Monogenic autoimmune diseases — lessons of self-tolerance

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The molecular defects recently identified in the rare monogenic autoimmune diseases (AIDs) have pinpointed critical steps in the pathways that contribute to the development of normal immune responses and self-tolerance. Recent studies of autoimmune polyendocrinopathy syndrome type 1, autoimmune lymphoproliferative syndrome, immunodysregulation, polyendocrinopathy and enteropathy, X-linked, IL-2 receptor α-chain deficiency, and, in particular, their corresponding mouse models, have revealed the details of the molecular mechanisms of normal immune tolerance, and exposed how defects in these mechanisms result in human autoimmunity. In addition to a deeper understanding of the immune system, detailed molecular characterization of monogenic AIDs will help us to understand the mechanisms behind common polygenic AIDs and, furthermore, to develop novel therapies and intervention strategies to treat them.

Introduction

Autoimmune diseases (AIDs) are a clinically important entity, consisting of at least 70 known or suspected diseases. Altogether 3–5% of the general population is affected by these diseases. Many AIDs are common in most populations and characteristically women are more frequently affected than men (typically 3:1 sex ratio) [1]. The aetiology of most AIDs is multifactorial, with a complex polygenic genetic background interacting with triggering environmental factors, most of which are unknown.

Only a few AIDs have monogenic traits [2]. These include autoimmune polyglandular syndrome type 1 (APS1; also called autoimmune polyendocrinopathy candidiasis ectodermal dystrophy [APECED]), autoimmune lymphoproliferative syndromes (ALPS) type 1, 2 and 3 immunodysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) and IL-2 receptor α-chain deficiency (IL-2Rα deficiency). Table 1 shows the major characteristics of the monogenic AIDs. The genetic characterization of defects behind these monogenic traits is a straightforward process with the currently available genome-wide tools when compared to gene-finding efforts in polygenic or complex AIDs. As the defect in each monogenic AID should expose a critical component of the pathways important for the normal development of immunological tolerance, the research of these diseases should provide essential lessons of complex AIDs.

In this review, we describe how recent research into monogenic autoimmune diseases has provided us with valuable information on central and peripheral tolerance mechanisms.

Section snippets

Genetics and clinical phenotype

APS1 (Online Mendelian inheritance in man [OMIM] number 240300) has a low overall global prevalence, similar to the other monogenic AIDs. APS1, however, is more frequent among some isolated populations such as the Finns (1:25 000), Sardinians (1:14 400) and Iranian Jews (1:9000). The patients develop multiple organ-specific autoimmune diseases, often starting in childhood or during teenage years (Table 1; [3, 4]). Hallmark symptoms include chronic Candida infection followed by autoimmune

Genetics and clinical phenotype

ALPS (OMIM 601859) is inherited as an autosomal dominant trait [35] and is characterized by the accumulation of a polyclonal population of double-negative T cells (CD3+ TCRαβ+ CD4 CD8) [36]. The phenotypic components of ALPS include lymphocytosis of CD4 CD8 T cells, non-malignant lymphadenopathy, splenomegaly, hypergammaglobulinemia and autoimmune manifestations, such as autoimmune haemolytic anaemia, idiopathic thrombocytopenic purpura and autoimmune neutropenia (Table 1).

Molecular defects in apoptosis

Three different

Genetics and clinical phenotype

IPEX (OMIM 304790) is a monogenic X-linked recessive syndrome [50], also known as XLAAD (X-linked autoimmunity-allergic dysregulation syndrome). The defective gene, Foxp3 (Xp11.23; also called JM2) was identified by the positional candidate approach [51]. Recently, involvement of an unidentified autosomal locus in IPEX has been reported, which suggests genetic heterogeneity in this syndrome [52]. The disease is very severe and usually results in early death. The disease phenotype includes

IL-2Rα deficiency — a defect of regulatory T cells

IL-2Rα deficiency (OMIM 606367), another rare monogenic AID affecting the peripheral immune system, was revealed when a deletion in the gene coding for the IL-2Rα chain (CD25) in regulatory T cells was detected in one patient [63]. The CD25 molecule has proven to be crucial for the generation, survival and suppressive function of regulatory T cells [64]. Consequently, the IL-2Rα deficiency resulted into impaired peripheral tolerance, which is normally executed by the CD4+CD25+ regulatory T

Conclusions

To conclude, the research into monogenic autoimmune diseases has demonstrated how detailed characterization of the molecular background of extremely rare diseases has provided us with novel information on the aetiology and pathogenesis of autoimmunity, and on human self-tolerance in general. Firstly, the established disease genes and mutations have provided the scientific community with specific diagnostic screening tools for these monogenic diseases. Secondly, new avenues for the

References and recommended reading

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

  • • of special interest

  • •• of outstanding interest

Acknowledgements

LP is supported by the Center of Excellence of the Academy of Finland, Biocentrum Helsinki, Finland and EU FP6 Program project Euraps. IU, MH and TI are supported by grants from the Academy of Finland, Finnish Cultural Foundation, Sigrid Juselius Foundation, Emil Aaltonen Foundation, Maud Kuistila Foundation, Helsinki Biomedical Graduate School and Helsinki Graduate School in Biotechnology and Molecular Biology.

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