Genetic and epigenetic insights into autoimmunity

Treatment of type 1 diabetes mellitus (T1DM) for individuals over the age of 30 years is often delayed. A recent large-scale population analysis used a genetic risk score to define T1DM in the first six decades of life, providing specific insights applicable to those >30 years of age.

Changes in DNA methylation patterns are emerging as an important feature in the development and progression of primary Sjögren syndrome. However, questions remain regarding the contribution of epigenetic (and genetic) factors to the recruitment and activation of autoreactive lymphocytes in the glandular tissues primarily affected by the disease.

A study of polymorphisms in the sensor IFIH1 exposes the evolutionary trade-off between a robust antiviral type I interferon response and the risk of interferon-mediated inflammation.

A newly identified insertion–deletion variant of the B cell activating factor (BAFF)-encoding TNFSF13B gene leads to increased levels of soluble BAFF and is associated with the development of systemic lupus erythematosus. The discovery raises a number of compelling questions for further investigation.

The identification of VGLL3 as a transcription (co-)factor that underlies the sex bias of the human immune system further underscores the relevance of research into this area.

A pioneering new study scrutinising the genetic aetiology of Sjögren syndrome across different ancestries and clinical subtypes shows that the striking heterogeneity of associations observed in Sjögren syndrome cannot be explained by subphenotype differences alone.

Autoimmune disease has been the subject of intense genetic study. In this Focus Review, Todd and colleagues describe recent advances and approaches in the genetic analysis of autoimmune disease.

Genome-wide approaches have advanced the study into mechanisms triggering autoimmunity. This Review illustrates how this has been achieved for twelve common autoimmune diseases, and discusses recent functional genomics approaches that have the potential to help define key immune molecular traits, cell types and cell states.

Technological advances have given valuable insight into the molecular mechanisms that underpin the association between HLA genetics and disease. Dendrou and colleagues review mechanisms of HLA–peptide–T cell receptor binding in health and disease and discuss how this knowledge may be translated into clinical benefit.

Our ability to interrogate the genetic and epigenetic processes that underpin disease are advancing rapidly. In this Review, Radstake and colleagues highlight insights gained into the pathogenesis of systemic sclerosis from the past 4 years of genetic and epigenetic research.

Lifestyle and environmental factors, some which are potentially modifiable, have important roles in the risk of multiple sclerosis (MS), and some of these risk factors, such as Epstein–Barr virus infection, smoking and obesity in adolescence, interact with genetic risk factors. Here, Olsson and colleagues summarize recent data on modifiable environmental and lifestyle factors in MS, with a focus on gene–environment interactions.

Results from genetic studies of primary sclerosing cholangitis have identified a number of risk loci associated with the disease. Here, Jiang and Karlsen comprehensively discuss the identity and function of risk genes, the potential roles they have in pathogenesis and future research efforts.

The clinical and metabolic heterogeneity of adult-onset autoimmune diabetes, which encompasses a spectrum of phenotypes, ranging from classic adult-onset type 1 diabetes mellitus to latent autoimmune diabetes in adults, represents a considerable challenge for the management of this disease. In this Review, the authors summarize the definition, pathophysiology and clinical features of adult-onset autoimmune diabetes and discuss their implications for treatment.

Genetic association studies have uncovered more than 100 genetic loci related to susceptibility to rheumatoid arthritis. This Review discusses the latest insights into rheumatoid arthritis pathogenesis gained from genetic studies and their application for drug discovery and development.

In this Review, the authors propose that disease-associated genetic variants modulate signalling downstream of B cell receptors, Toll-like receptors and cytokine receptors in B cells to drive autoimmune responses. This altered signalling favours a naive B cell repertoire that is skewed towards self-reactivity and promotes the peripheral activation of autoreactive B cell clones.

