Introduction to B Cells also called B-Lymphocytes
B cells are a type of white blood cell that produce antibodies and play a key role in the humoral immunity component of the adaptive immune system. The name B cell stands for bursa-derived cell, as they were first discovered in the bursa of Fabricius, a lymphoid organ in birds. However, in mammals, B cells originate from the bone marrow, which is the primary site of hematopoiesis and lymphopoiesis.
B cells develop from hematopoietic stem cells (HSCs) that reside in the bone marrow. HSCs are multipotent progenitor cells that can give rise to all types of blood cells, including red blood cells, platelets, granulocytes, monocytes, and lymphocytes. HSCs first differentiate into multipotent progenitor (MPP) cells, which retain the ability to generate both myeloid and lymphoid lineages. MPP cells then further differentiate into common lymphoid progenitor (CLP) cells, which are committed to the lymphoid lineage and can produce either B cells or T cells.
CLP cells that remain in the bone marrow undergo a series of developmental stages to become mature B cells. These stages are marked by various gene expression patterns and immunoglobulin gene rearrangements that result in the generation of a diverse repertoire of B cell receptors (BCRs). BCRs are membrane-bound antibodies that recognize specific antigens and initiate B cell activation and differentiation. Each B cell expresses a unique BCR with a distinct antigen specificity, which is determined by the combination of heavy chain and light chain variable regions.
The main stages of B cell development in the bone marrow are:
- Pro-B cell: This is the earliest stage of B cell development, characterized by the expression of CD19 and CD45R on the cell surface and the rearrangement of the immunoglobulin heavy chain (IgH) gene locus. Pro-B cells undergo V(D)J recombination, a process that randomly joins one variable (V), one diversity (D), and one joining (J) gene segment from a pool of hundreds of gene segments to form a functional IgH gene. This process generates diversity in the IgH variable region and allows pro-B cells to express a pre-BCR composed of an IgH chain paired with a surrogate light chain on the cell surface.
- Pre-B cell: This stage is characterized by the expression of CD20 and CD25 on the cell surface and the rearrangement of the immunoglobulin light chain (IgL) gene locus. Pre-B cells undergo VJ recombination, a process that randomly joins one V and one J gene segment from a pool of dozens of gene segments to form a functional IgL gene. This process generates diversity in the IgL variable region and allows pre-B cells to express a mature BCR composed of an IgH chain paired with an IgL chain on the cell surface.
- Immature B cell: This stage is characterized by the expression of CD21 and CD23 on the cell surface and the cessation of immunoglobulin gene rearrangement. Immature B cells express IgM as their primary BCR and undergo negative selection in the bone marrow to eliminate self-reactive clones. Negative selection involves binding of self-antigens to the BCR and inducing apoptosis, receptor editing, anergy, or ignorance depending on the strength and persistence of the signal. This process ensures central tolerance, which prevents autoimmune responses against self-tissues.
- Mature B cell: This stage is characterized by the expression of CD40 and MHC class II on the cell surface and the migration to peripheral lymphoid organs. Mature B cells express both IgM and IgD as their primary BCRs and undergo positive selection in secondary lymphoid tissues to encounter foreign antigens. Positive selection involves binding of foreign antigens to the BCR and receiving help from T helper cells to proliferate and differentiate into plasma cells or memory cells. Plasma cells secrete large amounts of antibodies specific for the antigen, while memory cells persist for long-term protection against future exposures.
B-cell development in the bone marrow is a complex process that involves multiple stages of differentiation, proliferation, and selection. The bone marrow is the primary site of B-cell maturation in adults, although some B cells can also develop in other organs such as the spleen and the gut-associated lymphoid tissue (GALT).
The first step of B-cell development in the bone marrow is the generation of common lymphoid progenitors (CLPs) from hematopoietic stem cells (HSCs). CLPs are multipotent cells that can give rise to either B cells or T cells. CLPs express several surface markers, such as CD34, CD127, and CD135, that distinguish them from other progenitor cells.
