Role of pre-TCR-alfa in immunodeficiency further unraveled

8 March 2024

Leuven doctors colloborated on an international study that discovered that mutations in the gene for pre-TCR-α can lead to immunodeficencies and auto-immune diseases in some carriers. The results have been published in the scientific journal Science.

Prof. dr. Rik Schrijvers, internist and allergologist at UZ Leuven: "Our research suggest that subtle genetic deviations in pre-TCR-α present in certain populations can be a risk factor for developing immunity issues.”

Pre-TCR-α is the abbreviation for the pre-T-celreceptor α, a protein that plays an important in part in the production of T-cells, which are part of our adaptive (acquired) immune system.

In the US, newborn babies have been screened for T-cell counts during the standard blood prick for several years to detect possible immune deficiencies.  Low values can indicate the urgent need for a stem cell transplant. 

“We were put into contact with a research group from Philadelphia that had identified children with a T-cell deficiency via the screening. They were found to have a mutation in the gene for pre-TCR-α. We had also seen evidence of pre-TCR-α deficiency in Leuven in one of our adult patients suffering from a form of immune deficiency," says dr. Frederik Staels, doctor-specialist in training who did who did his doctoral research on this subject. “Like us, our American colleagues did not know yet whether this link was relevant.”

We had seen evidence of pre-TCR-α deficiency in Leuven in one of our adult patients suffering from a form of immune deficiency

A pre-TCR-α deficiency can lead to immunodeficiency

The contacts grew into an international consortium with a nice multidisciplinary cooperation, with dr. Staels, prof. dr. Rik Schrijvers and prof. dr. Isabelle Meyts from UZ Leuven representing the Belgian branch.

Prof. dr. Rik Schrijvers, one of the principal investigators: “We were able to bring together data from patients with an abnormality in pre-TCR-α and databases from different places in the world. Some patients experienced infections, lymphoproliferation or autoimmune disorders at an early age, while others did not develop symptoms until adulthood. Surprisingly, there were also carriers without symptoms, which we call 'incomplete penetration' in hereditary diseases.”

Absence of pre-TCRα can be partially compensated in humans

“Previous lab animal research had suggested that pre-TCR-α was an essential link in the development of T-cellen, more specifically for the αβ-T-celreceptor. In our patients, we indeed saw more T cells with a different receptor, namely the γδ-T cell receptor, but strangely, still mainly T cells with the αβ receptor type”, according to prof. Schrijvers. “It would seem that pre-TCR-α deficiencies can be compensated.”

Risk factor for autoimmunity in South Asia and the Middle East

We only identified a few patients with pre-TCR-α genetic abnormalities, but they were found to be more frequent in South Asia and the Middle East. “In those regions, partial deficiency affects up to 1 in 4,000 people, who are also more likely to suffer from autoimmune diseases". The research suggests that the subtle genetic deviations in pre-TCR-α present in those populations could be a risk factor for developing immunity problems.”

Last edit: 28 March 2024