Human IgA-Expressing Bone Marrow Plasma Cells Characteristically Upregulate Programmed Cell Death Protein-1 Upon B Cell Receptor Stimulation

Abstract

The functions of bone marrow plasma cells (BMPC) beyond antibody production are not fully elucidated and distinct subsets of BMPC suggest potential different functions. Phenotypic differences were identified for human BMPC depending on CD19 expression. Since CD19 is a co-stimulatory molecule of the B-cell-receptor (BCR), and IgA+ and IgM+ BMPC express the BCR on their surface, we here studied whether CD19 expression affects cellular responses, such as BCR signaling and the expression of checkpoint molecules. We analyzed 132 BM samples from individuals undergoing routine total hip arthroplasty. We found that both CD19+ and CD19− BMPC expressed BCR signaling molecules. Notably, the BCR-associated kinase spleen tyrosine kinase (SYK) including pSYK was higher expressed in CD19+ BMPC compared to CD19− BMPC. BCR stimulation also resulted in increased kinase phosphorylation downstream of the BCR while expression of CD19 remained stable afterwards. Interestingly, the BCR response was restricted to IgA+ BMPC independently of CD19 expression. With regard to the expression of checkpoint molecules, CD19− BMPC expressed higher levels of co-inhibitory molecule programmed cell death protein-1 (PD-1) than CD19+ BMPC. IgA+ BMPC characteristically upregulated PD-1 upon BCR stimulation in contrast to other PC subsets and inhibition of the kinase SYK abrogated PD-1 upregulation. In contrast, expression of PD-1 ligand, B and T lymphocyte attenuator (BTLA) and CD28 did not change upon BCR activation of IgA+ BMPC. Here, we identify a distinct characteristic of IgA+ BMPC that is independent of the phenotypic heterogeneity of the subsets according to their CD19 expression. The data suggest that IgA+ BMPC underlie different regulatory principles and/or exert distinct regulatory functions.

Chimeric antigen receptor T cells in the fast lane among autoimmune disease therapies

“…This is consistent with both childhood vaccine specificities being enriched in the CD19‐negative bone marrow ASC population, 9,17,18 and with CD19‐negative ASCs being present in bone marrow aspiration samples from B‐cell cancer patients post anti‐CD19 CAR‐T‐cell infusion who also retained certain vaccine/pathogen reactivities 19 . Somewhat confusingly, however, vaccine‐specific Ab levels were also largely retained in atacicept‐treated patients, 10 indicating either those vaccine‐specific ASCs reside in a CD19‐negative, APRIL‐independent compartment or there is a broad distribution of specificities among bone marrow ASC compartments, which is suggested by other studies 20,21 . The complete characterisation of the different subpopulations of B cells and ASCs in both health and autoimmune disease will greatly assist in improved targeting of pathogenic, autoreactive B cells and ASCs.…”

“…19 Somewhat confusingly, however, vaccine-specific Ab levels were also largely retained in atacicept-treated patients, 10 indicating either those vaccine-specific ASCs reside in a CD19-negative, APRIL-independent compartment or there is a broad distribution of specificities among bone marrow ASC compartments, which is suggested by other studies. 20,21 The complete characterisation of the different subpopulations of B cells and ASCs in both health and autoimmune disease will greatly assist in improved targeting of pathogenic, autoreactive B cells and ASCs.…”

CD39 and CD326 Are Bona Fide Markers of Murine and Human Plasma Cells and Identify a Bone Marrow Specific Plasma Cell Subpopulation in Lupus

“…In B cells, CD81 is part of the BCR complex that includes CD21 and CD19 and reduces the threshold for B cell activation. It was believed that ASCs no longer had a functional BCR, but this idea has to be reconsidered in light with reports showing that IgM and IgA ASCs still have a functional surface BCR (4,57,58). Thus, CD81 may play a role in the activation of ASCs, being therefore also more than just a marker for their identification.…”

“…Different subsets of ASCs have been described in mouse and human. For instance, a subset of CD19human bone marrow ASCs expressing high levels of programmed cell death protein-1 was recently reported (4). Collectively, ASCs form a heterogeneous population containing several subpopulations with different functions.…”

Efficient CRISPR-Cas9-mediated mutagenesis in primary human B cells for identifying plasma cell regulators

“…Recent studies in mice have shown that PCs can also regulate immunity through production of anti-inflammatory cytokines such as interleukin (IL)-10 and IL-35. 1 , 2 , 3 , 4 Distinct PC subsets with protective and pathogenic functions have been identified by the expression of certain surface markers in both mouse and humans, 1 , 3 , 5 , 6 providing possible selective depletion approaches of the pathogenic cells in various diseases. Nevertheless, this strategy is limited as those surface markers are also expressed by other immune cell lineages.…”