Of genes and phenotypes: the immunological and molecular spectrum of combined immune deficiency.Defects of the gc‐JAK3 signaling pathway as a model

Abstract

Cytokines play a major role in lymphoid development. Defects of the common gamma chain (gamma(c)) or of the JAK3 protein in humans have been shown to result in a severe combined immune deficiency (SCID), with a profound defect in T and natural killer (NK)-cell development, whereas B-cell generation is apparently unaffected (T-B+NK-SCID). While extensive molecular and biochemical analysis of these patients has been instrumental in understanding better the biological properties of the gamma(c) and JAK3 protein, an unexpected phenotypic heterogeneity of gamma(c) and JAK3 deficiency has emerged, indicating the need for appropriate and extensive investigations even in patients with atypical presentations. At the same time, characterization of the defects has been instrumental in the development of novel therapeutic approaches, from in utero hematopoietic stem cell transplantation to gene therapy.

Mapping of Quantitative Trait Loci Determining NK Cell-Mediated Resistance to MHC Class I-Deficient Bone Marrow Grafts in Perforin-Deficient Mice

“…Deficiency in JAK3 in mice results in a lack of T, B, and NK cells. The NK cell deficiency is probably due to lack of IL-15 signaling (51,52). Interestingly, one report on patients with JAK3 deficiency describes a phenotype with mature T cells and only mild immunodeficiency.…”

Prevention of CD40-Triggered Dendritic Cell Maturation and Induction of T-Cell Hyporeactivity by Targeting of Janus Kinase 3

“…As we provide evidence that selective JAK3 inhibition also affects DC function, we propose that the clinical use of such an approach may profoundly affect the host immune response by targeting both DCs and activated T cells, which depend on cc -chain signaling. The systemic administration of glucocorticoids brings about metabolic and endocrine side-effects, and thus administration of JAK3 inhibitors could be advantageous, because of the restriction of the JAK3 signaling pathway to lymphoid and myeloid cells/organs (17).…”

“…Upon ligand-binding, receptorassociated JAKs are recruited, leading to their phosphorylation and subsequent activation of STAT (signal transducers and activators of transcription) proteins that dimerize and transactivate the transcription of specific target genes (16). Janus kinase 3 deficiency disables phosphorylation of the transcription factors STAT5a/b (17) and manifests as severe combined immunodeficiency (SCID). This disease is associated with a profound defect in the immune system with significant alterations in lymphocyte development, a functional incompetence and increased susceptibility for apoptosis in peripheral T cells (18).…”

Matched unrelated bone marrow transplant for T+ combined immunodeficiency

“…In recent years, patients with mutations in Jak-3, Zap-70, IL-2Ra and CD3 were reported to have autologous T cells and/or residual T-cell function, commonly referred to as T þ CID. [7][8][9][10] Moreover, even patients with X-linked SCID, such as those with the R222C mutation, may present as T þ CID. 11,12 Such patients present with near-normal or normal numbers of circulating T cells and responses to mitogens as well as having normal thymus morphology.…”