14.2.4: B Lymphocytes and Antibodies - Biology

Learning Objectives

  • Describe the production and maturation of B cells
  • Compare the structure of B-cell receptors and T-cell receptors
  • Compare T-dependent and T-independent activation of B cells
  • Compare the primary and secondary antibody responses

Humoral immunity refers to mechanisms of the adaptive immune defenses that are mediated by antibodies secreted by B lymphocytes, or B cells. This section will focus on B cells and discuss their production and maturation, receptors, and mechanisms of activation.

B Cell Production and Maturation

Like T cells, B cells are formed from multipotent hematopoietic stem cells (HSCs) in the bone marrow and follow a pathway through lymphoid stem cell and lymphoblast (see [link]). Unlike T cells, however, lymphoblasts destined to become B cells do not leave the bone marrow and travel to the thymus for maturation. Rather, eventual B cells continue to mature in the bone marrow.

The first step of B cell maturation is an assessment of the functionality of their antigen-binding receptors. This occurs through positive selection for B cells with normal functional receptors. A mechanism of negative selection is then used to eliminate self-reacting B cells and minimize the risk of autoimmunity. Negative selection of self-reacting B cells can involve elimination by apoptosis, editing or modification of the receptors so they are no longer self-reactive, or induction of anergy in the B cell. Immature B cells that pass the selection in the bone marrow then travel to the spleenfor their final stages of maturation. There they become naïve mature B cells, i.e., mature B cells that have not yet been activated.

Exercise (PageIndex{1})

Compare the maturation of B cells with the maturation of T cells.

B-Cell Receptors

Like T cells, B cells possess antigen-specific receptors with diverse specificities. Although they rely on T cells for optimum function, B cells can be activated without help from T cells. B-cell receptors (BCRs) for naïve mature B cells are membrane-bound monomeric forms of IgD and IgM. They have two identical heavy chains and two identical light chains connected by disulfide bonds into a basic “Y” shape (Figure (PageIndex{1})). The trunk of the Y-shaped molecule, the constant region of the two heavy chains, spans the B cell membrane. The two antigen-binding sites exposed to the exterior of the B cell are involved in the binding of specific pathogen epitopes to initiate the activation process. It is estimated that each naïve mature B cell has upwards of 100,000 BCRs on its membrane, and each of these BCRs has an identical epitope-binding specificity.

In order to be prepared to react to a wide range of microbial epitopes, B cells, like T cells, use genetic rearrangementof hundreds of gene segments to provide the necessary diversity of receptor specificities. The variable region of the BCR heavy chain is made up of V, D, and J segments, similar to the β chain of the TCR. The variable region of the BCR light chain is made up of V and J segments, similar to the α chain of the TCR. Genetic rearrangement of all possible combinations of V-J-D (heavy chain) and V-J (light chain) provides for millions of unique antigen-binding sites for the BCR and for the antibodies secreted after activation.

One important difference between BCRs and TCRs is the way they can interact with antigenic epitopes. Whereas TCRs can only interact with antigenic epitopes that are presented within the antigen-binding cleft of MHC I or MHC II, BCRs do not require antigen presentation with MHC; they can interact with epitopes on free antigens or with epitopesdisplayed on the surface of intact pathogens. Another important difference is that TCRs only recognize protein epitopes, whereas BCRs can recognize epitopes associated with different molecular classes (e.g., proteins, polysaccharides, lipopolysaccharides).

Activation of B cells occurs through different mechanisms depending on the molecular class of the antigen. Activation of a B cell by a protein antigen requires the B cell to function as an APC, presenting the protein epitopes with MHC II to helper T cells. Because of their dependence on T cells for activation of B cells, protein antigens are classified as T-dependent antigens. In contrast, polysaccharides, lipopolysaccharides, and other nonprotein antigens are considered T-independent antigens because they can activate B cells without antigen processing and presentation to T cells.

Exercise (PageIndex{2})

  1. What types of molecules serve as the BCR?
  2. What are the differences between TCRs and BCRs with respect to antigen recognition?
  3. Which molecule classes are T-dependent antigens and which are T-independent antigens?

