A subset of patients with autosomal recessive SCID are characterized by an abnormal sensitivity to ionizing radiation. They produce very few mature B and T cells because there is a failure of DNA rearrangement in their developing lymphocytes; only rare VJ or VDJ joints are seen, and most of these are abnormal. This type of SCID is due to defects in ubiquitous DNA repair proteins involved in repairing DNA doublestrand breaks, which are generated not only during antigen receptor gene rearrangement (see Section 55) but also by ionizing radiation. Owing to the increased radiosensitivity in these patients, this class of SCID is called radiationsensitive SCID (RSSCID) to distinguish it from SCID due to lymphocytespecific defects. Defects in the genes for Artemis, DNA proteinkinase catalytic subunit (DNAPKcs), and DNA ligase IV cause RSSCID (see Fig. 13.2). Because defects in repair of DNA breaks increase the risk of translocations during cell division that can lead to malignant transformation, patients with RSSCID variants are also more likely to develop cancer.
13-6 Defects in signaling from T-cell antigen receptors can cause severe immunodeficiency.
Several gene defects have been described that interfere with signaling through the Tcell receptor (TCR) and thus block the activation of T cells early in thymic development. Patients with mutations in the CD3δ, CD3ε, or CD3ζ chains of the CD3 complex have defective preTcell receptor signaling and fail to progress to the doublepositive stage of thymic development (see Fig. 13.2), resulting in SCID. Another lymphocyte signaling defect that leads to severe immunodeficiency is caused by mutations in the tyrosine phosphatase CD45. Humans and mice with CD45 deficiency show a marked reduction in peripheral Tcell numbers and also abnormal Bcell maturation. Severe immunodeficiency also occurs in patients who make a defective form of the cytosolic protein tyrosine kinase ZAP70, which transmits signals from the Tcell receptor (see Section 77). CD4 T cells emerge from the thymus in normal numbers, whereas CD8 T cells are absent. However, the CD4 T cells that mature fail to respond to stimuli that normally activate the cells through the Tcell receptor.
Wiskott–Aldrich syndrome (WAS), which is caused by a defect in the WAS gene on the X chromosome that encodes WAS protein (WASp), has shed new light on the molecular basis of signaling and immune synapse formation between various cells in the immune system. Although the disease also affects platelets and was first described as a bloodclotting disorder, it also causes immunodeficiency that is characterized by reduced Tcell numbers, defective NKcell cytotoxicity, and a failure of antibody responses (see Section 719). WASp is expressed in all hematopoietic cell lineages and is a key regulator of lymphocyte and platelet development and function through its transduction of receptormediated signals that induce reorganization of the cytoskeleton (see Section 925). Several signaling pathways downstream of the Tcell receptor are known to activate WASp (see Section 7.19). Activation of WASp in turn activates the Arp2/3 complex, which is essential for initiating actin polymerization that is critical for immune synapse formation and the polarized release of effector molecules by T cells. In patients with WAS, and in mice whose Was gene has been knocked out, T cells fail to respond normally to Tcell receptor crosslinking. It has also recently been suggested that WASp is required for the suppressive function of natural Treg cells, and this may help explain why patients with WASp are susceptible to autoimmune diseases.
13-7 Genetic defects in thymic function that block T-cell development result in severe immunodeficiencies.