B cell

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B lymphocyte cell
Blausen 0624 Lymphocyte B cell (crop).png
Animation of B cell
Details
Precursor Hematopoietic stem cell
System Immune system
Identifiers
Latin lymphocytus B
MeSH D001402
FMA 62869
Anatomical terms of microanatomy

B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. [1] They function in the humoral immunity component of the adaptive immune system. [1] 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. [2] 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. [2] In addition, B cells present antigens (they are also classified as professional antigen-presenting cells, APCs) and secrete cytokines. [1] In mammals B cells mature in the bone marrow, which is at the core of most bones. [3] In birds, B cells mature in the bursa of Fabricius, a lymphoid organ where they were first discovered by Chang and Glick, [4] which is why the B stands for bursa and not bone marrow, as commonly believed.

Contents

B cells, unlike the other two classes of lymphocytes, T cells and natural killer cells, express B cell receptors (BCRs) on their cell membrane. [1] BCRs allow the B cell to bind to a foreign antigen, against which it will initiate an antibody response. [1] B cell receptors are extremely specific, with all BCRs on a B cell recognizing the same epitope. [5]

Development

Early B cell development: from stem cell to immature B cell Early B cell development.jpg
Early B cell development: from stem cell to immature B cell
Transitional B cell development: from immature B cell to MZ B cell or mature (FO) B cell Transitional B cell development.PNG
Transitional B cell development: from immature B cell to MZ B cell or mature (FO) B cell

B cells develop from hematopoietic stem cells (HSCs) that originate from bone marrow. [6] [7] HSCs first differentiate into multipotent progenitor (MPP) cells, then common lymphoid progenitor (CLP) cells. [7] From here, their development into B cells occurs in several stages (shown in image to the right), each marked by various gene expression patterns and immunoglobulin H chain and L chain gene loci arrangements, the latter due to B cells undergoing V(D)J recombination as they develop. [8]

B cells undergo two types of selection while developing in the bone marrow to ensure proper development, both involving B cell receptors (BCR) on the surface of the cell. Positive selection occurs through antigen-independent signalling involving both the pre-BCR and the BCR. [9] [10] If these receptors do not bind to their ligand, B cells do not receive the proper signals and cease to develop. [9] [10] Negative selection occurs through the binding of self-antigen with the BCR; if the BCR can bind strongly to self-antigen, then the B cell undergoes one of four fates: clonal deletion, receptor editing, anergy, or ignorance (B cell ignores signal and continues development). [10] This negative selection process leads to a state of central tolerance, in which the mature B cells do not bind self antigens present in the bone marrow. [8]

To complete development, immature B cells migrate from the bone marrow into the spleen as transitional B cells, passing through two transitional stages: T1 and T2. [11] Throughout their migration to the spleen and after spleen entry, they are considered T1 B cells. [12] Within the spleen, T1 B cells transition to T2 B cells. [12] T2 B cells differentiate into either follicular (FO) B cells or marginal zone (MZ) B cells depending on signals received through the BCR and other receptors. [13] Once differentiated, they are now considered mature B cells, or naïve B cells. [12]

Activation

B cell activation: from immature B cell to plasma cell or memory B cell B cell activation naive to plasma cell.png
B cell activation: from immature B cell to plasma cell or memory B cell
Basic B cell function: bind to an antigen, receive help from a cognate helper T cell, and differentiate into a plasma cell that secretes large numbers of antibodies B cell function.png
Basic B cell function: bind to an antigen, receive help from a cognate helper T cell, and differentiate into a plasma cell that secretes large numbers of antibodies

