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Review
. 2018 Mar 22;378(12):1132-1141.
doi: 10.1056/NEJMra1713301.

Autoimmune Polyendocrine Syndromes

Eystein S Husebye  1 , Mark S Anderson  1 , Olle Kämpe  1
Affiliations
Review

Autoimmune Polyendocrine Syndromes

Eystein S Husebye et al. N Engl J Med. .
No abstract available

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Figures

Figure 1
Figure 1. Organ-specific Manifestations of Autoimmune Polyendocrine Syndromes
The main manifestations of autoimmune polyendocrine syndrome type 1 (APS-1, red box), autoimmune polyendocrine syndrome type 2 (APS-2, blue box) and X-linked immunodysregulation polyendocrinopathy enteropathy (IPEX, green box). Primary adrenal insufficiency and type 1 diabetes are shared between APS-1 and −2, respectively (red-blue box); Type 1 diabetes is shared between Aps-2 and IPEX (blue-green box).
Figure 2
Figure 2. Key Immunoregulatory Pathways Involved in the Pathogenesis of Autoimmune Polyendocrine Syndromes
Panel A, left illustrates normal central immune tolerance. The autoimmune regulator (AIRE) expressed in medullary thymic epithelial cells (mTEC) promotes expression of tissue-specific antigens (colored star, rectangle, triangle, and circle) which are expressed on the surface. Autoreactive T cells with affinity for self-proteins either die by apoptosis or become forkhead box P3 (FoxP3) expressing T regulatory cells (Tregs). When AIRE is lacking (right panel), autoreactive T cells escape to the general circulation and peripheral lymphoid organs where they can cause autoimmune reactions and the disease APS-1. Lack of Tregs also contribute to autoimmunity. Panel B, left depicts how FoxP3 positive Tregs harness autoreactive T cells by interacting with antigen presenting cells (APCs). FoxP3 mutations (right panel) or mutations in other genes key to the function of Tregs (cytotoxic T lymphocyte antigen 4 (CTLA4), cluster of differentiation 25 (CD25)) remove the inhibition of autoreactive T cells which then cause autoimmunity and immune polyendocrinopathy X-linked (IPEX) and IPEX-like syndromes. Panel C, Signal transducers and activators of transcription (STATs) are transducers of cell surface cytokine signaling (family members depicted at the cell surface). Mutations that lead to a constitutively active form of STAT1 or STAT3 promote autoimmunity (green arrows); loss of function mutations in STAT5b also lead to autoimmunity (red arrow with block). The exact mechanisms need to be further dissected but loss of STAT5b could be due to the improper expression of FOXP3, a known target of STAT5b.
Figure 3
Figure 3. Diagnostic Evaluation for APS
Patients with a clinical diagnosis of APS-1 (upper left box) should have the AIRE gene sequenced for autoimmune regulator (AIRE) mutations. Patients with a clinical phenotype suggestive for APS-1 (upper right box) should be screened for interferon autoantibodies before AIRE sequencing. Since interferon autoantibody screening currently is available only in research laboratories, consider to go directly to sequencing of AIRE. Combined immune deficiency (CID) due to hypomorphic recombination-activation gene (RAG) mutations including Omenn syndrome, and granulomatous disease and/or autoimmunity. Other abbreviations: POI, premature ovarian insufficiency; OSAD organ-specific autoimmunity; MG, myasthenia gravis.
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Comment in

  • Autoimmune Polyendocrine Syndromes.
    Yanai H. Yanai H. N Engl J Med. 2018 Jun 28;378(26):2542-3. doi: 10.1056/NEJMc1805308. N Engl J Med. 2018. PMID: 29952181 No abstract available.
  • Autoimmune Polyendocrine Syndromes.
    Sepe V, Velluzzi F, Songini M. Sepe V, et al. N Engl J Med. 2018 Jun 28;378(26):2543. doi: 10.1056/NEJMc1805308. N Engl J Med. 2018. PMID: 29952183 No abstract available.

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