Epstein‐Barr virus‐infected B cells of males with the X‐linked lymphoproliferative syndrome stimulate and are susceptible to T‐cell‐mediated lysis

Abstract

Primary infection with the Epstein-Barr virus (EBV) results in fatal infectious mononucleosis in up to 70% of males affected by the X-linked lymphoproliferative syndrome (XLP). This rare disease is often associated with diverse natural killer (NK)-, B-and T-cell deficiencies. We describe experiments testing whether the B lymphocytes of affected males play a role in the pathogenesis of XLP due to a low susceptibility to T-cell-mediated immunity. Using reverse transcriptionpolymerase chain reaction (RT-PCR) and immunohistochemistry we detected in these B cells the expression of viral proteins EBNA-1, EBNA-2, EBNA-3A, EBNA-3C, LMP-1 and LMP-2A, which provide targets for cytotoxic T cells. Major histocompatibility complex (MHC) class I, MHC class II and the B7 costimulatory molecule were present on the cell surface. Accordingly, the EBV-infected B cells were lysed in 51 Cr-release assays by T lymphocytes sharing MHC determinants with the targets. This MHC-restricted and specific lysis was confirmed in competition experiments using MHCspecific monoclonal antibodies (MAbs) and synthetic peptides. XLP-derived LCLs could also induce MHC class Irestricted memory and cytotoxic T lymphocytes. Thus, these XLP-derived B cells resembled normal LCIs in vitro with respect to induction of EBV-specific cytotoxic T cells (CTL), the ability to present EB viral antigens and the susceptibility to EBV-specific and MHC-restricted CTL-mediated killing. The failure of the immune system to eliminate these virusinfected B cells in XLP is clearly not caused by a B-cell-specific defect. Int.

Pathogenesis and mechanism of disease progression from hemophagocytic lymphohistiocytosis to Epstein–Barr virus‐associated T‐cell lymphoma: Nuclear factor‐κB pathway as a potential therapeutic target

“…The mutation or dysfunction of SAP protein will therefore lead to dysregulated or overt Th1 response in response to EBV infection. ( 24–26 ) The discovery of SAP mutation in XLP shed light on the pathogenesis of HPS, and dysregulated T‐cell activation with enhanced cytokine secretion is believed to represent the critical event in the subsequent disease process. ( 27 ) In HLH, a certain percentage of patients revealed mutations of perforin or Munc 13‐4 genes.…”

X‐linked lymphoproliferative disease: clinical, diagnostic and molecular perspective

“…Development of B‐cell lymphoproliferative disease in XLP initially led to the proposal that B cells in XLP patients may less susceptible to T cell‐mediated killing. However, the lack of SAP expression in B cells and evidence that XLP‐derived B cells resemble normal LCLs in vitro , with respect to induction of EBV‐specific cytotoxic T cells (CTL), the ability to present EBV viral antigens, and susceptibility to EBV‐specific and MHC‐restricted CTL‐mediated killing, suggest that the cellular defect is not B‐cell specific (Jager et al , 1998). Studies on specific T‐cell immunity to EBV are contradictory.…”