Primary Immune Regulatory Disorders

Primary immune regulatory disorders (PIRDs) encompass a broad group of inborn errors of immunity (IEIs) characterized predominantly by autoimmune, hyperinflammatory, and lymphoproliferative manifestations rather than infectious complications. Clinical categorization of PIRDs depends on the profile of autoimmunity and the severity of the underlying humoral and/or cellular immune deficiency. In addition to inflammation, several organ-specific autoimmune and hyperinflammatory features are common in PIRDs. Biallelic mutations in the lipopolysaccharide-responsive vesicle trafficking, beach- and anchor-containing gene (LRBA), resulting in lost or dysfunctional LRBA protein, contribute to abnormal recycling and intracellular trafficking of CTLA-4, leading to secondary CTLA-4 deficiency with dysfunctional Treg cells. As more PIRD-associated genes are unveiled and underlying pathophysiologic mechanisms are delineated, rapid genetic testing combined with the key diagnostic assays should continue to improve the recognition and treatment of distinct PIRDs.