B cell activation occurs in the secondary lymphoid organs (SLOs), such as the spleen and lymph nodes. [1] After B cells mature in the bone marrow, they migrate through the blood to SLOs, which receive a constant supply of antigen through circulating lymph. [14] At the SLO, B cell activation begins when the B cell binds to an antigen via its BCR. [15] Although the events taking place immediately after activation have yet to be completely determined, it is believed that B cells are activated in accordance with the kinetic segregation model [ citation needed ], initially determined in T lymphocytes. This model denotes that before antigen stimulation, receptors diffuse through the membrane coming into contact with Lck and CD45 in equal frequency, rendering a net equilibrium of phosphorylation and non-phosphorylation. It is only when the cell comes in contact with an antigen presenting cell that the larger CD45 is displaced due to the close distance between the two membranes. This allows for net phosphorylation of the BCR and the initiation of the signal transduction pathway[ citation needed ]. Of the three B cell subsets, FO B cells preferentially undergo T cell-dependent activation while MZ B cells and B1 B cells preferentially undergo T cell-independent activation. [16]

B cell activation is enhanced through the activity of CD21, a surface receptor in complex with surface proteins CD19 and CD81 (all three are collectively known as the B cell coreceptor complex). [17] When a BCR binds an antigen tagged with a fragment of the C3 complement protein, CD21 binds the C3 fragment, co-ligates with the bound BCR, and signals are transduced through CD19 and CD81 to lower the activation threshold of the cell. [18]

T cell-dependent activation

Antigens that activate B cells with the help of T-cell are known as T cell-dependent (TD) antigens and include foreign proteins. [1] They are named as such because they are unable to induce a humoral response in organisms that lack T cells. [1] B cell responses to these antigens takes multiple days, though antibodies generated have a higher affinity and are more functionally versatile than those generated from T cell-independent activation. [1]

Once a BCR binds a TD antigen, the antigen is taken up into the B cell through receptor-mediated endocytosis, degraded, and presented to T cells as peptide pieces in complex with MHC-II molecules on the cell membrane. [19] T helper (TH) cells, typically follicular T helper (TFH) cells recognize and bind these MHC-II-peptide complexes through their T cell receptor (TCR). [20] Following TCR-MHC-II-peptide binding, T cells express the surface protein CD40L as well as cytokines such as IL-4 and IL-21. [20] CD40L serves as a necessary co-stimulatory factor for B cell activation by binding the B cell surface receptor CD40, which promotes B cell proliferation, immunoglobulin class switching, and somatic hypermutation as well as sustains T cell growth and differentiation. [1] T cell-derived cytokines bound by B cell cytokine receptors also promote B cell proliferation, immunoglobulin class switching, and somatic hypermutation as well as guide differentiation. [20] After B cells receive these signals, they are considered activated. [20]

T-dependent B cell activation T-dependent B cell activation.png
T-dependent B cell activation

Once activated, B cells participate in a two-step differentiation process that yields both short-lived plasmablasts for immediate protection and long-lived plasma cells and memory B cells for persistent protection. [16] The first step, known as the extrafollicular response, occurs outside lymphoid follicles but still in the SLO. [16] During this step activated B cells proliferate, may undergo immunoglobulin class switching, and differentiate into plasmablasts that produce early, weak antibodies mostly of class IgM. [21]

Histology of a normal lymphoid follicle, with germinal center in the middle. Dark, light, mantle and marginal zones of a secondary follicle.png
Histology of a normal lymphoid follicle, with germinal center in the middle.

The second step consists of activated B cells entering a lymphoid follicle and forming a germinal center (GC), which is a specialized microenvironment where B cells undergo extensive proliferation, immunoglobulin class switching, and affinity maturation directed by somatic hypermutation. [22] These processes are facilitated by TFH and follicular dendritic cells within the GC and generate both high-affinity memory B cells and long-lived plasma cells. [16] [23] Resultant plasma cells secrete large numbers of antibodies and either stay within the SLO or, more preferentially, migrate to bone marrow. [22]

T cell-independent activation

Antigens that activate B cells without T cell help are known as T cell-independent (TI) antigens [1] and include foreign polysaccharides and unmethylated CpG DNA. [16] They are named as such because they are able to induce a humoral response in organisms that lack T cells. [1] B cell response to these antigens is rapid, though antibodies generated tend to have lower affinity and are less functionally versatile than those generated from T cell-dependent activation. [1]

