Chapter 30 - Primary immune regulatory disorders

Abstract

There are more than 400 different inborn errors of immunity (IEI), most of which clinically present with infectious complications including recurrent, severe, and/or unusual infections. Noninfectious complications associated to primary immune deficiency disorders (PIDD) have been increasingly recognized as a dominant phenotype in certain conditions. Primary immune regulatory disorders (PIRDs) refer to a group of IEI with immune dysregulation as their dominant feature. The clinical phenotype of PIRD is characterized by immune-mediated abnormalities such as autoimmunity, hyper/autoinflammation, nonmalignant lymphoproliferation, severe atopy, and, in some cases, malignancy. Given the varied presentation of PIRD, these patients can initially present to other medical specialties, making the allergist immunologist role pivotal in the search for a unifying diagnosis where a single defective gene involved in the regulation of the immune response is responsible for the PIRD diverse pathology. At the same time, understanding the mechanism of disease opens the door for organ damage surveillance, targeted therapy, and even curative treatments such as hematopoietic stem cell transplantation or gene therapy. To begin, we outline a historical background of PIRD. Then, we delineate the most representative PIRD entities through the overview of their clinical presentation, immune phenotyping, associated genotypes, and treatment considerations. For better comparison, we group PIRD into the following categories: (1) autoimmune lymphoproliferative syndrome (ALPS) and ALPS-like syndromes; (2) immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX), and IPEX-related disorders; and (3) common variable immunodeficiency (CVID), CVID-like, and profound/late-onset combined immune deficiency. We finally provide a discussion on the most remarkable trademarks of PIRD that should lead to clinical suspicion, and the critical steps of immune evaluation for these patients. Finally, we discuss the importance of achieving a diagnosis which can point to shifts in treatment and improve overall outcomes.