Plasma cell

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Plasma cell
Plasmacytoma ultramini1.jpg
Micrograph of malignant plasma cells (plasmacytoma), many displaying characteristic "clockface nuclei", also seen in normal plasma cells. H&E stain.
Plasmacell.jpg
Micrograph of a plasma cell with distinct clear perinuclear region of the cytoplasm, which contains large numbers of Golgi bodies.
Details
System Lymphatic system
Identifiers
Latin plasmocytus
MeSH D010950
TH H2.00.03.0.01006
FMA 70574
Anatomical terms of microanatomy

Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B cells [1] [2] and secrete large quantities of proteins called antibodies in response to being presented specific substances called antigens. These antibodies are transported from the plasma cells by the blood plasma and the lymphatic system to the site of the target antigen (foreign substance), where they initiate its neutralization or destruction. B cells differentiate into plasma cells that produce antibody molecules closely modeled after the receptors of the precursor B cell. [3]

Contents

Structure

Plasma cells with Dutcher and Russell bodies (H&E stain, 100x, oil) Dutcher and Russell bodies.jpg
Plasma cells with Dutcher and Russell bodies (H&E stain, 100×, oil)

Plasma cells are large lymphocytes with abundant cytoplasm and a characteristic appearance on light microscopy. They have basophilic cytoplasm and an eccentric nucleus with heterochromatin in a characteristic cartwheel or clock face arrangement. Their cytoplasm also contains a pale zone that on electron microscopy contains an extensive Golgi apparatus and centrioles. Abundant rough endoplasmic reticulum combined with a well-developed Golgi apparatus makes plasma cells well-suited for secreting immunoglobulins. [4] Other organelles in a plasma cell include ribosomes, lysosomes, mitochondria, and the plasma membrane.[ citation needed ]

Surface antigens

Terminally differentiated plasma cells express relatively few surface antigens, and do not express common pan-B cell markers, such as CD19 and CD20. Instead, plasma cells are identified through flow cytometry by their additional expression of CD138, CD78, and the Interleukin-6 receptor. In humans, CD27 is a good marker for plasma cells; naïve B cells are CD27−, memory B-cells are CD27+ and plasma cells are CD27++. [5]

The surface antigen CD138 (syndecan-1) is expressed at high levels. [6]

Another important surface antigen is CD319 (SLAMF7). This antigen is expressed at high levels on normal human plasma cells. It is also expressed on malignant plasma cells in multiple myeloma. Compared with CD138, which disappears rapidly ex vivo, the expression of CD319 is considerably more stable. [7]

Development

After leaving the bone marrow, the B cell acts as an antigen-presenting cell (APC) and internalizes offending antigens, which are taken up by the B cell through receptor-mediated endocytosis and processed. Pieces of the antigen (which are now known as antigenic peptides) are loaded onto MHC II molecules, and presented on its extracellular surface to CD4+ T cells (sometimes called T helper cells). These T cells bind to the MHC II-antigen molecule and cause activation of the B cell. This is a type of safeguard to the system, similar to a two-factor authentication method. First, the B cells must encounter a foreign antigen and are then required to be activated by T helper cells before they differentiate into specific cells. [8]

Upon stimulation by a T cell, which usually occurs in germinal centers of secondary lymphoid organs such as the spleen and lymph nodes, the activated B cell begins to differentiate into more specialized cells. Germinal center B cells may differentiate into memory B cells or plasma cells. Most of these B cells will become plasmablasts (or "immature plasma cells"), and eventually plasma cells, and begin producing large volumes of antibodies. Some B cells will undergo a process known as affinity maturation. [9] This process favors, by selection for the ability to bind antigen with higher affinity, the activation and growth of B cell clones able to secrete antibodies of higher affinity for the antigen. [10]

Immature plasma cells

Plasmablast, Wright stain. Plasmablast, Wright stain.png
Plasmablast, Wright stain.

The most immature blood cell that is considered of plasma cell lineage is the plasmablast. [11] Plasmablasts secrete more antibodies than B cells, but less than plasma cells. [12] They divide rapidly and are still capable of internalizing antigens and presenting them to T cells. [12] A cell may stay in this state for several days, and then either die or irrevocably differentiate into a mature, fully differentiated plasma cell. [12] Differentiation of mature B cells into plasma cells is dependent upon the transcription factors Blimp-1/PRDM1, BCL6, and IRF4. [10]

Function

Unlike their precursors, plasma cells cannot switch antibody classes, cannot act as antigen-presenting cells because they no longer display MHC-II, and do not take up antigen because they no longer display significant quantities of immunoglobulin on the cell surface. [12] However, continued exposure to antigen through those low levels of immunoglobulin is important, as it partly determines the cell's lifespan. [12]