As with TD antigens, B cells activated by TI antigens need additional signals to complete activation, but instead of receiving them from T cells, they are provided either by recognition and binding of a common microbial constituent to toll-like receptors (TLRs) or by extensive crosslinking of BCRs to repeated epitopes on a bacterial cell. [1] B cells activated by TI antigens go on to proliferate outside lymphoid follicles but still in SLOs (GCs do not form), possibly undergo immunoglobulin class switching, and differentiate into short-lived plasmablasts that produce early, weak antibodies mostly of class IgM, but also some populations of long-lived plasma cells. [24]

Memory B cell activation

Memory B cell activation begins with the detection and binding of their target antigen, which is shared by their parent B cell. [25] Some memory B cells can be activated without T cell help, such as certain virus-specific memory B cells, but others need T cell help. [26] Upon antigen binding, the memory B cell takes up the antigen through receptor-mediated endocytosis, degrades it, and presents it to T cells as peptide pieces in complex with MHC-II molecules on the cell membrane. [25] Memory T helper (TH) cells, typically memory follicular T helper (TFH) cells, that were derived from T cells activated with the same antigen recognize and bind these MHC-II-peptide complexes through their TCR. [25] Following TCR-MHC-II-peptide binding and the relay of other signals from the memory TFH cell, the memory B cell is activated and differentiates either into plasmablasts and plasma cells via an extrafollicular response or enter a germinal center reaction where they generate plasma cells and more memory B cells. [25] [26] It is unclear whether the memory B cells undergo further affinity maturation within these secondary GCs. [25] In vitro activation of memory B cells can be achieved through stimulation with various activators, such as pokeweed mitogen or anti-CD40 monoclonal antibodies, however, a study found a combination of R-848 and recombinant human IL-2 to be the most efficient activator. [27]

B cell types

Plasmablast, Wright stain. Plasmablast, Wright stain.png
Plasmablast, Wright stain.
Plasmablast
A short-lived, proliferating antibody-secreting cell arising from B cell differentiation. [1] Plasmablasts are generated early in an infection and their antibodies tend to have a weaker affinity towards their target antigen compared to plasma cell. [16] Plasmablasts can result from T cell-independent activation of B cells or the extrafollicular response from T cell-dependent activation of B cells. [1]
Plasma cell
A long-lived, non-proliferating antibody-secreting cell arising from B cell differentiation. [1] There is evidence that B cells first differentiate into a plasmablast-like cell, then differentiate into a plasma cell. [16] Plasma cells are generated later in an infection and, compared to plasmablasts, have antibodies with a higher affinity towards their target antigen due to affinity maturation in the germinal center (GC) and produce more antibodies. [16] Plasma cells typically result from the germinal center reaction from T cell-dependent activation of B cells, though they can also result from T cell-independent activation of B cells. [24]
Lymphoplasmacytoid cell
A cell with a mixture of B lymphocyte and plasma cell morphological features that is thought to be closely related to or a subtype of plasma cells. This cell type is found in pre-malignant and malignant plasma cell dyscrasias that are associated with the secretion of IgM monoclonal proteins; these dyscrasias include IgM monoclonal gammopathy of undetermined significance and Waldenström's macroglobulinemia. [28]
Memory B cell
Dormant B cell arising from B cell differentiation. [1] Their function is to circulate through the body and initiate a stronger, more rapid antibody response (known as the anamnestic secondary antibody response) if they detect the antigen that had activated their parent B cell (memory B cells and their parent B cells share the same BCR, thus they detect the same antigen). [26] Memory B cells can be generated from T cell-dependent activation through both the extrafollicular response and the germinal center reaction as well as from T cell-independent activation of B1 cells. [26]
B-2 cell
FO B cells and MZ B cells. [29]
Follicular (FO) B cell (also known as a B-2 cell)
Most common type of B cell and, when not circulating through the blood, is found mainly in the lymphoid follicles of secondary lymphoid organs (SLOs). [16] They are responsible for generating the majority of high-affinity antibodies during an infection. [1]
Marginal-zone (MZ) B cell
Found mainly in the marginal zone of the spleen and serves as a first line of defense against blood-borne pathogens, as the marginal zone receives large amounts of blood from the general circulation. [30] They can undergo both T cell-independent and T cell-dependent activation, but preferentially undergo T cell-independent activation. [16]
B-1 cell
Arises from a developmental pathway different from FO B cells and MZ B cells. [29] In mice, they predominantly populate the peritoneal cavity and pleural cavity, generate natural antibodies (antibodies produced without infection), defend against mucosal pathogens, and primarily exhibit T cell-independent activation. [29] A true homologue of mouse B-1 cells has not been discovered in humans, though various cell populations similar to B-1 cells have been described. [29]
Regulatory B (Breg) cell
An immunosuppressive B cell type that stops the expansion of pathogenic, pro-inflammatory lymphocytes through the secretion of IL-10, IL-35, and TGF-β. [31] Also, it promotes the generation of regulatory T (Treg) cells by directly interacting with T cells to skew their differentiation towards Tregs. [31] No common Breg cell identity has been described and many Breg cell subsets sharing regulatory functions have been found in both mice and humans. [31] It is currently unknown if Breg cell subsets are developmentally linked and how exactly differentiation into a Breg cell occurs. [31] There is evidence showing that nearly all B cell types can differentiate into a Breg cell through mechanisms involving inflammatory signals and BCR recognition. [31]

