Chapter 10

The induced expression of CD40L on TFH cells activates CD40 on B cells to increase B-cell survival, and also induces B-cell expression of co-stimulatory molecules, especially those of the B7 family. Activated T cells also express ________, which binds to CD30 expressed on B cells and promotes B-cell activation.

CD30 ligand (CD30L)

Centroblasts proliferate in the dark zone of the germinal center, named for its densely packed appearance. Stromal cells in the dark zone produce ________ (SDF-1), a ligand for CXCR4 that acts to retain centroblasts in this region. As time goes on, some centroblasts reduce their rate of cell division, enter the growth phase, pausing at the G2/M phase of the cell cycle, reduce CXCR4 expression, and begin to produce higher levels of surface immunoglobulin. These B cells are termed ________.

CXCL12; centrocytes

_________ allows the selected B cells to produce antibodies with a variety of effector functions. These B cells will differentiate either into plasma cells that secrete higher-affinity and class-switched antibody in the latter part of the primary immune response, or into memory B cells.

Class switching

Bound antibody is distinguishable from free immunoglobulin by its state of aggregation.

1. Free immunoglobulin does not cross-link Fc receptors 2. Aggregation of immunoglobulin on bacterial surface allows cross-linking of Fc receptors

The surface immunoglobulin that serves as the BCR plays two roles in B-cell activation in response to pathogens:

1. Like the antigen receptor on T cells, the BCR initiates a signaling cascade upon binding antigens derived from the microbe. 2. In addition, the BCR can deliver the antigen to intra- cellular sites for antigen processing, so that antigenic peptides bound to MHC class II molecules can be returned to the B-cell surface.

Induction of SAP in TFH cells allows SLAM family receptors to mediate sustained contact with B cells.

1. Low levels of SAP in T cells prevent sustained contact with B cells 2. Bcl-6 expressed by TFH cells induces SAP, which sustains contact mediated by SLAM receptors

T cells and B cells must recognize antigens contained within the same molecular complex in order to interact.

1. Specific T cells are activated by antigens that may reside within the viral particle 2. B cell that recognizes a surface epitope of a virus can process and present other antigen epitopes Together 1 and 2--> Viral-specific TFH cell provides help to B cells that recognize a linked epitope

Linked recognition was originally discovered through studies of the production of antibodies against haptens, which are small chemical groups that cannot elicit antibody responses on their own. But haptens that are coupled to a carrier protein become immunogenic (provokes immune response)—known as the hapten carrier effect—for two reasons:

1. The protein can carry multiple hapten groups, allowing it to cross-link B-cell receptors. 2. Also, T cells that are activated against peptides of the carrier protein can become TFH cells and strengthen the antibody response to the hapten.

Mast cells are thought to serve at least three important functions in host defense:

1. Their location near body surfaces allows them to recruit both pathogen-specific elements, such as antigen-specific lymphocytes, and non-specific effector elements, such as neutrophils, macrophages, basophils, and eosinophils, to sites where infectious agents are most likely to enter the internal milieu. 2. The inflammation they cause increases the flow of lymph from sites of antigen deposition to the regional lymph nodes, where naive lymphocytes are first activated. 3. The ability of mast-cell products to trigger muscular contraction can contribute to the physical expulsion of pathogens from the lungs or the gut.

B-cell activation requires a second signal either by thymus-dependent or thymus-independent antigens

1. Thymus-dependent: P1 3-Kinase/ Ras/MAPK and NIK/ RelB/p100 2. Thymus-independent:P1 3-Kinase/ Ras/MAPK and MyD88 / IKKy(NEMO)

Antibodies contribute to immunity in three main ways:

1. neutralization 2. opsonization 3. complement activation

AID is related to enzymes that deaminate cytosine to uracil in making nucleotide precursors for RNA and DNA synthesis. Its closest homolog,___________, is an RNA-editing enzyme that deaminates cytosine in the context of RNA. However, AID fulfills its activity in antibody gene diversification by acting on cytosine in the DNA of the immunoglobulin locus. When AID deaminates cytidine residues in the immunoglobulin V regions, somatic hypermutation is initiated; when cytidine residues in switch regions are deaminated, class switch recombination is initiated.

APOBEC1 (apolipoprotein B mRNA editing catalytic polypeptide 1)

After a naive follicular B cell first encounters specific antigen displayed by FDCs or macrophages, within a few hours it will become positioned in the outer follicles of lymphoid tissue close to the sites where antigen enters the lymph node or spleen. This positioning is orchestrated by the B cell's expression of a chemokine receptor, ______ (GPR183), whose ligands are oxysterols such as 7a, 25-dihydroxycholesterol.

EBI2

(sum) Antibody-coated pathogens are recognized by effector cells through ________ that bind to an array of constant regions (Fc portions) provided by the pathogen-bound antibodies. Binding activates the cell and triggers destruction of the pathogen, through either phagocytosis, granule release, or both.