T Cell-Independent Activation of B cells

Activation of B cells without the cooperation of helper T cells is referred to as T cell-independent activation and occurs when BCRs interact with T-independent antigens. T-independent antigens (e.g., polysaccharide capsules, lipopolysaccharide) have repetitive epitope units within their structure, and this repetition allows for the cross-linkageof multiple BCRs, providing the first signal for activation (Figure (PageIndex{2})). Because T cells are not involved, the second signal has to come from other sources, such as interactions of toll-like receptors with PAMPs or interactions with factors from the complement system.

Once a B cell is activated, it undergoes clonal proliferation and daughter cells differentiate into plasma cells. Plasma cells are antibody factories that secrete large quantities of antibodies. After differentiation, the surface BCRs disappear and the plasma cell secretes pentameric IgM molecules that have the same antigen specificity as the BCRs (Figure (PageIndex{2})).

The T cell-independent response is short-lived and does not result in the production of memory B cells. Thus it will not result in a secondary response to subsequent exposures to T-independent antigens.

Exercise (PageIndex{3})

  1. What are the two signals required for T cell-independent activation of B cells?
  2. What is the function of a plasma cell?

T Cell-Dependent Activation of B cells

T cell-dependent activation of B cells is more complex than T cell-independent activation, but the resulting immune response is stronger and develops memory. T cell-dependent activation can occur either in response to free protein antigens or to protein antigens associated with an intact pathogen. Interaction between the BCRs on a naïve mature B cell and a free protein antigen stimulate internalization of the antigen, whereas interaction with antigens associated with an intact pathogen initiates the extraction of the antigen from the pathogen before internalization. Once internalized inside the B cell, the protein antigen is processed and presented with MHC II. The presented antigen is then recognized by helper T cells specific to the same antigen. The TCR of the helper T cell recognizes the foreign antigen, and the T cell’s CD4 molecule interacts with MHC II on the B cell. The coordination between B cells and helper T cells that are specific to the same antigen is referred to as linked recognition.

Once activated by linked recognition, TH2 cells produce and secrete cytokines that activate the B cell and cause proliferation into clonal daughter cells. After several rounds of proliferation, additional cytokines provided by the TH2 cells stimulate the differentiation of activated B cell clones into memory B cells, which will quickly respond to subsequent exposures to the same protein epitope, and plasma cells that lose their membrane BCRs and initially secrete pentameric IgM (Figure (PageIndex{3})).

After initial secretion of IgM, cytokines secreted by TH2 cells stimulate the plasma cells to switch from IgM production to production of IgG, IgA, or IgE. This process, called class switching or isotype switching, allows plasma cellscloned from the same activated B cell to produce a variety of antibody classes with the same epitope specificity. Class switching is accomplished by genetic rearrangement of gene segments encoding the constant region, which determines an antibody’s class. The variable region is not changed, so the new class of antibody retains the original epitope specificity.

Exercise (PageIndex{4})

  1. What steps are required for T cell-dependent activation of B cells?
  2. What is antibody class switching and why is it important?

Primary and Secondary Responses

T cell-dependent activation of B cells plays an important role in both the primary and secondary responses associated with adaptive immunity. With the first exposure to a protein antigen, a T cell-dependent primary antibody responseoccurs. The initial stage of the primary response is a lag period, or latent period, of approximately 10 days, during which no antibody can be detected in serum. This lag period is the time required for all of the steps of the primary response, including naïve mature B cell binding of antigen with BCRs, antigen processing and presentation, helper T cell activation, B cell activation, and clonal proliferation. The end of the lag period is characterized by a rise in IgM levels in the serum, as TH2 cells stimulate B cell differentiation into plasma cells. IgM levels reach their peak around 14 days after primary antigen exposure; at about this same time, TH2 stimulates antibody class switching, and IgM levels in serum begin to decline. Meanwhile, levels of IgG increase until they reach a peak about three weeks into the primary response (Figure (PageIndex{4})).

