SEVERE COMBINED IMMUNODEFICIENCY CAUSED BY DEFECTS IN COMMON CYTOKINE RECEPTOR γc SIGNALING PATHWAYS

Abstract

Severe combined immunodeficiency (SCID) syndromes are a group of congenital disorders characterized by severe impairment of cellular and humoral immunity, leading to death at an early age. Human SCID comprises genotypically and phenotypically heterogeneous conditions of which the genetic basis for many of the underlying immunologic defects have been recently elucidated. All SCID phenotypes are defined by the absence of mature T cells. Other characteristics, including the presence or absence of B cells and natural killer (NK) cells and the particular genes involved, help to distinguish the various subtypes of these disorders (Fig. 1). One of the principal difficulties inherent in deciphering the pathogenesis of SCID syndromes is that different mutations in a single gene may give rise to distinct clinical conditions and that a similar clinical phenotype can result from mutations in different genes (Figs. 1 and 2). Complete deficiencies in the recombinase activating genes RAG1 and RAG2 block the generation of mature T and B lymphocytes by preventing antigen receptor gene rearrangements, 70 whereas NK cell development proceeds normally (T − NK + B − SCID). Deficiencies in RAG may not be the only cause of this SCID subtype: defects in other genes involved in the recombination process, such as Ku 70 and 86 proteins and DNA-dependent protein kinases, 4 could result in T − NK + B − SCID. Not all defects in the RAG genes generate typical T − NK + B − SCID. Mutations associated with partial RAG function recently were described in Omenn's syndrome, an immunodeficiency characterized by oligoclonal T- and B-cell development. 86 Defining the genetic basis of SCID syndromes remains a challenge. One prominent clinical immunologist described SCID syndromes as experiments of nature: a fitting characterization in that through these rare conditions, scientists and clinicians often can extract information regarding the essential roles of various gene products in the differentiation of the human lymphoid system. One of the most common subtypes of SCID is characterized by the selective blockade of T- and usually NK-cell differentiation, with the presence of poorly functioning B cells (T − NK − B + SCID). This immunologic phenotype is caused by deficiencies in signaling through a group of cytokine receptors that share the common cytokine receptor γ chain (γ c ). Like all SCIDs, disorders characterized by perturbations in the function of γ c -dependent cytokines can give rise to considerable heterogeneity with respect to the immunologic presentation and the molecular basis for the underlying disease pathology. This article summarizes the clinical considerations for T − NK − B + SCID and its atypical variants, the role of the γ c cytokine network in normal lymphopoiesis and in the pathophysiology of these diverse human SCID syndromes, and analyzes γ c mutations in typical and atypical SCID syndromes.