Long-lived plasma cell

Last updated February 19, 2024

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.^[1] 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.^[2]

Initially, it was believed that memory B cells replenish LLPCs.^[1] However, allergen-specific IgE production through bone marrow transplantation in non-allergic individuals suggests LLPCs may be long-lived. Allergies developed without antigenic re-stimulation.^[2] That led to the understanding that LLPCs are long-lived cells, contributing to the sustained production of specific antibodies^[3]

Niche of LLPCs

The niche for long-lived plasma cells is a subject of ongoing research, and while some aspects are understood, many questions remain. LLPCs are not inherently long-lived, and their survival relies on accessing specific pro-survival niches in the bone marrow (BM), secondary lymphoid organs, mucosal tissues, and sites of inflammation. The BM has traditionally been considered the primary residence for LLPCs, offering a dynamic microenvironment that supports the formation of complex niches. However, recent studies have revealed that LLPCs can also reside in other locations, such as gut-associated lymphoid tissue (GALT), where they primarily produce IgA antibodies.^[2]

Cell Markers

Clear markers that distinguish LLPCs have yet to be fully elucidated. However, LLPCs exhibit a gene expression signature characterised by down regulating antigen presentation and B-cell receptor (BCR) function-related genes. Conversely, only a tiny number of genes are upregulated in LLPC. That includes anti-apoptotic genes such as MCL1 and ZNF667, ER stress-associated genes like ERO1LB and MANF, and the retention of TFBS and SRF in the bone marrow.^[2]

Furthermore, expression levels of surface markers, such as CD38 and CD19, vary among plasma cells and are associated with functional differences. These differences include the production of either high-affinity or low-affinity antibodies by the plasma cells.^[4]

Moreover, intrinsic and extrinsic factors contribute to the survival of LLPCs through various mechanisms. LLPCs rely on intrinsic signals for their long-term survival and function. Unique metabolic pathways, including autophagy and the unfolded protein response (UPR), are essential for LLPCs to cope with the high protein load and ER stress of continuous antibody production.^[2]

Intrinsic factors:

BCMA (B-cell maturation antigen): Up regulation of anti-apoptotic genes prevents LLPC from undergoing programmed cell death.
STAT3 (Signal transducer and activator of transcription 3): LLPC responds to interleukin 6 (IL-6), IL-10, and IL-21 signaling, which triggers downstream survival signaling associated with these cytokines.
Aiolos: This factor promotes the generation of LLPC that produce high-affinity antibodies.
CD93: There may be a connection between CD93 and the regulation of BLIMP-1, a key transcription factor that influences the mature phenotype of LLPC and their production of high-affinity antibodies.
CD28: Signaling through the Vav/Grb2 motif can induce NF-κB signaling and expression of BLIMP-1. CD28 engagement with its ligands CD80/CD86 promotes signaling through dendritic cells (DC) and upregulation of IL-6.
Autophagy (Atg5): LLPC utilises autophagy as a recycling mechanism to supply metabolic substrates and eliminate misfolded proteins.
Metabolic profile: LLPC takes up glucose for antibody glycosylation. They can also switch to glycolysis and import pyruvate into mitochondria under non-optimal conditions.
ENPP1: This enzyme regulates glucose homeostasis and the metabolic pathway in LLPC.^[2]

Extrinsic factors: The LLPC niche consists of various extrinsic factors that support the survival and function of LLPCs.

Stromal cells expressing CXCL12 are a homing signal for LLPCs expressing the CXCR4 receptor, facilitating their migration to specific niches.
Megakaryocytes and basophils produce soluble factors like APRIL and BAFF, which contribute to the survival of LLPCs.
LLPCs engage in interactions with dendritic cells (DCs), T follicular helper cells (Tfh), and regulatory T cells (Tregs) through cell surface interactions and cytokines, further influencing their survival and function LLPC.^[2]

LLPCs versus naïve B cells

Morphologically, LLPCs exhibit distinct alterations, such as an expansion of rough endoplasmic reticulum (ER), reflecting their specialised role in antibody production.^[5] Most mRNA synthesised by LLPCs is dedicated to immunoglobulins, indicating their primary function and the loss of other cellular abilities.^[6] The following two tables show the significant properties between naïve B cells and plasma cells.