During the primary response, some of the cloned B cells are differentiated into memory B cells programmed to respond to subsequent exposures. This secondary response occurs more quickly and forcefully than the primary response. The lag period is decreased to only a few days and the production of IgG is significantly higher than observed for the primary response (Figure (PageIndex{4})). In addition, the antibodies produced during the secondary response are more effective and bind with higher affinity to the targeted epitopes. Plasma cells produced during secondary responses live longer than those produced during the primary response, so levels of specific antibody remain elevated for a longer period of time.

Exercise (PageIndex{5})

  1. What events occur during the lag period of the primary antibody response?
  2. Why do antibody levels remain elevated longer during the secondary antibody response?

Key Concepts and Summary

  • B lymphocytes or B cells produce antibodies involved in humoral immunity. B cells are produced in the bone marrow, where the initial stages of maturation occur, and travel to the spleen for final steps of maturation into naïve mature B cells.
  • B-cell receptors (BCRs) are membrane-bound monomeric forms of IgD and IgM that bind specific antigen epitopes with their Fab antigen-binding regions. Diversity of antigen binding specificity is created by genetic rearrangement of V, D, and J segments similar to the mechanism used for TCR diversity.
  • Protein antigens are called T-dependent antigens because they can only activate B cells with the cooperation of helper T cells. Other molecule classes do not require T cell cooperation and are called T-independent antigens.
  • T cell-independent activation of B cells involves cross-linkage of BCRs by repetitive nonprotein antigen epitopes. It is characterized by the production of IgM by plasma cells and does not produce memory B cells.
  • T cell-dependent activation of B cells involves processing and presentation of protein antigens to helper T cells, activation of the B cells by cytokines secreted from activated TH2 cells, and plasma cells that produce different classes of antibodies as a result of class switching. Memory B cells are also produced.
  • Secondary exposures to T-dependent antigens result in a secondary antibody response initiated by memory B cells. The secondary response develops more quickly and produces higher and more sustained levels of antibody with higher affinity for the specific antigen.

Multiple Choice

Which of the following would be a T-dependent antigen?

A. lipopolysaccharide
B. glycolipid
C. protein
D. carbohydrate


Which of the following would be a BCR?

A. CD4
D. IgD


Which of the following does not occur during the lag period of the primary antibody response?

A. activation of helper T cells
B. class switching to IgG
C. presentation of antigen with MHC II
D. binding of antigen to BCRs


Fill in the Blank

________ antigens can stimulate B cells to become activated but require cytokine assistance delivered by helper T cells.


T-independent antigens can stimulate B cells to become activated and secrete antibodies without assistance from helper T cells. These antigens possess ________ antigenic epitopes that cross-link BCRs.


Critical Thinking

A patient lacks the ability to make functioning T cells because of a genetic disorder. Would this patient’s B cells be able to produce antibodies in response to an infection? Explain your answer.

The Immune System&mdashthe Body&rsquos Defense Against Infection

To understand how COVID-19 vaccines work, it helps to first look at how our bodies fight illness. When germs, such as the virus that causes COVID-19, invade our bodies, they attack and multiply. This invasion, called an infection, is what causes illness. Our immune system uses several tools to fight infection. Blood contains red cells, which carry oxygen to tissues and organs, and white or immune cells, which fight infection. Different types of white blood cells fight infection in different ways:

  • Macrophages are white blood cells that swallow up and digest germs and dead or dying cells. The macrophages leave behind parts of the invading germs, called &ldquoantigens&rdquo. The body identifies antigens as dangerous and stimulates antibodies to attack them.
  • B-lymphocytes are defensive white blood cells. They produce antibodies that attack the pieces of the virus left behind by the macrophages.
  • T-lymphocytes are another type of defensive white blood cell. They attack cells in the body that have already been infected.

The first time a person is infected with the virus that causes COVID-19, it can take several days or weeks for their body to make and use all the germ-fighting tools needed to get over the infection. After the infection, the person&rsquos immune system remembers what it learned about how to protect the body against that disease.

The body keeps a few T-lymphocytes, called &ldquomemory cells,&rdquo that go into action quickly if the body encounters the same virus again. When the familiar antigens are detected, B-lymphocytes produce antibodies to attack them. Experts are still learning how long these memory cells protect a person against the virus that causes COVID-19.

