More than Meets the Eye: Monogenic Autoimmunity Strikes Again
Authors: Mark S. Anderson, Jean-Laurent Casanova
Journal: Immunity (2015)

Autoimmunity is often familial, suggesting that inborn genetic variations might underlie its development. Curiously, autoimmunity has long been thought to be typically polygenic. Contrary to this prediction and consistent with growing discoveries of monogenic autoimmunity, Oftedal et al. discovered heterozygous dominant-negative AIRE mutations in patients with certain forms of autoimmunity. Autoimmunity is often familial, suggesting that inborn genetic variations might underlie its development. Curiously, autoimmunity has long been thought to be typically polygenic. Contrary to this prediction and consistent with growing discoveries of monogenic autoimmunity, Oftedal et al. discovered heterozygous dominant-negative AIRE mutations in patients with certain forms of autoimmunity. The genetic basis of autoimmunity is a complex problem that awaits a simple solution. More-complex problems, such as gravity and life, were explained, respectively, with a single equation and a double helix. When the proposed solution to a problem is more complicated than the problem itself, there is often something wrong. This is neatly illustrated with the results obtained by the traditional approach in complex genetics, best exemplified by genome-wide association studies (GWASs). Many polymorphisms were proposed to be weakly associated with a variety of autoimmune diseases. In reviewing these data, missing intelligibility is a greater problem than missing heritability. The assumption behind these large population-based genetic studies has been the idea that there is both phenotypic and genetic homogeneity. Autoimmune diseases were claimed to exist as a few distinctive entities and patients with each condition were thought to share a genetic predisposition. Understandably, on such premises, most if not all GWASs failed to reveal novel mechanisms that would illuminate pathogenesis and to provide causal relationships that would benefit patients. This failure is also explained, for maladies that affect patients in reproductive age, by the assumption that there would be no fitness cost and common variants could be causal. By contrast, patient-based genetic studies, including studies of single patients, have been very successful (Casanova et al., 2014Casanova J.L. Conley M.E. Seligman S.J. Abel L. Notarangelo L.D. J. Exp. Med. 2014; 211: 2137-2149Crossref PubMed Scopus (169) Google Scholar, Cheng and Anderson, 2012Cheng M.H. Anderson M.S. Annu. Rev. Immunol. 2012; 30: 393-427Crossref PubMed Scopus (69) Google Scholar). Mendelian forms of autoimmunity have been incredibly instructive in how immune tolerance is maintained and how autoimmunity develops. Countless patients have benefited from these advances. Autoimmune polyglandular syndrome type 1 (APS1 [MIM: 240300]) is a Mendelian disorder characterized by multiple organ-specific autoimmune diseases. The most prevalent clinical features include two autoimmune endocrine conditions, adrenal insufficiency and hypoparathyroidism, as well as a chronic infectious disease, mucocutaneous candidiasis (Cheng and Anderson, 2012Cheng M.H. Anderson M.S. Annu. Rev. Immunol. 2012; 30: 393-427Crossref PubMed Scopus (69) Google Scholar). The latter disease is also autoimmune; APS1 subjects develop autoantibodies to IL-17A and IL-17F, two cytokines that play a critical role in protective immunity against Candida. Affected individuals also develop many other autoimmune problems, such as vitiligo and pernicious anemia, which vary between individuals. From a genetic perspective, the disease is typically inherited in an autosomal-recessive (AR) fashion and the defective gene, AIRE (encoding AIRE, for autoimmune regulator), was first identified in humans through a superb positional cloning effort in the late 1990s. Some mutations were nonsense and frameshift, suggesting that they were loss of function. The identification of AIRE opened up a new rich area of biology where we have now come to appreciate that AIRE operates as a critical transcriptional regulator to promote the broad display of tissue-specific antigens in the thymus for the induction of tolerance (Anderson et al., 2002Anderson M.S. Venanzi E.S. Klein L. Chen Z. Berzins S.P. Turley S.J. von Boehmer H. Bronson R. Dierich A. Benoist C. Mathis D. Science. 2002; 298: 1395-1401Crossref PubMed Scopus (1867) Google Scholar). Given that AIRE is such a key regulator of tolerance, could heterozygous AIRE mutations underlie autosomal-dominant (AD) autoimmunity, by haploinsufficiency or negative dominance? In this issue of Immunity, Oftedal et al., 2015Oftedal B.E. Hellesen A. Erichsen M.M. Bratland E. Vardi A. Perheentupa J. Kemp E.H. Fiskerstrand T. Viken M.K. Weetman A.P. et al.Immunity. 