title: TLR7 influences germinal center selection in murine SLE.
abstract: 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.
authors: Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Manhasset, New York, 11030, United States of America.
authors: Alexis
authors: A
authors: Boneparth
authors: Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Manhasset, New York, 11030, United States of America.
authors: Weiqing
authors: W
authors: Huang
authors: Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Manhasset, New York, 11030, United States of America.
authors: Ramalingam
authors: R
authors: Bethunaickan
authors: Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Manhasset, New York, 11030, United States of America.
authors: Megan
authors: M
authors: Woods
authors: Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Manhasset, New York, 11030, United States of America.
authors: Ranjit
authors: R
authors: Sahu
authors: Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Manhasset, New York, 11030, United States of America.
authors: Shitij
authors: S
authors: Arora
authors: Biostatistics Unit, Feinstein Institute for Medical Research, Manhasset, New York, 11030, United States of America.
authors: Meredith
authors: M
authors: Akerman
authors: Biostatistics Unit, Feinstein Institute for Medical Research, Manhasset, New York, 11030, United States of America.
authors: Martin
authors: M
authors: Lesser
authors: Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Manhasset, New York, 11030, United States of America.
authors: Anne
authors: A
authors: Davidson
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D060966:Clonal Selection, Antigen-Mediated / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D018858:Germinal Center / Q000276:immunology* / Q000378:metabolism*; D016130:Immunophenotyping; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype; D013154:Spleen / Q000166:cytology / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D051199:Toll-Like Receptor 7