What happens after vaccination?

After you have been vaccinated, some of the cells that are responsible for protecting you against disease — your B lymphocytes — detect the antigens in the vaccine. The B lymphocytes will react as if the real infectious organism was invading your body. They multiply to form an army of identical cells that are able to respond to the antigens in the vaccine. The cloned cells then evolve into one of 2 types of cells:

The plasma cells produce antibodies (Y- or T-shaped molecules), which are trained specifically to attach to and inactivate the organism you are being vaccinated against.

This response from your immune system, generated by the B lymphocytes, is known as the primary response. It takes several days to build to maximum intensity, and the antibody concentration in the blood peaks at about 14 days.

Your body continues making antibodies and memory B cells for a couple of weeks after vaccination. Over time, the antibodies will gradually disappear, but the memory B cells will remain dormant in your body for many years.

B Lymphocytes and the Immune Response (With Diagram)

Read this article to learn about B Lymphocytes and the Immune Response !

To understand how B lymphocytes are caused to se­crete antibodies during an immune response, let’s consider a case in which a person acquires either a bacterial or viral infection.

Two events must generally occur if B lymphocytes are to be activated (Fig. 25- 12).

First, antigens present on the surface of (or re­leased by) the pathogen become bound to antibodies in the plasma membranes of one or more of the millions of clones of B lymphocytes. Binding of the antigen to the surface of the B lymphocytes does not by itself cause activation of the clone. Instead, antigens must also be taken up during nonspecific phagocytosis of antigen-bearing particles by macrophages (i.e., phagocytic cells that act as scavengers in the body’s tissues). The antigens taken up by the macrophages are degraded or “processed” and fragments contain­ing antigenic determinants are then displayed at the cell surface.

Macrophages that carry out this process are referred to as antigen-presenting cells. The anti­genic determinant is then recognized by one or more clones of T cells possessing T-cell receptors for the an­tigen. T cells that recognize and are activated by antigen-presenting cells are called T helper cells.

Ac­tivated T helper cells then interact with the B lympho­cytes to which antigen had already been bound. The interaction between T helper cells and B lymphocytes serves to activate the B lymphocytes causing the rapid proliferation of the clone, thereby yielding plasma cells and memory cells (Fig. 25-12). Only the plasma cells produce and secrete antibodies. The memory cells are kept in reserve and will be called on to re­spond during a second (or subsequent) infection by the same antigen-bearing pathogen.

Antibodies secreted by plasma cells may have sev­eral different effects:

(1) They may interact with free (i.e., soluble) antigens causing precipitation

(2) They may interact with surface antigens of the pathogen (i.e., particulate antigens) causing agglutination or

(3) They may promote complement fixation.

Precipitation of Soluble Antigens:

Antigens may have one or more antigenic determi­nants (Fig. 25-13). If one antigenic determinant is present, the antigen is said to be mono-determinant if two are present, the antigen is bi-determinant, and so on. Most antibodies are bivalent, meaning that they can simultaneously combine with up to two antigenic determinants.

As Figure 25-13 illustrates the prod­ucts formed by interaction of immunoglobulin and antigen depend on the number of antigenic determi­nants that are present. Two mono-determinant anti­gens can be cross-linked by a single antibody (Fig. 25- 13a), but the product is not usually insoluble unless the antigen itself is very large. However, if two anti­genic determinants are present, cross-linking by the antibody can produce chains of antigens that are in­soluble and form precipitates (Fig. 25-13b). Multi- determinant antigens react with antibody to produce cross-linked networks or lattices that are insoluble (Fig. 25-13c).

Interactions between antibodies and free antigens can be considerably more complex than those illus­trated in Figure 25-13. For example, some antibodies may exist as dimers (e.g., IgA) or pentamers (e.g., IgM) (see Fig. 25-3) these antibodies can simulta­neously bind four or more antigenic determinants. Moreover, antigens may possess more than one kind of antigenic determinant, each determinant capable of reacting with a different antibody.

