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RNA-seq analysis of splenic IgG1 or IgM plasma cells

ABSTRACT: In a typical primary immune response, the BCR is brought about by IgM to IgG isotype switching, wherein B cells switched to IgG give rise to more long-lived plasma cells (LLPCs). How such isotype-driven bias takes place still remains unclear. Here, we showed that IgG1 germinal center (GC) B cells presented higher levels of antigens to Tfh cells, making the resultant plasma cells more proliferate than IgM ones, and that BCR signal through IgM conferred more Bim-dependent apoptosis on their plasma cells, together dominating the numbers of IgG1 over IgM plasma cells in the secondary lymphoid tissues. In addition, IgG1 plasma cells were more prone to migrate to bone marrow than IgM ones. Hence, our findings suggest that differential activities in antigen presentation and signaling through IgG1 type BCRs contribute to enrichment of IgG1 plasma cells in the bone marrow long-lived plasma cell compartment.

ORGANISM(S): Mus musculus

PROVIDER: GSE312785 | GEO | 2026/07/11

REPOSITORIES: GEO

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Project description:Majority of B cell malignancies originate in the germinal centers (GCs), where B cells undergo activation to mutationally diversify their antibody genes and switch from the default Immunoglobulin M (IgM) or IgD B cell receptor (BCR) to IgG, IgA or IgE BCR isotypes. Similar to normal B cells, malignant B cells rely on signals emanating from the BCR for their survival and growth. While studies have primarily focused on elucidating the functions of IgM-mediated signaling in lymphoma pathogenesis, GC-derived lymphomas also express IgG and IgA BCR isotypes that greatly differ from IgM in their signaling potential. How these distinct non-IgM BCRs contribute to the pathogenesis of B cell malignancies is not well understood. Interestingly, B cell lymphoma patients expressing IgG BCR isotypes show better prognosis and survival than those expressing IgM BCR isotype. Consistent with this, we show that Diffuse Large B Cell Lymphoma (DLBCL) patients with higher IgG1 expression are associated with lower stages of disease than those with higher IgM expression. To directly test the roles of distinct BCR isotypes, we developed isogenic lymphoma cells that either express IgM or IgG1 BCRs. Interestingly, the IgG1-switched lymphoma cells fail to form tumors in mice whereas their IgM counterparts establish aggressive tumors. Moreover, co-transplantation of IgG1 and IgM expressing human and mouse lymphoma cells leads to emergence of tumors expressing IgM (and not IgG1), demonstrating that IgM BCRs are strongly favored over IgG1. Mechanistically, IgG1 expressing lymphoma cells and non-malignant activated B cells have reduced survival which is associated with a dysfunctional mitochondrial state triggered by stronger calcium responses in IgG1 in comparison to IgM cells. Genetic reversal of IgG1 to IgM or pharmacological dampening of the calcium signaling is sufficient to correct the mitochondrial defects and rescue the survival of IgG1 B cells. Our findings demonstrate that distinct BCR isotypes are inherently unique in their activities and can differentially impact B cell lymphoma pathogenesis.

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RNA-seq analysis of splenic IgG1 or IgM plasma cells

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