X-linked severe combined immune

Currently, more than 400 human somatic cell gene therapy protocols are being tested. Most of these involve the use of genetically modified cells to treat noninherited diseases. For example, normal copies of the p53 tumor suppressor gene are inserted into lung tumors to halt tumor progression, and genetically modified cells have been used to create new coronary vessels in patients with coronary heart disease. Success has also been achieved in the treatment of hereditary disease (most notably, the recent successful treatment of X-linked severe combined immune deficiency see Clinical Correlate). 

In 2000, French researchers announced the first gene therapy cure in nine children with X-linked severe combined immune deficiency (X-SCID). This rare condition is caused by the inherited loss of a protein that is part of the docking site for critical immune system signal proteins. Because of this defect, children with X-SCID have no mature, working lymphocytes—critical immune system cells. 

X-linked severe combined immune deficiency (X-SCID)— Absence of a functioning immune system inherited with the X chromosome. X-linked refers to inheritance with the X chromosome, one of the chromosomes involved in determining gender. In humans, women have two X chromosomes, and men have an X and a Y chromosome. X-linked genes can only be inherited by a boy from his mother, since his father would have given him his Y chromosome. 

Gansbacher B (2003). Report of a second serious adverse event in a clinical trial of gene therapy for X-linked severe combined immune deficiency (X-SCID). Position of the European Society of Gene Therapy (ESGT). /. Gene Med. 5 261-262. 

The theoretical complications posed by random chromosomal integration became a medical reality in 2002, when two children who had received retroviral-based gene therapy 2 years previously developed a leukaemic-like condition. The initial clinical trial aimed to treat X-linked severe combined immunodeficiency (SCID-X1), a hereditary disorder in which T-lymphocytes and NK cells in particular do not develop, due to a mutation in the gene coding for the yc cytokine receptor subunit. The clinical consequence is near abolition of a functional immune system. 

Although the a-chain is very important (and fundamental for the appearance of high-affinity IL-2R), the y-chain has a key role based on its molecular pluripresence (found in IL-4, IL-7, IL-9, and IL-15 receptors but possibly not the IL-13 receptor), constitutive expression by lymphoid cells, and genetic defect in the immune response. The latter results in X-linked severe combined immunodeficiency (XSCID) characterized by profoundly diminished ceU-mediated and humoral immunity. 

Among the four Jak kinases, Jak-1, Jak-2, Jak-3, and Tyk-2, the yc users all signal via Jak-1 and Jak-3 [30, 31]. This could be explained by the ability of Jak-1 to associate with the chain conferring the specificity for each receptor, namely 1L-2R3 [32, 33], IL-4Ra [34], IL-7Ra [35], and IL-9Ra [36], and probably lL-21Ra [37], whereas Jak-3 associates primarily with yc [33, 35]. The importance of the yc was demonstrated by the discovery that mutations in yc cause X-linked severe combined immunodeficiency (SCID) [30, 38], also named the bubble boy disease. In this disease, both cellular and humoral immunity are defective. In fact, T and NK cells do not develop and even if B cells are present, they are nonfunctional [30, 38]. Interestingly, mutations in Jak-3 were found to cause an autosomal recessive form of SCID [39] and the essential role of Jak-3 in lymphoid development was established [40]. This clearly demonstrated the important role of the Jak-STAT signaling pathway. 

Primary immunodeficiency diseases (PIDs) are defects of the immune system that are due to genetic abnormalities or some failure in normal embryological development. They are usually apparent at birth or develop shortly thereafter. Approximately 70 PIDs have been described, including those specihc for humoral immunity (e.g., X-linked agammaglobulinemia, immune globulin [Ig] A dehciency), cellular immunity (e.g., DiGeorge s syndrome), or both (e.g., severe combined immunodehciency syndrome). 

---