Finally, the pre­dominant form of interaction that takes place between antibodies and antigens is influenced by the respec­tive concentrations of the interacting species. Small soluble complexes are favored when there is an excess of antibody chains of cross-linked antigens are fa­vored when there is an antigen excess and cross- linked lattices are favored by nearly equal amounts of antibody and antigen. Regardless of the nature of the products formed, antigen-antibody complexes are eventually eliminated by the phagocytic action of mac­rophages.

Antibodies that interact with antigens present in the surfaces of invading microorganisms or other foreign particles cause agglutination (Fig. 25-14). During ag­glutination the particles become cross-linked to form small masses, and the masses are eliminated by the phagocytic action of macrophages.

As illustrated in Figure 25-14, the plasma mem­branes of macrophages possess receptors that recog­nize and bind the C-terminal or Fc regions of immunoglobulin heavy chains (see Fig. 4-35). Conse­quently, the macrophage receptors are called Fc re­ceptors. Because the Fc regions of the immunoglobulin’s include constant domains, macrophage Fc receptors can bind a variety of different antibodies. Interaction between a macrophage and a mass of ag­glutinated cells is followed by phagocytosis.

Although the mechanism is not fully understood, foreign cells that have attached antibodies can also be destroyed by K (or killer) cells. Killer cells bind the agglutinated mass by interacting with the Fc regions of antibodies but do not internalize it. Instead, it is thought that there is the transfer of toxic substances from the K cell to the pathogen.

Complement Fixation:

The complement system is part of still another mecha­nism by which antibodies defend the body against in­vasion by pathogens. Complement consists of more than a dozen proteins that circulate in the blood. The binding of antibodies to a cluster of antigenic determi­nants in the surfaces of bacteria triggers a cascade of reactions in which the complement proteins (many of which are proenzymes) are sequentially activated.

The cascade is initiated by the binding of a small com­plex of the complement proteins to the constant re­gions of antibodies that are bound to the bacterial an­tigens. In the ensuing reactions, additional complement proteins are bound and activated, eventu­ally forming a lytic complex that creates an open chan­nel through the bacterial surface.

By disorganizing the bacterium’s plasma membrane and allowing water to enter the cell by osmosis, the bacterium is killed. Complement fixation by antibody-coated bacteria and the lysis of the invading cells that follows is the most common defense mechanism attributable to B-cell- secreted antibodies.

Immunologic Memory:

Figure 25-15 shows the relationship between time and the appearance of antibodies in response to a first exposure to a given antigen. Following a short lag pe­riod, antibodies begin to appear in the blood, rising to and maintaining a plateau level for some time before falling again. This characteristic response curve is called a primary immune response.

As long as the an­tibody content of the blood remains at its plateau level, a condition of active immunity exists. The re­sponse to a second exposure to the same antigen—the secondary immune response—is much more dra­matic.

The lag period is shorter, the response is more intense (i.e., greater quantities of antibody are pro­duced) and the elevated antibody level is maintained for a longer period of time. The difference between the two responses indicates that the body has “re­membered” its earlier exposure to the antigen.

Immunologic memory may be explained in the fol­lowing way. The initial exposure to antigen causes dif­ferentiation of B lymphocytes into memory cells as well as plasma cells. Whereas the plasma cells have a relatively short life span in which they are actively en­gaged in antibody secretion, memory cells do not se­crete antibody and continue to circulate in the blood and lymph for months or years. These memory cells are able to respond more quickly to the reappearance of the same antigen than undifferentiated B lympho­cytes. Memory cells are also produced by the multi­plication and differentiation of T lymphocytes.

Autoimmune Diseases:

The immune system normally produces antibodies against foreign proteins but not against the native proteins of the body, that is, the immune system can distinguish between “self” and “non-self.” Yet one’s own proteins will readily be regarded as antigens by the immune system of another organism. Thus, each individual’s tissues possess a myriad of proteins (and other chemical substances) that are potential anti­gens.

The capability to distinguish self from non-self de­velops very early in life. In the 1950s, P. B. Medawar carried out a series of elegant experiments that bear on this concept. Adult mice from one strain reject skin grafts from another strain that is, the recipient’s im­mune system produces antibodies against antigens in the donor’s tissue and this leads to the destruction of the donor’s cells.

