X-linked lymphoproliferative syndrome. Natural history of the immunodeficiency.

Abstract

A B S T R A C T The X-linked lymphoproliferative syndrome is characterized by immunodeficiency to Epstein-Barr virus (EBV) manifested by severe or fatal infectious mononucleosis and acquired immunodeficiency. We studied immune responses in six males of a well-characterized kindred with the X-linked lymphoproliferative syndrome. Two males were studied before and during acute fatal EBV infection. Both individuals demonstrated normal cellular and humoral immunity before EBV infection. During acute EBV infection, both individuals developed vigorous cytotoxic cellular responses against EBV-infected and -iipinfected target cells. Anomalous killer and natural killer T cell activity was demonstrated against a va'-riety of lymphoid cell lines, autologous fibroblasts and autologous hepatocytes. Effector cells responsible for anomalous killing reacted with a pan-T cell monoclonal antibody, and belonged to the OKT.8 T cell subset. Death in each case was caused by liver failure, but one patient developed extensive liver necrosis, whereas the other developed a massive infiltration of the liver with EBV-infected immunoblasts after aggressive immunosuppressive therapy. Immunological studies were performed on four males who had survived EBV infection years previously. They demonstrated global cellular immune defects with deficiencies of lymphocyte proliferative responses to mitogens and antigens, humoral immune deficiencies, abnormalities of regulatory T cell subsets and deficient natural killer cell activity. We propose that an aberrant immune response triggered by acute EBV infection results in unregulated anomalous killer and natural killer cell activity against EBV infected and uninfected cells. These studies suggest that global immune defects appearing in males with X-linked lymphopro-

Abnormal T Cell Receptor Signal Transduction of CD4 Th Cells in X-Linked Lymphoproliferative Syndrome

“…XLP patients appear to be normal in their response to childhood infections before they encounter EBV (44,73). A unique feature of EBV infection is the extraordinary proliferation of activated Ag-specific T cells and the EBV-infected B cells (73).…”

“…PBMC were isolated from 10 ml heparinized blood specimens from healthy volunteers and two individuals with XLP from a previously wellcharacterized kindred (44) by centrifugation through lymphocyte separation medium (Organon Teknika, Malvern, PA), followed by washing in RPMI 1640 culture medium. PBMC from each individual were individually washed, resuspended in RPMI 1640, and then distributed in 1 ml volumes containing ϳ10 6 cells into 12-well tissue culture plates.…”

Cutting Edge: Functional Requirement for SAP in 2B4-Mediated Activation of Human Natural Killer Cells as Revealed by the X-Linked Lymphoproliferative Syndrome

“…Recently, the gene mutated in the inherited immunodeficiency X-linked lymphoproliferative syndrome (XLP) 3 (reviewed in Ref. 6) was identified as SLAM (signaling lymphocytic activation molecule-associated protein)-associated protein (SAP; also known as DSHP and SH2D1A) and encodes a small SH2-domain containing protein (7)(8)(9). SAP interacts with a unique tyrosine-based motif (TxYxxV/I) present in the cytoplasmic domains of 2B4 and SLAM (7, 10 -12), cell surface molecules that, when ligated, result in activation of NK cells and T cells, respectively (13)(14)(15).…”

Suppressor T cell clones from patients with acute Epstein-Barr virus-induced infectious mononucleosis.

“…Recovery is followed by a long-lasting and generally asymptomatic latent state of infection (7,39,40). Suppression of the normal immune response by agents such as cyclosporin A (26) or an anti-T cell monoclonal antibody (27) and suppression in association with congenital or acquired immunodeficiencies (18,19,25) have, however, resulted in the emergence of EBV-induced malignancies.…”

“…This has been attributed to the vigorous host immune response, consisting ofactivated suppressor (8-1 1) and/or cytotoxic T cells (12)(13)(14)(15)(16)(17), that develops during the course of the disease. Patients with a congenital disorder of this immune response, referred to as the X-linked lymphoproliferative syndrome, experience fatal episodes of infectious mononucleosis (18,19).…”