Newly discovered cell may unlock secrets of type 1 diabetes

A recent scientific discovery was so remarkable, the online science news service EurekAlert! compared it to “finding medicine’s version of the Loch Ness monster”: a new type of immune cell that may play a key role in the development of type 1 diabetes.

The group’s research, published as a featured article in the May 2019 issue of the journal Cell, identified an unusual lymphocyte, a type of white blood cell, that is a dual expressor, or DE, cell. It’s a hybrid between two cells involved in the immune system, B lymphocytes and T lymphocytes.

The cell was discovered by a research team from Johns Hopkins University School of Medicine, IBM Research and four collaborating institutions. On the team was Chunfa Jie, Ph.D., a biostatistician in the department of biochemistry and nutrition at DMU. Through analysis of the data generated on the Adaptive Biotech’s ImmunoSEQ platform using the next-generation sequencing technologies, he identified a predominated clonotype in the dual expressors of type 1 diabetes (T1D). Other collaborating scientists on the team then showed those DEs encode a potent CD4 T cell autoantigen in its antigen binding site.

Chunfa Jie, Ph.D.

Jie and Patrick Cahan, Ph.D., a computational biologist at Johns Hopkins University, also performed analyses on the single-cell RNA-sequenced data to characterize the unique gene expression profiles of the DE cells and reconstruct the B-cell and T-cell receptors of the DE cell.

“Some researchers commented on PlumX Metrics, an online platform allowing people to interact with individual pieces of research output, that this finding may be revolutionizing what we know about type 1 diabetes,” Jie says. “The textbooks may need to be rewritten.”

The principal investigator on the research is Abdel-Rahim Hamad, M.V.Sc., Ph.D., associate professor of pathology at Johns Hopkins School of Medicine. He and Jie are longtime scientific collaborators.

“Our findings not only show that the X cell exists, but that there is strong evidence for it being a major driver of the autoimmune response believed to cause type 1 diabetes,” says Hamad told EurekAlert!.

Previously known as juvenile diabetes, type 1 diabetes can occur at any age and is estimated to affect 1.25 million Americans. With the disorder, the immune system mistakes the beta cells in the pancreas that produce insulin, the hormone that regulates a person’s blood sugar level, as hazards and eliminates them. The newly discovered cell may explain the underlying mechanism at the cellular level responsible for this.

“What is unique about the entity we found is that it can act as both a B cell and a T cell,” Hamad said. “This probably accentuates the autoimmune response because one lymphocyte is simultaneously performing the functions that normally require the concerted actions of two.”

B and T lymphocytes possess different cell receptors that work together to help identify and target antigens – the bacteria, viruses and other foreign invaders that trigger an immune response. Scientists have long believed that in type 1 diabetes, the B and T cells instead seek out and attack normal cells, including the beta cells that produce insulin, which leads to the high blood sugar levels that characterize diabetes. The DE lymphocyte that the researchers discovered and its cell protein, known as the x-Id peptide, occur more frequently in the blood of type 1 diabetes patients than in nondiabetic subjects.

“This finding, combined with our conclusion that the x-Id peptide primes T cells to direct the attack on insulin-producing cells, strongly supports a connection between DE cells and type 1 diabetes,” Hamad said.

Jie says the researchers will further investigate that link and the characteristics of the DE cell. Their work was supported by grants from the National Institutes of Health and the Norman Raab Foundation; this fall, the group received an additional grant from the Los Angeles-based W.M. Keck Foundation, which will provide further support. Founded with the goal of generating far-reaching benefits for humanity, the Keck Foundation is highly selective in funding projects that are high-risk with the potential for transformative impact.

Most important, Jie says, is what the research may lead to.

“Type 1 diabetes affects so many people. There’s currently no way to cure it,” he says. “This continued research may allow us to find ways to prevent it and cure it.”

The group’s paper published in Cell is titled “A Public BCR Present in a Unique Dual-Receptor-Expressing Lymphocyte from Type 1 Diabetes Patients Encodes a Potent T Cell Autoantigen.” (“BCR” refers to the cell receptor of B lymphocytes.) It has generated much excitement in the world of biomedical science, including more than 3,500 social media “shares” in less than a month.

Cell is a top biological science journal,” Jie says. “We made a good contribution to the biomedical literature. It is an excellent teamwork. Many thanks to Dr. Jeff Gray and Ms. Mollie Lyon at the DMU research office for their great support.”

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