The lifespan, class of antibodies produced, and the location that the plasma cell moves to also depends on signals, such as cytokines, received from the T cell during differentiation. [13] Differentiation through a T cell-independent antigen stimulation (stimulation of a B cell that does not require the involvement of a T cell) can happen anywhere in the body [9] and results in short-lived cells that secrete IgM antibodies. [13] The T cell-dependent processes are subdivided into primary and secondary responses: a primary response (meaning that the T cell is present at the time of initial contact by the B cell with the antigen) produces short-lived cells that remain in the extramedullary regions of lymph nodes; a secondary response produces longer-lived cells that produce IgG and IgA, and frequently travel to the bone marrow. [13] For example, plasma cells will likely secrete IgG3 antibodies if they matured in the presence of the cytokine interferon-gamma. Since B cell maturation also involves somatic hypermutation (a process completed before differentiation into a plasma cell), these antibodies frequently have a very high affinity for their antigen.

Plasma cells can only produce a single kind of antibody in a single class of immunoglobulin. In other words, every B cell is specific to a single antigen, but each cell can produce several thousand matching antibodies per second. [14] This prolific production of antibodies is an integral part of the humoral immune response.

Long-lived plasma cells

The current findings suggest that after the process of affinity maturation in germinal centers, plasma cells develop into one of two types of cells: short-lived plasma cells (SLPC) or long-lived plasma cells (LLPC). LLPC mainly reside in the bone marrow for a long period of time and secrete antibodies, thus providing long-term protection. LLPC can maintain antibody production for decades or even for the lifetime of an individual, [15] [16] and, unlike B cells, LLPC do not need antigen restimulation to generate antibodies. Human LLPC population can be identified as CD19– CD38hi CD138+ cells. [17]

The long-term survival of LLPC are dependent on a specific environment in the bone marrow, the plasma cell survival niche. [18] Removal of an LLPC from its survival niche results in its rapid death. A survival niche can only support limited number of LLPC, thus the niche’s environment must protect its LLPC cells but be able to accept new arrivals. [19] [20] The plasma cell survival niche is defined by a combination of cellular and molecular factors and though it has yet to be properly defined, molecules such as IL-5, IL-6, TNF-α, stromal cell-derived factor-1α and signalling via CD44 have been shown to play a role in the survival of LLPC. [21] LLPC can also be found, to a lesser degree, in gut-associated lymphoid tissue (GALT), where they produce IgA antibodies and contribute to mucosal immunity. Recent findings suggest that plasma cells in the gut do not necessarily need to be generated de novo from active B cells but there are also long-lived PC, suggesting the existence of a similar survival niche. [22] Tissue specific niches that allow for the survival of LLPC have been also described in nasal-associated lymphoid tissues (NALT), human tonsillar lymphoid tissues and human mucosa or mucosa-associated lymphoid tissues (MALT). [23] [24] [25] [26]

Originally it was thought that the continuous production of antibodies is a result of constant replenishment of short-lived plasma cells by memory B cell re-stimulation. Recent findings, however, show that some PC are truly long-lived. The absence of antigens and the depletion of B cells does not appear to have an effect on the production of high-affinity antibodies by the LLPC. Prolonged depletion of B cells (with anti-CD20 monoclonal antibody treatment that affects B cells but not PC) also did not affect antibody titres. [27] [28] [29] LLPC secrete high levels of IgG independently of B cells. LLPC in bone marrow are the main source of circulating IgG in humans. [30] Even though IgA production is traditionally associated with mucosal sites, some plasma cells in bone marrow also produce IgA. [31] LLPC in bone marrow have been observed producing IgM. [32]

Clinical significance

Plasmacytoma, multiple myeloma, Waldenström macroglobulinemia, heavy chain disease, and plasma cell leukemia are cancers of the plasma cells. [33] Multiple myeloma is frequently identified because malignant plasma cells continue producing an antibody, which can be detected as a paraprotein. Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell dyscrasia characterized by the secretion of a myeloma protein into the blood and may lead to multiple myeloma. [34]

Common variable immunodeficiency is thought to be due to a problem in the differentiation from lymphocytes to plasma cells. The result is a low serum antibody level and risk of infections.

Primary amyloidosis (AL) is caused by the deposition of excess immunoglobulin light chains which are secreted from plasma cells.

