Epstein-Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation.

The signaling lymphocyte activation molecule (SLAM)-associated protein, SAP, was first identified as the protein affected in most cases of X-linked lymphoproliferative (XLP) syndrome, a rare genetic disorder characterized by abnormal responses to Epstein-Barr virus infection, lymphoproliferative syndromes, and dysgammaglobulinemia. SAP consists almost entirely of a single SH2 protein domain that interacts with the cytoplasmic tail of SLAM and related receptors, including 2B4, Ly108, CD84, Ly9, and potentially CRACC. SLAM family members are now recognized as important immunomodulatory receptors with roles in cytotoxicity, humoral immunity, autoimmunity, cell survival, lymphocyte development, and cell adhesion. In this review, we cover recent findings on the roles of SLAM family receptors and the SAP family of adaptors, with a focus on their regulation of the pathways involved in the pathogenesis of XLP and other immune disorders.

SLAM Family Receptors and SAP Adaptors in Immunity

A panel of 24 healthy seropositive donors have been followed prospectively over a period of 15 months and monitored (1) for the level of EB virus shedding in the throat by means of a sensitive cord-blood transformation assay; (2) for the level of virus-infected B cells in the blood via a new in vitro protocol where "spontaneous transformation" can be seen to titrate against input cell number; (3) for anti-EB viral antibody titres and (4) for the prevailing level of virus-specific memory T cells in the circulation. Six donors shed easily detectable levels of EB virus into throat washings on every occasion of testing, whilst 16 other donors shed lower levels of virus detectable in throat washings on a majority (10 donors) or on a minority (6 donors) of test occasions; only 2/24 donors gave no evidence of virus shedding at any time. There was a direct relationship between the EB virus shedder status of an individual (i.e., the level of virus replication in the pharynx) and the number of infected B cells present in the circulation. These results indicate that chronic, usually low-grade, replication of the virus at some permissive site in the oro- and/or naso-pharynx is very often a stable accompaniment of the asymptomatic EB virus carrier state, and may indeed be essential for the long-term maintenance of that state.

A re-examination of the Epstein-Barr virus carrier state in healthy seropositive individuals.

SAP (SLAM-associated protein) was identified in 1998 as an adaptor molecule involved in the intracellular signaling pathways elicited through the cell surface receptor SLAM and as the protein defective in the human immunodeficiency X-linked lymphoproliferative disease (XLP). During the past eight years, it has been established that the SLAM family of cell surface receptors (SLAM, 2B4, NTB-A, Ly9, CD84) and the SAP family of adaptors (SAP, EAT-2, ERT) play critical roles in lymphocyte development, differentiation, and acquisition of effector functions. Studies of these proteins have shown unexpected roles in cytokine production by T cells and myeloid cells, T cell-dependent humoral immune responses, NK cell-mediated cytotoxicity, and NKT cell development. This review highlights recent findings that have improved our understanding of the roles of the SLAM and SAP families of molecules in immune regulation and discusses how perturbations in the signaling pathways involving these proteins can result in different disease states.

Regulation of Cellular and Humoral Immune Responses by the SLAM and SAP Families of Molecules

X-linked lymphoproliferative disease (XLP) is an inherited immune defect caused by mutations in the Src homology 2 domain-containing gene 1A, which encodes the adapter protein, signaling lymphocytic activation molecule (SLAM)-associated protein (SAP). SAP is expressed in T cells, natural killer (NK) cells, and NKT cells, where it binds to the cytoplasmic domain of the surface receptor SLAM (CD150) and the related receptors, 2B4 (CD244), CD84, Ly9 (CD229), NK-T-B-antigen, and CD2-like receptor-activating cytotoxic T cells. SAP also binds to the Src family tyrosine kinase Fyn and recruits it to SLAM, which leads to the generation of downstream phosphotyrosine signals. While the roles of the SLAM family receptors are only beginning to be understood, experiments suggest that these molecules regulate important aspects of lymphocyte function, such as proliferation, cytokine secretion, cytotoxicity, and antibody production. Thus, in XLP patients who lack functional SAP, the SLAM family receptors may not signal properly. This property likely contributes to the phenotypes of XLP, including fulminant infectious mononucleosis, lymphoma, and hypogammaglobulinemia. Further studies of SAP and the SLAM family receptors will provide insights into XLP and elucidate the signaling events regulating lymphocyte ontogeny and function.

Molecular and cellular pathogenesis of X-linked lymphoproliferative disease

https://www.amjmed.com/article/0002-9343(82)90923-8/pdf

Epstein-Barr virus-induced diseases in boys with the X-linked lymphoproliferative syndrome (XLP): update on studies of the registry.

In 1974, an 11-year-old white boy with the X-linked lymphoproliferative syndrome developed hyper-IgM after becoming infected with Epstein-Barr virus. However, he failed to develop normal i...

Delayed Onset of Infectious Mononucleosis Associated with Acquired Agammaglobulinemia and Red Cell Aplasia

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Epstein-Barr virus-induced diseases in boys with the X-linked lymphoproliferative syndrome (XLP): update on studies of the registry.

Delayed Onset of Infectious Mononucleosis Associated with Acquired Agammaglobulinemia and Red Cell Aplasia