The next step is the commitment of CLPs to the B-cell lineage. This is mediated by the transcription factors E2A, EBF1, and PAX5, which activate the expression of genes essential for B-cell development, such as CD19, CD79a, and CD79b. These genes encode for components of the pre-B-cell receptor (pre-BCR), which is a surrogate receptor for immunoglobulin (Ig) heavy chain. The pre-BCR plays a crucial role in the survival and proliferation of early B-cell progenitors.
The subsequent stages of B-cell development in the bone marrow are characterized by the rearrangement of Ig genes and the expression of different Ig classes on the cell surface. The Ig genes consist of variable (V), diversity (D), joining (J), and constant (C) segments that undergo somatic recombination to generate diverse antigen receptors. The Ig heavy chain gene rearranges first, followed by the Ig light chain gene. The order of Ig gene rearrangement defines four main stages of B-cell development in the bone marrow:
- Pro-B cells: These are the earliest B-cell progenitors that initiate Ig heavy chain gene rearrangement. They express CD19 and CD79a on their surface, but lack Ig expression.
- Pre-B cells: These are intermediate B-cell progenitors that have successfully rearranged their Ig heavy chain gene and express a functional pre-BCR on their surface. They also express CD19, CD79a, CD79b, and CD20. Pre-B cells can be further divided into two subtypes: large pre-B cells and small pre-B cells. Large pre-B cells are actively proliferating and undergo allelic exclusion, which ensures that only one Ig heavy chain allele is expressed per cell. Small pre-B cells are quiescent and initiate Ig light chain gene rearrangement.
- Immature B cells: These are late B-cell progenitors that have successfully rearranged their Ig light chain gene and express a functional B-cell receptor (BCR) on their surface. They also express CD19, CD79a, CD79b, CD20, and IgM. Immature B cells undergo negative selection in the bone marrow, which eliminates self-reactive cells that bind to self-antigens.
- Mature B cells: These are fully differentiated B cells that exit the bone marrow and enter the peripheral circulation. They express CD19, CD79a, CD79b, CD20, IgM, and IgD on their surface. Mature B cells can further differentiate into plasma cells or memory cells upon encountering antigens.
B-cell development in the bone marrow is a highly regulated process that ensures the generation of a diverse and self-tolerant repertoire of antigen receptors. The process is influenced by various factors, such as cytokines, chemokines, stromal cells, and microenvironmental signals. Dysregulation of B-cell development in the bone marrow can lead to immunodeficiency or autoimmunity.
CLPs are a type of oligopotent cells that develop from HSCs and give rise to B cells, T cells, and natural killer (NK) cells. These are the three main types of lymphocytes that are involved in adaptive and innate immunity. CLPs are generated in the bone marrow and can be identified by the expression of certain cell surface markers, such as CD127 (IL-7 receptor), CD135 (Flt3), and CD117 (c-Kit). CLPs can also be distinguished from common myeloid progenitors (CMPs) by the lack of expression of CD34 and CD16/32.
CLPs undergo a series of differentiation steps to produce mature lymphocytes. The first step is the commitment to either the B cell or the T/NK cell lineage. This is influenced by various factors, such as cytokines, transcription factors, and microenvironmental cues. For example, IL-7 and Flt3 ligand promote B cell development, while Notch signaling and IL-15 favor T/NK cell development. The second step is the rearrangement of the immunoglobulin (Ig) or T cell receptor (TCR) genes, which generate diversity and specificity in antigen recognition. This process involves the random joining of variable (V), diversity (D), and joining (J) gene segments by a mechanism called V(D)J recombination. The third step is the selection and maturation of lymphocytes that express functional and non-autoreactive receptors. This involves positive and negative selection events that eliminate cells that fail to recognize self-MHC molecules or bind too strongly to self-antigens. The final step is the migration of mature lymphocytes to secondary lymphoid organs, such as the spleen, lymph nodes, and mucosal tissues, where they encounter antigens and mount immune responses.