However, when living spleen cells (which carry the same antigens as skin cells) from one strain of mice were injected into newborn mice of a different strain and the skin graft experiments re­peated when the newborn mice reached adulthood, the results were entirely different.

Newborn mice that had been exposed to the spleen cells of another strain accepted skin grafts from that strain later in life. This is interpreted to mean that the spleen cells had been transferred to the new born mice while the mice were at an early enough stage of development to accept the spleen cells as “self’ by the maturing mouse immune system.

In rare cases, individuals begin to produce antibod­ies against their own antigens. These antibodies are called autoantibodies and the diseases resulting from their presence are the autoimmune diseases. Among these diseases are paroxysmal cold hemoglobinuria (antibodies against one’s own red blood cells), myas­thenia gravis (antibodies against one’s own muscle cell acetylcholine receptors), and systemic lupus erythe­matosus (antibodies against one’s own nuclear DNA).

The causes of autoimmune diseases are not entirely clear and several different mechanisms seem to be in­volved. Clones of lymphocytes prepared to respond to a non-self (i.e., foreign) antigen that is structurally similar to self may undergo mutation during clonal ex­pansion, thereby producing cells that now respond to self.

It has recently become clear that T and B cells re­ active to self antigens are present even in normal indi­viduals. However, in normal individuals T suppressor cells serve to suppress the activity of these cells and thereby prevent autoimmune diseases.


B cells develop from hematopoietic stem cells (HSCs) that originate from bone marrow. [5] [6] HSCs first differentiate into multipotent progenitor (MPP) cells, then common lymphoid progenitor (CLP) cells. [6] 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. [7]

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 signaling involving both the pre-BCR and the BCR. [8] [9] If these receptors do not bind to their ligand, B cells do not receive the proper signals and cease to develop. [8] [9] 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). [9] 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. [7]

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. [10] Throughout their migration to the spleen and after spleen entry, they are considered T1 B cells. [11] Within the spleen, T1 B cells transition to T2 B cells. [11] 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. [12] Once differentiated, they are now considered mature B cells, or naive B cells. [11]

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. [13] At the SLO, B cell activation begins when the B cell binds to an antigen via its BCR. [14] 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. [15]

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). [16] 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. [17]

T cell-dependent activation Edit

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. [18] T helper (TH) cells, typically follicular T helper (TFH) cells recognize and bind these MHC-II-peptide complexes through their T cell receptor (TCR). [19] Following TCR-MHC-II-peptide binding, T cells express the surface protein CD40L as well as cytokines such as IL-4 and IL-21. [19] 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. [19] After B cells receive these signals, they are considered activated. [19]

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. [15] The first step, known as the extrafollicular response, occurs outside lymphoid follicles but still in the SLO. [15] 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. [20] 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. [21] These processes are facilitated by TFH cells within the GC and generate both high-affinity memory B cells and long-lived plasma cells. [15] Resultant plasma cells secrete large amounts of antibody and either stay within the SLO or, more preferentially, migrate to bone marrow. [21]

T cell-independent activation Edit

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. [15] 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. [22]

Memory B cell activation Edit

Memory B cell activation begins with the detection and binding of their target antigen, which is shared by their parent B cell. [23] 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. [24] 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. [23] 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. [23] 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. [23] [24] It is unclear whether the memory B cells undergo further affinity maturation within these secondary GCs. [23]

  • 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. [15] Plasmablasts can result from T cell-independent activation of B cells or the extrafollicular response from T cell-dependent activation of B cells. [1] – 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. [15] 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. [15] 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. [22]
  • 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. [25] – 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). [24] 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. [24]
  • B-2 cell – FO B cells and MZ B cells. [26]
      (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). [15] They are responsible for generating the majority of high-affinity antibodies during an infection. [1] – 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. [27] They can undergo both T cell-independent and T cell-dependent activation, but preferentially undergo T cell-independent activation. [15]
  • Autoimmune disease can result from abnormal B cell recognition of self-antigens followed by the production of autoantibodies. [29] 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. [29]

