EBV-Encoded Latent Membrane Protein 1 Cooperates with BAFF/BLyS and APRIL to Induce T Cell-Independent Ig Heavy Chain Class Switching

Abstract

By substituting the H chain C region of IgM with that of IgG, IgA, or IgE, class switching enables Abs to acquire new effector functions that are crucial for the neutralization of invading pathogens. Class switching occurs through class switch DNA recombination (CSR) and usually requires engagement of CD40 on B cells by CD40 ligand on Ag-activated CD4+ T cells. CSR must be tightly regulated because abnormal IgG and IgA production favors the onset of autoimmunity, whereas increased switching to IgE leads to atopy. These inflammatory disorders can be triggered or exacerbated by EBV infection. In this study, we show that EBV induces CD40-independent CSR from Cμ to multiple downstream Cγ, Cα, and Cε genes through latent membrane protein 1 (LMP1), a CD40-like viral protein that signals in a ligand-independent fashion. LMP1-induced CSR is associated with transcriptional activation of germline Cγ, Cα, and Cε genes and triggers the up-regulation of activation-induced cytidine deaminase, a crucial component of the CSR machinery. In addition, LMP1 induces B cells to express B cell-activating factor of the TNF family and a proliferation-inducing ligand, two molecules that mediate B cell survival and T cell-independent Ab production. B cell-activating factor of the TNF family and a proliferation-inducing ligand cooperate with LMP1 to induce Ig class switching because their neutralization by appropriate soluble decoy receptors attenuates CSR in LMP1-expressing B cells. By showing that LMP1 triggers T cell-independent CSR, our findings suggest that EBV could play an important role in the pathogenesis of disorders with aberrant IgG, IgA, and/or IgE production.

Characterization of the Uracil-DNA Glycosylase Activity of Epstein-Barr Virus BKRF3 and Its Role in Lytic Viral DNA Replication

“…Notably, EBV-encoded latent membrane protein 1 (LMP1) induces CD40-independent CSR from C to multiple downstream C␥, C␣, and Cε genes in B cells. This induction is associated with up-regulation of AID (23). Moreover, EBV infection of human B cells resulting in AID expression has been investigated, and increasing numbers of mutations in p53 were also seen in culture with time (15).…”

Human peripheral blood and bone marrow Epstein–Barr virus‐specific T‐cell repertoire in latent infection reveals distinct memory T‐cell subsets

“…Despite the relatively benign course in most carriers, EBV reactivation is considered as a risk-factor both for malignant transformation and autoimmune diseases. The ability of the EBV encoded protein Correspondence: Professor Carmen Scheibenbogen e-mail: carmen.scheibenbogen@charite.de LMP-1 to induce T-cell-independent immunoglobulin class switch DNA recombination and BAFF, a B-cell activating factor, that rescues self-reactive T cells, is considered to play an important role in the pathogenesis of EBV-related autoimmune and lymphoproliferative disease [4]. EBV is causatively linked to nasopharyngeal carcinoma and B-cell malignant diseases such as endemic Burkitt's lymphoma, Hodgkin's lymphoma and posttransplant lymphoproliferative diseases (PTLD) [5][6][7].…”

The role of APRIL and BAFF in lymphocyte activation

“…Antibody class switching, which occurs in B cells, requires cytokines and, in the case of T-dependent antigens, CD154. CD154-independent class-switch recombination does, however, occur in a BAFF-and APRILdependent manner that might be particularly relevant for the production of IgA, as one particular strain of APRIL-null mice displays a selective IgA deficiency and decreased IgA responses to mucosal T-dependent antigens [45,48,49]. BAFF and APRIL induce isotype switching to IgG 1 and IgA and, with the help of IL-4, to IgE [50 ].…”