A Guide to Plasma Cell Markers

Plasma cells, also known as antibody-secreting cells or plasma B cells, arise when various B cell subsets encounter an antigen, present it on the cell surface via MHC II, and become activated by cognate interactions with T helper cells. As terminally differentiated B cells, plasma cells produce antigen-specific antibodies in support of adaptive immunity.

Plasma cells express many markers of B cells, from which they originate, but they also express plasma cell-specific markers. This article reviews plasma cell markers as outlined in recent literature.

Markers of Human Plasma Cell Subsets

B cells can differentiate into short-lived plasmablasts or long-lived plasma cells upon antigenic stimulation.

Plasmablasts, or short-lived plasma cells, are generated in an extrafollicular response to T cell-dependent antigens, or antigens that only stimulate B cells with help from T cells. Upon receiving the antigenic signal, B cells differentiate into proliferative B lymphoblasts and then short-lived plasmablasts. These plasmablasts produce a substantial, albeit unrefined, proportion of the antibodies associated with an immune response. The transcription factors IRF4, XBP1, and BLIMP1 are critical for this differentiation process.

Early in the differentiation process, plasmablasts are IgD^–CD27^lo/+CD38⁺⁺CD24^–. As they differentiate, they begin expressing higher levels of CD27 and CD38. Whereas mature plasmablasts express CD20, early plasmablasts may or not express this marker. Mature plasmablasts can also be identified as Ki67⁺, a common marker of proliferating cells. 

Figure: This table highlights prominent plasma cell subsets and associated markers in mice and humans.

A regulatory subset of plasmablasts, called IL-10+ plasmablasts, emerges from naive B cells in disease contexts like autoimmunity and cancer. Plasma cell transcription factors BLIMP1 and IRF4 control the differentiation of this specialized population. In addition, like short-lived plasmablasts, IL-10+ plasmablasts are CD19⁺, CD24^–, CD38⁺, CD27⁺, and CD138^–. These two plasmablast populations can be distinguished by their expression of CD20: IL-10+ plasmablasts express low to intermediate levels of the marker, whereas normal plasmablasts do not express it at all.

Additional markers of plasmablasts include CD19, CD44, CD45, CXCR3, CXCR4, KLF4, MS4A1, TNFRSF17, and HLA-DR.

Long-lived plasma cells are generated from clusters of activated B cells, called B cell follicles. With help from T follicular helper cells, these B cells proliferate to form the germinal centers in which high-affinity, long-lived plasma cells are selected. In addition to sharing the same core signature as short-lived plasmablasts (IgD^–CD27^lo/+CD38⁺⁺CD24^–), long-lived plasma cells are CD19^+/–CD20^–CD138⁺. 

Mouse-Specific Plasma Cell Markers

Mouse and human plasma cells share many markers. The same transcription factors that drive plasma cell fate in humans (IRF4, XBP1, and BLIMP1) also do so in mice. Plasma cells of both species also share CD19, CD44, TNFRSF17, CXCR3, CD138, and CD45. However, most of the core human plasma cell markers described above—namely, CD24, CD27, CD38—are not found on mice plasma cells.

There are also several mouse-specific plasma cell markers. For example, mouse plasmablasts cells express CD22 and CD44, neither of which are present on human plasmablasts. As for long-lived plasma cells, mouse-specific markers include TNFRSF13B, CD98, CD28, Ly6k, Ly6c, Ly6a, ITGA4, CD93. One reason for the differences in marker profiles between species is the lack of homologs. Indeed, there are no human equivalents of Ly6k, Ly6c, and Ly6a. 

Markers of Plasma Cell Function

As antibody-secreting cells, plasma cells naturally produce immunoglobulin (Ig) proteins, including IgA, IgM, IgD, and IgG. Naive B cells express mostly IgM and some IgD on their cell surface. Upon activation, B cells lose IgD expression and may undergo class-switching from IgM to another Ig class. Most class switching occurs in germinal centers where long-lived plasma cells are generated. The class-switching process requires ligation of CD40 (on B cells) by CD40 ligand (on T cells).  

