Appreciating the complexity of the immune system and its role in many diseases

The Winer lab has helped establish three sub-specialties that are fueling the field

Dan Winer, MD, imagines a world where his child or future grandchildren will read in a class textbook or online course about one of his scientific discoveries. He is off to a good start so far, helping to develop new and emerging branches of immunology seemingly with every research topic he undertakes.

The Buck Associate Professor focuses on the many facets of the immune system to uncover the impact they have on every system in the body.

“Early in my career, I thought that the immune system is so important that it probably contributes to nearly every disease in one way or another, and that is turning out to be true,” says Winer.

Winer’s first textbook-worthy finding materialized more than a decade ago, when he and his colleagues discovered that the adaptive immune system plays a really important role in diabetes that develops in association with obesity. Before then, it was generally thought that while type-1 diabetes is a classic autoimmune disease, type-2 diabetes had little to no connection with immunology, especially adaptive immunology, the part of the immune system containing T and B cells.

As a postdoctoral fellow at the Stanford Blood Center, he and his colleagues identified that the B cells and T cells of the immune system played a role in regulating blood sugar and also adipose tissue inflammation, fundamentally changing how the development of insulin resistance and type-2 diabetes is approached. This finding turns out to be true for many other chronic diseases as well.

“I consider this work a roadmap for other diseases,” says Winer. “For instance, many other chronic diseases that were also never linked to adaptive immunological problems inside tissues later have been shown to possess similar abnormalities.” Parkinson’s disease, and Alzheimer’s disease, for example, both have B and T cell abnormalities linked to the conditions.

“Now it is in textbooks or online media, and it is incredible to think that it was unknown just a short time ago,” he says. “My daughter, Kara, is going to learn about this in school and say ‘wow, that’s what Dad did!’”

The idea that both arms, innate and adaptive, of the immune system plays a significant role in the development of metabolic disorders was so revolutionary at the time, that around 2011 a new field of immunology was coined: “immunometabolism.” Winer and his colleagues, including his twin brother, Shawn, at the University of Toronto and Stanford University were instrumental in laying down the foundations of how adaptive immune cells control metabolic diseases. “It doesn’t happen every day that you get to help the early development of a new field of medicine,” he says.

But for Winer, the new fields he is fostering keep coming at a steady clip. His lab at the University of Toronto was the first to show that the immune system living in the intestines can control systemic diseases linked to diet or aging, like insulin resistance. His work was related to obesity, but recently the process has been shown to be occurring in neurological diseases.

“We keep finding things that are then being applied to other diseases of aging,” he says. “T cells and B cells inside tissues, and now the gut immune cells are a focal point of controlling inflammation across the body in many diseases.”

Over the last few years, Winer’s work has added to immunology textbooks again, this time putting together a new theory about how the immune system senses danger. He presents compelling evidence that immune cells respond not only to the classical chemical signals (sensing the presence of a pathogen) but also utilize mechanical signals (information about the physical environment, such as stiffness, tension, or pressure).

As he was researching diabetes and obesity, he noticed that as fat tissue becomes inflamed, it also stiffens and develops scars. There was scarce research on what that meant for the immune system, so he got to work exploring the idea. “Years ago, probably around 2015,we started working on the idea that mechanical forces in the cellular environment can actually shape or fine-tune inflammatory responses,” he says. For example, in some cells, more stiffness or pressure can elicit a stronger immune response.

This new field, now called ‘mechanoimmunology’, became the second new field of biology in which he got an early start.  “Since 2020, mechanoimmunology is really starting to gain traction amongst immunologists,” he says.

 Field number three is well underway in his Buck laboratory. An offshoot of his mechanoimmunology studies, Winer is intrigued by how immune cell function is altered under the reduced gravity environment of space travel. “That lack of gravity has profound effects on immune cell function,” he says. The immune system weakens, latent viruses reactivate and some aspects of the processes of aging may be greatly accelerated.

The study of the immune system in space or its simulated environments, called “astroimmunology,” is just beginning. “The research is still very early but in the next 10 years it is going to be unbelievable how many people will want to be involved in this field,” he says.

“Overall, I want to understand new roles of the immune system in unexpected conditions or environments,” he says. “One finding builds on another, and someone else will build on that in 20 years, so that eventually maybe my grandkids will read about something built upon work I did.”