TLR7 influences germinal center selection in murine SLE.
TLR7 enhances germinal center maturation and migration of B cells to the dark zone where proliferation and somatic hypermutation occur. Our goal was to determine how Tlr7 dose influences selection of the autoreactive B cell repertoire in NZW/BXSB. Yaa mice bearing the site-directed heavy chain trans...
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doaj-2217da48348848cebb435c32d916496a2020-11-25T02:22:10ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01103e011992510.1371/journal.pone.0119925TLR7 influences germinal center selection in murine SLE.Alexis BoneparthWeiqing HuangRamalingam BethunaickanMegan WoodsRanjit SahuShitij AroraMeredith AkermanMartin LesserAnne DavidsonTLR7 enhances germinal center maturation and migration of B cells to the dark zone where proliferation and somatic hypermutation occur. Our goal was to determine how Tlr7 dose influences selection of the autoreactive B cell repertoire in NZW/BXSB. Yaa mice bearing the site-directed heavy chain transgene 3H9 that encodes for the TLR7 regulated anti-CL response. To create a physiologic setting in which autoreactive B cells compete for survival with non-autoreactive B cells, we generated bone marrow chimeras in which disease onset occurred with similar kinetics and the transferred 3H9+ female non-Yaa, male Yaa or male TLR7(-/Yaa) cells could be easily identified by positivity for GFP. Deletion of 3H9 B cells occurred in the bone marrow and the remaining 3H9 follicular B cells manifested a decrease in surface IgM. Although there were differences in the naïve repertoire between the chimeras it was not possible to distinguish a clear pattern of selection against lupus related autoreactivity in TLR7(-/Yaa) or female chimeras. By contrast, preferential expansion of 3H9+ B cells occurred in the germinal centers of male Yaa chimeras. In addition, although all chimeras preferentially selected 3H9/Vκ5 encoded B cells into the germinal center and plasma cell compartments, 3H9 male Yaa chimeras had a more diverse repertoire and positively selected the 3H9/Vκ5-48/Jκ4 pair that confers high affinity anti-cardiolipin activity. We were unable to demonstrate a consistent effect of Tlr7 dose or Yaa on somatic mutations. Our data show that TLR7 excess influences the selection, expansion and diversification of B cells in the germinal center, independent of other genes in the Yaa locus.http://europepmc.org/articles/PMC4368537?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alexis Boneparth Weiqing Huang Ramalingam Bethunaickan Megan Woods Ranjit Sahu Shitij Arora Meredith Akerman Martin Lesser Anne Davidson |
spellingShingle |
Alexis Boneparth Weiqing Huang Ramalingam Bethunaickan Megan Woods Ranjit Sahu Shitij Arora Meredith Akerman Martin Lesser Anne Davidson TLR7 influences germinal center selection in murine SLE. PLoS ONE |
author_facet |
Alexis Boneparth Weiqing Huang Ramalingam Bethunaickan Megan Woods Ranjit Sahu Shitij Arora Meredith Akerman Martin Lesser Anne Davidson |
author_sort |
Alexis Boneparth |
title |
TLR7 influences germinal center selection in murine SLE. |
title_short |
TLR7 influences germinal center selection in murine SLE. |
title_full |
TLR7 influences germinal center selection in murine SLE. |
title_fullStr |
TLR7 influences germinal center selection in murine SLE. |
title_full_unstemmed |
TLR7 influences germinal center selection in murine SLE. |
title_sort |
tlr7 influences germinal center selection in murine sle. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2015-01-01 |
description |
TLR7 enhances germinal center maturation and migration of B cells to the dark zone where proliferation and somatic hypermutation occur. Our goal was to determine how Tlr7 dose influences selection of the autoreactive B cell repertoire in NZW/BXSB. Yaa mice bearing the site-directed heavy chain transgene 3H9 that encodes for the TLR7 regulated anti-CL response. To create a physiologic setting in which autoreactive B cells compete for survival with non-autoreactive B cells, we generated bone marrow chimeras in which disease onset occurred with similar kinetics and the transferred 3H9+ female non-Yaa, male Yaa or male TLR7(-/Yaa) cells could be easily identified by positivity for GFP. Deletion of 3H9 B cells occurred in the bone marrow and the remaining 3H9 follicular B cells manifested a decrease in surface IgM. Although there were differences in the naïve repertoire between the chimeras it was not possible to distinguish a clear pattern of selection against lupus related autoreactivity in TLR7(-/Yaa) or female chimeras. By contrast, preferential expansion of 3H9+ B cells occurred in the germinal centers of male Yaa chimeras. In addition, although all chimeras preferentially selected 3H9/Vκ5 encoded B cells into the germinal center and plasma cell compartments, 3H9 male Yaa chimeras had a more diverse repertoire and positively selected the 3H9/Vκ5-48/Jκ4 pair that confers high affinity anti-cardiolipin activity. We were unable to demonstrate a consistent effect of Tlr7 dose or Yaa on somatic mutations. Our data show that TLR7 excess influences the selection, expansion and diversification of B cells in the germinal center, independent of other genes in the Yaa locus. |
url |
http://europepmc.org/articles/PMC4368537?pdf=render |
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