Fc receptors

The ________ are a family of cell-surface molecules that bind the Fc portion of immunoglobulins. Each member of the Fc family recognizes immunoglobulin of one or a few closely related heavy-chain isotypes through a recognition domain on the a-chain of the Fc receptor. Most Fc receptors are themselves members of the immunoglobulin gene superfamily. Different cell types bear different sets of Fc receptors, and the isotype of the antibody thus determines which types of cells will be engaged in a given response.

Fc receptors

The selective transport of IgG from mother to fetus is due to an IgG transport protein in the placenta, ________, which is closely related in structure to MHC class I molecules.

FcRn (neonatal Fc receptor)

B-cell activation by antigens on microbial surfaces can be greatly stimulated by the concurrent deposition of complement on these pathogens. The _________ contains the cell-surface proteins CD19, CD21, and CD81. When _____, or complement receptor 2 (CR2), binds to the complement fragments C3d and C3dg that are deposited on microbial surfaces, it is brought near to the activated B-cell receptor bound to the same surface. CD21 and CD19 are associated with each other, and CD19 becomes phosphorylated by the activated B-cell receptor. This recruits PI 3-kinase, which then stimulates several downstream pathways, enhancing proliferation, differentiation, and antibody production

B-cell co-receptor complex; CD21

Once in the follicle, naive B cells encounter the soluble TNF-family cytokine _______, which is secreted by FDCs, stromal cells, and dendritic cells and which acts as a survival factor for B cells. BAFF can act through three receptors but its major actions in promoting survival are through BAFF-R. BAFF-R signals through TRAF3 to activate the non-canonical NFkB pathway, as described for CD40, and, like CD40 signaling, induces expression of Bcl-2. Two other receptors for BAFF are TACI and BCMA, although BAFF has a relatively low affinity for BCMA. TACI and BCMA also bind the related cytokine APRIL, and they signal through TRAF2, 5, and 6 to induce signaling pathways involved in B-cell activation.

BAFF

When B cells have undergone affinity maturation and class switching, some eventually exit from the light zone and start to differentiate into plasma cells that produce large amounts of antibody. In B cells, the transcription factors Pax5 and _______ inhibit the expression of transcription factors required for plasma-cell differentiation, and both Pax5 and Bcl-6 are downregulated when the B cell starts differentiating. The transcription factor IRF4 then induces the expression of ________, a transcriptional repressor that switches off genes required for B-cell proliferation, class switching, and affinity maturation. B cells in which BLIMP-1 is induced become plasma cells; they cease proliferating, increase the synthesis and secretion of immunoglobulins, and change their cell-surface properties.

Bcl-6; BLIMP-1

(sum) The initial interaction between B and T cells occurs at the border of the T-cell and B-cell areas of secondary lymphoid tissue, to which antigen-activated helper T cells and B cells migrate in response to chemokines. Further interactions between T cells and B cells continue after migration into the follicle and the formation of a _________.

germinal center

Not all B cells activated by TFH cells will migrate to the outer follicle and eventually establish a primary focus. Instead, some move into a primary lymphoid follicle together with their associated TFH cells, where they continue to proliferate and ultimately form a _______; follicles with germinal centers are also called _____________.

germinal center; secondary lymphoid follicles

(sum) B-cell activation by many antigens requires both binding of the antigen by the B-cell surface immunoglobulin—the B-cell receptor—and interaction of the B cell with antigen-specific _________.

helper T cells

The fine tuning of antibody responses to increase the affinity of the antibody for the antigen and the switching to most immunoglobulin classes other than IgM depend on the interaction of antigen-stimulated B cells with _________ and other cells in the peripheral lymphoid organs.

helper T cells

Many antibodies that neutralize viruses do so by directly blocking the binding of virus to surface receptors. The _________ of influenza virus, for example, binds to terminal sialic acid residues on the carbohydrates of glycoproteins present on epithelial cells of the respiratory tract. It is known as " because it recognizes and binds to similar sialic acid residues on chicken red blood cells and agglutinates these red blood cells. Antibodies against the " can prevent infection by the influenza virus. Such antibodies are called _________, and, as with the neutralization of toxins, high-affinity IgA and IgG antibodies are particularly important.

hemagglutinin; virus-neutralizing antibodies

(sum) The high affinity receptor for IgE is expressed constitutively by mast cells and basophils. It differs from other Fc receptors in that it can bind free monomeric antibody, thus enabling an immediate response to pathogens at their site of first entry into the tissues. When IgE bound to the surface of a mast cell is aggregated by binding to antigen, it triggers the release of ________ and many other mediators that increase the blood flow to sites of infection; it thereby recruits antibodies and effector cells to these sites. Mast cells are found principally below epithelial surfaces of the skin and beneath the basement membrane of the digestive and respiratory tracts. Their activation by innocuous substances is responsible for many of the symptoms of acute allergic reactions.

histamine

(chapter sum) The ______ to infection involves the production of antibody by plasma cells derived from B lymphocytes, the binding of this antibody to the pathogen, and the elimination of the pathogen by phagocytic cells and molecules of the humoral immune system.

