GWAS implicates a role for quantitative immune traits and threshold effects in risk for human autoimmune disorders

doi:10.1016/j.coi.2012.09.003

Current Opinion in Immunology

Volume 24, Issue 5, October 2012, Pages 538-543

https://doi.org/10.1016/j.coi.2012.09.003 Get rights and content

Genome wide association studies in human autoimmune disorders have provided a long list of alleles with rather modest degrees of risk. A large fraction of these associations are probably owing to either quantitative differences in gene expression or amino acid changes that regulate quantitative aspects of the immune response. While functional studies are still lacking for most of these associations, we present examples of autoimmune disease risk alleles that influence quantitative changes in lymphocyte activation, cytokine signaling and dendritic cell function. The analysis of immune quantitative traits associated with autoimmune loci is clearly going to be an important component of understanding the pathogenesis of autoimmunity. This will require both new and more efficient ways of characterizing the normal immune system, as well as large population resources in which genotype–phenotype correlations can be convincingly demonstrated. Future development of new therapies will depend on understanding the mechanistic underpinnings of immune regulation by these new risk loci.

Highlights

► A large number of associations for autoimmunity have been identified, generally involving common variants of modest effect. ► Many associations defined by GWAS are in non-coding regions and appear to regulate quantitative effects on gene expression. ► A large fraction of the common variants act through quantitative changes in thresholds for immune signaling and activation.

Section snippets

Simple model of autoimmunity: autoantigen presentation and thresholds of immune activation in the adaptive immune system

Given the diversity of autoantigens that have been identified, many models of autoimmunity understandably emphasize role of autoantigen presentation in the context of a class I or class II MHC molecule to T cells and B cells, as shown in Figure 1. Much of disease specificity (whether a person develops rheumatoid arthritis [RA] or type 1 diabetes) is likely to be determined by this combination of factors. For example, if the autoantigen is gliadin presented in a DQ2 class II MHC molecule, then a

Thresholds for TCR and BCR signaling in autoimmunity

The original PTPN22 associations with type 1 diabetes [4] and rheumatoid arthritis [5], now expanded to many other autoimmune diseases, have emphasized the importance of signaling thresholds in disease predisposition, and, at the same time have demonstrated how difficult it is to conclusively determine how these threshold effects cause disease risk. PTPN22 encodes an intracellular tyrosine phosphatase that dephosphorylates activating tyrosines on src kinases such as Lck, as well as other

Quantitative traits in cytokine pathways

Cytokines, their receptors and signaling components are clearly important for regulating a wide variety of immunological activities, and it is therefore not surprising that many of the genetic regions implicated by GWAS contain genes in these pathways. However, relatively few studies in humans have directly demonstrated an effect of disease associated polymorphisms on cytokine function. It is often challenging to identify the exact causative variant(s) that explain a genetic association,

Immune regulation by dendritic cells

Highlighted by the 2011 Nobel Prize, dendritic cells have taken center stage as potent initiators of immune responses as well as mediating immune tolerance, both central and peripheral [34]. Many of the peripheral tolerance mechanisms appear to depend on Treg cells as well as the production of TGFβ. A deficiency of TGFβ signaling in DC leads to experimental autoimmune colitis. DC specific knockout of genes associated with human autoimmunity on GWAS, such as Blimp1 and TNFAIP3, leads to

Population resources for genotype–phenotype studies of quantitative immune traits

These results suggest that many GWAS discoveries in autoimmune diseases will be associated with rather subtle changes in immune responsiveness and/or immune regulatory differences that are quantitative in nature. This may be owing to the presence of structural amino acid changes, as in PTPN22, or changes in gene regulation that are specific to particular cells and stages of differentiation. In order to dissect these relationships, a large population resource of human subjects carrying the

Conclusion

GWAS and related gene discovery approaches have revealed the importance and complexity of identifying and understanding the functional consequences of genetic variation on biological systems. As described in this review for immune-mediated traits, we are beginning to unravel the quantitative effects of risk alleles on the immune response. The examples provided here, together with the unique resources such as repositories of healthy controls and patients, offer hope that new avenues for therapy

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

PKG is supported by grants from the National Institutes of Health (RO1-AR-44422; RO1-AI-68759; RC2AR059092-01) and the Alliance for Lupus Research, in addition to support from Eileen Ludwig Greenland and the Boas family. BD is supported by the Alliance for Lupus Research. RMP is supported by grants from the NIH (R01-AR057108, R01-AR056768, U01-GM092691, R01-AR059648), and holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund.

