Researchers at the Garvan Institute of Medical Research have identified the cellular glitches responsible for a rare genetic disorder called activated PI3K Delta syndrome 2 (APDS2).
This disorder, along with another immunodeficiency disorder, is caused by genetic variations that disrupt immune cell signaling through a protein known as PI3K, which plays a crucial role in the function of immune cells.
The results of the study show us “how signalling in the immune system needs to be tightly balanced to make an effective response to infection. Sometimes it’s turned down and you have a problem, and sometimes signalling being turned up can interfere with an immune response,” adds senior author Associate Professor Elissa Deenick.
The function of immune cells, including their growth, proliferation, survival, migration, and function, depends on the crucial role played by PI3K. The researchers discovered that genetic variations in the PIK3R1 gene cause APDS2, and variations in PIK3CD cause APDS1, both of which result in increased PI3K signaling.
However, these disorders exhibit distinct immune effects due to their subtle differences in specific cells, timescales, and mechanisms. In APDS2, fewer B cells are produced in response to vaccination, while in APDS1, the number of T cells is reduced. Poor antibody responses result from both disorders.
Furthermore, APDS2 variations appear to affect non-immune cells, causing growth delays.
In general, these findings provide insights into the signals that are necessary to achieve effective vaccine responses.
“Even for people who don’t have these two rare genetic conditions, other genes can impact these pathways – which could contribute to why different people have varied responses to vaccinations,” adds co-author Dr. Tina Nguyen.
The results highlight the delicacy of immune cell signaling and how even minor disruptions can result in immune deficiency or dysfunction. They represent a significant advancement towards comprehending the molecular mechanisms and devising more precise and effective therapies for these disorders.
“People with mysterious conditions often face challenges in obtaining an accurate diagnosis and understanding the root causes of their health issues. With better access to genomic testing,” explains senior investigator Professor Stuart Tangye, “it’s going to become much easier for patients to receive diagnoses for conditions like APDS2.
“Knowing the genetic basis of a disease can enable targeted, personalised treatment plans that give patients the best chance of effective management or, hopefully over time, a cure.”
The Journal of Experimental Medicine published the research. The subsequent stage entails exploring how to track individual responses to therapy, creating blood tests that can monitor immune health and dysfunction to provide the appropriate drug at the right dose and time.
Source: 10.1084/jem.20221020
