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Early Generated B-1-Derived B Cells Have the Capacity To Progress To Become Mantle Cell Lymphoma-like Neoplasia in Aged Mice
J Immunol. 2018 Jul 15;201(2) :804-813
PMID: 29898964    PMCID: PMC6036230    URL: https://www.ncbi.nlm.nih.gov/pubmed/29898964
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In mice, fetal/neonatal B-1 cell development generates murine CD5(+) B cells (B1a) with autoreactivity. We analyzed B1a cells at the neonatal stage in a VH11/D/JH knock-in mouse line (VH11t) that generates an autoreactive antiphosphatidylcholine BCR. Our study revealed that antiphosphatidylcholine B1a cells develop in liver, mature in spleen, and distribute in intestine/colon, mesenteric lymph node (mLN), and body cavity as the outcome of B-1 cell development before B-2 cell development. Throughout life, self-renewing B-1 B1a cells circulate through intestine, mesenteric vessel, and blood. The body cavity-deposited B1a cells also remigrate. In old age, some B1a cells proceed to monoclonal B cell lymphocytosis. When neonatal B-1 B1a cells express an antithymocyte/Thy-1 autoreactivity (ATA) BCR transgene in the C.B17 mouse background, ATA B cells increase in PBL and strongly develop lymphomas in aging mice that feature splenomegaly and mLN hyperplasia with heightened expression of CD11b, IL-10, and activated Stat3. At the adult stage, ATA B cells were normally present in the mantle zone area, including in intestine. Furthermore, frequent association with mLN hyperplasia suggests the influence by intestinal microenvironment on lymphoma development. When cyclin D1 was overexpressed by the Emu-cyclin D1 transgene, ATA B cells progressed to further diffused lymphoma in aged mice, including in various lymph nodes with accumulation of IgM(hi)IgD(lo)CD5(+)CD23(-)CD43(+) cells, resembling aggressive human mantle cell lymphoma. Thus, our findings reveal that early generated B cells, as an outcome of B-1 cell development, can progress to become lymphocytosis, lymphoma, and mantle cell lymphoma-like neoplasia in aged mice.
1550-6606 Hayakawa, Kyoko ORCID: http://orcid.org/0000-0003-3157-5897 Formica, Anthony M Nakao, Yuka Ichikawa, Daiju Shinton, Susan A ORCID: http://orcid.org/0000-0003-2649-1904 Brill-Dashoff, Joni ORCID: http://orcid.org/0000-0002-8596-5877 Smith, Mitchell R ORCID: http://orcid.org/0000-0003-1428-8765 Morse, Herbert C 3rd Hardy, Richard R R01 AI113320/AI/NIAID NIH HHS/United States Journal Article United States J Immunol. 2018 Jun 13. pii: jimmunol.1800400. doi: 10.4049/jimmunol.1800400.