B cells are lymphocytes that originate from hematopoietic stem cells (HSCs) in the bone marrow. They undergo a complex process of maturation and differentiation before they can participate in the adaptive immune response. B cell maturation in adults involves several stages, each characterized by the expression of specific genes and surface markers. The main stages of B cell maturation in adults are:
- Pro-B cells: These are the earliest identifiable B cell progenitors in the bone marrow. They express CD34, a marker of HSCs, and CD19, a marker of B lineage cells. They also rearrange their immunoglobulin (Ig) heavy chain genes through a process called V(D)J recombination, which generates diversity in the antigen-binding sites of antibodies.
- Pre-B cells: These are the next stage of B cell development in the bone marrow. They express CD19 and CD20, another marker of B lineage cells. They also express a surrogate light chain (SLC), which pairs with the rearranged Ig heavy chain to form a pre-B cell receptor (pre-BCR). The pre-BCR signals the pro-B cells to stop further heavy chain rearrangement and to initiate light chain rearrangement. The pre-B cells also undergo clonal expansion and allelic exclusion, which ensure that each B cell expresses only one type of antibody.
- Immature B cells: These are the final stage of B cell development in the bone marrow. They express CD19, CD20, and CD21, a marker of mature B cells. They also express IgM on their surface, which is the first antibody class produced by B cells. The immature B cells test their IgM for self-reactivity through a process called negative selection, which eliminates potentially harmful autoreactive B cells. The surviving immature B cells exit the bone marrow and migrate to the peripheral lymphoid organs, such as the spleen and lymph nodes.
- Mature B cells: These are the functional B cells that participate in the immune response. They express CD19, CD20, CD21, and CD40, a co-stimulatory molecule that interacts with T helper cells. They also express IgM and IgD on their surface, which are two different antibody classes that recognize the same antigen. The mature B cells circulate between the blood and the lymphoid organs, where they encounter antigens and become activated. Upon activation, they undergo further differentiation into plasma cells or memory B cells.
Plasma cells are antibody-secreting effector cells that reside in the bone marrow or other tissues. They produce large amounts of antibodies specific for the antigen that activated them. Memory B cells are long-lived cells that retain their antigen specificity and can quickly respond to subsequent exposures to the same antigen.
B cell maturation in adults is a highly regulated process that ensures the generation of a diverse and functional repertoire of antibodies that can protect against various pathogens and diseases.
Pre-B cells are immature B cells that have not yet expressed surface immunoglobulin (Ig) or light chains. They are found in the bone marrow, where they undergo rearrangement of their Ig heavy chain genes and express a surrogate light chain called VpreB. This allows them to form a pre-B cell receptor (pre-BCR) that signals for further development and proliferation.
Mature B cells are the final product of B cell maturation in the bone marrow. They have completed the rearrangement of both their Ig heavy and light chain genes and express surface IgM and IgD as antigen receptors. They also express other surface molecules that help them interact with antigens, T cells, and other immune cells. Mature B cells exit the bone marrow and circulate in the blood and lymph, where they encounter antigens and initiate immune responses.
The clonal selection theory is a fundamental concept in immunology that explains how B cells and T cells recognize and respond to specific antigens. The theory was first proposed by Niels Jerne and David Talmage in 1957 and later refined by Frank Macfarlane Burnet and Gustav Nossal in 1959.
The clonal selection theory states that each immunologically competent B cell or T cell possesses a unique receptor for either an antigen or an epitope (a small part of an antigen). These receptors are generated randomly by gene rearrangement during the development of lymphocytes in the bone marrow (for B cells) or the thymus (for T cells). As a result, there is a large diversity of receptors in the lymphocyte population, each capable of binding to one or a few closely related antigens.
When an antigen enters the body, it encounters the lymphocytes in the blood or the lymphoid tissues. Only those lymphocytes that have receptors that can bind to the antigen are activated by it. This process is called antigen recognition. The activated lymphocytes then proliferate and differentiate into effector cells that carry out the immune response. This process is called clonal expansion. The effector cells can be either plasma cells that secrete antibodies (for B cells) or cytotoxic T cells that kill infected cells (for T cells). The antibodies or cytotoxic T cells have the same specificity as the receptors of the original lymphocytes.
