Autoimmune Diseases: Why Diabetes rather than Arthritis?

11/11/2019

Most autoimmune diseases share as much as 30 to 50 percent of their candidate genes in common: then how can we explain that one specific disease develops instead of another? In a new study published i

INDIANAPOLIS, IND. -- Autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, multiple sclerosis etc., are a case of “mistaken identity;” the immune system that is supposed to protect us starts instead to attack our own tissues. 

Most autoimmune diseases have a strong genetic component, with candidate genes that increase risk or provide protection against the disease. Several autoimmune diseases have as much as 30 to 50 percent of their candidate genes in common, which raises the question of why one individual may develop type 1 diabetes and another may develop rheumatoid arthritis.

A study co-led by Decio L. Eizirik, a WELBIO researcher at Université libre de Bruxelles’ Centre for Diabetes Research, and Senior Research Fellow at the Indiana Biosciences Research Institute (IBRI) provides insight to understand this phenomenon. While most of the research in the field has focused on the role for these candidate genes on the immune system, Decio L. Eizirik’s team has investigated their impact on pancreatic beta cells that produce insulin.

Published in Nature Genetics Nov. 2, 2019, this work was done in collaboration with colleagues from Barcelona, Oxford, Pisa and the National Institute of Health (USA). The researchers have discovered that many of these candidate genes affect the function and survival of pancreatic beta cells and the generation of signals that alert and attract the immune system. These dysfunctional signals lead to a misguided dialog between the beta cells and the immune system, rendering beta cells a potential target for the immune system. This immune “attack” happens under special conditions, for instance secondary to local inflammation caused by a viral infection or other “danger signals.”

The teams involved in the project have studied in detail the chromatin behaviour of beta cells exposed to pro-inflammatory signals. The chromatin is a complex of DNA and protein present in the cell nucleus that allows close packaging of long DNA molecules; for gene transcription to occur, chromatin must “open” and provide access to transcription factors. In the present project, the researchers’ observations indicate that binding of tissue-specific transcription factors (factors that regulate expression of specific genes, such as insulin, in beta cells) “open” the chromatin: this allows binding of pro-inflammatory transcription factors induced in the beta cells by local inflammation. This process is amplified in individuals genetically predisposed to type 1 diabetes and may culminate in progressive beta cell death and diabetes.

The present study has clarified the role for pancreatic beta cells in type 1 diabetes and provided an explanation for the reasons behind the immune system targeting beta cells. This “amplifying loop” mechanism also could explain other autoimmune diseases: binding of tissue-specific transcription factors, within an inflammatory context and in genetically predisposed individuals, could generate signals that would attract and activate immune cells against specific target tissues. This intriguing hypothesis must be tested in novel studies comparing different autoimmune diseases.

About the Indiana Biosciences Research Institute

The Indiana Biosciences Research Institute (IBRI) is an independent, nonprofit discovery science and applied research institute currently targeting diabetes, metabolic disease, poor nutrition and related health data science.  Inspired by Indiana’s leading life sciences companies, research universities and philanthropic community, the IBRI is building a world-class organization of researchers, innovators and entrepreneurs to catalyse scientific discovery and its applications, resulting in improved health outcomes for Indiana patients and beyond. For more information about the IBRI, visit https://www.indianabiosciences.org/.

References

The impact of pro-inflammatory cytokines on the β-cell regulatory landscape provides new insights into the genetics of type 1 diabetes
Ramos-Rodríguez M., Raurell-Vila H., Colli ML., Alvelos MI., Subirana M., Juan-Mateu J., Norris R., Turatsinze JV., Nakayasu ES., Webb-Robertson BJ., Inshaw JRJ., Marchetti P., Piemonti L., Esteller M., Todd JA., Metz TO., Eizirik DL., Pasquali L.

DOI: 10.1038/s41588-019-0524-6

Lisa Soard
IBRI
(773) 559-5586
lsoard@indianabiosciences.org

2019 Annual Report cover

The IBRI 2019 Annual Report is now available. The report theme is “Catalyze, Complement, Connect,” which correlates with the IBRI's goals to seek solutions for health problems, enhance the Indiana life sciences ecosystem, and expedite solutions for the most pressing health issues.