Autoimmune amelogenesis imperfecta in patients with APS-1 and coeliac disease

Ameloblasts are specialized epithelial cells in the jaw that have an indispensable role in tooth enamel formation—amelogenesis 1 . Amelogenesis depends on multiple ameloblast-derived proteins that function as a scaffold for hydroxyapatite crystals. The loss of function of ameloblast-derived proteins...

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Published in:	Nature (London) Vol. 624; no. 7992; pp. 653 - 662
Main Authors:	Gruper, Yael, Wolff, Anette S. B., Glanz, Liad, Spoutil, Frantisek, Marthinussen, Mihaela Cuida, Osickova, Adriana, Herzig, Yonatan, Goldfarb, Yael, Aranaz-Novaliches, Goretti, Dobeš, Jan, Kadouri, Noam, Ben-Nun, Osher, Binyamin, Amit, Lavi, Bar, Givony, Tal, Khalaila, Razi, Gome, Tom, Wald, Tomáš, Mrazkova, Blanka, Sochen, Carmel, Besnard, Marine, Ben-Dor, Shifra, Feldmesser, Ester, Orlova, Elisaveta M., Hegedűs, Csaba, Lampé, István, Papp, Tamás, Felszeghy, Szabolcs, Sedlacek, Radislav, Davidovich, Esti, Tal, Noa, Shouval, Dror S., Shamir, Raanan, Guillonneau, Carole, Szondy, Zsuzsa, Lundin, Knut E. A., Osicka, Radim, Prochazka, Jan, Husebye, Eystein S., Abramson, Jakub
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 21-12-2023 Nature Publishing Group
Subjects:	14/19 14/28 14/63 38/39 38/77 38/91 631/250/38 64/60 692/699/3017 82 82/1 82/51 82/75 82/80 AIRE protein AIRE Protein / deficiency Ameloblasts Ameloblasts / metabolism Amelogenesis Imperfecta Amelogenesis Imperfecta / complications Amelogenesis Imperfecta / immunology Antigens Antigens / immunology Antigens / metabolism Autoantibodies Autoantibodies / immunology Autoimmune diseases Breakdown Celiac Disease Celiac Disease / complications Celiac Disease / immunology Congenital anomalies Congenital diseases Crystal defects Crystals Dental enamel Dental Enamel / immunology Dental Enamel / metabolism Enamel Epithelial cells Epithelium Genes Humanities and Social Sciences Humans Hydroxyapatite Immunoassay Immunoglobulin A Immunoglobulin A / immunology Immunological tolerance Intestines / immunology Intestines / metabolism Jaw Life Sciences multidisciplinary Mutation Polyendocrinopathies, Autoimmune Polyendocrinopathies, Autoimmune / complications Polyendocrinopathies, Autoimmune / immunology Proteins Proteins / immunology Proteins / metabolism Science Science (multidisciplinary) Teeth Thymus gland
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Summary:	Ameloblasts are specialized epithelial cells in the jaw that have an indispensable role in tooth enamel formation—amelogenesis 1 . Amelogenesis depends on multiple ameloblast-derived proteins that function as a scaffold for hydroxyapatite crystals. The loss of function of ameloblast-derived proteins results in a group of rare congenital disorders called amelogenesis imperfecta 2 . Defects in enamel formation are also found in patients with autoimmune polyglandular syndrome type-1 (APS-1), caused by AIRE deficiency 3 , 4 , and in patients diagnosed with coeliac disease 5 – 7 . However, the underlying mechanisms remain unclear. Here we show that the vast majority of patients with APS-1 and coeliac disease develop autoantibodies (mostly of the IgA isotype) against ameloblast-specific proteins, the expression of which is induced by AIRE in the thymus. This in turn results in a breakdown of central tolerance, and subsequent generation of corresponding autoantibodies that interfere with enamel formation. However, in coeliac disease, the generation of such autoantibodies seems to be driven by a breakdown of peripheral tolerance to intestinal antigens that are also expressed in enamel tissue. Both conditions are examples of a previously unidentified type of IgA-dependent autoimmune disorder that we collectively name autoimmune amelogenesis imperfecta. A large fraction of patients with APS-1 and coeliac disease develop enamel dystrophy, characterized by the presence of autoantibodies against the enamel matrix, which are generated through the breakdown of either central (APS-1) or peripheral (coeliac) tolerance to a battery of ameloblast-sepecific proteins.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0028-0836 1476-4687
DOI:	10.1038/s41586-023-06776-0