Roles of Bone Morphogenetic Protein Receptor 1A in Germinal Centers and Long-Lived Humoral Immunity

Abstract

In response to T-dependent Ag, germinal centers (GC) generate bone marrow-resident plasma cells (BMPC) and memory B cells (MBC). In this study, we demonstrate that the bone morphogenetic protein receptor 1A (BMPR1A) signaling pathway, which regulates differentiation and self-renewal in multiple stem cell populations, regulates GC dynamics and resultant establishment of BMPC and MBC. Expression studies using quantitative PCR and novel Bmpr1a.IRES.EGFP reporter mice demonstrated that Bmpr1a expression is upregulated among GC B cells (GCBC) and subsets of MBC, bone marrow plasmablasts, and BMPC. In immunized mice carrying B cell-targeted Bmpr1a gene deletions, the GC response was initially diminished. Subsequently, the GCBC compartment recovered in size, concurrent with accumulation of GCBC that carried unmodified rather than deleted Bmpr1a alleles. Similarly, the resulting classswitched MBC and BMPC carried retained non-recombined alleles. Despite the strong selective pressure for leaky B cells that retained Bmpr1a, there was a permanent marked reduction in switched bone marrow Ab-forming cells (plasmablasts + plasma cells), BMPC, MBC, and Ag-specific serum IgM in mice carrying B cell-targeted Bmpr1a gene deletions. These findings demonstrate a novel role for BMPR1A in the modulation of the B cell response and in the establishment of long-term memory. ImmunoHorizons, 2021, 5: 284-297.

XistDeletion in B Cells Results in Systemic Lupus Erythematosus Phenotypes

“…In addition to changes in X-linked gene expression, we identified autosomal transcriptional changes in Xist cKO B cells with SLE phenotypes. In CD11c+ ABCs from Xist cKO High mice, upregulated autosomal genes were enriched for genes involved in lymphocyte activation, including Bcl3 (important for antigen-specific autoantibody formation) 73 , Bmpr1a (upregulated in some memory B cell subsets) 74 , Cxcr4 (plays a role in B cell homeostasis and trafficking) 75 , and Fas (upregulated in ABCs from patients with SLE) 41 . In CD11c+ ABCs from pristane-treated Xist cKO mice, upregulated autosomal genes were enriched for genes involved in immune processes, including Pik3r6 (mediates signaling pathways that regulate proliferation, class-switch recombination, and plasma cell differentiation) 76 , Sh3kbp1 (poises B cells to respond to BCR stimulation) 77 , and Zbtb20 (involved in plasma cell differentiation via Irf4) 78 .…”

Bone morphogenetic proteins, activins, and growth and differentiation factors in tumor immunology and immunotherapy resistance

“…The BMPR-IA signaling pathway regulates differentiation and self-renewal in several stem-cell populations in the germinal center. Mouse germinal-center B cells showed increased expression of BMPR-IA, and the targeted deletion of BMPR-IA impaired the germinal-center reaction and reduced differentiation from plasmablasts to antibody-producing plasma cells ( 161 ). One study identified that although human germinal-center B cells express high levels of BMPRI and low levels of BMPRII, naïve B cells show low levels of BMPRI and high levels of BMPRII ( 162 ).…”