The clonal selection theory also explains how memory cells are formed. Memory cells are long-lived lymphocytes that remain in a quiescent state after an immune response. They have receptors that are identical to those of the effector cells that participated in the response. If the same antigen is encountered again, the memory cells can quickly reactivate and produce a faster and stronger immune response. This is called secondary immune response or immunological memory.
The clonal selection theory has several implications for immunology. It implies that:
- The immune system can recognize and respond to a vast number of antigens, even those that have never been encountered before.
- The immune system can distinguish self from non-self, as lymphocytes that react to self-antigens are eliminated during development (a process called negative selection).
- The immune system can generate diversity and specificity of receptors by gene rearrangement and somatic hypermutation (a process that introduces mutations in the receptor genes during clonal expansion).
- The immune system can adapt and improve its response to repeated exposure to the same antigen by affinity maturation (a process that selects for lymphocytes with higher affinity receptors during clonal expansion) and class switching (a process that changes the type of antibody produced by B cells).
The clonal selection theory is widely accepted as the basis of adaptive immunity. It has been supported by experimental evidence and mathematical models. However, it does not explain all aspects of immune regulation, such as how tolerance to self-antigens is maintained or how autoimmunity occurs. Therefore, other theories and mechanisms have been proposed to complement the clonal selection theory.
Plasma cells are the final differentiated form of B cells that secrete large amounts of antibodies. They are derived from the activated B cells that have undergone clonal expansion and class switching in response to antigen stimulation. The transformation of selected B cells to plasma cells involves several molecular and cellular changes, such as:
- Increased expression of immunoglobulin genes: The activated B cells undergo somatic hypermutation and affinity maturation, which introduce point mutations in the variable regions of the immunoglobulin genes. This results in the generation of B cell clones with higher affinity for the antigen. The B cells also switch from expressing IgM and IgD to other immunoglobulin classes, such as IgG, IgA, or IgE, depending on the cytokine signals and the type of antigen. This process is called class switching or isotype switching and involves recombination of the constant region genes of the immunoglobulin heavy chain.
- Increased expression of plasma cell-specific genes: The activated B cells also upregulate the expression of genes that are essential for plasma cell function and survival, such as XBP1, BLIMP1, IRF4, and PAX5. These transcription factors regulate the expression of genes involved in antibody secretion, endoplasmic reticulum expansion, metabolic adaptation, and protection from apoptosis. For example, XBP1 induces the expression of genes that enhance the protein folding and transport capacity of the endoplasmic reticulum, which is necessary for the high rate of antibody synthesis by plasma cells. BLIMP1 represses the expression of genes that are associated with B cell differentiation and activation, such as BCL6, CD19, and CD20, and promotes the expression of genes that are specific for plasma cells, such as J chain and syndecan-1.
- Morphological changes: The activated B cells undergo drastic changes in their morphology as they differentiate into plasma cells. They increase in size and cytoplasmic volume, lose their surface immunoglobulin and other B cell markers, develop a prominent Golgi apparatus and rough endoplasmic reticulum, and reduce their nucleus-to-cytoplasm ratio. These changes reflect the high metabolic activity and antibody production of plasma cells.
The transformation of selected B cells to plasma cells is a critical step in humoral immunity, as it enables the generation of long-lived antibody-secreting cells that can provide protection against pathogens. Plasma cells can either reside in the secondary lymphoid organs or migrate to other tissues, such as the bone marrow or mucosal surfaces, where they can persist for long periods of time. Some plasma cells can also differentiate into memory B cells, which can rapidly respond to subsequent antigen exposure.
B cells mature in two distinct phases: the antigen-independent phase and the antigen-dependent phase. The antigen-independent phase occurs in the bone marrow, where B cells develop from common lymphoid progenitors (CLPs) to immature B cells. The antigen-dependent phase occurs in the peripheral lymphoid organs, where B cells encounter antigens and undergo further differentiation and activation.
The antigen-independent phase of B cell maturation consists of several stages: early pro-B, late pro-B, pre-B, immature B, and transitional B. In each stage, B cells undergo gene rearrangement, proliferation, and selection.