    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. [32]

    Helper T Lymphocytes

    The TH lymphocytes function indirectly to identify potential pathogens for other cells of the immune system. These cells are important for extracellular infections, such as those caused by certain bacteria, helminths, and protozoa. TH lymphocytes recognize specific antigens displayed in the MHC II complexes of APCs. There are two major populations of TH cells: TH1 and TH2. TH1 cells secrete cytokines to enhance the activities of macrophages and other T cells. TH1 cells activate the action of cyotoxic T cells, as well as macrophages. TH2 cells stimulate naïve B cells to destroy foreign invaders via antibody secretion. Whether a TH1 or a TH2 immune response develops depends on the specific types of cytokines secreted by cells of the innate immune system, which in turn depends on the nature of the invading pathogen.

    The TH1-mediated response involves macrophages and is associated with inflammation. Recall the frontline defenses of macrophages involved in the innate immune response. Some intracellular bacteria, such as Mycobacterium tuberculosis, have evolved to multiply in macrophages after they have been engulfed. These pathogens evade attempts by macrophages to destroy and digest the pathogen. When M. tuberculosis infection occurs, macrophages can stimulate naïve T cells to become TH1 cells. These stimulated T cells secrete specific cytokines that send feedback to the macrophage to stimulate its digestive capabilities and allow it to destroy the colonizing M. tuberculosis. In the same manner, TH1-activated macrophages also become better suited to ingest and kill tumor cells. In summary TH1 responses are directed toward intracellular invaders while TH2 responses are aimed at those that are extracellular.

    14.2.4: B Lymphocytes and Antibodies - Biology

    What is the immune system?

    The immune system helps to protect us against diseases caused by tiny invaders (called pathogens) such as viruses, bacteria, and parasites. The immune system is made up of specialized organs, cells, and tissues that all work together to destroy these invaders. Some of the main organs involved in the immune system include the spleen, lymph nodes, thymus, and bone marrow.

    The immune system develops all kinds of cells that help to destroy disease causing microbes. Some of these cells are specifically designed for a certain kind of disease. All throughout the body, disease fighting cells are stored in the immune system waiting for the signal to go to battle.

    The immune system is able to communicate throughout the entire body. When pathogens are detected, messages are sent out, warning that the body is being attacked. The immune system then directs the correct attacking cells to the problem area to destroy the invaders.

    Antigens and Antibodies

    Scientists call the invaders that can cause disease antigens. Antigens trigger an immune response in the body. One of the main immune responses is the production of proteins that help to fight off the antigens. These proteins are called antibodies.

    How do the antibodies know which cells to attack?

    In order to work properly, the immune system must know which cells are good cells and which are bad. Antibodies are designed with specific binding sites that only bind with certain antigens. They ignore "good" cells and only attack the bad ones.

    You can see from the picture below that the antibodies each have a specially designed binding site. They will only bind with the antigen that has a "marker" that matches up perfectly.

    Types of Immunity Cells

    • B cells - B cells are also called B lymphocytes. These cells produce antibodies that bind to antigens and neutralize them. Each B cell makes one specific type of antibody. For example, there is a specific B cell that helps to fight off the flu.
    • T cells - T cells are also called T lymphocytes. These cells help to get rid of good cells that have already been infected.
    • Helper T cells - Helper T cells tell B cells to start making antibodies or instruct killer T cells to attack.
    • Killer T cells - Killer T cells destroy cells that have been infected by the invader.
    • Memory cells - Memory cells remember antigens that have already attacked the body. They help the body to fight off any new attacks by a specific antigen.
    • Active immunity - When our bodies develop immunities over time through the immune system this is called active immunity. Whenever we are exposed to a disease (and sometimes get sick), the immune system learns how to fight off the disease. The next time that disease invades, our body is ready for it and can quickly produce antibodies to prevent infection. We can also gain active immunity from vaccines.
    • Passive immunity - When we are born, our bodies may already have some immunity. Babies get antibodies from their mother as they are growing in the womb. They may also gain some antibodies from their mother's milk. It is also possible to get antibodies from an animal or another person through immunoglobulin treatments. These are all passive immunities because they weren't developed by our body's own immune system.

