B cell

Basic B cell function: bind an antigen, receive help from a cognate helper T cell, and differentiate into a plasma cell that secretes large amounts of antibodies

3D rendering of a B cell

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 by secreting antibodies.^[1] Additionally, B cells present antigen (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.^[2] In birds, B cells mature in the bursa of Fabricius, a lymphoid organ. (The "B" from B cells comes from the name of this organ, where it was first discovered by Chang and Glick,^[2] and not from bone marrow as commonly believed).

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 a specific antigen, against which it will initiate an antibody response.^[1]

Development

B cells develop from hematopoietic stem cells (HSCs) that originate from bone marrow.^[3] HSCs first differentiate into multipotent progenitor (MPP) cells, then common lymphoid progenitor (CLP) cells.^[3] 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.^[4]

Early B cell development: from stem cell to immature B cell

B cells undergo two types of selection while developing in the bone marrow to ensure proper development. Positive selection occurs through antigen-independent signaling involving both the pre-BCR and the BCR.^[5][6] If these receptors do not bind to their ligand, B cells do not receive the proper signals and cease to develop.^[5][6] 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).^[6] This negative selection process leads to a state of central tolerance, in which the mature B cells don't bind with self antigens present in the bone marrow.^[4]

To complete development, immature B cells migrate from the bone marrow to the spleen as well as pass through two transitional stages: T1 and T2.^[7] Throughout their migration to the spleen and after spleen entry, they are considered T1 B cells.^[8] Within the spleen, T1 B cells transition to T2 B cells.^[8] 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.^[9] Once differentiated, they are now considered mature B cells, or naive B cells.^[8]

Transitional B cell development: from immature B cell to MZ B cell or mature (FO) B cell

While immature and during the T1 phase, B cells express BCR of class IgH, but BCR expression changes to the classes IgM and IgD after transition into the T2 phase and while mature up to activation.^[8]

Activation

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.^[10] At the SLO, B cell activation begins when the B cell binds to an antigen via its BCR.^[11] 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.^[12]

B cell activation: from immature B cell to plasma cell or memory B cell

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).^[13] 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.^[14]

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 response 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.^[15] T helper (T_H) cells, typically follicular T helper (T_FH) cells, that were activated with the same antigen recognize and bind these MHC-II-peptide complexes through their T cell receptor (TCR).^[16] Following TCR-MHC-II-peptide binding, T cells express the surface protein CD40L as well as cytokines such as IL-4 and IL-21.^[16] 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.^[16] After B cells receive these signals, they are considered activated.^[16]

Now 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.^[12] The first step, known as the extrafollicular response, occurs outside of lymphoid follicles but still in the SLO.^[12] 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.^[17] 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.^[18] These processes are facilitated by T_FH cells within the GC and generate both high-affinity memory B cells and long-lived plasma cells.^[12] Resultant plasma cells secrete large amounts of antibody and either stay within the SLO or, more preferentially, migrate to bone marrow.^[18]

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.^[12] 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 of 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.^[19]

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.^[20] 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.^[21] 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.^[20] Memory T helper (T_H) cells, typically memory follicular T helper (T_FH) cells, that were derived from T cells activated with the same antigen recognize and bind these MHC-II-peptide complexes through their TCR.^[20] Following TCR-MHC-II-peptide binding and the relay of other signals from the memory T_FH 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.^[20][21] It is unclear whether the memory B cells undergo further affinity maturation within these secondary GCs.^[20]

B cell types

• 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.^[12] 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.^[12] 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.^[12] Plasma cells typically result from the germinal center reaction from T cell-dependent activation of B cells, however they can also result from T cell-independent activation of B cells.^[19]
• 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.^[22]
• 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 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).^[21] 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.^[21]
• 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).^[12] 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.^[23] They can undergo both T cell-independent and T cell-dependent activation, but preferentially undergo T cell-independent activation.^[12]
• B-1 cell - Arises from a developmental pathway different from FO B cells and MZ B cells.^[24] 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.^[24] 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.^[24]
• B-2 cell - FO B cells and MZ B cells.^[24]
• 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.^[25] Also, it promotes the generation of regulatory T (Treg) cells by directly interacting with T cells to skew their differentiation towards Tregs.^[25] No common Breg cell identity has been described and many Breg cell subsets sharing regulatory functions have been found in both mice and humans.^[25] It is currently unknown if Breg cell subsets are developmentally linked and how exactly differentiation into a Breg cell occurs.^[25] There is evidence showing that nearly all B cell types can differentiate into a Breg cell through mechanisms involving inflammatory signals and BCR recognition.^[25]

B cell-related pathology

Autoimmune disease can result from abnormal B cell recognition of self-antigens followed by the production of autoantibodies.^[26] Autoimmune diseases where disease activity is correlated with B cell activity include scleroderma, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, and rheumatoid arthritis.^[26]

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.^[27][28]

Epigenetic

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.^[29]

References