Monogenic inborn errors of immunity in autoimmune disorders

Area of Science:

• Immunology
• Genetics
• Pediatrics

Background:

• Autoimmune diseases (AID) can be challenging to diagnose and manage, particularly in pediatric populations.
• Monogenic inborn errors of immunity (PIRD) are increasingly recognized as a significant contributor to autoimmunity.
• Understanding the prevalence and characteristics of PIRD in patients with AID is crucial for improving diagnostic and therapeutic strategies.

Purpose of the Study:

• To estimate the prevalence of monogenic inborn errors of immunity (PIRD) in a cohort of patients with autoimmune diseases (AID).
• To identify common PIRD and associated autoimmune manifestations.
• To evaluate the utility of clinical and immunological parameters in predicting PIRD.

Main Methods:

• Retrospective analysis of 56 patients with autoimmune diseases, focusing on clinical presentation, immunological workup, and genetic testing.
• Assessment of specific immunological parameters including CD19, CD4, CD8, NK cell counts, and immunoglobulin levels.
• Genetic analysis for pathogenic variants in primary immunodeficiency-related (PIRD) genes.

Main Results:

• 28 out of 56 patients (50%) had pathogenic variants in PIRD genes, indicating a high prevalence of underlying PIRD.
• Hematological and gastrointestinal manifestations were the most common autoimmune diseases (AID) associated with PIRD.
• LRBA deficiency and STAT1 gain-of-function (GOF) were identified as the most frequent PIRD.
• Routine immunological tests and the Johnson-Myhre Syndrome (JMS) criteria showed limited sensitivity and predictive value for PIRD.
• Early diagnosis through exome sequencing led to targeted therapies like transplant, sirolimus, abatacept, baricitinib, and ruxolitinib.

Conclusions:

• A significant proportion of pediatric patients with autoimmune diseases harbor underlying primary immunodeficiencies.
• Early diagnosis of PIRD in AID patients through genetic approaches like exome sequencing is critical for altering prognosis.
• Identifying PIRD opens avenues for novel therapeutic interventions and improved patient outcomes.