EBV-encoded latent membrane protein 1 cooperates with BAFF/BLyS and APRIL to induce T cell-independent Ig heavy chain class switching.
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 C( micro ) to multiple downstream C(gamma), C(alpha), and C(epsilon) 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 C(gamma), C(alpha), and C(epsilon) 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.
He
Bing
B
Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.
Raab-Traub
Nancy
N
Casali
Paolo
P
Cerutti
Andrea
A
D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000502:physiology; D053264:B-Cell Activating Factor; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000276:immunology; D018922:HL-60 Cells; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology*; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis* / Q000235:genetics; D007137:Immunoglobulin alpha-Chains / Q000096:biosynthesis / Q000235:genetics; D007139:Immunoglobulin epsilon-Chains / Q000096:biosynthesis / Q000235:genetics; D007148:Immunoglobulin mu-Chains / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology; D009479:Neuropeptides / Q000096:biosynthesis / Q000502:physiology*; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000276:immunology; D011995:Recombination, Genetic; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014158:Transcription, Genetic / Q000276:immunology; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D014763:Viral Matrix Proteins / Q000235:genetics / Q000502:physiology*
D000276:Adjuvants, Immunologic; D053264:B-Cell Activating Factor; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D007143:Immunoglobulin Heavy Chains; D007137:Immunoglobulin alpha-Chains; D007139:Immunoglobulin epsilon-Chains; D007148:Immunoglobulin mu-Chains; D008565:Membrane Proteins; D016328:NF-kappa B; D009479:Neuropeptides; D009687:Nuclear Proteins; C114631:TNFSF13 protein, human; C505719:TNFSF13B protein, human; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D014409:Tumor Necrosis Factor-alpha; D014763:Viral Matrix Proteins; D003564:Cytidine Deaminase