2015; 42 (this issue): 1185-1196Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar report multiple dominant-negative mutations of AIRE underlying AD APS1. These data suggest that mutations in AIRE might be more widespread in patients with autoimmunity than previously thought. A first hint for this idea was provided by a multiplex family with autoimmunity segregating with a missense heterozygous AIRE mutation in the SAND domain (Cetani et al., 2001Cetani F. Barbesino G. Borsari S. Pardi E. Cianferotti L. Pinchera A. Marcocci C. J. Clin. Endocrinol. Metab. 2001; 86: 4747-4752Crossref PubMed Scopus (146) Google Scholar), the disease-causing role of which was confirmed in a mouse knock-in model (Su et al., 2008Su M.A. Giang K. Zumer K. Jiang H. Oven I. Rinn J.L. Devoss J.J. Johannes K.P. Lu W. Gardner J. et al.J. Clin. Invest. 2008; 118: 1712-1726Crossref PubMed Scopus (118) Google Scholar). Here, Oftedal et al., 2015Oftedal B.E. Hellesen A. Erichsen M.M. Bratland E. Vardi A. Perheentupa J. Kemp E.H. Fiskerstrand T. Viken M.K. Weetman A.P. et al.Immunity. 2015; 42 (this issue): 1185-1196Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar describe multiple familial and sporadic instances of autoimmunity associated with rare variants of AIRE that cluster in its PHD1 domain (Figure 1). One multiplex pedigree, in particular, provided a strong genetic case for AD inheritance. An APS1 patient with a single heterozygous AIRE mutation in the PHD1 domain had two separate partners whose children harbored the heterozygous AIRE mutation and developed APS1. The authors then identified other patients with APS1-like features who harbored heterozygous PHD1 mutations. Screening larger cohorts of patients with vitiligo or pernicious anemia also identified patients carrying heterozygous PHD1 mutations. Finally, scanning public databases revealed that PHD1 mutations, some of which might be dominant negative, reach an estimated frequency of about 0.0008, which is in the range of several autoimmune conditions that affect about 1 in 1,000 people. When compared with patients bearing bi-allelic mutations in AIRE and showing the classic AR APS1 phenotype, patients carrying mono-allelic dominant-negative mutations typically show a narrower, organ-specific phenotype of later onset and better outcome—the novel AD APS1 phenotype. Patients with isolated features of APS1 like vitiligo or pernicious anemia might harbor a single, rare, dominant-negative variant in AIRE. Many questions arise from these provocative findings. First, what molecular insights can be garnered? Among the multiple domains of AIRE, the CARD/HSR domain is involved in self-multimerization and the PHD1 domain is a histone code reader that binds to H3 histone tails with the K4me0 mark. Thus, in-frame mutations in only one PHD1 domain might inhibit the function of an entire AIRE multimer. How much negative dominance is going on in vivo with PHD1 mutations? Is there preferential interference for some but not all transcriptional targets of AIRE? Currently, this is difficult to ascertain because of the limitations in assessing AIRE function with the in vitro cell transfection model that was deployed in the current study. In a previous study of a mouse knock-in model of a dominant-negative AIRE SAND mutation, global interference of AIRE targets in vivo was observed (Su et al., 2008Su M.A. Giang K. Zumer K. Jiang H. Oven I. Rinn J.L. Devoss J.J. Johannes K.P. Lu W. Gardner J. et al.J. Clin. Invest. 2008; 118: 1712-1726Crossref PubMed Scopus (118) Google Scholar). Interference of the PHD1 domain could have a different effect. Another interesting question is why such mutations in the PHD1 domain had been previously missed. Autoimmunity was perhaps not finely studied in heterozygous relatives of APS1 subjects with PHD1 mutations. Also, some PHD1 mutations might be less or not dominant negative, or perhaps the current study has enrichment for unique cohorts and patients. Indeed, pernicious anemia and vitiligo are more common autoimmune diseases than APS1 but are seen in APS1. Heterozygous AIRE mutations might therefore contribute to specific autoimmune conditions, which had not been previously mined for rare mutations. Finally, could haploinsufficiency at the human AIRE locus also predispose to even milder forms of autoimmunity, as suggested by one of the two mouse models that examined this question (Liston et al., 2004Liston A. Gray D.H. Lesage S. Fletcher A.L. Wilson J. Webster K.E. Scott H.S. Boyd R.L. Peltonen L. Goodnow C.C. J. Exp. Med. 2004; 200: 1015-1026Crossref PubMed Scopus (248) Google Scholar, Su et al., 2008Su M.A. Giang K. Zumer K. Jiang H. Oven I. Rinn J.L. Devoss J.J. Johannes K.P. Lu W. Gardner J. et al.J. Clin. Invest. 