REHOVOT, ISRAEL—December 2, 2023— Enamel, the hardest and most mineral-rich substance in the human body, covers and protects our teeth. But in one of every 10 people – and one-third of children with celiac disease – this layer appears defective, failing to protect the teeth properly. As a result, teeth become more sensitive to heat, cold and sour food, and they may decay faster. In most cases, the cause of the faulty enamel production is unknown.
Now, a study published recently in Nature by Prof. Jakub Abramson and his team at the Weizmann Institute of Science may shed light on this problem by revealing a new children’s autoimmune disorder that hinders proper tooth enamel development. The disorder is common in people with a rare genetic syndrome and in children with celiac disease, and these findings could help develop strategies for early detection and prevention.
Tooth enamel is made up primarily of mineral crystals that are gradually deposited on protein scaffolds. Once the crystals are in place, the protein scaffold is dismantled, leaving behind a thin but exceptionally hard layer that covers and protects our teeth. However, a strange phenomenon was identified in people with a rare genetic disorder known as APS-1: Although the enamel layer of their milk teeth forms perfectly normally, something causes faulty enamel development in their permanent teeth. Since people with APS-1 suffer from a variety of autoimmune diseases, Abramson and his team hypothesized that the observed enamel defects could be a result of their immune systems attacking their own proteins or cells that are necessary for enamel formation.
In general, autoimmune diseases occur when the immune system’s T cells or antibodies mistakenly trigger an immune response against the body’s own cells or tissues. To prevent these incidents of “friendly fire,” T cells developing in the thymus gland need to first be educated to discriminate between the body’s own proteins and those of foreign origin. To this end, T cells are presented with short segments of self-proteins that make up various tissues and organs in the body. When a “poorly educated” T cell erroneously identifies a self-protein in the thymus as a target for attack, it’s labeled as dangerous and is destroyed so that it can’t cause any damage after being released from the thymus.
This critical education step is impaired in APS-1 patients as a result of a mutation in a gene known as the autoimmune regulator (Aire). Aire is essential for the T cell education process, producing a protein that is responsible for the collection of self-proteins presented to the T cells in the thymus. In their new study, scientists from Abramson’s lab in Weizmann’s Immunology and Regenerative Biology Department, led by research student Yael Gruper, sought to learn how mutations in the Aire gene lead to deficient tooth enamel production.
The researchers discovered that in the absence of Aire, proteins that play a key role in the development of enamel are not presented to the T cells in the thymus gland. As a result, T cells that are liable to identify these proteins as targets are released from the thymus, and they encourage the production of antibodies to the enamel proteins. However, researchers weren’t sure why these autoantibodies damage permanent teeth and not baby teeth.
The answer to this question lies in the fact that milk teeth develop in the embryonic stage, when the immune system is not yet fully formed and cannot create autoantibodies. In contrast, the development of enamel on permanent teeth starts at birth and continues until around the age of six, when the immune system is mature enough to thwart enamel development.
Researchers also found a correlation between high levels of antibodies to enamel proteins and the severity of the harm to enamel development in children with APS-1. This strengthens the assumption that the presence of enamel-specific autoantibodies in childhood can potentially lead to dental problems.
When the researchers looked into deficiencies in enamel development in people with other autoimmune diseases, they found a very similar phenomenon in children with celiac disease, a relatively common autoimmune disorder that affects around 1% of people in the West. When people with celiac disease are exposed to gluten, their immune systems attack and destroy the cellular layer lining the small intestine, leading to attacks on other self-proteins in the intestine.
In an attempt to understand how celiac disease causes damage to tooth enamel, the researchers first examined whether people with this disease have autoantibodies that attack enamel. They found that a large proportion of celiac patients have these autoantibodies, as do people with APS-1, but it wasn’t clear why the antibodies developed when the “education” that takes place in the thymus gland of these patients seemed normal. The researchers hypothesized that some proteins are found in both the intestine and the dental tissue and that these proteins play an important role in the development of tooth enamel. In this case, the antibodies that identify proteins in the intestine might move through the bloodstream to the dental tissue, where they could disrupt the enamel production process.
