title: Targeted strategies directed at the molecular defect: Toward precision medicine for select primary immunodeficiency disorders.
abstract: Primary immunodeficiency disorders (PIDs) represent a range of genetically determined diseases that typically have increased susceptibility to infections and in many cases also have evidence of immune dysregulation that often presents as autoimmunity. Most recently, the concept of gain-of-function mutations associated with PIDs has become well recognized and adds a new dimension to the understanding of this group of disorders, moving beyond the more commonly seen loss-of-function mutations. The rapidly expanding genetic defects that have been identified in patients with previously uncharacterized PIDs has opened up the potential for targeted therapy directed at the specific disease-causing abnormality. This has been driven by linking PID-specific genetic defects to the associated unique abnormalities in cellular signaling pathways amenable to directed therapies. These include agents that either block overactive or enhance underresponsive cellular pathways. Selected primary immunodeficiencies were chosen, the genetic defects of which have been recently characterized and are amenable to targeted therapy, as a reflection of the power of precision medicine.
authors.affiliation: Laboratory of Clinical Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.affiliation: Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Md. Electronic address: tfleishe@mail.nih.gov.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Fleisher
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000361:Agammaglobulinemia / Q000235:genetics; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D007239:Infections / Q000235:genetics; D026901:Membrane Transport Proteins / Q000235:genetics; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D057285:Precision Medicine; D000081207:Primary Immunodeficiency Diseases; D050794:STAT1 Transcription Factor / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics; D014860:Warts / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D026901:Membrane Transport Proteins; D019869:Phosphatidylinositol 3-Kinases; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C583905:SLC44A4 protein, human; C494079:STAT1 protein, human; C494086:STAT3 protein, human; C428703:LRBA protein, human
keywords: Personalized medicine; autoimmunity; immune dysregulation; mutation; primary immunodeficiency disorders; therapy