- Early pro-B cells are the first stage of B cell development. They express CD19 and CD45R (B220) on their surface, but not immunoglobulin (Ig). They undergo heavy chain gene rearrangement at the D-J and V-DJ regions to generate diversity in the Ig variable region.
- Late pro-B cells are the second stage of B cell development. They express CD19, CD45R, and a surrogate light chain (SLC) composed of VpreB and λ5 on their surface. They also express a pre-B cell receptor (pre-BCR) composed of a μ heavy chain and a SLC. The pre-BCR signals for proliferation and allelic exclusion of the heavy chain gene.
- Pre-B cells are the third stage of B cell development. They express CD19, CD45R, SLC, and pre-BCR on their surface. They undergo light chain gene rearrangement at the V-J region to generate diversity in the Ig variable region. They also undergo negative selection to eliminate self-reactive cells.
- Immature B cells are the fourth stage of B cell development. They express CD19, CD45R, and IgM on their surface. They are the first cells to express a functional B cell receptor (BCR) composed of a μ heavy chain and a κ or λ light chain. They also undergo negative selection to eliminate self-reactive cells.
- Transitional B cells are the fifth stage of B cell development. They express CD19, CD45R, IgM, and IgD on their surface. They are the first cells to co-express two classes of Ig on their surface. They migrate from the bone marrow to the spleen, where they undergo positive selection to receive survival signals from the microenvironment.
The antigen-dependent phase of B cell maturation consists of several stages: naive B, activated B, germinal center B, memory B, and plasma cells. In each stage, B cells undergo antigen recognition, proliferation, differentiation, and selection.
- Naive B cells are the first stage of the antigen-dependent phase. They express CD19, CD45R, IgM, and IgD on their surface. They circulate in the blood and lymph and enter the secondary lymphoid organs (such as lymph nodes and spleen), where they encounter antigens.
- Activated B cells are the second stage of the antigen-dependent phase. They express CD19, CD45R, IgM or IgD (depending on the class switching), and activation markers (such as CD69 and CD86) on their surface. They are activated by antigens that bind to their BCRs and by helper T cells that provide co-stimulatory signals (such as CD40L and cytokines). They proliferate and differentiate into two types of cells: germinal center B cells or plasma cells.
- Germinal center B cells are the third stage of the antigen-dependent phase. They express CD19, CD45R, IgM or IgD (depending on the class switching), and germinal center markers (such as CD38 and GL7) on their surface. They are located in the germinal centers of the secondary lymphoid organs, where they undergo somatic hypermutation (SHM) and affinity maturation to increase the affinity of their BCRs for antigens. They also undergo class switching to change their Ig class from IgM or IgD to IgG, IgA, or IgE. They compete for survival signals from follicular dendritic cells (FDCs) that present antigens in complex with complement or antibodies. They also undergo positive selection by helper T cells that recognize their peptide-MHC II complexes.
- Memory B cells are the fourth stage of the antigen-dependent phase. They express CD19, CD45R, IgM or IgD (depending on the class switching), and memory markers (such as CD27 and CD80) on their surface. They are derived from germinal center B cells that have high affinity for antigens and receive survival signals from helper T cells. They circulate in the blood and lymph and enter the secondary lymphoid organs upon re-exposure to antigens. They rapidly differentiate into plasma cells or germinal center B cells upon activation by antigens and helper T cells.
- Plasma cells are the fifth stage of the antigen-dependent phase. They express CD19, CD38, MHC II, and high levels of IgM or IgD (depending on the class switching) on their surface. They also secrete large amounts of antibodies specific for antigens into the blood and lymph. They are derived from activated B cells or memory B cells that have received differentiation signals from helper T cells or cytokines. They reside in the bone marrow or other tissues where they provide long-term humoral immunity.
