autoimmune polyglandular syndromes

This term is used to describe two very rare autoimmune syndromes associated with type 1 diabetes, and known as APS-1 (autoimmune polyglandular syndrome -1, also known as APECED) and the IPEX (Immune dysfunction, Polyendocrinopathy, Enteropathy, X-linked) syndrome. It also embraces a polygenic syndrome of multiple autoimmunity known as APS-2 (Schmidt's syndrome), in which the central component, autoimmune Addison's disease, is associated with type 1 diabetes or autoimmune thyroid disease. APS-1 and IPEX are single gene disorders arising from mutations of the AIRE (autoimmune regulator) gene and FOXP3 (forkhead box P3) gene respectively; APS-2 is polygenic. One common feature is that the manifestations of altered immunity in these conditions are influenced by the interplay between MHC Class II alleles and non-HLA genes involved in immune recognition and response. These syndromes provide further proof of principle that type 1 diabetes is an immune-mediated condition, and have yielded valuable insight into mechanisms underlying the development of autoimmunity. This page provides a general overview of the three syndromes, and its daughter pages should be consulted for further details of each condition.

Introduction: Maintenance of Immune Tolerance

The maintenance of immunity is based upon the ability of our immune systems to generate an almost infinite repertoire of T cell responses against foreign antigens whilst preventing the development of responses directed against self-tissue.

Image 1: Unprogrammed T cell precursors encounter peptides presented by the MHC. Cells with high affinity T cell receptors are capable of self-recognition and are deleted. Weak affinity receptors are not needed and the cell dies by neglect. Positive selection allows cells with useful capacity for antigen recognition to enter the circulation.
Image 1: Unprogrammed T cell precursors encounter peptides presented by the MHC. Cells with high affinity T cell receptors are capable of self-recognition and are deleted. Weak affinity receptors are not needed and the cell dies by neglect. Positive selection allows cells with useful capacity for antigen recognition to enter the circulation.
Central tolerance refers to the ability of the thymus to monitor maturing T cells, which include effector T cells required for host defence and regulatory T cells needed to suppress unwanted immune responses. Negative selection in the thymus deletes T cells with high affinity for self-tissues, and positive selection monitors the repertoire of effector and regulatory T cells entering the circulation.

Peripheral tolerance is maintained by regulatory T cells, which provide a back-up defence against potentially autoreactive T cells which may have escaped the central monitoring process. Such cells are rendered unresponsive by signals from the regulatory T cells[1].

Autoimmune polyglandular syndromes

These are syndromes characterized by failure of self-tolerance directed against both endocrine and non-endocrine tissues, and in some instances also with immune deficiency. Autoimmune thyroid disorders and type 1 diabetes are common manifestations; but a wide range of other autoimmune disorders are also associated.

The HLA system plays a major permissive role in determining susceptibility to organ-specific autoimmunity, and HLA alleles play an important role in determining the phenotypic pathway taken by each affected individual with polyglandular autoimmunity.

APS-1 and IPEX are each of considerable scentific interest because they are "experiments of nature" which have identified key steps in the development of immune recognition and response. APS-2, a less distinctive entity, merges with the spectrum of organ-specific self-immunity encountered in type 1 diabetes.


APS-1 is a rare autosomal recessive disorder with three major components:

  • Chronic mucocutaneous candidiasis
  • Hypoparathyroidism
  • Adrenocortical failure

In 1997 the condition was shown to be caused by mutations in the AIRE gene[2], a previously unknown gene (21q22.3). At least 58 mutations are known, but the condition is most commonly encountered in Finns, Iranian Jews and Sardinians. The most common (Finnish) mutation is R257X, present in the homozygous or heterozygous state.

The AIRE gene

This is short for autoimmune regulator gene, which codes for an autoimmune regulator protein. This is located in the thymus and helps in the protective recognition of self antigens. Failure of such recognition predisposes to T-cell mediated autoimmunity. For unknown reasons AIRE mutations mainly affect tolerance to endocrine tissues including the adrenals, parathyroid and thyroid glands and islet beta cells.

