International Team of Researchers Details Genetic Cause of Immune Dysregulatory Disease

A new immune dysregulatory disease, first identified in a patient at Children’s Hospital of Philadelphia (CHOP), has been deeply characterized as part of a global collaborative effort. While extremely rare, patients with this genetic disorder have been identified as newborns, adolescents and adults, and may experience significant infectious or autoimmune complications, in addition to abnormal T cell counts, but more research will be needed now that this rare disorder has been identified. The findings were published today in the journal Science.

The pre-TCRa (PTCRA) gene was first identified in the 1990s. The gene plays a major role in the early stages of differentiation of T cells in the thymus and is needed for the development of classical alpha beta (ab) T cells. The thymus is a vital organ in T cell differentiation, allowing cells to mature and perform DNA recombination to create their T cell receptors (TCR), which include a and b chains. The TCRb chain is created first, and the gene product of PTCRA allows that chain to be tested for function during development. Initial work focused on mouse models of PTCRA deficiency, with evidence of severely impaired ab T cell development in the thymus and increase in gd T cell development. Prior to discovery of patients with PTCRA deficiency, researchers speculated that a disease involving a loss of function of this gene would be associated with an absence of classical, ab, T cells and a fatal disease if not treated from birth.

One of the study’s co-senior authors is Sarah E. Henrickson, MD, PhD, an attending physician and Assistant Professor in the Division of Allergy and Immunology at CHOP, whose lab is focused on T cell dysfunction in chronic inflammation and rare genetic immune dysregulatory syndromes. She identified the first patient with pre-TCRα deficiency after a newborn screened positive for severe combined immune deficiency (SCID) nearly a decade ago. After uncovering the mutations in PTCRA via whole exome sequencing, she investigated the mechanism of impact in the proband, defined as the first person in a family identified with a genetic condition. After presenting findings at North American and European immune deficiency conferences, researchers from around the world learned about the phenotype of the initial patients with loss of function variants in the PTCRA gene. Since then, Dr. Henrickson has worked with an international group of collaborators that has worked closely as a team to uncover the mechanism of impact across lifespan in PTCRA deficiency and in the mouse model of this disease. The study summarizes the details of 10 patients with PTCRA deficiency. The study also found that 1 in 4,000 people of Middle Eastern or South Asian descent may have a variant in PTCRA that partially reduces protein function and increases the risk of autoimmunity.

Henrickson said that while this study offers reassurance that many patients diagnosed with PTCRA deficiency as newborns do not encounter serious infectious or autoimmune symptoms in early childhood, though T cell counts may be abnormal especially at birth and in early life, it did find that a subset of adult patients with PTCRA deficiency have severe infections and autoimmunity.  She also notes that this study highlights the tremendous power of international collaboration in rare disease research.

“This study characterized the different ways PTCRA deficiency may appear in patients, including a group of patients with reduced but not absent function of PTCRA who were more likely to develop autoimmune diseases that may be related to dysfunction of the PTCRA gene,” Henrickson said. “We need to follow our pediatric patients closely to properly study how this condition evolves as they transition into adulthood and the additional steps they may need to take to remain healthy.”

Other study co-authors from CHOP include Judith R. Kelsen, MD, and Soma Jyonouchi, MD.

Read more about the study here.