Autoimmune disease can result from abnormal B cell recognition of self-antigens followed by the production of autoantibodies. [32] Autoimmune diseases where disease activity is correlated with B cell activity include scleroderma, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, post-infectious IBS, and rheumatoid arthritis. [32]

Malignant transformation of B cells and their precursors can cause a host of cancers, including chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, follicular lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, and plasma cell malignancies such as multiple myeloma, Waldenström's macroglobulinemia, and certain forms of amyloidosis. [33] [34]

Abnormal B cells may be relatively large and some diseases include this in their names, such as diffuse large B-cell lymphomas (DLBCLs) and intravascular large B-cell lymphoma.

Patients with B cell alymphocytosis are predisposed to infections. [35]

Epigenetics

A study that investigated the methylome of B cells along their differentiation cycle, using whole-genome bisulfite sequencing (WGBS), showed that there is a hypomethylation from the earliest stages to the most differentiated stages. The largest methylation difference is between the stages of germinal center B cells and memory B cells. Furthermore, this study showed that there is a similarity between B cell tumors and long-lived B cells in their DNA methylation signatures. [36]

See also

Related Research Articles

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">Plasma cell</span> White blood cell that secretes large volumes of antibodies

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.

<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.

In immunology, central tolerance is the process of eliminating any developing T or B lymphocytes that are autoreactive, i.e. reactive to the body itself. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides. Lymphocyte maturation occurs in primary lymphoid organs such as the bone marrow and the thymus. In mammals, B cells mature in the bone marrow and T cells mature in the thymus.

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">Marginal zone</span> Part of the spleen

The marginal zone is the region at the interface between the non-lymphoid red pulp and the lymphoid white-pulp of the spleen.

<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.

<span class="mw-page-title-main">Follicular dendritic cells</span> Immune cells found in lymph nodes

Follicular dendritic cells (FDC) are cells of the immune system found in primary and secondary lymph follicles of the B cell areas of the lymphoid tissue. Unlike dendritic cells (DC), FDCs are not derived from the bone-marrow hematopoietic stem cell, but are of mesenchymal origin. Possible functions of FDC include: organizing lymphoid tissue's cells and microarchitecture, capturing antigen to support B cell, promoting debris removal from germinal centers, and protecting against autoimmunity. Disease processes that FDC may contribute include primary FDC-tumor, chronic inflammatory conditions, HIV-1 infection development, and neuroinvasive scrapie.

