Druggable monogenic immune defects hidden in diverse medical specialties: Focus on overlap syndromes

Abstract

In the last two decades two new paradigms changed our way of perceiving primary immunodeficiencies: An increasing number of immune defects are more associated with inflammatory or autoimmune features rather than with infections. Some primary immune defects are due to hyperactive pathways that can be targeted by specific inhibitors, providing innovative precision treatments that can change the natural history of diseases. In this article we review some of these “druggable” inborn errors of immunity and describe how they can be suspected and diagnosed in diverse pediatric and adult medicine specialties. Since the availability of precision treatments can dramatically impact the course of these diseases, preventing the development of organ damage, it is crucial to widen the awareness of these conditions and to provide practical hints for a prompt detection and cure.

Keywords: Inborn errors of immunity; Primary immunodeficiency diseases; Precision treatments; Immunodysregulation; Autoimmunity; Overlap syndromes

Core Tip: High-throughput genetic testing have allowed to describe monogenic immune disorders, characterized by combinations of infective, inflammatory, autoimmune, lymphoproliferative, neoplastic features. The term “inborn errors of immunity” (IEIs) is increasingly proposed instead of “primary immunodeficiency” to include defects with a prevalently dysregulatory pathogenesis, resulting in autoimmunity, inflammation, lymphoproliferation, risk of malignancies. It is crucial to widen the awareness of these disorders, as they may mimic multifactorial disorders (rheumatology, gastroenterology, hematology, dermatology, allergology) and some of these are druggable. The awareness of druggable IEIs is the focus of this review, with the aim of favoring a prompter diagnosis and a better cure.