A new study reveals a counterintuitive cellular strategy that may protect insulin-producing cells from destruction during type 1 diabetes. Type 1 diabetes is an autoimmune disease that accounts for about 5% of the nearly 30 million diagnosed cases of diabetes in the United States, according to the Centers for Disease Control and Prevention. The disease impairs T-cells, immune cells circulating in the body that help maintain the critical balance between destroying injured cells and preserving healthy cells. When this balance is off, subsets of T-cells can go unchecked and destroy needed cells, such as insulin-producing cells in the pancreas.
In the study published in Diabetes, researchers at Case Western Reserve University School of Medicine highlighted a potential root cause for the dysfunctional immune response seen in type 1 diabetes. Previous studies have pointed to inhibiting a protein called c-Rel as one way to protect against autoimmunity in diseases like arthritis. The study clearly shows that, against expectation, this could instead accelerate disease progression and lead to earlier onset of certain diseases, including type 1 diabetes.
“c-Rel protein is required for the function of two different types of T-lymphocytes that have opposing function,” explained Parameswaran Ramakrishnan, PhD, lead author of the study and assistant professor of pathology at Case Western Reserve School of Medicine. One type of T-cell helps carry out immune responses, and can become overactive and attack healthy tissues. The other type of T-cell helps suppress this activity and regulate appropriate immune responses. According to Ramakrishnan, “c-Rel is critical in regulating both overlapping and distinct sets of genes in these T-cell types.”
Ramakrishnan and colleagues created genetically engineered diabetic mice that lacked c-Rel to investigate the protein’s role in diabetes. After checking to be sure the genetic tinkering didn’t impact other proteins that could confound the results, the researchers measured T-cell numbers and found mice without c-Rel had a 75-80% reduction in a specific subset of T-cells, called T regulatory cells, needed to suppress autoimmunity.
The researchers collected T-cells from the pancreases of c-Rel deficient mice and found T-cells that carry out immune responses showed enhanced proliferation within the organ, suggesting over-activity in the absence of a sufficient number of T regulatory cells. This indicated to the researchers that c-Rel is required to turn down autoimmune responses and to maintain protective T-cell populations.
Mice without c-Rel were not healthy. Their pancreases were infiltrated with immune cells ready to destroy—similar to what is seen in humans during prediabetes. All of the mice lacking c-Rel became diabetic by 17 weeks of age, compared to 80% of control mice by 25 weeks of age. The accelerated diabetes could be reversed when the researchers gave the genetically engineered mice supplemental T regulatory cells containing c-Rel, although the researchers could not prevent diabetes in the mice entirely.
“We were expecting that absence of c-Rel will prevent spontaneous diabetes development in non-obese diabetic mice. But to our surprise, we found an opposite effect, where 100% of the c-Rel deficient animals developed the disease at twice faster rate,” said Ramakrishnan.
Ramakrishnan’s team plans to use their newly created animal model to further research c-Rel immune regulation in type 1 diabetes. They also plan to create additional genetically engineered mice with unique forms of c-Rel to use in the studies.
Nearly one out of every 11 people is diagnosed with diabetes in the United States, according to the Centers for Disease Control. Although a person can develop type 1 diabetes at any time, it is usually diagnosed during childhood and there is no way to prevent or cure it. Studies like Ramakrishnan’s are an important step toward understanding diabetic molecular mechanisms and may lead to new therapies to combat the disease.
The study was a collaborative effort between the Department of Pathology at Case Western Reserve School of Medicine and the Division of Biology and Biological Engineering at California Institute of Technology.
The study was supported by grants from Mizutani Foundation for Glycoscience (120022), the Clinical and Translational Science Collaborative of Cleveland (CTSC UL1-TR-000439 from the National Center for Advancing Translational Sciences component of the National Institutes of Health and NIH roadmap for Medical Research), the National Institute of Allergy and Infectious Diseases (1R01-AI-116730-01A1) to P.R., the National Institute of General Medical Sciences (2R01-GM-039458 to D.B.), the NIH (AI-64590 to M.A.Y.), and support from an American Association of Immunologists Careers in Immunology Fellowship to J.A.T and P.R.
For more information about Case Western Reserve University School of Medicine, please visit the School of Medicine's website.
Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and is among the nation's top medical schools for research funding from the National Institutes of Health. The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. The School's innovative and pioneering Western Reserve2 curriculum interweaves four themes--research and scholarship, clinical mastery, leadership, and civic professionalism--to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century. Nine Nobel Laureates have been affiliated with the School of Medicine.
Annually, the School of Medicine trains more than 800 MD and MD/PhD students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News & World Report's "Guide to Graduate Education."
The School of Medicine is affiliated with University Hospitals Cleveland Medical Center, MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002. case.edu/medicine.
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