B cells express various molecules on their surface that serve different functions in the development, activation, and differentiation of B cells. Some of the important surface molecules on B cells are:
- Immunoglobulins (Ig): These are the antigen receptors on B cells that bind to specific epitopes on the antigen. B cells can express either IgM or IgD as surface immunoglobulins, depending on their stage of maturation and activation. IgM is the first immunoglobulin to be expressed by B cells and is involved in the primary immune response. IgD is expressed by mature naive B cells and may have a role in regulating B cell activation and tolerance.
- B cell co-receptor complex: This consists of three molecules: CD19, CD21, and CD81. CD19 is a signal transduction molecule that amplifies the signal from the antigen receptor. CD21 is also known as complement receptor 2 (CR2) and binds to the complement component C3d that is attached to the antigen. This enhances the antigen recognition by B cells and lowers the threshold for activation. CD81 is a tetraspanin protein that facilitates the association of CD19 and CD21.
- Major histocompatibility complex (MHC) class II molecules: These are molecules that present processed antigen peptides to helper T cells. B cells can internalize the antigen bound to their immunoglobulins and process it into peptides that are loaded onto MHC class II molecules. The MHC class II-peptide complex is then displayed on the surface of B cells for recognition by T cell receptors on helper T cells. This interaction is essential for the activation and differentiation of B cells into plasma cells or memory cells.
- CD40: This is a member of the tumor necrosis factor (TNF) receptor family that binds to CD40 ligand (CD40L) on helper T cells. The CD40-CD40L interaction provides a co-stimulatory signal for B cell activation and also induces class switching from IgM to other immunoglobulin classes such as IgG, IgA, or IgE. Class switching allows B cells to produce antibodies with different effector functions and tissue distribution.
- B220: This is also known as CD45R and is a tyrosine phosphatase that regulates the signal transduction from the antigen receptor and other surface molecules. B220 is expressed by all B cells except plasma cells and is used as a marker for identifying B cells in flow cytometry.
- CD5: This is a molecule that is expressed by a subset of B cells called B-1 cells. B-1 cells are found mainly in the mucosal tissues and produce natural antibodies against common antigens such as bacterial polysaccharides. CD5 may have a role in regulating the self-reactivity and survival of B-1 cells.
These are some of the surface molecules on B cells that play important roles in their development, activation, and differentiation. Understanding these molecules can help us better appreciate the diversity and complexity of B cell responses to different types of antigens.
B cells can recognize and bind to antigens that are either free in the blood or lymph, or displayed on the surface of other cells. However, most antigens require the help of T cells to fully activate B cells and induce them to produce antibodies. These antigens are called thymus-dependent antigens, because they depend on the presence of functional T cells that have matured in the thymus.
The activation of B cells by thymus-dependent antigens involves two main steps: T-cell-antigen receptor recognition and co-stimulatory interactions.
The first step is the recognition of the antigen by both the B cell and the helper T cell. The B cell uses its surface immunoglobulin (IgM or IgD) as a receptor to bind to the antigen. The antigen-bound B cell then internalizes the antigen and processes it into peptide fragments. These peptide fragments are then presented on the surface of the B cell in association with major histocompatibility complex (MHC) class II molecules. The MHC class II-peptide complex is recognized by a specific helper T cell that has a complementary T-cell receptor (TCR). The TCR binds to the MHC class II-peptide complex and initiates a signal transduction cascade in both the B cell and the helper T cell.
The second step is the co-stimulation of both the B cell and the helper T cell by additional molecules on their surfaces. These molecules provide a second signal that is necessary for the full activation and proliferation of both cell types. One of the most important co-stimulatory interactions is between CD40 ligand (CD40L) on the helper T cell and CD40 on the B cell. CD40L is induced on the helper T cell after TCR recognition, and binds to CD40 on the B cell, enhancing its expression of MHC class II and co-stimulatory molecules such as B7. CD40 also activates a transcription factor called nuclear factor kappa B (NF-κB), which regulates genes involved in B-cell survival, proliferation, differentiation, and antibody production.
