Friendly Fireby EMILY AYSHFORD | illustrations by CHRISTINA WHEELER
Exploring the origins of autoimmunity to find new therapies.
The National Institutes of Health estimates that up to 23.5 million Americans suffer from an autoimmune disease, and the prevalence is rising. Some autoimmune diseases are life-threatening; most require a lifetime of treatment. Some, such as Type 1 diabetes, multiple sclerosis, lupus and rheumatoid arthritis, are well known; others are rare and difficult to diagnose.
Understanding and treating these diseases requires new ways of thinking about the immune system, at the cellular, molecular and genetic levels, as well as at the organ and body-wide levels. Northwestern physicians and scientists are collaborating to examine just how this system functions — and how they can use that information to both find innovative therapies and stimulate it to work even better.
Above: Colored transmission electron micrograph of a section through a mast cell. Image by Steve Gschmeissner/Science Source
Inner Workings of Cells
While T-cells help provide immunity to the body, a subset of those cells, regulatory T-cells (Treg cells), modulate the immune system and suppress aberrant immune responses against self-antigens. They also maintain helpful bacteria in the gut (even in fetuses in utero), thus ensuring the body does not become inappropriately inflamed. Now, Northwestern scientists have discovered that a specific mitochondrial protein complex is essential to this immunosuppressive activity. The study was
published in Nature.
It started five years ago, with what seemed like a simple question, posed by Navdeep Chandel, PhD, the David W. Cugell, MD, Professor of Medicine in the Division of Pulmonary and Critical Care and of Biochemistry and Molecular Genetics: What do mitochondria do in a Treg cell? When investigators in Chandel’s lab removed mitochondrial function from Treg cells in mice, the mice rapidly developed autoimmune diseases. The Treg cells were alive and functioning without mitochondria, but they weren’t doing their job keeping inflammation in check.
Investigators found that by removing a specific protein within mitochondrial complex III, the cell suffered a buildup of the metabolite L-2-hydroxyglutarate (L-2HG) that diminished the function of DNA demethylases enzymes. This action, in turn, altered DNA methylation marks that suppressed the ability of Treg cells to function as an immune system referee.
“It’s very much a network,” explains Chandel’s collaborator and study co-author Benjamin Singer, MD, assistant professor of Medicine in the Division of Pulmonary and Critical Care and of Biochemistry and Molecular Genetics. “When you change one little piece, the downstream effects are dramatic.”
That built-up metabolite could be an underlying cause for autoimmune disorders, according to Chandel.
“It opens a whole new way of thinking about cell biology and diseases,” he says. Understanding the cellular metabolic mechanisms that cause autoimmunity could also provide a new way for the body to harness autoimmunity in situations where it is preferable — in fighting tumors, for example.
“The real dream would be to uncover a causal mechanism that leads to medication or cell-based therapies,” Singer adds.
From Laboratory Mistake to Discovery
Brown studies how the immune system’s lymphocyte cells are affected by the body’s innate cells. Innate cells provide the body with general immunity by acting as barriers and recruiting immune cells to sites of infection. One type of these innate cells is mast cells, which are found in most tissues of the body, including the brain and spinal cord. They work as a first defense to protect the body against pathogens. They also play a role in allergic reactions.
Because more than 75 percent of those diagnosed with an autoimmune disease are women, when immunologists like Brown study the diseases in mice they usually use only females. While studying female mice with multiple sclerosis (MS), Brown found that the disease was reduced significantly in those mice that had been genetically engineered to lack mast cells. But the research was flipped on its head when a new graduate student conducted the same study using male mice. The experiment was an accident — the student did not know the lab only used female mice in its experiments. The results were striking.
“We got the exact opposite response,” Brown says. “While females without mast cells had disease reduction, males without mast cells got very sick.” That finding led Brown to ask a different question. Instead of focusing on what caused MS in female mice, she began to search for what conferred protection in male mice.
It turned out that testosterone primes male mast cells to make a guardian molecule called IL-33, which protects against autoimmunity. When Brown gave female mice IL-33, she found that not only did it prevent MS from developing, but it also reversed established disease. The findings were published in Proceedings of the National Academy of Sciences of the United States of America (PNAS).
“That’s the holy grail in MS,” she says. “Not only do you want to stop progression, but you also want to reverse the damage already done.”
Her lab is now studying whether IL-33 treatment in mice is safe and free from possible damaging side effects with hopes of ultimately using this molecule to treat human patients. Though human trials are further down the road, Brown’s research has been rejuvenated by the finding. “We really have in sight the possibility that there is a therapy that can reverse MS,” she says.
Whole System Approach
Understanding what happens within a cell’s mitochondria or how a disease reacts to a molecule is just one part of understanding how immunity and autoimmunity work throughout the body’s complex network.
That’s why Singer and his colleague, Richard Wunderink, MD, professor of Medicine in the Division of Pulmonary and Critical Care, are conducting a multi-year investigation that examines all the cells — bacteria and immune cells — within the lungs of patients with pneumonia so severe that they are on ventilators in the ICU. Using bioinformatics, the investigators hope to put together all the pieces of the puzzle that determines why some patients with pneumonia respond to antibiotics, while others don’t.
“To do that, we are taking a systems biology approach,” Wunderink says.
A routine clinical procedure called non-bronchoscopic bronchoalveolar lavage allows access to these patients’ lungs. It involves squirting saline solution deep within the lungs and then sucking it back out to obtain a rich collection of cells, including bacteria, viruses, fungi and immune system cells. The investigators then separate out those cells, measure them and sequence them to get a systems-level understanding of the immune response.
“Our hypothesis is that an interaction among all these cells is allowing bacteria to survive, affecting immunity,” Wunderink says. “We don’t just need to kill bacteria better. We need to find a way to modulate that interaction between bacteria and the human immune system. We are trying to put the whole picture together.”
“We need to find a way to modulate that interaction between bacteria and the human immune system. We are trying to put the whole picture together.”
Where Immunity Goes Right — and Wrong
Proteins offer clues to how our immune system responds:
- In studying lupus, investigators found that the loss of a protein called Bim in immune cells called macrophages led to
the development of a lupus-like disease in mice. The research, conducted by Harris Perlman, PhD, the Mabel Greene Myers Professor of Medicine and chief of Rheumatology in the Department of Medicine, shows that the protein may help control macrophage function and could be a target for lupus treatment.
- When a patient has a heart attack, key heart cells called cardiomyocytes die and need to be cleared away for the heart to heal. Research led by Edward Thorp, PhD, associate professor of Pathology and Pediatrics, identified a protein called MerTK that enables macrophages to engulf the dying cells and promoted anti-inflammatory proteins that encourage healing. His team also found that a protein called CD47 prevented this clearing, and by blocking the protein, they could enhance healing.
- Scientists have discovered that three proteins — POP1, POP2 and POP3 — play a role in controlling inflammatory processes and preventing systemic inflammation. Most recently, Christian Stehlik, PhD, adjunct professor of Medicine in the Division of Rheumatology, found that POP2 inhibited a key inflammatory pathway.