From clinical observations and molecular dissection to novel therapeutic strategies for primary immunodeficiency disorders

Abstract

The field of primary immunodeficiency diseases (PID) is rapidly expanding with more than 300 genetically defined disorders that have been clinically described and molecularly analyzed. The molecular dissection of these entities has led to the discovery of new immunologic pathways and to novel and effective disease-specific therapies. This review provides a summary of these primary immune defects categorized by clinical phenotype and molecular similarity as defined by the International Union of Immunologic Societies (IUIS) Expert Committee for PID. In this synopsis, we discuss the molecular basis of various categories of PIDs including, but not limited to, severe combined immunodeficiencies, primary antibody deficiencies, immune dysregulation syndromes, as well as defects of the innate immune system such as phagocytic abnormalities, autoinflammatory fever syndromes, and complement deficiencies. We have attempted to focus on current strategies to prevent complications, ameliorate symptoms, or cure these disorders by promptly using antimicrobial therapies, immunoglobulin replacement, and hematopoietic stem cell transplantation. In addition, we will explore novel therapies such as molecularly targeted immunosuppression with monoclonal antibodies and specific immunomodulatory agents. Finally, we address experimental therapies targeting specific molecular defects, including gene therapy and gene editing.

Keywords: disease-specific therapies; gene therapy; hematopoietic stem cell transplantation; molecular basis of PID; primary immune deficiencies (PID); single gene defects in PID.