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Citation Excerpt :
In addition, a functional link between TNF-α −308 allele 2 and MG was assumed since peripheral blood mononuclear cells (PBMCs) from patients positive for the TNF-α-308 allele 2 had higher secretion of TNF-α when activated in vitro [68]. Interestingly, a gender bias in MG at the HLA loci was described [69,70]. In a recent study, the allele frequency difference in female versus male patients was observed not only at the HLA-DRA but also at the TNF-α loci [57].
Myasthenia Gravis (MG) is a paradigm of organ-specific autoimmune disease (AID). It is mediated by antibodies that target the neuromuscular junction. The purpose of this review is to place MG in the general context of autoimmunity, to summarize the common mechanisms between MG and other AIDs, and to describe the specific mechanisms of MG. We have chosen the most common organ-specific AIDs to compare with MG: type 1 diabetes mellitus (T1DM), autoimmune thyroid diseases (AITD), multiple sclerosis (MS), some systemic AIDs (systemic lupus erythematous (SLE), rheumatoid arthritis (RA), Sjogren's syndrome (SS)), as well as inflammatory diseases of the gut and liver (celiac disease (CeD), Crohn's disease (CD), and primary biliary cirrhosis (PBC)).
Several features are similar between all AIDs, suggesting that common pathogenic mechanisms lead to their development. In this review, we address the predisposing factors (genetic, epigenetic, hormones, vitamin D, microbiota), the triggering components (infections, drugs) and their interactions with the immune system [1], [2]. The dysregulation of the immune system is detailed and includes the role of B cells, Treg cells, Th17 and cytokines. We particularly focused on the role of TNF-α and interferon type I whose role in MG is very analogous to that in several other AIDS. The implication of AIRE, a key factor in central tolerance is also discussed.
Finally, if MG is a prototype of AIDS, it has a clear specificity compared to the other AIDS, by the fact that the target organ, the muscle, is not the site of immune infiltration and B cell expansion, but exclusively that of antibody-mediated pathogenic mechanisms. By contrast, the thymus in the early onset subtype frequently undergoes tissue remodeling, resulting in the development of ectopic germinal centers surrounded by high endothelial venules (HEV), as observed in the target organs of many other AIDs.
The putative role of proteolytic pathways in the pathogenesis of Type 1 diabetes mellitus: The 'autophagy' hypothesis
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This has stimulated investigations on their etiopathogenesis. With the advent of new tools, such as genome wide association studies (GWAS) [4], evidence was provided for new susceptibility loci and candidate genes in the disease process including the immunological synapse and T cell activation [5]. Among organ-specific autoimmune disorders, insulin-dependent diabetes mellitus [Type 1 diabetes mellitus (T1D)] is a polygenic autoimmune disease, which occurs in human leukocyte antigens (HLAs) genetically predisposed individuals as a consequence of organ-specific immune destruction of the insulin-producing β cells in the islets of Langerhans within the pancreas [6] by autoreactive T cells.
Autoimmune diseases are a heterogeneous group of disorders affecting different organs and tissues. New tools, such as genome-wide association studies, have provided evidence for new susceptibility loci and candidate genes in the disease process including common susceptibility genes involved in the immunological synapse and T cell activation. Close linkages have been found in a number of diseases, including ankylosing spondylitis, multiple sclerosis, Crohn’s disease and insulin-dependent diabetes mellitus (Type 1 diabetes mellitus). Evidence for some association with Type 1 diabetes was previously found in the region containing 5q15/ERAP1 (endoplasmic reticulum aminopeptidase 1) (rs30187, ARTS1).
Recent data suggest that in eukaryotic cells in addition to the ubiquitin/proteasome system another proteolytic pathway may have a significant role in the autoimmunity process, i.e. the autophagic pathway which constitutes the principal regulated catabolic process mediated by lysosomes. Autophagy could play a role in MHC class I and class II self-antigen presentation at the basis of the autoimmunity process. Furthermore cross-talk among different proteolytic pathways was recently highlighted i.e. components processed in the ubiquitin/proteasome system possibly engaged in autophagic pathways.
T1D is an autoimmune disease characterised by the destruction of pancreatic beta cells by autoreactive T cells. Immunological abnormalities can precede months to years the initial symptoms and clinical diagnosis. Our hypothesis suggests that in the autoimmune process autophagy can intervene at different levels, during the thymic selection process of T lymphocytes causing escape of autoreactive T cells, at the initiation stage of the disease, in the preclinical period or subsequently to the disease onset having a role at the level of perpetuation of the autoimmunity process.
Supporting evidence derives from the already reported discovery of polymorphisms in autophagy-related genes in patients affected by several autoimmune conditions such as Systemic Lupus Erithematosus. In addition deregulated autophagy was detected in T cells from lupus-prone mice and also found in T cells from patients. Autophagy was found activated in osteoclasts from RA patients as demonstrated by the increased expression of Atg7 and Beclin-1.
Our hypothesis to be unraveled could have, if correct, relevant implications for the management of autoimmune conditions such as Type 1 diabetes. In principle, novel therapeutic approaches could be established by targeting deregulated autophagy offering novel opportunities to personalized medicine in patients affected by the disease.
Renegade homeostatic cytokine responses in T1D: Drivers of regulatory/effector T cell imbalance
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Consistent with the functions of these cytokines, therapies that augment IL-2 or block IL-7 or IL-15 can restore a beneficial Treg/Teff ratio in animal models of lost tolerance. In many autoimmune diseases, there are inherent defects in homeostatic cytokine pathways including IL-2, IL-7 and IL-15 [19]. Thus, we suggest that signatures of IL-2, IL-7 and IL-15 may also be biomarkers of disease progression in autoimmunity and cytokine-based therapies may be used to manipulate these responses.
Homeostatic cytokines contribute to the balance between regulatory and effector T cells (Tregs and Teffs respectively) and are necessary to maintain peripheral tolerance. These cytokines include IL-2 that supports Treg and IL-7 and IL-15 that drive Teff. In overt settings of lost tolerance (i.e. graft rejection), IL-2 Treg signatures are decreased while IL-7 and IL-15 Teff signatures are often enhanced. Similar cytokine profile imbalances also occur in some autoimmune diseases. In type 1 diabetes (T1D), there are underlying defects in the IL-2 pathway and Teff cytokine blockade can prevent and treat diabetes in NOD mice. In this review, we summarize evidence of IL-2, IL-7 and IL-15 genetic and cellular alterations in T1D patients. We then discuss how the combined effect of these cytokine profiles may together contribute to altered Treg/Teff ratios and functions in T1D. Implications for combination therapies and suggestions for integrated cytokine and Treg/Teff biomarker development are then proposed.
The Crafoord Prize in Polyarthritis 2013: Significant discoveries and remaining challenges
2013, Seminars in Arthritis and Rheumatism
XFOXO in the hole: Leveraging GWAS for outcome and function
2013, Cell
Citation Excerpt :
Nevertheless, in the case of autoimmune diseases, GWASs have been particularly fruitful in terms of identifying large numbers of reproducible associations and have revealed intriguing overlaps between different autoimmune disorders that involve both the innate and adaptive immune systems (Cho and Gregersen, 2011). While coding region variants with defined effects on immune function have been identified, many GWAS associations appear to involve regulatory functions that can be tied to quantitative immune traits (Gregersen et al., 2012). The report by Lee et al. (2013) in this issue of Cell provides a beautiful integration of genetic, clinical, and functional data in mouse and human to shed light on the pathway influenced by such a noncoding SNP.
GWAS studies of autoimmune disorders have yielded hundreds of replicated associations, but moving from genetic association to functional studies with potential clinical relevance is a challenge. Leveraging GWAS data, Lee et al. now identify FOXO3 activity as predictive of disease severity in Crohn’s disease and rheumatoid arthritis as well as malaria, likely by acting through regulation of cytokine production in monocytes.
Genome-wide association studies of hematologic phenotypes: A window into human hematopoiesis
2013, Current Opinion in Genetics and Development
Citation Excerpt :
Rare variant studies of hematologic traits are just now being reported and will likely have improved power to detect new variants in the ensuing years [61•]. As illustrated by the studies of hematologic malignancies and autoimmune conditions, important lessons can be learned about susceptibility to these diseases by studying aspects of normal human hematopoiesis [53,56]. As new studies surmount these challenges in the coming years, our understanding of human hematopoiesis will undoubtedly improve significantly.
The study of human hematopoiesis is often limited by the inability to manipulate this process in vivo and differences that exist between humans and commonly employed model organisms. However, human genetics provides a way to gain insight into natural variation in a variety of hematologic phenotypes and creates an opportunity to better understand hematopoiesis. In this review, we discuss how genome-wide association studies are revealing common genetic variation that is associated with hematologic traits and diseases. We discuss how the resulting insight from these studies promises to increase our understanding of human hematopoiesis and outline the challenges that lay ahead in this field.

