%0 Journal Article %1 Minamitani15092015 %A Minamitani, Takeharu %A Yasui, Teruhito %A Ma, Yijie %A Zhou, Hufeng %A Okuzaki, Daisuke %A Tsai, Chiau-Yuang %A Sakakibara, Shuhei %A Gewurz, Benjamin E. %A Kieff, Elliott %A Kikutani, Hitoshi %D 2015 %J Proceedings of the National Academy of Sciences %K myown %N 37 %P 11612-11617 %R 10.1073/pnas.1514484112 %T Evasion of affinity-based selection in germinal centers by Epstein–Barr virus LMP2A %U http://www.pnas.org/content/112/37/11612.abstract %V 112 %X Epstein–Barr virus (EBV) infects germinal center (GC) B cells and establishes persistent infection in memory B cells. EBV-infected B cells can cause B-cell malignancies in humans with T- or natural killer-cell deficiency. We now find that EBV-encoded latent membrane protein 2A (LMP2A) mimics B-cell antigen receptor (BCR) signaling in murine GC B cells, causing altered humoral immune responses and autoimmune diseases. Investigation of the impact of LMP2A on B-cell differentiation in mice that conditionally express LMP2A in GC B cells or all B-lineage cells found LMP2A expression enhanced not only BCR signals but also plasma cell differentiation in vitro and in vivo. Conditional LMP2A expression in GC B cells resulted in preferential selection of low-affinity antibody-producing B cells despite apparently normal GC formation. GC B-cell–specific LMP2A expression led to systemic lupus erythematosus-like autoimmune phenotypes in an age-dependent manner. Epigenetic profiling of LMP2A B cells found increased H3K27ac and H3K4me1 signals at the zinc finger and bric-a-brac, tramtrack domain-containing protein 20 locus. We conclude that LMP2A reduces the stringency of GC B-cell selection and may contribute to persistent EBV infection and pathogenesis by providing GC B cells with excessive prosurvival effects.

@article{Minamitani15092015, abstract = {Epstein–Barr virus (EBV) infects germinal center (GC) B cells and establishes persistent infection in memory B cells. EBV-infected B cells can cause B-cell malignancies in humans with T- or natural killer-cell deficiency. We now find that EBV-encoded latent membrane protein 2A (LMP2A) mimics B-cell antigen receptor (BCR) signaling in murine GC B cells, causing altered humoral immune responses and autoimmune diseases. Investigation of the impact of LMP2A on B-cell differentiation in mice that conditionally express LMP2A in GC B cells or all B-lineage cells found LMP2A expression enhanced not only BCR signals but also plasma cell differentiation in vitro and in vivo. Conditional LMP2A expression in GC B cells resulted in preferential selection of low-affinity antibody-producing B cells despite apparently normal GC formation. GC B-cell–specific LMP2A expression led to systemic lupus erythematosus-like autoimmune phenotypes in an age-dependent manner. Epigenetic profiling of LMP2A B cells found increased H3K27ac and H3K4me1 signals at the zinc finger and bric-a-brac, tramtrack domain-containing protein 20 locus. We conclude that LMP2A reduces the stringency of GC B-cell selection and may contribute to persistent EBV infection and pathogenesis by providing GC B cells with excessive prosurvival effects.}, added-at = {2016-11-17T00:30:02.000+0100}, author = {Minamitani, Takeharu and Yasui, Teruhito and Ma, Yijie and Zhou, Hufeng and Okuzaki, Daisuke and Tsai, Chiau-Yuang and Sakakibara, Shuhei and Gewurz, Benjamin E. and Kieff, Elliott and Kikutani, Hitoshi}, biburl = {https://www.bibsonomy.org/bibtex/2923715ee77ecf7772a6ff1cdf2bfc617/bgewurz}, doi = {10.1073/pnas.1514484112}, eprint = {http://www.pnas.org/content/112/37/11612.full.pdf}, interhash = {14a15c4e335c48d66a92e98ab057c173}, intrahash = {923715ee77ecf7772a6ff1cdf2bfc617}, journal = {Proceedings of the National Academy of Sciences}, keywords = {myown}, number = 37, pages = {11612-11617}, timestamp = {2016-11-17T00:30:02.000+0100}, title = {Evasion of affinity-based selection in germinal centers by Epstein–Barr virus LMP2A}, url = {http://www.pnas.org/content/112/37/11612.abstract}, volume = 112, year = 2015 }