Histone deacetylases (HDACs) and histone acetyltransferases mediate reversible acetylation of histones and many other non-histone proteins to regulate gene expression and protein function. Here, the authors describe the myriad activities of HDACs in CD4⁺ T cells and the potential use of HDAC inhibitors as therapeutics for immune-mediated diseases.

The modification of epigenetic markers has become an attractive approach to cancer treatment. Here, Prinjha and colleagues discuss the use of epigenetic modulators in inflammatory diseases, which could be particularly amenable to this approach, as immune memory is often encoded in epigenetic changes. Although the field is still at an early stage, many compounds have been found to be more specific than previously thought and could soon enter clinical trials for autoimmune and inflammatory conditions.

Epigenetic alterations are increasingly being associated with the pathogenesis of inflammatory rheumatic diseases. In this Review, Ballestar and Li outline the current state of research into the role of epigenetics in such diseases and the possibility of epigenetic-targeting therapies.

Many autoimmune diseases are known to occur alongside coeliac disease and, in some instances, patients see improvements in both if coeliac disease is diagnosed and treated. Shared genetic traits have been identified between coeliac disease and many of these forms of autoimmunity. In this Review, an overview is presented of the genetic and immunological features of coeliac disease, its overlap with other autoimmune diseases and implications for screening strategies.

Fine-mapping and functional studies highlight potential causal risk variants for rheumatoid arthritis and type 1 diabetes, including missense variants at DNASE1L3, PTPN22, SH2B3, and TYK2, and noncoding variants at MEG3, CD28–CTLA4, and IL2RA.

The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS).  Here the authors find that DNA methylation at HLA-DRB1 gene mediates the effect of DRB1*15:01 and of a protective HLA variant on HLA-DRB1 expression and the risk of MS.

Various autoimmune diseases have sex-linked biases. Gudjonsson and colleagues find that the transcription factor VGLL3 is associated with a female-biased molecular signature linked to susceptibility to autoimmune disease.

The authors use tiled CRISPR activation for functional enhancer discovery across two autoimmunity risk loci, CD69 and IL2RA, and identify elements with features of stimulus-responsive enhancers, including an IL2RA enhancer that harbours a fine-mapped autoimmunity risk variant.

Insight into the genetic influence on the immune response is important for the understanding of interindividual variability in human pathologies. Here, the authors generate transcriptome data from human blood monocytes stimulated with various immune stimuli and provide a time-resolved response eQTL map.

Greg Gibson and colleagues integrate summary-level GWAS and eQTL data with RNA-seq data from a cohort of pediatric Crohn's disease and report transcriptional risk scores that identify patients who will progress to complicated disease. Their dissection of eQTL effects may be used to distinguish genes whose association with disease is through promotion or protection.

Nucleic acid sensing is important to ensure that an innate immune response is only mounted against microbial nucleic acid. Here, the authors identify loss-of-function mutations in the DNASE2 gene that cause type I interferon-mediated autoinflammation due to enhanced systemic interferon signaling.

Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong ethnic and gender bias. In a transancestral genetic association study, Langefeldet al. identify 24 novel regions associated with risk to lupus and propose a cumulative hits hypothesis for loci conferring risk to SLE.

Eric Schadt and colleagues present a predictive causal model of the immune component of inflammatory bowel disease through integration of genetic, regulatory and transcriptional data. They prioritize and validate 12 of the top key drivers experimentally in mouse colitis models and human macrophages.

Many SNPs associated with inflammatory bowel disease are located in non-coding genomic regions. Here, the authors perform CAGE-sequencing on descending colon biopsies of Crohn’s disease and ulcerative colitis patients to map transcription start sites and enhancer activity for analysis of regulatory regions.

Single-nucleotide polymorphisms in the gene encoding the cytosolic viral sensor IFIH1 are linked to a variety of autoimmune diseases. Rawlings and colleagues demonstrate that one such common polymorphism results in IFIH1 with more-potent activation and can act synergistically with other genetic backgrounds to manifest autoimmune disease.

