Chapter 15 - Severe Combined Immunodeficiency as Diseases of Defective Cytokine Signaling

Abstract

Severe combined immunodeficiency (SCID) represents a syndrome encompassing a spectrum of diseases characterized by profoundly defective immune function. SCID was recognized in the 1950s and 1960s as a clinical syndrome with characteristic findings and to be either of autosomal recessive or X-linked inheritance. Over the next 60 years, clinical and molecular studies of this fatal disease emphasized the central role that adaptive immunity plays in humans, and have led to novel diagnostic and treatment strategies. There are multiple causes of SCID, but at least three forms of molecularly defined SCID are diseases of defective signaling by hormones of the immune system known as cytokines. These types of SCID include the most common form, X-linked (X)SCID, as well as JAK3-deficient SCID and IL-7Rα-deficient SCID. XSCID results from mutations in the common cytokine receptor γ chain, γc, which is a critical component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21; JAK3-deficient SCID results from mutations in JAK3, a cytoplasmic protein that physically associates with γc and is critical for the actions of all six γc-dependent cytokines. IL-7Rα-deficiency causes a somewhat less severe immunodeficiency in terms of cellular defects, as is discussed in detail herein, but still results in SCID. The knowledge of the causes of these diseases has elucidated basic mechanisms of human immunology which, in turn, have provided insight into the molecular basis of these complex diseases. Moreover, identification of the genetic causes has improved prenatal and postnatal diagnosis and provided the possibility of gene therapy.