Immunology Research Finds New Immune Disease Target

A medical mystery inspired a Yale-led study with potential treatments for autoimmune diseases. A young girl had blood cell issues, breathing problems, and diarrhea, along with low antibody levels and recurrent infections. She was treated with steroids and immunoglobulin therapy. Dr. Carrie Lucas’s lab at Yale studies rare immune disorders in children caused by single gene mutations to better understand human immunology.

Genome sequencing revealed that the girl’s symptoms were due to mutations causing a deficiency in PI3Kγ, a signaling molecule in immune cells. This mutation led to immune damage in her gut and lungs and reduced her antibody levels. This discovery was published in Nature Communications in September 2019.

Lucas’s team at Yale School of Medicine then explored the role of PI3Kγ in antibody response and found it helps B cells become antibody-secreting cells. This new understanding, published in Nature Immunology on July 3, could help treat autoimmune diseases by blocking PI3Kγ to reduce antibody overproduction.

Lucas said, “These single-gene defect diseases teach us fundamental biology. We’re hopeful this could lead to new autoimmune treatments.”

B cells become antibody-producing cells through activation when an antigen binds to their receptors. This forms germinal centers, like factories for B cells to turn into antibody-secreting cells (ASCs) or memory cells. Memory cells help the body remember antigens for a faster response if they return. At the same time, ASCs release large amounts of antibodies to fight invaders.

Carrie Lucas, PhD, explains that understanding this process better could lead to new ways to treat autoimmune diseases.  

PI3Kγ is crucial for B cell differentiation. Inspired by a patient’s genetic mutation and low antibody levels, Lucas’Lucas’ team investigated PI3Kγ’sPI3Kγ’s role in antibody production.

They created genetically modified mice lacking PI3Kγ and exposed them to microbes. These mice had defective antibody production, showing PI3Kγ is vital for antibodies in both mice and humans.

The team then used mouse models to remove PI3Kγ from specific immune cells, like B cells and T cells. They found that without PI3Kγ, B cells had reduced antibody production, similar to their patient. This showed that PI3Kγ is necessary for B cells to function correctly. PI3Kγ is crucial during B cell differentiation into antibody-secreting cells, not during activation or germinal center formation.

Lucas is excited about their findings from patient-driven research, which revealed a crucial role in B cell differentiation and a potential target for treating autoimmune diseases. Current autoimmune treatments often eliminate B cells, increasing infection risks.

PI3K inhibitors, used for some cancers, might help control overactive immune systems. Lucas’s team, with Dr. Neil Romberg, tested a PI3Kγ-targeting drug on human tonsil models, finding it blocked B cells from becoming antibody-secreting cells. This supports their mouse data, indicating it could help stop excessive antibody responses.

Future studies will test PI3K inhibitors in mouse models for autoimmunity. Lucas emphasizes that studying rare genetic diseases can provide essential insights into broader health issues.

“We started with a patient, identified the gene, and discovered new mechanisms, which could help treat autoimmunity,” Lucas said.

Journal reference:

1. akeda, A.J., Maher, T.J., Zhang, Y. et al. Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology. Nature communications. DOI: 10.1038/s41467-019-12311-5.
2. Lanahan, S.M., Yang, L., Jones, K.M. et al. PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells. Nature Immunology. DOI: 10.1038/s41590-024-01890-1.