Yuta Kochi and colleagues perform expression quantitative trait loci (eQTL) analysis on five subsets of immune cells individually sorted from blood from 105 individuals. They develop an integrated analysis pipeline of expression and epigenomic data along with gene association to identify cell-specific candidate causal genes and apply this to rheumatoid arthritis.

Most of the more than 200 known genetic risk loci for inflammatory bowel disease (IBD) reside in regulatory regions. Here, the authors provide eQTL datasets for six circulating immune cell types and ileal, colonic and rectal biopsies to map regulatory modules and identify potential causative genes for IBD.

Neuromyelitis optica (NMO) is a rare autoimmune condition characterized by inflammation and demyelination of the optic nerve and the spinal cord. Here, Estrada et al. identify NMO susceptibility variants in the MHC region and find that autoantibody-positive NMO genetically overlaps with lupus.

Natural killer (NK) cells can acquire ‘memory’ signatures. Sun and colleagues examine the dynamic ATAC-seq and functional RNA-seq changes observed upon generation of NK cell memory and show distinct roles for transcription factors STAT1 and STAT4.

T help 17 (Th17) cells are important mediators for both protective and pathogenic immune reactions, but how their functions are regulated at the epigenetic level is not understood. Here the authors show that TRIM28, a cofactor for transcriptional regulation, is important for epigenetic activation of Th17-related gene loci during Th17 response.

Low dose of the heat shock protein gp96 can drive effector T-cell responses, yet high-dose gp96 is immunosuppressive by expanding the regulatory T-cell population. Here the authors explain this dichotomy by showing that high-dose gp96 can drive plasmacytoid dendritic cell expression of neuropilin-1, thus functionally supporting interaction with Treg cells.

Linking transcription factors with disease loci implicates EBNA2, encoded by Epstein–Barr virus, in autoimmune diseases. Applying the method more widely identifies associations for hundreds of transcription factors, illuminating disease mechanisms.

The transcriptional program activated by Smad2/Smad3 is critical for the induction and function of regulatory T cells. Here the authors show that the expression of Smad3 is modulated by the complementary functions of a methyltransferase Ash1l and an lncRNA lnc-Smad3 on the promoter accessibility of the mouseSmad3locus.

Tiam1 is a guanine nucleotide exchange factor for the Rho-family GTPase Rac1. Here, the authors show that nuclear Tiam1 and Rac1 bind to RORγt on the IL-17 promoter, activating its transcription, and that inhibiting Tiam1/Rac1 is beneficial in a mouse model of autoimmunity.

Germinal centre (GC) reactions are driven by T follicular helper (Tfh) cells and their dysregulation can cause autoimmune disease. Here the authors show that the orphan receptor DR6 is a Tfh cell marker that binds syndecan-1 on GC B cells driving autoimmunity in lupus-prone mice.

Analysis of ATAC-seq and RNA-seq data from stimulated T cells identifies genetic variants that disrupt transcription factor binding sites within ATAC-seq peaks. ATAC quantitative trait loci (ATAC-QTLs) are enriched for autoimmune disease-associated variants.

In the germinal center (GC), B and T cells interact to induce the production of protective antibodies against threats. Here the authors show that microRNA miR-146a modulates CD40 signaling in GC B cells, while both miR-146a and miR-146b synergize to control GC T cell responses, thereby implicating intricate controls of GC response by miR-146.

Proliferation of synoviocytes contributes to joint damage in rheumatoid arthritis. Here the authors show that targeting of these cells by a vector, consisting of a baculovirus conjugated to an adenovirus carrying the pro-apoptotic gene PUMA, has therapeutic efficacy in a rat arthritis model.

Disease risk variants can exert their influence on phenotypes by altering epigenome function. Here, Pelikan et al. show that variants inducing allelic imbalance in histone marks in lymphoblastoid cell lines from lupus patients are enriched in autoimmune disease haplotypes and influence gene expression.