University of Virginia Health System

Plasma Cell
(Plasmacyte)

(a) Plasma cell- Bone marrow aspirate smear, Wright-Giemsa stain, 1000x

(b) Mott Cell- Bone marrow aspirate smear, Wright-Giemsa stain, 500x

(c) Dutcher bodies- Bone marrow aspirate smear, Wright-Giemsa stain, 1000x

Dutcher Body and Mott Cell Comparison- Bone marrow aspirate, Wright-Giemsa stain, 1000x

(d) Russell Bodies- Bone Marrow Biopsy, H&E stain, 400x

Russell Body- Bone marrow aspirate, Wright-Giemsa stain, 1000x

(e) Flamed plasma cell- Bone marrow aspirate smear, Wright-Giemsa stain, 1000x

(f) Binucleated plasma cell- Bone marrow aspirate smear, Wright-Giemsa stain, 1000x

(g) Plasmablast- Bone marrow aspirate smear, Wright-Giemsa stain, 1000x

(h) Plasmacytoid lymphocyte- Bone marrow aspirate smear, Wright-Giemsa stain, 1000x

Description:

Plasma cells have a very distinctive appearance by light microscopy on a Wright-Giemsa stained bone marrow aspirate, and represent 1-4% of nucleated bone marrow cells in normal subjects. They vary in size from 10-20 μm, and their cytoplasmic margins frequently are irregular in appearance. The nucleus is round and characteristically eccentric in location. The chromatin is mature with variable clumping. A well developed perinuclear Golgi complex (hof) is almost always present. The cytoplasm is abundant and usually deep blue (basophilic) in color, but lighter shades of blue are seen. Other features that are seen more frequently in malignant plasma cell disorders may be observed in bone marrow aspirates from normal subjects. These include Mott (morula) cells which have grape-like cytoplasmic inclusions which contain immunoglobulin (b). Similar inclusions that represent immunoglobulin accumulation in the perinuclear cisternae with subsequent invagination into the nucleus, giving the appearance of being intranuclear, are referred to as plasma cells with Dutcher bodies (c). A single large homogenous immunoglobulin containing inclusion referred to as a Russell body also may be seen, but more often seen in fixed sections (d). Flamed plasma cells characterized by an eosinophilic staining at the periphery or sometimes the entire cytoplasm (e). These flamed cells are observed not infrequently in patients with IgA myelomas. Multinucleated plasma cells also are seen (f). Immature plasma cells (plasmablasts) rarely are seen in normal bone marrow aspirates (g). Plasmacytoid lymphocytes (h), the characteristic cells seen in Waldenstrom's macroglobulinemia are seen not infrequently in normal bone marrow aspirates. These cells are very small plasma cells, and unlike small lymphocytes, usually have a visible Golgi complex.

Development, Function and Trafficking:

Plasma cells represent terminally differentiated antibody-secreting B cells after undergoing antigenic stimulation. Most are derived from germinal centers where näive B cells come in contact with antigen and subsequently undergo T cell-dependent proliferation and differentiation to form memory B cells or precursor plasma cells. The T cells involved are antigen-specific, having been generated after being activated by the presentation of peptides from the same antigen that initiated the B cell activation.  These antigen-specific T cells are of the helper T 2 (Th 2) subset. During this developmental phase, in the germinal center marked expansion of the activated B cells occurs along with somatic hypermutation, positive selection, and class (isotype) switching. These various activities occur in specific areas within the germinal center. The initial expansion and somatic hypermutation takes place in the "dark zone" which is proximal to the T cell zone, and is composed of centroblasts (large cleaved and non-cleaved transformed B cells), follicular dendritic cells (DCs), and a variable number of tingible body macrophages that engulf the many B cells that undergo apoptosis during this phase. Somatic hypermutation is the result of single base-pair substitutions in the variable regions of the immunoglobulin genes. The final result is a "fine tuning" of the antigen reactive site (idiotype, Id) of the immunoglubulin molecule. In the "light basal zone" located between the proximal "dark zone" and the "apical light zone", positive selection favoring high-affinity BCRs occurs as a result of interaction between the B cells with antigen-antibody-complement complexes on the DCs. B cells not positively selected undergo apoptosis. In the "apical light zone", further differentiation to memory B cells or plasma cell precursors occurs along with class switching from sIgM and/or sIgD bearing B cells to cells that synthesize either IgG, IgM, IgA, IgE and IgD (clonal selection). The interaction between the CD40 receptor that appears on the B cells and DCs during activation and the CD40 ligand on Th 2 cells is crucial for class switching to occur. The importance of this interaction is exemplified by the primary immunodeficiency syndrome, hyperimmunoglobulin M that results from certain mutations in the CD40 ligand gene.

