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iNature
Long-lasting antibody immunity relies on long-lived plasma cells (LLPCs)
that reside primarily in bone marrow (BM).
However, due to the rarity of LLPCs, it is not yet possible to define their phenotype or determine their heterogeneity
.
On October 31, 2022, Qi Hai of Tsinghua University and Wang Jianbin jointly published a joint newsletter entitled "Heterogeneous plasma cells and long-lived subsets in response to immunization, autoantigen and microbiota" online in the journal Nature Immunology Through single-cell mRNA sequencing, cytology, and genetic pulse-chasing mouse models, the study found that IgG and IgM LLPCs showed the EpCAM hi CXCR3- phenotype, while IgA LLPCs were Ly6AhiTigit-
.
IgG and IgA LLPC are mainly contributed by high somatic mutations after immunity or infection, while cells
with innate properties and common antibodies are found in the IgA and IgM LLPC compartments.
In particular, IgM LLPCs are highly enriched in common clones shared by different individual animals, differentiate in a T cell-independent manner, and have affinity for autoantigens and antigens of microbial origin
.
Together, this work sheds light on different pathways for LLPC development and paves the way
for a deeper understanding of the cellular and molecular basis of long-term antibody immunity.
.
After initial differentiation in secondary lymphoid organs or inflammatory tissues, some of these cells enter niches in the bone marrow (BM) and survive as LLPCs, continuing to survive to the lifetime of the host without repeated antigen stimulation
.
LLPCs are an important component of humoral immune memory and are the basis for
vaccine-induced long-term protection.
Therefore, it is crucial
to understand the distinction and maintenance of LLPCs.
However, the rarity of LLPC has hampered its research
.
In humans, LLPC is estimated to account for only about 25% of total bone marrow PCs (BMPCs), and less than 10 LLPCs
induced by a given vaccine can be found in 1 ml of BM.
It is estimated that in mice, BM contains only 20,000-30,000 virus-specific LLPCs
after lymphocytic choriomeningitis virus infection.
Another difficulty arises from the fact that PC and BM in secondary lymphoid organs appear to be heterogeneous populations
of cells derived from different B cell precursors (e.
g.
, B1 or B2 cells) through different activation pathways and different stages of differentiation.
In mice, all of these PCs express a shared set of surface and intracellular markers, such as CD138, XBP1, BLIMP1 (encoded by prdm1), and IRF
.
Therefore, identifying true LLPCs in all PCs remains a challenge, a prerequisite for
a deeper understanding of the biological basis of cell differentiation and maintenance.
LLPCs that persist long after protein immunity typically carry B cell receptors (BCRs), which are severely mutated and have a high affinity, suggesting their germinal center (GC) origin
.
Therefore, it is generally accepted that the help of T cells and the maturation of affinity in GC responses are critical
to the development and longevity of LLPCs.
Transcriptomic analysis of large spleen PCs and BMPCs at the population level showed that relative enrichment of LLPC in these regions was expected
by upregulation of genes associated with metabolism, chemotaxis, and cell-cell interactions in BM compartments.
Whether and how GC experiences facilitate these changes has not been clarified, and it is not clear whether these changes are unique to LLPC
.
Mature B cells include two major lines, B1 cells and regular B2 cells
.
B1 cells are innate B cells that develop in the fetal and neonatal stages and are found in
the peritoneum, pleural cavity, and solid organs.
The antigen receptor repertoire in B1 cells differs from B2 cells, including BCRs that are preferentially rearranged during early development, and recognizes common autoantigens and microbial products
.
Both the B1 and B2 lineages of B cells can produce PCs, but LLPC is thought to be primarily derived from B2 cells, which is consistent
with the concept of GC dependence.
PCs with B1 lineage characteristics can be found in mouse BMs, although whether they represent LLPC is unclear
.
To better characterize LLPC and explore its heterogeneity and function, the study combined single-cell RNA sequencing (scRNA-seq) to analyze the transcriptome and BCR composition of immature and immunized mouse spleen PCs (SPPCs) and BMPCs, immunospectroscopy to identify subpopulation-defined surface markers, and genetic pulse chase methods to estimate the half-lives of PC subpopulations
.
The results suggest that mouse antigen-specific IgA and IgG LLPCs can be uniquely identified
by the surface phenotypes of Ly6A hi Tigit- and EpCAMhiCXCR3-, respectively.
The researchers further reported an unmutated subset of IgM LLPC that develops in resting mice in a T-cell-independent manner but is transcriptionally similar
to T cell-dependent antigen-induced IgG LLPC.
These cells are partially dependent on the microbiome and are rich in common antibody sequences, including those found in B1a cells that recognize autoantigens and commensal microbes
.
Overall, the study characterized PC subpopulations in mouse SP and BM, measured their half-lives and identified long-lived populations
.
The results suggest that PC lifespan is associated with specific transcriptome states that form
relatively early in PC development.
Future studies are necessary to understand the differences in IgM BMPCs between species and how innate B-like cells develop into LLPCs
.
Therefore, an understanding of the mechanisms may be key
to improving our ability to plan the specific, homotypic, and long-lived PCs needed for vaccine development and antibody-mediated diseases.
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