B-cells
Name	Function
Surface Immunoglobulin (Ig)	Naïve B cells express surface Ig, which serves as the B cell receptor (BCR) for antigen recognition.
Surface MHC Class II	Naïve B cells present antigens to helper T cells through surface major histocompatibility complex class II (MHC II) molecules, initiating T cell-dependent immune responses.
Inducible Growth	Naïve B cells can be stimulated to proliferate and differentiate upon encountering an antigen and appropriate co-stimulatory signals.
Somatic Hypermutation	During the germinal centre reaction, naïve B cells undergo somatic hypermutation, which introduces random mutations in the variable regions of their immunoglobulin genes. This process leads to generating B cells with increased affinity for the antigen.
Isotype Switch	Naïve B cells can undergo isotype switching, a process that changes the constant region of the immunoglobulin molecule, allowing for the production of different antibody isotypes with distinct effector functions.


Plasma Cells
Name	Function
Intrinsic High-Rate Ig Secretion	Plasma cells are highly specialised antibody-secreting cells. They have a large and active endoplasmic reticulum, which enables them to produce and secrete a high volume of immunoglobulins.
Downregulated Surface MHC Class II	Plasma cells have significantly reduced surface expression of MHC Class II molecules. As a result, they have limited antigen presentation capability.
Limited Inducible Growth	Unlike naïve B cells, plasma cells have limited proliferative capacity. Once they differentiate from B cells, they focus on antibody production rather than further expansion.
No Somatic Hypermutation	Plasma cells do not undergo somatic hypermutation. Instead, they represent the end product of the germinal centre reaction and are responsible for producing high-affinity antibodies generated by the mutated B cells.^[7]

Memory versus plasma fate

Following an immune response, B cells undergo affinity maturation, which improves the strength of their antibodies' binding to a specific antigen. B cells, with higher affinity antibodies, are selected for survival and undergo further division and affinity maturation rounds in specialised structures called germinal centers (GCs). This process involves somatic hypermutation (SHM), resulting in genetic changes that enhance the antibody's affinity. B cells with higher affinity antibodies can take two paths:

Plasma Cells: These B cells differentiate into plasma cells, which migrate to survival niches, such as the bone marrow. Plasma cells continuously secrete antibodies throughout a person's lifetime.
Memory B Cells: These B cells can become memory B cells without differentiating into plasma cells. They retain their original antibody form (IgM+) and have fewer genetic mutations. Memory B cells either recirculate through the body or reside in specific tissues. They can quickly respond to secondary infections and can switch antibody classes.

Overall, plasma cells provide continuous antibody production, while memory B cells offer a reservoir of pre-existing B cells that can mount a rapid and effective immune response upon re-exposure to the antigen.^[8]

The immune system has two main lines of defense in providing long-lasting protection against a pathogen's reinfection: long-lived plasma cells and memory B cells. Long-lived plasma cells produce protective antibodies, and memory B cells can respond to reinfection by pathogens and their variants. The first wall comprises long-lived plasma cells in the bone marrow. These plasma cells secrete particular antibodies that have been carefully selected to target the antigens of the previously encountered pathogen. These antibodies form a barrier against reinfection with homologous pathogens. However, variant pathogens can find holes in this wall. Those pathogens then encounter the second wall, namely memory B cells, which were less highly selected and maintain a broader range of antigen affinities and specificities. The memory B cells are activated via the variant pathogen to differentiate into long-lived plasma cells or to reenter the germinal centers to replenish the memory B cell pool^[9]

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 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, however, can be generated to recognize virtually any molecule in existence. 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.