Many other factors are involved in the overall development of antigen-specific memory B cells and plasma cell precursors within the germinal center. These include the interactions of other surface molecules on the activated B cells, the Th 2 cells, and DCs. For example, another result of the CD40-CD40 ligand interaction is the upregulation of CD80 and CD86 on both B cells and DCs. Interaction of these two ligands with their receptor, CD28 on Th 2 cells activates T cells. In contrast, when the CD80 and CD86 ligand with cytotoxic T-lymphocyte-associated antigen (CTLA-4) T cell anergy or tolerance results. Cytokines such as Il-2, Il-4, Il-6, and transforming growth factor β are also important (e.g. Il-4 drives the class switching to IgG-1).

From the "apical light zone" both antigen-specific memory B cells and plasma cell precursors exit and travel through afferent lymphatics to the blood stream and subsequently home to various sites. Most cells destined to secrete IgG and IgM go to the bone marrow while those destined to secrete IgA and IgE go to MALT areas. In adults, more than 1 million specific antibodies, as determined by difference in structure of the Id portion of antibody molecules, are produced and secreted. This number of polyclonal antibodies emerge despite the fact that the majority of B cell precursors in the bone marrow are eliminated during the antigen-independent B cell development in the bone marrow and the further antigen-dependent development in peripheral areas such as lymph nodes.

IgG antibodies are of 4 subclasses and represent more than 80% of the total plasma antibodies. IgA, representing 2 subsets, accounts for 10-15%, IgM around 5%, IgD less than 0.5%, and IgE less than 0.05%. IgG antibodies have the longest half-life, approximately 21 days, IgA about 6 days, IgM 5 days, and IgD and IgE both less than 3 days.

The basic structure of antibodies is that of two heavy chains, either IgG, IgA, IgM, IgD or IgE and two light chains, either kappa (κ) or lambda (λ), but not both on the same molecule. The specificity of an antibody is determined by the structure of the antigen reactive sites (2 per basic molecule) located in the Fab portion of the molecule where the variable and hypervariable regions of both light and heavy chains reside. The structure of most antibodies in plasma is that of the basic immunoglobulin molecule. IgM, however, is composed of 5 basic IgM molecules and a J chain, a glycoprotein also synthesized by plasma cells, and has a molecular weight of around 1 million compared to a molecular weight of 200,000 or less for most of the other plasma immunoglobulins. IgA antibodies found in secretions throughout MALT areas are composed of 2 basic IgA molecules, mostly IgA-1, a J chain, and another glycoprotein, secretory piece, synthesized by the epithelial cells in these areas. Because of the restriction in the light chain expression, clonality of immunoglobulins and B cells at various stages of development can be determined by whether they express kappa or lambda, but not both. Polyclonal immunoglobulins and B cells express both with a κ:λ ratio of 2:1.

Mature plasma cells do not divide. Thus, to maintain the steady level of plasma immunoglobulins the number of antibody secreting plasma cells (ASPs) must be maintained. There are at least three mechanisms by which ASPs are maintained in adequate numbers throughout the life of the host:

1. A steady flow of new plasma cells from differentiating B cells undergoing either a primary immune response or memory B cells undergoing a secondary (anamnestic) immune response.
2. The existence of long-lived plasma cells, some of which may survive for the lifespan of the host. Since the number of plasma cells in the bone marrow is very stable throughout the life of the host, and new plasma cells are arriving constantly, it is felt that there is competition for survival. Factors favoring long survival include interaction with reticular stromal cells in the microenvironment of the bone marrow, and certain cytokines (e.g. Il-6). Not all plasma cells are long-lived. Some are short-lived (half-life of only a few days), especially immature plasma cells that emerge during the early phase of an ongoing immune response.
3. Non-antigen driven differentiation of memory B cells through pattern recognition receptors (PRPs) such as Toll-like receptors in response to both self antigens and those from microorganisms.

Plasma cells rarely are seen on a peripheral blood smear from a normal subject. They are seen in small numbers in patients undergoing chronic antigenic stimulation (e.g. active rheumatoid arthritis).

General References:

1. Calame KL, Lin KI, Tunyaplin C. Regulatory mechanisms that determine the development and function of plasma cells. Annu Rev Immunal 2003; 21:205-30.
2. McHeyzer-Williams LJ, McHeyzer MG. Antigen-specific memory B cell development. Annu Rev Immunal. 2005;23:487-513
3. Manz RA, Hauser AE, Falk H, Radbruch A. Maintenance of serum antibody levels. Annu Rev Immunal; 2005;23:367-86
4. Jiang H, Chess L. Regulation of immune response by T cells. N Engl J Med. 2006; 354:166-76

For all publication requests, please complete the image permission form and we will respond to your request shortly.