The class of antibody a plasma cell secretes depends on the cell's developmental stage and which signals it receives. For example, IL-5 and TGF-β favor IgA production, IL-4 favors IgG1 and IgE production, and IFN-γ favors IgG2a and IgG3 production. In general, plasmablasts are capable of producing any Ig class, whereas more mature plasma cells preferentially produce IgA and IgG.        

Although their primary function is to produce antibodies, plasma cells also express other proteins that help them home to the bone marrow, where the majority of long-lived plasma cells reside, or sites of inflammation. Long-lived plasma cells sense the bone marrow-derived CXCL12 ligand via its receptor CXCR4 to home to bone marrow. Once there, plasma cells are retained via the membrane proteins VLA4, CD44, CD28, and CD93 and survive via actions of bone marrow-derived TNFSF13 (also known as APRIL) on plasma cell TNFRSF17 (also known as BCMA). By contrast, plasma cells use CXCR3 to follow inflammatory chemotactic cues (the inflammatory chemokines CXCL9, CXCL10 and CXCL11) to sites of inflammation.

IL-10+ plasmablasts dampen immune responses in autoimmunity and cancer by producing the anti-inflammatory cytokine IL-10.

Myeloma Markers

Multiple myeloma (MM), a cancer of plasma cells, occurs when a mature B cell does not stop proliferating after antigen-specific activation. The dysregulated proliferation of myelomatous plasma cells results in a spike in monoclonal antibody production, which can be used to diagnose the condition.

Proliferation is not the only aspect of plasma cells that becomes dysregulated in myeloma; their expression profile also changes. For example, malignant plasma cells may begin to express markers such as CD28, CD33, CD56, or CD117 and downregulate the memory B cell marker CD27.

Myeloma markers can be used to monitor patients for minimal residual disease (MRD), an application in which flow cytometry is used to quantify minute levels of myeloma present after treatment. The combination of the core plasma cell markers CD138 and CD38 with myeloma-specific markers CD45, CD19, CD56, CD27, CD81, and CD117 can be used to identify MRD in virtually any patient with myeloma. CD54, CD200, and CD37 are markers with more heterogeneous expression among patients with MM. It is important to note that no single marker alone can distinguish cancerous plasma cells from normal ones.

Table of Plasma Cell Markers

The table below lists human and mouse proteins characterizing various subsets of plasma cells as described by recent review literature. The majority of proteins listed are membrane markers expressed on the cell surface, but also included are other defining proteins, including transcription factors and signaling proteins, such as cytokines. Accompanying each marker are links to relevant antibodies and ELISA kits, as these immunodetection tools are routinely used in cell characterization studies via flow cytometry and immunostaining. The associated products are offered by a variety of manufacturers and can serve as a useful reference for plasma cell and myeloma immunophenotyping.

Note: *Some markers are protein isoforms, multi-subunit protein complexes, or protein families composed of several distinct genes. Information on Protein Type, Localization, and Size (kDa) obtained from UniProt.org (for human genes only). 

References

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2. Rosser EC, Mauri C. Regulatory B cells: origin, phenotype, and function. Immunity. 2015;42(4):607-612. doi:10.1016/j.immuni.2015.04.005

3. Flores-Montero J, de Tute R, Paiva B, et al. Immunophenotype of normal vs. myeloma plasma cells: Toward antibody panel specifications for MRD detection in multiple myeloma. Cytometry B Clin Cytom. 2016;90(1):61-72. doi:10.1002/cyto.b.21265

4. Tellier J, Nutt SL. Standing out from the crowd: How to identify plasma cells. Eur J Immunol. 2017;47(8):1276-1279. doi:10.1002/eji.201747168

5. Brynjolfsson SF, Persson Berg L, Olsen Ekerhult T, et al. Long-Lived Plasma Cells in Mice and Men. Front Immunol. 2018;9:2673. Published 2018 Nov 16. doi:10.3389/fimmu.2018.02673

6. Sanz I, Wei C, Jenks SA, et al. Challenges and Opportunities for Consistent Classification of Human B Cell and Plasma Cell Populations. Front Immunol. 2019;10:2458. Published 2019 Oct 18. doi:10.3389/fimmu.2019.02458