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, 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.

The T helper cells (T_h cells), also known as CD4⁺ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4⁺ cells are mature T_h cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4⁺ cells determines susceptibility to a broad class of autoimmune diseases.

A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells, B cells, and Innate lymphoid cells (ILCs), of which natural killer cells are an important subtype. They are the main type of cell found in lymph, which prompted the name "lymphocyte". Lymphocytes make up between 18% and 42% of circulating white blood cells.

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.

Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B cells 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, 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.

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.

The adaptive immune system, also known as the acquired immune system, or specific immune system is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system is one of the two main immunity strategies found in vertebrates.

In immunology, affinity maturation is the process by which T_FH cell-activated B cells produce antibodies with increased affinity for antigen during the course of an immune response. With repeated exposures to the same antigen, a host will produce antibodies of successively greater affinities. A secondary response can elicit antibodies with several fold greater affinity than in a primary response. Affinity maturation primarily occurs on membrane immunoglobulin of germinal center B cells and as a direct result of somatic hypermutation (SHM) and selection by T_FH cells.

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.

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 (B_GC) 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.

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.

Polyclonal B cell response is a natural mode of immune response exhibited by the adaptive immune system of mammals. It ensures that a single antigen is recognized and attacked through its overlapping parts, called epitopes, by multiple clones of B cell.

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.

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.

PR domain zinc finger protein 1, or B lymphocyte-induced maturation protein-1 (BLIMP-1), is a protein in humans encoded by the gene PRDM1 located on chromosome 6q21. BLIMP-1 is considered a 'master regulator' of hematopoietic stem cells, and plays a critical role in the development of plasma B cells, T cells, dendritic cells (DCs), macrophages, and osteoclasts. Pattern Recognition Receptors (PRRs) can activate BLIMP-1, both as a direct target and through downstream activation. BLIMP-1 is a transcription factor that triggers expression of many downstream signaling cascades. As a fine-tuned and contextual rheostat of the immune system, BLIMP-1 up- or down-regulates immune responses depending on the precise scenarios. BLIMP-1 is highly expressed in exhausted T-cells – clones of dysfunctional T-cells with diminished functions due to chronic immune response against cancer, viral infections, or organ transplant.

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

A neutralizing antibody (NAb) is an antibody that defends a cell from a pathogen or infectious particle by neutralizing any effect it has biologically. Neutralization renders the particle no longer infectious or pathogenic. Neutralizing antibodies are part of the humoral response of the adaptive immune system against viruses, intracellular bacteria and microbial toxin. By binding specifically to surface structures (antigen) on an infectious particle, neutralizing antibodies prevent the particle from interacting with its host cells it might infect and destroy.

Somatic hypermutation is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it. A major component of the process of affinity maturation, SHM diversifies B cell receptors used to recognize foreign elements (antigens) and allows the immune system to adapt its response to new threats during the lifetime of an organism. Somatic hypermutation involves a programmed process of mutation affecting the variable regions of immunoglobulin genes. Unlike germline mutation, SHM affects only an organism's individual immune cells, and the mutations are not transmitted to the organism's offspring. Because this mechanism is merely selective and not precisely targeted, somatic hypermutation has been strongly implicated in the development of B-cell lymphomas and many other cancers.

Immunological memory is the ability of the immune system to quickly and specifically recognize an antigen that the body has previously encountered and initiate a corresponding immune response. Generally, they are secondary, tertiary and other subsequent immune responses to the same antigen. The adaptive immune system and antigen-specific receptor generation are responsible for adaptive immune memory.

