Research Reveals Potential Target for Immune Diseases

 A medical mystery served as the genesis for a Yale-led study that has promising implications for treating a range of autoimmune diseases.

A young girl entered the clinic suffering from blood cell abnormalities, difficulty breathing, and later, diarrhea. She also had been diagnosed with recurrent infections due to low levels of antibody production. Her doctors treated her with corticosteroids to reduce her lung and gut inflammation and immunoglobulin replacement therapy to restore her antibody levels.

The lab of Carrie Lucas, PhD, associate professor of immunobiology at Yale School of Medicine, works with children living with rare immune disorders that stem from a single (monogenic) gene mutation with the goal of better understanding the intricate circuitry of human immunology.

Through genome sequencing, Lucas discovered that the girl’s symptoms were caused by mutations that created a deficiency in phosphatidylinositol 3-kinase-gamma (PI3Kγ), a signaling molecule that is found in immune cells. Immune defects caused by this mutation, the research team found, were driving immune-mediated damage in the girl’s gut and lungs, and also decreasing her antibody levels. The team published its initial discovery in September 2019 in Nature Communications.

The discovery spurred Lucas’ team to dig deeper into the biological connection between PI3Kγ and antibody response. Now, the scientists have found that PI3Kγ plays an essential role in allowing activated B cells, a type of immune cell, to differentiate into antibody-secreting cells. Beyond helping to understand disease from rare cases of human PI3Kγ deficiency, the researchers hope that other patients can also benefit from this new knowledge. By therapeutically blocking PI3Kγ, clinicians might be able to treat the overproduction of antibodies that causes the symptoms of many autoimmune diseases. The team published its new findings in Nature Immunology on July 3.

“These sorts of monogenic, single-gene defect diseases help us learn fundamental biology directly from patients,” says Lucas, who was the study’s principal investigator. “We’re excited that this could potentially help us find a new way to intervene in autoimmunity.”

Antibodies are one of the key components of the adaptive (or acquired) immune system and target foreign invaders such as bacteria or viruses. B cells play a vital role in antibody production and in immune memory that protects us from reinfection.

We’re excited that this could potentially help us find a new way to intervene in autoimmunity.

Carrie Lucas, PhD

B cells become activated when an antigen [a substance that triggers the body’s immune response] binds to its receptors. Once activated, B cells form what are called “germinal centers.” “We think of germihttps://americanscientists.org/nal centers as factories for B cells to become optimal antibody secreters and choose cell fates to support that function,” says Lucas.

B cells have multiple potential fates, including becoming memory cells or antibody-secreting cells (ASC). The role of memory cells is to “remember” specific antigens so that the body can more rapidly initiate an immune response if the antigen returns. In turn, ASCs begin releasing very large amounts of antibodies that target the intruder into the blood. However, immunobiologists have not understood all the details of the differentiation process of B cells.