Hans D. Ochs, M.D. (Seattle, US)
Primary Immunodeficiencies (PID) are characterized by recurrent, often life threatening infections caused by microorganisms that may include bacterial, viral, fungal or opportunistic agents. As the understanding of PID progressed, it became apparent that many PID patients suffered from autoimmune complications and that for some affected individuals the predominant symptoms were those of autoimmunity. First observed in a subset of X-linked PIDs, such as Wiskott-Aldrich syndrome, CD40L deficiency and X-linked agammaglobulinemia, autoimmune complications were subsequently seen frequently in patients with APECED, CD25 and STAT5B deficiencies. While late complement (C) component deficiencies were associated with systemic infections by encapsulated organisms, deficiencies of early C-components resulted in autoimmune complications such as SLE. Long-term follow up of CVID patients identified a subgroup in which autoimmune complications occurred and predicted reduced quality of life and premature death. As the genetic heterogeneity of CVID was recognized and specific single gene defects were identified, new molecular pathways were discovered that resulted in antibody or lymphocyte-induced autoimmune processes. The discovery of FOXP3 as the gene responsible for IPEX and its impact on the generation of regulatory T cells (Treg) led to the concept of immune dysregulation. Further probing of the disease causing molecular basis of patients with an IPEX-Iike phenotype and normal FOXP3 gene led to the discovery of novel gene defects in patients with a CVID- and IPEX-Iike presentation that included STAT1 gain of function (GOF) and STAT3-GOF mutations, CTLA4 haplo-insufficiency, mutations in LRBA. A defect in apoptosis due to genomic or somatic mutations in FAS, FAS-Iigand or Caspase 10 cause the clinical phenotype of Autoimmune Lymphoproliferative Syndrome (ALPS) characterized by autoimmune cytopenias and increased risk of lymphoma. The identification of the molecular basis of these single gene defects causing PID with autoimmune complications has important implications for specific therapies that include immunosuppression, kinase inhibitors, specific agonists (CTLA4-Ig) or stem cell transplantation.