    Vaccines introduce microbes that are already killed or modified so we don't get sick. However, the immune system doesn't know this. It builds up defenses and antibodies against the disease. When the real disease tries to attack, our body is ready and can quickly neutralize the antigens.


    Studies in mouse models of pre-malignancy suggest that B-cell-mediated inflammation may be important in promoting the progression to invasive malignancy. Given the huge promise of reversing the pre-malignant phenotype to reduce the cancer burden, there is an urgent need to understand the role of B cells in human metaplasia, dysplasia and in situ cancer and how they mediate progression through these stages to decide whether B-cell-directed strategies may be of value in reducing the progression of pre-malignancy.

    Studies examining B cells with a regulatory phenotype (Bregs) consistently suggest that Breg infiltration may enhance tumour progression. The factors that induce Bregs in human malignancy need to be defined. Specifically are there particular microbes, TLR ligands or cancer cell produced cytokines in the TME that polarise B cells to a Breg phenotype [14, 102]. Currently used B-cell depleting antibodies cannot distinguish between effector and regulatory B-cell subsets therefore, meticulous phenotypic characterisation and study of this subset in the TME [14, 102] is required to identify Breg specific targets that can be exploited to selectively deplete Breg populations but more fundamentally to fully understand the role of Bregs in human cancer. There are some current potential anti-Breg strategies. In vivo murine studies have displayed selective Breg depletion using LXA4 without affecting conventional B-cell proliferation, differentiation and germinal centre formation thus promoting anti-tumour responses [87]. An alternate to Breg depletion would be repolarisation of this subpopulation into B effector cells, as has been shown with TLR9 ligands in vitro [22, 23]. Adoptive transfer of CpG-pulsed B cells with effector phenotypes into patients with established cancer could be employed to shift the balance in favour of an anti-tumour B-cell response within the TME.

    More work is needed to understand the anti-tumour impact of antibodies against tumour associate antigens, particularly CTags which appear to be strong immunogens, and to identify new humoural immunity targets. The disappointing results of the MAGRIT trial vaccinating NSCLC patients in the adjuvant setting [103] should not be taken as suggesting that harnessing the anti-tumour antibody response should be deprioritised: mono-epitopic vaccination as cancer therapy has a long history of failure. Multi-valent vaccines, preferably against personalised B-cell antigens, are one option. Building on the model of the chimaeric antigen receptor T cells (CART), highly specific B-cell receptors to critical tumour antigens could be cloned into autologous B cells and transferred into patients with resultant high specificity and high affinity anti-tumour Ig production. Alternatively, antibodies could be produced ex vivo and adoptively transferred. Given the role of B-cell PD-1 expression in mediating B-cell hypo-responsiveness, the role of PD-1 blockade in augmenting these strategies should be explored, as a research priority. Understanding B-cell biology will help to refine the understanding behind the effects of checkpoint blockade on the immune milieu. Toxicity from these therapies is the Achilles heel of this treatment strategy. As was alluded to earlier, work in mice and humans has demonstrated that PD-L1 hi Bregs play a role in the suppression of humoral immunity through Tfh cell regulation moreover, these cells are resistant to classical anti-CD20 therapy [93]. Firmly understanding the ontogeny of these B cells and their relationship to other B-cell subsets, including other Breg phenotypes is of paramount importance if we hope to be able to refine therapeutic strategies so as to augment anti-tumour protective immunity and dampen down autoimmune and hence toxic responses.

    Finally, large scale prospective and careful B-cell sub-type specific and microenvironment segment specific analyses are required in lung cancer and in other cancers to clarify the role of B cells in modulating the responsiveness to checkpoint blockade and in mediating the toxicity to these therapies. These studies will define the role of B-cell-targeted strategies in augmenting the activity of, reducing resistance to and the ameliorating toxicity of this crucial class of anti-cancer agents.

    Watch the video: Βιολογία Α Λυκείου - Ομάδες αίματος και μεταγγίσεις (January 2022).