain which are present in abundance because of both increased rates of pathogenic genes (for example, TNFSF5, encoding CD40L) con- apoptosis and defects in mechanisms responsible for their clearance. tribute to disease expression. Also, six SLE susceptibility loci map The T cell response to antigen is aberrant in and late signaling events to the X chromosome, four of which (TLR7, TMEM187, IRAK1 (Fig. 2) and results in misbalanced levels of cytokines, including decreased (MyD88-interacting kinase) and the IFN-α-inducible CXorf21) can IL-2 and increased IL-17 production.