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. 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">CD22</span> Lectin molecule

CD22, or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins. It is found on the surface of mature B cells and to a lesser extent on some immature B cells. Generally speaking, CD22 is a regulatory molecule that prevents the overactivation of the immune system and the development of autoimmune diseases.

<span class="mw-page-title-main">CD69</span> Human lectin protein

CD69 is a human transmembrane C-Type lectin protein encoded by the CD69 gene. It is an early activation marker that is expressed in hematopoietic stem cells, T cells, and many other cell types in the immune system. It is also implicated in T cell differentiation as well as lymphocyte retention in lymphoid organs.

<span class="mw-page-title-main">GPR183</span> Protein-coding gene in the species Homo sapiens

G-protein coupled receptor 183 also known as Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) is a protein (GPCR) expressed on the surface of some immune cells, namely B cells and T cells; in humans it is encoded by the GPR183 gene. Expression of EBI2 is one critical mediator of immune cell localization within lymph nodes, responsible in part for the coordination of B cell, T cell, and dendritic cell movement and interaction following antigen exposure. EBI2 is a receptor for oxysterols. The most potent activator is 7α,25-dihydroxycholesterol (7α,25-OHC), with other oxysterols exhibiting varying affinities for the receptor. Oxysterol gradients drive chemotaxis, attracting the EBI2-expressing cells to locations of high ligand concentration. The GPR183 gene was identified due to its upregulation during Epstein-Barr virus infection of the Burkitt's lymphoma cell line BL41, hence its name: EBI2.

<span class="mw-page-title-main">Marginal-zone B cell</span>

Marginal-zone B cells are noncirculating mature B cells that in humans segregate anatomically into the marginal zone (MZ) of the spleen and certain other types of lymphoid tissue. The MZ B cells within this region typically express low-affinity polyreactive B-cell receptors (BCR), high levels of IgM, Toll-like receptors (TLRs), CD21, CD1, CD9, CD27 with low to negligible levels of secreted-IgD, CD23, CD5, and CD11b that help to distinguish them phenotypically from follicular (FO) B cells and B1 B cells.

Within the immune system, Follicular B cells are a type of B cell that reside in primary and secondary lymphoid follicles of secondary and tertiary lymphoid organs, including spleen and lymph nodes. Antibody responses against proteins are believed to involve follicular B cell pathways in secondary lymphoid organs.

<span class="mw-page-title-main">Follicular B helper T cells</span>

Follicular helper T cells (also known as T follicular helper cells and abbreviated as TFH), are antigen-experienced CD4+ T cells found in the periphery within B cell follicles of secondary lymphoid organs such as lymph nodes, spleen and Peyer's patches, and are identified by their constitutive expression of the B cell follicle homing receptor CXCR5. Upon cellular interaction and cross-signaling with their cognate follicular (Fo B) B cells, TFH cells trigger the formation and maintenance of germinal centers through the expression of CD40 ligand (CD40L) and the secretion of IL-21 and IL-4. TFH cells also migrate from T cell zones into these seeded germinal centers, predominantly composed of rapidly dividing B cells mutating their Ig genes. Within germinal centers, TFH cells play a critical role in mediating the selection and survival of B cells that go on to differentiate either into long-lived plasma cells capable of producing high affinity antibodies against foreign antigen, or germinal center-dependent memory B cells capable of quick immune re-activation in the future if ever the same antigen is re-encountered. TFH cells are also thought to facilitate negative selection of potentially autoimmune-causing mutated B cells in the germinal center. However, the biomechanisms by which TFH cells mediate germinal center tolerance are yet to be fully understood.

<span class="mw-page-title-main">Naive B cell</span> B cell not yet exposed to an antigen

In immunology, a naive B cell is a B cell that has not been exposed to an antigen. These are located in the tonsils, spleen, and primary lymphoid follicles in lymph nodes.

<span class="mw-page-title-main">Centroblast</span> Enlarged B cell in the germinal center of lymphoid follicles

In immunology, 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 helper T 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.

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