See also

Related Research Articles

<span class="mw-page-title-main">Antibody</span> Protein(s) forming a major part of an organisms immune system

An antibody (Ab) is the secreted form of a B cell receptor; the term immunoglobulin (Ig) can refer to either the membrane-bound form or the secreted form of the B cell receptor, but they are, broadly speaking, the same protein, and so the terms are often treated as synonymous. Antibodies are large, Y-shaped proteins belonging to the immunoglobulin superfamily which are used by the immune system to identify and neutralize foreign objects such as bacteria and viruses, including those that cause disease. Antibodies can recognize virtually any size antigen with diverse chemical compositions from molecules. Each antibody recognizes one or more specific antigens. This term literally means "antibody generator", as it is the presence of an antigen that drives the formation of an antigen-specific antibody. Each tip of the "Y" of an antibody contains a paratope that specifically binds to one particular epitope on an antigen, allowing the two molecules to bind together with precision. Using this mechanism, antibodies can effectively "tag" a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly.

<span class="mw-page-title-main">B cell</span> Type of white blood cell

B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasma membrane where they serve as a part of B-cell receptors. When a naïve or memory B cell is activated by an antigen, it proliferates and differentiates into an antibody-secreting effector cell, known as a plasmablast or plasma cell. In addition, B cells present antigens and secrete cytokines. In mammals, including marsupials B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricius, a lymphoid organ where they were first discovered by Chang and Glick, which is why the B stands for bursa and not bone marrow, as commonly believed.

<span class="mw-page-title-main">Multiple myeloma</span> Cancer of plasma cells

Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, anemia, kidney dysfunction, and infections may occur. Complications may include hypercalcemia and amyloidosis.

Humoral immunity is the aspect of immunity that is mediated by macromolecules – including secreted antibodies, complement proteins, and certain antimicrobial peptides – located in extracellular fluids. Humoral immunity is named so because it involves substances found in the humors, or body fluids. It contrasts with cell-mediated immunity. Humoral immunity is also referred to as antibody-mediated immunity.

<span class="mw-page-title-main">Immunoglobulin A</span> Antibody that plays a crucial role in the immune function of mucous membranes

Immunoglobulin A is an antibody that plays a role in the immune function of mucous membranes. The amount of IgA produced in association with mucosal membranes is greater than all other types of antibody combined. In absolute terms, between three and five grams are secreted into the intestinal lumen each day. This represents up to 15% of total immunoglobulins produced throughout the body.

<span class="mw-page-title-main">Memory B cell</span> Cell of the adaptive immune system

In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescent state, sometimes for decades. Their function is to memorize the characteristics of the antigen that activated their parent B cell during initial infection such that if the memory B cell later encounters the same antigen, it triggers an accelerated and robust secondary immune response. Memory B cells have B cell receptors (BCRs) on their cell membrane, identical to the one on their parent cell, that allow them to recognize antigen and mount a specific antibody response.

Gut-associated lymphoid tissue (GALT) is a component of the mucosa-associated lymphoid tissue (MALT) which works in the immune system to protect the body from invasion in the gut.

<span class="mw-page-title-main">CD40 (protein)</span> Mammalian protein found in humans

Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.

<span class="mw-page-title-main">Germinal center</span> Lymphatic tissue structure

Germinal centers or germinal centres (GCs) are transiently formed structures within B cell zone (follicles) in secondary lymphoid organs – lymph nodes, ileal Peyer's patches, and the spleen – where mature B cells are activated, proliferate, differentiate, and mutate their antibody genes during a normal immune response; most of the germinal center B cells (BGC) are removed by tingible body macrophages. There are several key differences between naive B cells and GC B cells, including level of proliferative activity, size, metabolic activity and energy production. The B cells develop dynamically after the activation of follicular B cells by T-dependent antigen. The initiation of germinal center formation involves the interaction between B and T cells in the interfollicular area of the lymph node, CD40-CD40L ligation, NF-kB signaling and expression of IRF4 and BCL6.

<span class="mw-page-title-main">B-cell receptor</span> Transmembrane protein on the surface of a B cell

The B-cell receptor (BCR) is a transmembrane protein on the surface of a B cell. A B-cell receptor is composed of a membrane-bound immunoglobulin molecule and a signal transduction moiety. The former forms a type 1 transmembrane receptor protein, and is typically located on the outer surface of these lymphocyte cells. Through biochemical signaling and by physically acquiring antigens from the immune synapses, the BCR controls the activation of the B cell. B cells are able to gather and grab antigens by engaging biochemical modules for receptor clustering, cell spreading, generation of pulling forces, and receptor transport, which eventually culminates in endocytosis and antigen presentation. B cells' mechanical activity adheres to a pattern of negative and positive feedbacks that regulate the quantity of removed antigen by manipulating the dynamic of BCR–antigen bonds directly. Particularly, grouping and spreading increase the relation of antigen with BCR, thereby proving sensitivity and amplification. On the other hand, pulling forces delinks the antigen from the BCR, thus testing the quality of antigen binding.