View all citing articles on Scopus

View full text

GWAS implicates a role for quantitative immune traits and threshold effects in risk for human autoimmune disorders

Highlights

Section snippets

Simple model of autoimmunity: autoantigen presentation and thresholds of immune activation in the adaptive immune system

Thresholds for TCR and BCR signaling in autoimmunity

Quantitative traits in cytokine pathways

Immune regulation by dendritic cells

Population resources for genotype–phenotype studies of quantitative immune traits

Conclusion

References and recommended reading

Acknowledgements

Am J Hum Genet

Am J Hum Genet

Nat Genet

Complement factor H polymorphism in age-related macular degeneration

Science

Genomics and the multifactorial nature of human autoimmune disease

N Engl J Med

A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes

Nat Genet

Protein tyrosine phosphatases in lymphocyte activation and autoimmunity

Nat Immunol

PEST domain-enriched tyrosine phosphatase (PEP) regulation of effector/memory T cells

Science

Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant

Nat Genet

Genetic variation in PTPN22 corresponds to altered function of T and B lymphocytes

J Immunol

PTPN22 deficiency cooperates with the CD45 E613R allele to break tolerance on a non-autoimmune background

J Immunol

The autoimmune disease-associated PTPN22 variant promotes calpain-mediated Lyp/Pep degradation associated with lymphocyte and dendritic cell hyperresponsiveness

Nat Genet

PTPN22 alters the development of regulatory T cells in the thymus

J Immunol

Cutting edge: the PTPN22 allelic variant associated with autoimmunity impairs B cell signaling

J Immunol

The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans

J Clin Invest

Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease

Nat Genet

Identification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-up

Hum Mol Genet

Integrating autoimmune risk loci with gene-expression data identifies specific pathogenic immune cell subsets

Am J Hum Genet