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Like all big discoveries, this one begins with a story.
Carrie Lucas, an associate professor at the Yale School of Medicine, first learned about a young girl who had abnormal blood cell levels through her clinical colleagues at the National Institutes of Health (NIH). The girl later developed trouble breathing and diarrhea. Lucas was intrigued because the patient’s immune disease had two components: immunodeficiency and inflammation. The girl’s antibody levels were low, which caused her to suffer from a cycle of reinfection in her lungs. She also had inflammation in her gut and lungs. Previously, her doctors gave her anti-inflammatory drugs and antibodies to increase her defenses against infection.
The girl’s immune system was malfunctioning, but it wasn’t clear how or why. Our immune system consists of the innate and the adaptive system. The innate system recognizes invading microorganisms and responds to pathogens quickly. However, these initial defenses are sometimes not enough, so the innate system communicates with the adaptive system to mount a more specific response to an invading microbe. B cells are a part of the adaptive system. They are a type of white blood cell that can transform into antibody-secreting cells (ASC). The B cell receptors (BCR) on their surface recognize and bind to antigens—foreign molecules in our bodies. Once BCRs are secreted by ASCs, they are referred to as antibodies. Antibodies, “Y”-shaped proteins that recognize and bind to intruding antigens, block microbes from causing infections and alert the immune system to attack the foreign substance.
Lucas, whose lab focuses on children with rare genetic immune disorders, was determined to uncover what was happening to the young girl. After sequencing her genome, Lucas and her team discovered that the girl had a mutation that causes a decreased production of phosphatidylinositol 3-kinase-gamma (PI3Kγ), a signaling molecule in the immune system. Lucas was fascinated by the unexpected connection between this molecule and antibody production since prior knowledge would not have predicted low antibodies from PI3Kγ deficiency. Further research conducted by scientists in the lab revealed that PI3Kγ plays a crucial role in the ability of B cells to become ASCs. “What’s great about this type of discovery is that it starts with patients with rare diseases who we aim to help by uncovering why are they sick, both from a genetic and immunological standpoint, and it advances to a better understanding of the fundamental biology of how our immune systems work, offering opportunities to apply that new knowledge across a range of disease context,” Lucas said.
To determine that this mutation was responsible for the young girl’s symptoms, the Lucas Lab used a mouse model that lacked the PIK3CG gene, which encodes PI3Kγ. As a first assessment, they co-housed the lab mice with mice from a pet store. Unlike lab mice, which have a very ‘clean’ microbiome due to the controlled laboratory environment, pet-store mice possess a more diverse gut microbiome developed through more interactions with the natural environment and other animals. Taking into account the fact that gut microbiota have a major impact on immune cells was important when imitating human PI3Kγ deficiency. Co-housing the lab mice with the pet store mice simulated those external factors in the human patient’s environment that could be implicated in the development of disease symptoms. They found that the lab mice with the deficient gene developed symptoms similar to those of the human patient, establishing a causal relationship between the gene loss and the disease symptoms.
These findings can potentially be applied to a wide range of diseases. Lucas highlighted diseases like lupus and rheumatoid arthritis, in which the immune system mistakenly reacts against the body’s healthy cells. “Some of these diseases are characterized by antibodies that bind to your tissues, so it raises the idea that now that we have learned from this rare disease that PI3Kγ is so important for the step of becoming an ASC, maybe we could help patients who have antibody-mediated disease by inhibiting this [signaling molecule] so disease-causing antibodies are reduced,” Lucas said. From the discovery of a rare mutation in a single patient to the dedicated research in Yale’s labs, this story emphasizes the potential for patient-driven research to produce great advances in knowledge and, in the long run, new avenues for treatment options for a range of diseases.