References

1 2 Radbruch, Andreas (2006). "Competence and competition: the challenge of becoming a long-lived plasma cell". Nature Reviews Immunology. 6 (1): 741–750. doi:10.1038/nri1886. PMID 16977339. S2CID 23664563.
1 2 3 4 5 6 7 Lightman, Shivana M.; Utley, Adam; Lee, Kelvin P. (2019). "Survival of Long-Lived Plasma Cells (LLPC): Piecing Together the Puzzle". Frontiers in Immunology. 10: 965. doi: 10.3389/fimmu.2019.00965 . PMC 6510054 . PMID 31130955.
↑ Brynjolfsson, Siggeir F. (2017). "Long-lived plasma cells in human bone marrow can be either CD19+ or CD19–". Blood Advances. 1 (13): 835–838. doi:10.1182/bloodadvances.2017004481. PMC 5727810 . PMID 29296727.
↑ Jessica, Halliley (2015). "Long-lived Plasma Cells Are Contained Within the CD19−CD38hiCD138+ Subset in Human Bone Marrow". Immunity. 43 (1): 131-145.
↑ Goldfinger, Meidan (2019). "Protein synthesis in plasma cells is regulated by crosstalk between endoplasmic reticulum stress and mTOR signaling". European Journal of Immunology. 41 (2): 491–502. doi: 10.1002/eji.201040677 . PMID 21268018. S2CID 25122090.
↑ Nguyen, Doan (2019). "Factors Affecting Early Antibody Secreting Cell Maturation Into Long-Lived Plasma Cells". Frontiers in Immunology. 10: 2138. doi: 10.3389/fimmu.2019.02138 . PMC 6749102 . PMID 31572364.
↑ Wu. "Department of Food Science National Taiwan Ocean University" (PDF). Retrieved 2023-06-22.
↑ Kealy, Liam (2021). "Advances in understanding the formation and fate of B-cell memory in response to immunization or infection". Oxford Open Immunology. 21.
↑ Munir, Akkaya (2019). "B cell memory: building two walls of protection against pathogens". Nature Reviews Immunology. 20 (1): 229-238.

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[Andreas_Radbruch-1] 1 2 Radbruch, Andreas (2006). "Competence and competition: the challenge of becoming a long-lived plasma cell". Nature Reviews Immunology. 6 (1): 741–750. doi:10.1038/nri1886. PMID 16977339. S2CID 23664563.

[Shivana-2] 1 2 3 4 5 6 7 Lightman, Shivana M.; Utley, Adam; Lee, Kelvin P. (2019). "Survival of Long-Lived Plasma Cells (LLPC): Piecing Together the Puzzle". Frontiers in Immunology. 10: 965. doi: 10.3389/fimmu.2019.00965 . PMC 6510054 . PMID 31130955.

[Siggeir-3] Brynjolfsson, Siggeir F. (2017). "Long-lived plasma cells in human bone marrow can be either CD19+ or CD19–". Blood Advances. 1 (13): 835–838. doi:10.1182/bloodadvances.2017004481. PMC 5727810 . PMID 29296727.

[4] Jessica, Halliley (2015). "Long-lived Plasma Cells Are Contained Within the CD19−CD38hiCD138+ Subset in Human Bone Marrow". Immunity. 43 (1): 131-145.

[5] Goldfinger, Meidan (2019). "Protein synthesis in plasma cells is regulated by crosstalk between endoplasmic reticulum stress and mTOR signaling". European Journal of Immunology. 41 (2): 491–502. doi: 10.1002/eji.201040677 . PMID 21268018. S2CID 25122090.

[6] Nguyen, Doan (2019). "Factors Affecting Early Antibody Secreting Cell Maturation Into Long-Lived Plasma Cells". Frontiers in Immunology. 10: 2138. doi: 10.3389/fimmu.2019.02138 . PMC 6749102 . PMID 31572364.

[7] Wu. "Department of Food Science National Taiwan Ocean University" (PDF). Retrieved 2023-06-22.

[8] Kealy, Liam (2021). "Advances in understanding the formation and fate of B-cell memory in response to immunization or infection". Oxford Open Immunology. 21.

[9] Munir, Akkaya (2019). "B cell memory: building two walls of protection against pathogens". Nature Reviews Immunology. 20 (1): 229-238.

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