2008; 118: 1712-1726Crossref PubMed Scopus (118) Google Scholar)? What does this study tell us about the genetic architecture of autoimmunity? In patients with AD APS1, there is a causal relationship between genotype and phenotype, with an immunological mechanism and therefore clinical implications. Variants of similarly low frequency in other genes might also drive autoimmunity in other patients. AD forms of autoimmunity are likely to exceed AR forms. The three types of AD inheritance might operate, as recently illustrated by haploinsufficiency at the CTLA4 locus (Kuehn et al., 2014Kuehn H.S. Ouyang W. Lo B. Deenick E.K. Niemela J.E. Avery D.T. Schickel J.N. Tran D.Q. Stoddard J. Zhang Y. et al.Science. 2014; 345: 1623-1627Crossref PubMed Scopus (607) Google Scholar) and gain-of-function at the IFIH1 locus (Rice et al., 2014Rice G.I. del Toro Duany Y. Jenkinson E.M. Forte G.M. Anderson B.H. Ariaudo G. Bader-Meunier B. Baildam E.M. Battini R. Beresford M.W. et al.Nat. Genet. 2014; 46: 503-509Crossref PubMed Scopus (402) Google Scholar). This novel genetic architecture of autoimmunity based on rare variants, monogenic drivers, and genetic heterogeneity contrasts point by point with the traditional model of common variants, polygenic inheritance, and genetic homogeneity. GWASs based on the latter model yielded relative risks around 2, in the best cases, which were statistically but neither biologically nor medically significant. So far, the HLA associations of the pre-GWAS era have provided the best results of complex genetics in the realm of autoimmunity. For example, HLA-DQ8 and HLA-B27 are strong determinants of type 1 diabetes and ankylosing spondylitis, respectively, with relative risks in the range of 30. Although the penetrance of AD APS1 is incomplete, the relative risk conferred by pathogenic AIRE mutations is probably much higher. To measure both the penetrance and relative risk, it will be necessary to sequence AIRE in large cohorts of healthy individuals and autoimmune patients and to characterize experimentally in-depth all mutant alleles. When compared with AIRE mutations, the HLA alleles can be seen as disease-modifying, but not disease-causing, alleles. The HLA alleles of AD APS1 patients might even be modifiers that influence their autoimmune phenotype, as suggested by HLA DQ 0602 being protective for type 1 diabetes in AR APS1 patients. Why did it take so long for monogenic forms of autoimmunity to gain recognition? Mendelian traits have often been neglected because of their supposed rarity, with the perpetual comparison of complex/common versus Mendelian/rare diseases. This dates back to the turn of the 20th century, when biometricians attacked Mendelism. Because most phenotypes do not segregate as Mendelian traits, it was believed that the core Mendelian principles of genetics were also wrong. This controversy is not yet entirely settled, and the term Mendelian is still used in two ways, referring to monogenic traits (not necessarily fully penetrant) or to fully penetrant traits (not necessarily monogenic). Moreover, there is obviously no pure Mendelian trait, both fully monogenic and fully penetrant, as there is no single-gene organism defining a single-organism population. Even cystic fibrosis and sickle-cell disease are not, strictly speaking, Mendelian disorders. Therefore, although Mendelian disorders might be individually rare exceptions (albeit collectively numerous), “non-Mendelian monogenic disorders” might be much more common, individually and collectively, and perhaps closer to the rule than exceptions. The present study points to the importance of such disorders in autoimmunity. Of course, not all autoimmune patients carry monogenic lesions: autoimmunity could be digenic, with two loci of equal weight, or perhaps even trigenic. It could be somatic too, as illustrated by the impact of somatic FAS mutations (Magerus-Chatinet et al., 2011Magerus-Chatinet A. Neven B. Stolzenberg M.C. Daussy C. Arkwright P.D. Lanzarotti N. Schaffner C. Cluet-Dennetiere S. Haerynck F. Michel G. et al.J. Clin. Invest. 2011; 121: 106-112Crossref PubMed Scopus (94) Google Scholar). Overall, recent breakthroughs in monogenic autoimmunity remind us of the heuristic importance of a key Darwinian concept, referred to in biology as population thinking by Ernst Mayr and in medicine as chemical individuality by Archibald Garrod: all living organisms are unique (Casanova et al., 2014Casanova J.L. Conley M.E. Seligman S.J. Abel L. Notarangelo L.D. J. Exp. Med. 2014; 211: 2137-2149Crossref PubMed Scopus (169) Google Scholar). There are only patients, each being unique—diseases are words used by default across patients, pending the discovery of patient-specific pathogenesis. Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune DiseasesOftedal et al.ImmunityJune 16, 2015In BriefThis paper by Husebye and colleagues directly links heterozygous mutations in the autoimmune regulator (AIRE) gene to organ-specific autoimmunity, including APS-1. The authors show that these mutations cluster within the first PHD domain of AIRE and exert a dominant-negative effect on wild-type AIRE in vitro. Full-Text PDF Open Archive