Fig.13.10 X-linked lymphoproliferative disease (XLP) is caused by inherited defects in SAP and XIAP, resulting in abnormal SLAM and TNF family receptor signaling, respectively. SlaM is an immune receptor family, members of which are expressed by t cells, B cells, natural killer (nK) cells, dendritic cells, and macrophages. Signaling is initiated via homotypic or heterotypic interactions between family members. SlaM signaling recruits the Src homology 2 (SH2) domain-containing factor SaP, which recognizes tyrosine-based motifs in the cytoplasmic domain of SlaM to activate the Src-related tyrosine kinase Fyn (left upper panel). Fyn then phosphorylates additional tyrosine residues of SlaM to recruit additional signaling components. Mutation in SaP in patients with XlP1 (right upper panel) disrupts activation of Fyn and SlaM signaling, thereby impairing tand nK-cell cytotoxicity, which results in severe epstein–Barr virus (eBV) infections and lymphoma. Defective SlaM signaling also impairs upregulation of inducible t-cell co-stimulator (iCOS) expression in tFH cells, which results in impaired antibody responses. activation of apoptosis-inducing caspases by tnF family receptors, such as Fas, is normally inhibited by XiaP (lower panel). XiaP interacts with both initiator caspases (8 and 9) and executioner caspases (3 and 7) through its baculoviral inhibitory repeat (BiR) domain to inhibit their actions. in XlP2 patients, XiaP is defective, resulting in abnormal regulation of caspase activation that leads to the complex clinical phenotype that includes lymphoproliferation and defective control of eBV.
Section 1311). Moreover, defective SLAM signaling between TFH cells and B cells of XLP1 patients causes impaired Tdependent antibody responses and hypogammaglobulinemia.
Defects in the XIAP protein, which normally binds the TNFreceptorassociated factors TRAF1 and TRAF2 and inhibits the activation of apoptosisinducing caspases (see Section 723), lead to a similar Xlinked syndrome called XLP2 (see Fig. 13.10). XIAP deficiency results in the enhanced apoptosis and turnover of activated T cells and NK cells. Paradoxically, this leads to a lymphoproliferative phenotype similar to XLP1, the basis of which is not well understood. As in XLP1, there is also severe depletion of NKT cells, indicating that, like SAP, XIAP is required for the normal maintenance of these cells. As in XLP1, there is also defective control of EBV infection in XLP2, although this is less prominent. The exact reason for the impaired suppression of EBV latency in these immunodeficiencies remains to be defined.
13-13 Immunodeficiency is caused by inherited defects in the development of dendritic cells.
Our understanding of the diversity and function of dendritic cells has been advanced from studies of mice with genetargeted deletion of transcription factors that result in the loss of subsets of these cells, and from the defects in protection against specific pathogens that result as a consequence of the loss of these subsets. In humans, where study of the development and function of dendritic cells is more challenging, the identification of primary immune deficiencies that result from defects in genes that encode the transcription factors GATA2 and IRF8 has begun to provide insights into the relative roles of these cells in different species.