Since many celiac patients have previously been found to develop sensitivity to cow’s milk, the researchers decided to focus on the k-casein protein, a major component of dairy products. Strikingly, they found that the human equivalent of k-casein is one of the main components of the scaffold necessary for enamel formation. This led them to hypothesize that antibodies produced in the intestines of celiac patients in response to certain food antigens, such as k-casein, may subsequently cause collateral damage to the development of enamel in the teeth, similar to the way in which antibodies against gluten can eventually trigger autoimmunity against the intestine.
They further discovered that most of the children diagnosed with celiac had high levels of antibodies against k-casein from cows’ milk, which can also react against k-casein’s human equivalent expressed in the enamel matrix. This showed that, in theory, the same antibodies that are produced in the intestine against the milk protein could act against the human k-casein in the teeth.
These findings could have implications for the food industry. “Similarly to the lessons learned from gluten, we can assume that the consumption of large quantities of dairy products could lead to the production of antibodies against k-casein,” Abramson explains. “This protein increases the amount of cheese that can be produced from milk, so the dairy industry deliberately raises its concentration in cow's milk. Our study, however, found that the milk k-casein is a potent immunogen, which may potentially trigger an immune response that can harm the body itself.”
Tooth enamel flaws are common, not just among people with celiac disease or APS-1, and these findings could lead to improved enamel development in the future.
“Many people suffer from impaired tooth enamel development for unknown reasons,” Abramson says. “It is possible that the new disorder we discovered, along with the possibility of diagnosing it in a blood or saliva test, will give their condition a name. Most important, early diagnosis in children may enable preventive treatment in the future.” – Prof Jakub Abramson, Weizmann Institute of Science
Also participating in the study were Prof. Anette S. B. Wolff and Prof. Eystein S. Husebye from the University of Bergen and Haukeland University Hospital, Norway; Liad Glanz, Dr. Yonatan Herzig, Dr. Jan Dobeš, Dr. Noam Kadouri, Osher Ben-Nun, Amit Binyamin, Bar Lavi, Tal Givony, Razi Khalaila, Tom Gome and Carmel Sochen from Weizmann’s Immunology and Regenerative Biology Department; Dr. František Špoutil, Goretti Aranaz Novaliches, Dr. Blanka Mrázková, Dr. Radislav Sedláček and Dr. Jan Procházka from the Institute of Molecular Genetics of the Czech Academy of Sciences; Eng. Dr. Adriana Osičková, Dr. Tomáš Wald and Eng. Dr. Radim Osička from the Institute of Microbiology of the Czech Academy of Sciences; Prof. Mihaela Cuida Marthinussen from the University of Bergen and Oral Health Centre of Expertise, Norway; Marine Besnard and Dr. Carole Guillonneau from Nantes Université, France; Dr. Shifra Ben-Dor and Ester Feldmesser from Weizmann’s Life Sciences Core Facilities Department; Elizaveta M. Orlova from the Institute of Paediatric Endocrinology, Moscow; Prof. Csaba Hegedűs, Dr. István Lampé, Dr. Tamás Papp and Prof. Zsuzsa Szondy from the University of Debrecen, Hungary; Prof. Szabolcs Felszeghy from the University of Debrecen, Hungary, and the University of Eastern Finland; Prof. Esti Davidovich from the Hebrew University-Hadassah School of Dental Medicine; Dr. Noa Tal, Prof. Dror S. Shouval and Prof. Raanan Shamir from Schneider Children’s Medical Center of Israel; and Prof. Knut E. A. Lundin from the University of Oslo.
Prof. Jakub Abramson holds the Eugene and Marcia Applebaum Professorial Chair. His research is supported by Joseph and Sarah Bollag.