Clinical Features

The condition is notable for its phenotypic variability, the most constant features is chronic mucocutaneous candidiasis, often developing in early chidhood and present in 2/3 of the Finnish series[3].

Hypoparathyroidism is the next most common component, and may present as fits in childhood. Tooth enamel and nails may also be affected.

The third major component is adrenocortical failure (Addison's disease).

Other features include type 1 diabetes (typically presenting after childhood) alopecia, vitiligo, keratoconjunctivitis, gonadal failure, hypothyroidism, hepatitis, and malabsorptive diarrhoea.

More rarely described features include tubulointerstitial nephritis, asplenia and oral or oesophageal carcinoma in the Finnish series 2.

Type 1 diabetes develops in 15-20%. HLA DRB115-DQB10602 appears protective against diabetes, as in the general population.


IPEX is a very rare syndrome marked by aggressive autoimmunity and usually - but not invariably - results in early death[4]. Since the condition is X-linked, only males are affected. It is due to mutations in FOXP3, a key transcription factor for regulatory T cells, and work with a mouse model known as scurfy has confirmed that immune hyper-reactivity results from a lack of functional regulatory T cells. Clinical features are highly variable and include early onset type 1 diabetes, hypothyroidism, severe enteropathy, eczema, anaemia and thrombocytopenia. Haemopoietic stem cell transplantation has sometimes been effective in its treatment.

Clinical Features

A family history of early male neonatal death may easily be missed, and birthweight is usually normal. The condition manifests within weeks or months as a triad of:

  • Intractable diarrhoea
  • Type 1 diabetes
  • Eczema

Severe enteropathy with watery or bloody diarrhoea may begin during breast feeding (and is thus unrelated to dietary gluten); parenteral feeding is usually needed for survival.

Type 1 diabetes often develops within days of birth and can be very hard to control with insulin

Children who survive the neonatal period are subject to a widening spectrum of other immune manifestations affecting the thyroid, blood components, liver or kidneys.


Forkhead box p3 is a master regulator for the function of thymic-derived regulatory T cells. The corresponding cells are present in normal quantities in IPEX but do not function effectively[5]


Type 1 diabetes is closely associated with a number of other organ-specific autoimmune conditions, most probably due to overlapping HLA susceptibility. APS-2 (also known as Schmidt syndrome) describes Addison's disease in conjunction with autoimmune thyroid disease, type 1 diabetes, or both3. Other associated autoimmune conditions include coeliac disease, pernicious anaemia, stiff man syndrome and alopecia, and multiple autoimmune conditions are typically present in close family members. Doubt exists as to whether APS-2 is a distinct entity or simply one manifestation of a spectrum of polyendocrine autoimmunity.

Genetic Aspects

Autoimmune Addison's is closely associated with the_ HLA-DR3_ haplotype; the highest risk genotype is HLA-DR3/4-DQ2/8, found in 30% of patients. Within this subgroup, the HLA-DR4 subtype DRB1 *0404 confers the highest risk of Addison's itself, whereas DQA1 *0501,DQB *0201 gives the highest risk of developing both Addison's and type 1 diabetes. A person with type 1 diabetes who has the DRB *0404 allele and 21-hydroxylase antibodies has a 100-fold risk of developing Addison's.


Although these three conditions are conventionally lumped together, APS-1 and IPEX represent "human knock-out models" of immune dysfunction due to altered function in a single gene, whereas APS-2 has many features in common with other manifestations of altered organ-specific immunity in type 1 diabetes. They all provide evidence of the way in which the interaction of MHC and non-HLA genes can find expression in a very wide spectrum of autoimmune manifestations.


  1. ^ Michels AW, Gottlieb PA. Autoimmune polyglandular syndromes. Nat Rev Endocrinol 2010;6:270-277

  2. ^ Finnish-German APECED Consortium. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet 1997;17:399-403

  3. ^ Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab 2006;91:2843-50

  4. ^ Powell BR et al, An X-linked syndrome of diarrhoea, polyendocrinopathy and fatal infection in infancy. J Pediatr 1982;100:731-7

  5. ^ Barzaghi F et al. IPEX: a paradigm of immunodeficiency with autoimmunity. Frontiers in Immunology 2012;31 July 2012


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