Another important co-stimulatory interaction is between CD28 on the helper T cell and B7 on the B cell. CD28 is constitutively expressed on naive helper T cells, and binds to B7 on activated B cells, providing a positive feedback loop that enhances T-cell activation and cytokine production. Cytokines such as interleukin-2 (IL-2), interleukin-4 (IL-4), and interleukin-5 (IL-5) are secreted by helper T cells and act on B cells to promote their growth, differentiation, class switching, and antibody secretion.
The co-stimulatory interactions between B cells and helper T cells are essential for generating a robust humoral immune response against thymus-dependent antigens. Without these interactions, B cells would not be able to produce high-affinity antibodies of different classes and subclasses, nor generate long-lived plasma cells and memory cells that can provide lasting protection against reinfection.
One of the remarkable features of B cells is their ability to change the class of immunoglobulin they produce without altering the antigen specificity. This process is called class switching or isotype switching. It allows B cells to produce different types of antibodies with different effector functions, such as complement activation, opsonization, neutralization, or antibody-dependent cellular cytotoxicity (ADCC).
Class switching occurs after B cells are activated by antigen and helper T cells. It involves a recombination event in the immunoglobulin heavy chain gene locus, which deletes the constant region genes for IgM and IgD and brings a different constant region gene next to the variable region gene. The variable region gene encodes the antigen-binding site and remains unchanged during class switching. The constant region gene determines the class of immunoglobulin and its effector function.
The most common class switch is from IgM to IgG, which is mediated by cytokines such as IL-4, IL-10, and IFN-γ. IgG antibodies have a longer half-life than IgM and can cross the placenta to provide passive immunity to the fetus. IgG antibodies also have higher affinity for Fc receptors on phagocytes and natural killer (NK) cells, which enhances their ability to opsonize and kill pathogens.
B cells can also switch to other classes of immunoglobulin, such as IgA, IgE, or IgD. IgA antibodies are mainly produced by mucosal B cells and are secreted into external secretions such as saliva, tears, breast milk, and intestinal fluid. IgA antibodies protect mucosal surfaces from pathogens and toxins by neutralizing them or preventing their adherence. IgE antibodies are produced by B cells in response to allergens or parasites. IgE antibodies bind to mast cells and basophils and trigger degranulation and release of inflammatory mediators such as histamine and leukotrienes. IgE antibodies are responsible for allergic reactions and immunity against helminths. IgD antibodies are mainly expressed on the surface of naive B cells and have an unclear function.
Class switching is a regulated process that depends on the type of antigen, the cytokine environment, and the signals from T cells. Class switching enhances the diversity and adaptability of the humoral immune response by allowing B cells to produce different types of antibodies with different effector functions. Class switching also contributes to affinity maturation, which is the process of selecting B cells with higher affinity for the antigen during a secondary immune response.
B cells are not only responsible for producing antibodies, but also for generating long-lasting immunity against pathogens. When B cells encounter an antigen that matches their specific B cell receptor (BCR), they become activated and differentiate into two types of effector cells: plasma cells and memory cells.
Plasma cells are the main antibody-producing cells of the immune system. They secrete large amounts of antibodies that bind to the antigen and neutralize it or mark it for destruction by other immune cells. Plasma cells have a short lifespan and are mostly found in the lymph nodes, spleen, and bone marrow.
Memory cells are long-lived B cells that retain the memory of the antigen and can quickly respond to a subsequent exposure. Memory cells have a different phenotype than plasma cells and express high levels of surface immunoglobulin (Ig), mainly IgG. Memory cells circulate in the blood and lymphoid tissues and can rapidly differentiate into plasma cells upon reactivation by the same or a similar antigen. Memory cells provide the basis for the secondary immune response, which is faster and stronger than the primary response.
The production of plasma cells and memory cells is regulated by several factors, including the type of antigen, the presence of helper T cells, and the signals from cytokines and co-stimulatory molecules. Depending on these factors, B cells can undergo different pathways of differentiation, such as germinal center (GC) or extrafollicular (EF) responses. GC responses occur in the follicles of secondary lymphoid organs and involve somatic hypermutation and class switching of the BCR, resulting in high-affinity antibodies and long-term memory. EF responses occur outside the follicles and involve rapid proliferation and differentiation of B cells into short-lived plasma cells that produce low-affinity antibodies.
