Primary immunodeficiency diseases: past, present and future

Fuleihan, Ramsaya; Etzioni, Amosb

More than 180 primary immunodeficiency diseases (PIDs) have been described over the past 60 years and improved therapeutic options have become available with safe and effective immunoglobulin replacement products, enzyme replacement therapy specifically for adenosine deaminase deficiency, improved protocols for stem cell transplantation using bone marrow, peripheral blood or cord blood as well as the development of gene therapy for several of the PIDs. However, the cellular, molecular and genetic causes of many PIDs remain to be determined. This issue of Current Opinion in Allergy and Clinical Immunology is devoted to primary immunodeficiency diseases and includes reviews of recent progress in the field, the history of how these advances were possible and newer technology that will help uncover the genetic causes of PIDs in the near future. Ochs and Hitzig (pp. 577587) review the progress in our understanding of PIDs since the first report on agammaglobulinemia in 1952 as well as the preceding advances in modern medicine that allowed the discovery of PIDs and the development of modern therapeutic options to treat them. A critical issue in the diagnosis of PIDs is a high degree of suspicion on the part of the primary care physician. Twenty years ago, the Jeffrey Modell Foundation published 10 warning signs to aid physicians in suspecting PIDs and initiating an evaluation. O'Sullivan and Cant (pp. 588594) review recent reports that evaluate the validity of the 10 warning signs and propose warning signs targeted to different physician groups in order to improve their sensitivity and specificity. Common variable immunodeficiency (CVID) is the most common symptomatic immunodeficiency, yet the pathogenesis of most cases on CVID remains unknown. In this issue, Resnick and Cunningham-Rundles (pp. 595601) review the recent advances in identifying the genetic causes of CVID including results from genome-wide association studies , recent clinical findings from cohort studies and the implications for the treatment of CVID. IgA deficiency is the most common immunodeficiency although frequently asymptomatic, but its genetic cause remains unknown. Wang and Hammarstrom (pp. 602608) review the recent advances in our understanding of IgA deficiency, the association with autoimmunity as well as the correlation with genes within and outside the MHC region.

Apoptosis plays an important role in immune homeostasis, and defects in apoptotic pathways have been identified in patients with lymphoproliferation and autoimmune disease. In this issue, Fleisher and Oliveira (pp. 609615) review the recent discoveries of the genetic causes of defective apoptosis and describe the common and distinguishing clinical features and laboratory findings in each of these entities. The pathogenesis of chronic mucocutaneous candidiasis had remained a mystery even after discovering the genetic defects in AIRE in autoimmune polyendocrinopathy syndrome type I. Identification of the role of IL-17 in immunity to fungal disease has led to the discovery of the pathogenesis of chronic mucocutaneous candidiasis in different PIDs as reviewed in this issue by Puel, Casanova and colleagues (pp. 616622). Many of the genetic causes of PIDs were discovered using classical methods such as positional cloning or candidate gene sequencing. Recent advances in DNA sequencing technology have allowed whole-genome and whole-exome sequencing at more affordable costs. The application of this technology to identify the gene defects in PIDs is reviewed by Chou, Ohsumi and Geha (pp. 623628). The authors describe the strengths and limitations of this technology including the need for functional studies to confirm the role of affected genes in PIDs. Investigation of PIDs has taught us about the development and function of the immune system, and the rapid progress in cellular and molecular biology is allowing us to uncover the causes and pathogenesis of many of the PIDs.