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Human IgG1 (B-cell receptor) Fc peptide glycan analysis, LC-MS

ABSTRACT: Since few data are available on glycans expressed by human BCRs, we aimed to analyze the Fc glycans of membrane-bound IgG after BCR capture and tryptic digestion by LC-MS. For this purpose, human B-cell lines from Burkitt Lymphoma (Ramos) expressing IgG1-BCRs in the presence or absence of Fc glycans (FcG) were analyzed. The B-cell lines were generated by transduction of the BCR-negative MDL-AID KO cell line with N(297) or mutant Q(297) IgG-BCRs. The BCR sequences used were derived from single-cell sorted human B cells isolated from patients with the autoimmune disease rheumatoid arthritis. Two BCRs were directed towards citrullinated antigens (2G9 and 3F3), while a third BCR was directed against tetanus toxoid (D2). In addition, we analyzed the Fc glycan profile of IgG secreted (sIgG) by human Ramos B cells for comparison.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Cell Culture

DISEASE(S): Rheumatoid Arthritis

SUBMITTER: Theresa Kissel

LAB HEAD: Rene E.M. Toes

PROVIDER: PXD047089 | Pride | 2023-12-11

REPOSITORIES: Pride

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			Action	DRS
	2021GLY00003MX5_3F3_FcG_negative.mzXML	Mzxml
	2021GLY00003MX5_3F3_FcG_positive.mzXML	Mzxml
	2021GLY00003MX5_MDL_AID_KO.mzXML	Mzxml
	2022GLY00056MX5_D2_FcG_negative.mzXML	Mzxml
	2022GLY00056MX5_D2_FcG_positive.mzXML	Mzxml

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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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Human IgG1 (B-cell receptor) Fc peptide glycan analysis, LC-MS

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