Treg Gene Defects Drive Early Childhood Polyautoimmunity, and Targeted Drugs Are Improving Control

Regulatory T cells are the immune system's main safeguard against self-reactivity. When genes in their pathway fail, the result is a group of inborn errors of immunity called tregopathies, a term coined in 2018. The 2024 IUIS classification lists defects in FOXP3, IL2RA, IL2RB, CTLA4, LRBA, DEF6, NBEAL2, STAT3 gain-of-function, BACH2, FERMT1 and IKZF1 gain-of-function. These disorders are rare and clinically varied, so they are often recognized late, and the delay can mean irreversible organ damage.

This retrospective case series from a pediatric immunology department in Mumbai, India, reviewed records of 26 patients with a genetic diagnosis of tregopathy. Variants were classified as pathogenic or likely pathogenic under ACMG-AMP 2015 criteria. Patients with variants of uncertain significance and no strong clinical correlation were excluded. Segregation analysis or flow cytometry functional studies were used where available. Patients were grouped clinically as ALPS-like, CVID-like or IPEX-like. The analysis was descriptive only.

The cohort comprised 13 patients with LRBA deficiency, 5 with CTLA4 defects, and 2 each with IPEX, CD25 deficiency, STAT3 gain-of-function and FERMT1 deficiency. Median age at onset was about 4 years (range 2 days to 40 years). Median diagnostic delay was 2 years (range 1 month to 27 years). It was longest for the CVID-like phenotype (2 years), then ALPS-like (1.7 years), and shortest for IPEX-like (10 months). The male-to-female ratio was 17:9, half were born to consanguineous parents, and 8 had a family history of autoimmunity or infection-related death. Autoimmune cytopenia was the most common manifestation. Others included autoimmune hepatitis, inflammatory bowel disease, enteropathy, type 1 diabetes, thyroiditis, CNS vasculitis, glomerulonephritis and dermatitis. Most had lymphoproliferation. Of those tested, 7/21 had hypogammaglobulinemia, 13/22 had low B-cell subsets, and 6/22 had low CD3 counts.

Before diagnosis, treatment was a mix of corticosteroids, cyclosporine, azathioprine and rituximab. After molecular diagnosis, 12 patients started mTOR inhibitors (sirolimus), 4 abatacept, and 2 JAK inhibitors, with better control of autoimmunity. Some patients had complete control on sirolimus, while others had only partial control or side effects such as hypertriglyceridemia and infections. Five children underwent HSCT and four are doing well. Individual patient tables show at least two deaths, including patients who declined transplant.

The authors conclude that a high index of suspicion for monogenic disease in early-onset polyautoimmunity can shorten diagnostic delay, and that pathway-targeted therapy can substantially improve outcomes. Caveats are the small, single-center, retrospective design, the heterogeneous genotypes, the lack of a comparison group, and the absence of formal statistics. The text available for this summary was also truncated, so the discussion and some outcome details could not be reviewed.