Lymphopoiesis (lĭm'fō-poi-ē'sĭs) is the generation of lymphocytes, one of the five types of white blood cells (WBCs). It is more formally known as lymphoid hematopoiesis.

<span class="mw-page-title-main">CD19</span> Biomarker for B cell lineage

B-lymphocyte antigen CD19, also known as CD19 molecule, B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene CD19. In humans, CD19 is expressed in all B lineage cells. Contrary to some early doubts, human plasma cells do express CD19, as confirmed by others. CD19 plays two major roles in human B cells: on the one hand, it acts as an adaptor protein to recruit cytoplasmic signaling proteins to the membrane; on the other, it works within the CD19/CD21 complex to decrease the threshold for B cell receptor signaling pathways. Due to its presence on all B cells, it is a biomarker for B lymphocyte development, lymphoma diagnosis and can be utilized as a target for leukemia immunotherapies.

<span class="mw-page-title-main">Isotype (immunology)</span>

In immunology, antibodies are classified into several types called isotypes or classes. The variable (V) regions near the tip of the antibody can differ from molecule to molecule in countless ways, allowing it to specifically target an antigen . In contrast, the constant (C) regions only occur in a few variants, which define the antibody's class. Antibodies of different classes activate distinct effector mechanisms in response to an antigen . They appear at different stages of an immune response, differ in structural features, and in their location around the body.

B1 cells are a sub-class of B cell lymphocytes that are involved in the humoral immune response. They are not part of the adaptive immune system, as they have no memory, but otherwise, B1 cells perform many of the same roles as other B cells: making antibodies against antigens and acting as antigen-presenting cells. These B1 cells are commonly found in peripheral sites, but less commonly found in the blood. These cells are involved in antibody response during an infection or vaccination.

<span class="mw-page-title-main">J chain</span> Protein-coding gene in the species Homo sapiens

The Joining (J) chain is a protein component that links monomers of antibodies IgM and IgA to form polymeric antibodies capable of secretion. The J chain is well conserved in the animal kingdom, but its specific functions are yet to be fully understood. It is a 137 residue polypeptide, encoded by the IGJ gene.

The following outline is provided as an overview of and topical guide to immunology:

In hematology, plasma cell dyscrasias are a spectrum of progressively more severe monoclonal gammopathies in which a clone or multiple clones of pre-malignant or malignant plasma cells over-produce and secrete into the blood stream a myeloma protein, i.e. an abnormal monoclonal antibody or portion thereof. The exception to this rule is the disorder termed non-secretory multiple myeloma; this disorder is a form of plasma cell dyscrasia in which no myeloma protein is detected in serum or urine of individuals who have clear evidence of an increase in clonal bone marrow plasma cells and/or evidence of clonal plasma cell-mediated tissue injury. Here, a clone of plasma cells refers to group of plasma cells that are abnormal in that they have an identical genetic identity and therefore are descendants of a single genetically distinct ancestor cell.

<span class="mw-page-title-main">Microbial symbiosis and immunity</span>

Long-term close-knit interactions between symbiotic microbes and their host can alter host immune system responses to other microorganisms, including pathogens, and are required to maintain proper homeostasis. The immune system is a host defense system consisting of anatomical physical barriers as well as physiological and cellular responses, which protect the host against harmful microorganisms while limiting host responses to harmless symbionts. Humans are home to 1013 to 1014 bacteria, roughly equivalent to the number of human cells, and while these bacteria can be pathogenic to their host most of them are mutually beneficial to both the host and bacteria.

<span class="mw-page-title-main">Centroblast</span>

A centroblast generally refers to an activated B cell that is enlarged and is rapidly proliferating in the germinal center of a lymphoid follicle. They are specifically located in the dark zone of the germinal center. Centroblasts form from naive B cells being exposed to follicular dendritic cell cytokines, such as IL-6, IL-15, 8D6, and BAFF. Stimulation from helper T cells is also required for centroblast development. Interaction between CD40 ligand on an activated T helper cell and the B cell CD40 receptor induces centroblasts to express activation-induced cytidine deaminase, leading to somatic hypermutation, allowing the B cell receptor to potentially gain stronger affinity for an antigen. In the absence of FDC and helper T cell stimulation, centroblasts are unable to differentiate and will undergo CD95-mediated apoptosis.

Long-lived plasma cells (LLPCs) are a distinct subset of plasma cells that play a crucial role in maintaining humoral memory and long-term immunity. They continuously produce and secrete high-affinity antibodies into the bloodstream, conversely to memory B cells, which are quiescent and respond quickly to antigens upon recall.

References

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