How Does Friendly Fire Happen in the Pancreas?

Type 1 diabetes is an autoimmune disease in which the body destroys its own beta cells in the pancreas.* Researchers are still seeking to find out what causes this malfunction of the immune system in order to intervene therapeutically in the processes. A team led by Dr. Carolin Daniel, group leader at the Institute of Diabetes Research (IDF) of Helmholtz Zentrum München, has now discovered a further piece in solving this puzzle.

“For the first time, we were able to show that in the affected children an increased number of specific immune cells are found in the blood at the beginning of the autoimmune response,” said Daniel. She and her team had previously analyzed blood samples of children in a biobank established by Professor Anette-Gabriele Ziegler, director of the IDF, within the framework of large-scale cohort studies.

According to the authors, these special immune cells are so-called insulin-specific T follicular helper cells (TFH). They appear in the lymph nodes, among other organs, and initiate attacks of the immune system by promoting the production of antibodies by B cells. Now the scientists have found increased frequencies of these cells in samples of children with recent onset of islet cell autoimmunity – an early stage of type 1 diabetes.

In the search for the causes of the increase in TFH cells during autoimmune activation in children, the scientists discovered a previously unknown signaling pathway. “Our analyses showed that a molecule called miRNA92a** triggers a chain of molecular events, which ultimately leads to the increase in these immune cells,” said IDF doctoral student Isabelle Serr, explaining the complex mechanism. “In particular, during this process, miRNA92a interferes with the formation of important signaling proteins such as KLF2 and PTEN.”

Use in therapy and diagnostics

To check whether this newly discovered mechanism is suitable for therapeutic intervention, the scientists investigated the effect of a so-called antagomir, which specifically binds to miRNA92a molecules and blocks their effect. In an experimental model of type 1 diabetes and in the humanized model, this treatment resulted in a significantly lower autoimmune response.

“The targeted inhibition of miRNA92a or the downstream signaling pathway could open up new possibilities for the prevention of type 1 diabetes,” said Professor Ziegler. “Furthermore, the insulin-specific TFH cells could serve as biomarkers to determine the treatment success of the insulin vaccinations we perform.”

Further Information

* In type 1 diabetes, the insulin-producing cells in the Langerhans islets of the pancreas are destroyed because they are attacked by the body’s immune system (formation of islet autoantibodies against structures of the beta cells). As a result, the body can no longer be adequately supplied with insulin. If the destruction of the beta cells exceeds a certain degree, the disease becomes manifest and blood glucose levels rise due to insulin deficiency.

** microRNAs (miRNAs) are noncoding RNAs which play an important role in gene regulation and in particular in the inactivation of genes. In general, they have a size of 21 to 23 nucleotides, so they are very short – hence the name.

Background:
In previous studies, the researchers led by Dr. Carolin Daniel had already shown that a vaccination with optimized insulin mimetopes can slow the immune response against the beta cells of the pancreas. In particular, the regulatory T-cells of the immune system contributed to the prevention of self-destruction. https://www.helmholtz-muenchen.de/en/press-media/press-releases/2016/press-relea…

Original Publication:
Serr, I. et al. (2016). miRNA92a targets KLF2 and PTEN signaling to promote human T follicular helper precursors in T1D islet autoimmunity, DOI: 10.1073/pnas.1606646113

The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. http://www.helmholtz-muenchen.de/en

Technical University of Munich (TUM) is one of Europe’s leading research universities, with more than 500 professors, around 10,000 academic and non-academic staff, and 40,000 students. Its focus areas are the engineering sciences, natural sciences, life sciences and medicine, combined with economic and social sciences. TUM acts as an entrepreneurial university that promotes talents and creates value for society. In that it profits from having strong partners in science and industry. It is represented worldwide with a campus in Singapore as well as offices in Beijing, Brussels, Cairo, Mumbai, San Francisco, and São Paulo. Nobel Prize winners and inventors such as Rudolf Diesel, Carl von Linde, and Rudolf Mößbauer have done research at TUM. In 2006 and 2012 it won recognition as a German “Excellence University.” In international rankings, TUM regularly places among the best universities in Germany. http://www.tum.de/en/homepage

The Institute of Diabetes Research (IDF) focuses on the pathogenesis and prevention of type 1 diabetes and type 2 diabetes and the long-term effects of gestational diabetes. A major project is the development of an insulin vaccination against type 1 diabetes. The IDF conducts long-term studies to examine the link between genes, environmental factors and the immune system for the pathogenesis of type 1 diabetes. Findings of the BABYDIAB study, which was established in 1989 as the world’s first prospective birth cohort study, identified risk genes and antibody profiles. These permit predictions to be made about the pathogenesis and onset of type 1 diabetes and will lead to changes in the classification and the time of diagnosis. The IDF is part of the Helmholtz Diabetes Center (HDC). http://www.helmholtz-muenchen.de/en/idf/index.html

The German Center for Diabetes Research (DZD) is a national association that brings together experts in the field of diabetes research and combines basic research, translational research, epidemiology and clinical applications. The aim is to develop novel strategies for personalized prevention and treatment of diabetes. Members are Helmholtz Zentrum München – German Research Center for Environmental Health, the German Diabetes Center in Düsseldorf, the German Institute of Human Nutrition in Potsdam-Rehbrücke, the Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Medical Center Carl Gustav Carus of the TU Dresden and the Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the Eberhard-Karls-University of Tuebingen together with associated partners at the Universities in Heidelberg, Cologne, Leipzig, Lübeck and Munich. http://www.dzd-ev.de/en/index.html

Contact for the Media
Department of Communication, Helmholtz Zentrum München – German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, 85764 Neuherberg, Germany – Tel. +49 (0)89 3187 2238 – Fax: +49 (0)89 3187 3324 – E-mail: presse@helmholtz-muenchen.de

Scientific Contact
Dr. Carolin Daniel, Helmholtz Zentrum München – German Research Center for Environmental Health (GmbH), Institute for Diabetes Research, Young Investigator Group “Immunological Tolerance in Type 1 Diabetes”, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany – Tel. +49 (0)89 3187 2188 – E-mail: carolin.daniel@helmholtz-muenchen.de