The effector functions of B cells are essential for protecting the body from various pathogens, such as bacteria, viruses, fungi, and parasites. B cells also play a role in immune regulation, tolerance, and autoimmunity by producing cytokines and presenting antigens to T cells.
One of the most important features of the adaptive immune system is its ability to generate immunological memory. This means that after an initial exposure to a specific antigen, the immune system can remember it and mount a stronger and faster response if it encounters the same antigen again. This type of immunity is both active and adaptive, and it is the basis of vaccination.
The first time that B cells encounter an antigen, they undergo a primary immune response. This involves the activation of B cells by antigen recognition and T cell help, the proliferation and differentiation of B cells into plasma cells and memory B cells, and the production of antibodies that are specific for the antigen. The primary immune response takes several days to reach its peak, and it is mainly mediated by IgM antibodies.
However, if the same antigen is encountered again, the memory B cells that were generated during the primary response are quickly activated and transformed into plasma cells. This leads to a secondary immune response, which is characterized by a higher magnitude, a shorter lag time, a longer duration, and a higher affinity of antibodies. The secondary immune response is mainly mediated by IgG antibodies, which have undergone class switching and somatic hypermutation to improve their ability to bind and neutralize the antigen.
The rapid appearance of antibody in secondary immune responses is due to several factors:
- Memory B cells have a lower activation threshold than naive B cells, meaning that they can respond to lower doses of antigen or antigen presented by non-professional antigen-presenting cells.
- Memory B cells express higher levels of surface molecules that enhance their survival, proliferation, and differentiation, such as CD40, CD80, CD86, and MHC II.
- Memory B cells can migrate to secondary lymphoid organs more efficiently than naive B cells, where they can interact with antigen and T cells.
- Memory B cells can secrete antibodies faster than naive B cells, because they have already undergone class switching and somatic hypermutation and do not need to rearrange their immunoglobulin genes.
The rapid appearance of antibody in secondary immune responses provides a great advantage for the host, as it can prevent or limit the infection by neutralizing the pathogen before it can cause damage. It also contributes to the clearance of antigens and immune complexes from the circulation and tissues. The secondary immune response is therefore essential for maintaining long-term immunity against recurrent or persistent infections.
B-cells are able to recognize and bind to a wide range of antigens, which are molecules that trigger an immune response. However, not all antigens can activate B-cells to produce antibodies and memory cells. Depending on the type of antigen, B-cells may require the help of another type of immune cell called T-helper cells. Based on this requirement, antigens can be classified into two types: thymus-independent and thymus-dependent.
Thymus-independent antigens are antigens that can activate B-cells without the involvement of T-helper cells. These antigens are usually polymeric molecules, such as polysaccharides or lipopolysaccharides, that can cross-link multiple B-cell receptors and provide a strong and persistent signal to the B-cell. Thymus-independent antigens can induce the production of plasma cells and IgM antibodies, but they cannot induce class switching, affinity maturation, or memory cell formation. Therefore, the antibody response to these antigens is relatively weak and short-lived.
Thymus-dependent antigens are antigens that require the co-operation of T-helper cells to stimulate B-cell activation. These antigens are usually protein molecules that can be processed and presented by B-cells in association with MHC class II molecules on their surface. The complex of antigen and MHC class II is recognized by the T-cell receptor on a specific T-helper cell, which then activates the B-cell through various interactions and cytokines. Thymus-dependent antigens can induce the production of plasma cells and various classes of antibodies (IgM, IgG, IgA, IgE), as well as affinity maturation and memory cell formation. Therefore, the antibody response to these antigens is more robust and long-lasting.
The distinction between thymus-independent and thymus-dependent antigens is important for understanding how B-cells generate a diverse and effective humoral immune response against different types of pathogens. It also has implications for vaccine design, as some vaccines may contain only thymus-independent antigens (such as polysaccharide vaccines) or only thymus-dependent antigens (such as protein vaccines), or a combination of both (such as conjugate vaccines).
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