Tracing the Spectrum of Inborn Errors of Immunity from Past to Present

Human inborn errors of immunity (IEI), previously termed primary immunodeficiency disorders, have a historical lineage dating back seven decades.The narrative of these diseases started with the seminal identification of agammaglobulinemia as the causative disorder in a boy with recurrent bacterial infections in 1952 (1).This description was followed in 1958 by a report of several Swiss infants with alymphocytosis and agammaglobulinemia, receiving the designation of Swiss-type agammaglobulinemia (2).Studies of patients with IEI diseases have taught us much about the complexities of the way that our immune system develops and functions.Following Miller's (3) discovery in 1961 of the immunological roles of the thymus, Cooper (4) discovered the dual roles of the thymus and bursa-dependent cell lineages, achieving the concept of T and B lymphocytes and adaptive immunity in 1965 (4).This concept enabled us to classify Bruton and Swiss agammaglobulinemia as B-and T-cell deficiencies, revealing the essential role of these cells in protection against infections.Specific therapies for IEI came swiftly in the intervening years after their discovery.Starting with the use of gammaglobulins for antibody deficiency by Ogden Bruton, Charles Janeway, and David Gitlin (5,6), this was continued with the first pioneer-matched allogeneic hematopoietic stem cell transplantation (HSCT) by Robert Good and his colleagues in 1968 (7).At around that time, Humphrey Kay and his colleagues developed thymic transplantation for DiGeorge syndrome (8).These steps symbolized heroic interventions for diseases previously deemed incurable and most often fatal.Despite the strides in the clinical management of IEI, elucidating disease-associated genes has been a protracted endeavor spanning several decades.For instance, Ataxiatelangiectasia was first reported in 1926 by two Czech neurologists (9), while the discovery of the responsible Abstract Human inborn errors of immunity (IEI) constitute a constellation of genetic disorders with profound implications for immune system function, leading to recurrent infections, immune dysregulations, and malignancies.The field of IEI has undergone a tremendous evolution over the course of seventy years, with substantial strides in comprehending the clinical and immunological aspects of monogenic disorders.Furthermore, these endeavors have synergized with innovative therapeutic modalities, forging a trajectory toward enhanced patient care.These advances promise to favorably transform the outcomes of many IEI to provide patients with increased life expectancy and improved quality of life.In this special issue of the Turkish Journal of Immunology, we will survey some recent advances in the field of IEI with a focus on disease pathogenesis and outcomes.