humoral immune response

Many pathogens multiply in the body's extracellular spaces, and even intracellular pathogens can spread by moving through the extracellular fluids. The extracellular spaces are protected by the ________, in which antibodies produced by B cells act to destroy extracellular microorganisms and their products, and prevent the spread of intracellular infections.

humoral immune response

Genetic deficiency of CD40 ligand greatly reduces class switching and causes abnormally high levels of plasma IgM, a condition known as __________. People with this defect lack antibodies of classes other than IgM and exhibit severe humoral immunodeficiency, manifested as repeated infections with common bacterial pathogens.

hyper IgM syndrome

The first antigen receptors expressed by B cells are IgM and IgD, and the first antibody produced in an immune response is always IgM. Later in the immune response, the same assembled V region may be expressed in IgG, IgA, or IgE antibodies. This change is known as class switching (or _______), and, unlike the expression of IgD, it involves irreversible DNA recombination. It is stimulated in the course of an immune response by external signals such as cytokines released by TFH cells.

isotype switching

(sum) Fc receptors comprise a family of proteins, each of which recognizes immunoglobulins of particular __________. -Fc receptors on macrophages and neutrophils recognize the constant regions of IgG or IgA antibodies bound to a pathogen and trigger the engulfment and destruction of such bacteria. Binding to the Fc receptor also induces the production of microbicidal agents in the intracellular vesicles of the phagocyte. -Eosinophils are important in the elimination of parasites too large to be engulfed; they bear Fc receptors specific for the constant region of IgG, as well as receptors for IgE; aggregation of these receptors triggers the release of toxic substances onto the surface of the parasite. -NK cells, tissue mast cells, and blood basophils also release their granule contents when their Fc receptors are engaged.

isotypes

For T-dependent antibody responses, the T cells involved are activated by the same antigen as is recognized by the B cells; this is called ________. However, the peptide recognized by the TFH cell is likely to differ from the protein epitope recognized by the B cell's antigen receptor.

linked recognition

Proliferating germinal center B cells displace the resting B cells toward the periphery of the follicle, forming a ______ of resting cells around the two distinguishable areas of activated B cells, called the ________ and the _______.

mantle zone; light zone; dark zone

The second class of thymus-independent antigens—TI-2 antigens—consists of molecules that have highly repetitive structures, such as bacterial capsular polysaccharides. These contain no intrinsic B-cell-stimulating activity. Whereas TI-1 antigens can activate both immature and mature B cells, TI-2 antigens can activate only mature B cells. Responses to several TI-2 antigens are prominently made by _________, a subset of nonrecirculating B cells that line the border of the splenic white pulp, and by B-1 cells

marginal zone B cells;

(chapter sum) IgM antibodies are produced early in an infection by conventional B cells and are also made in the absence of infection by subsets of nonconventional B cells in particular locations (as natural antibodies). IgM has a major role in protecting against infection in the bloodstream, whereas isotypes secreted later in an adaptive immune response, such as IgG, diffuse into the tissues. Antigens that have highly repeating antigenic determinants and that contain mitogens— called TI antigens—can elicit IgM and some IgG independently of T-cell help, and this provides an early protective immune response. Multimeric IgA is produced in the lamina propria and is transported across epithelial surfaces, whereas IgE is made in small amounts and binds avidly to receptors on the surface of basophils and ______.

mast cells

IgE antibody is present only at very low levels in blood or extracellular fluid, but is bound avidly by receptors on ______ that are found just beneath the skin and mucosa and along blood vessels in connective tissue.

mast cells

When pathogens cross epithelial barriers and establish a local focus of infection, the host must mobilize its defenses and direct them to the site of pathogen growth. One way in which this is achieved is to activate the cells known as ________. " are large cells containing distinctive cytoplasmic granules that contain a mixture of chemical mediators, including histamine, that act rapidly to make local blood vessels more permeable.

mast cells

A role for mast cells in the clearance of parasites is suggested by the accumulation of mast cells in the intestine, known as _________, that accompanies helminth infection, and by observations in W/WV mutant mice, which have a profound mast-cell deficiency caused by a mutation in the gene c-kit.

mastocytosis

Other germinal center B cells differentiate into ________. " cells are long-lived descendants of cells that were once stimulated by antigen and had proliferated in the germinal center. They divide very slowly if at all; they express surface immunoglobulin but secrete no antibody, or do so only at a low rate.

memory B cells

Peptide:MHC class II complexes are recognized by antigen-specific helper T cells that have already differentiated in response to the same pathogen. The effector T cells express surface molecules and cytokines that help the B cell to proliferate and to differentiate into antibody-secreting cells and into _______, and a structure called the germinal center is formed during an intermediate phase of the antibody response, before the emergence of long-term plasma cells that generate antibody or of memory B cells.

memory B cells

The uridine produced by AID represents a dual lesion in DNA; not only is uridine foreign to normal DNA, but it is now a mismatch with the guanosine nucleoside on the opposite DNA strand. The presence of uridine in DNA can trigger several types of DNA repair—including the ______ and ________ pathways—which further alter the DNA sequence. The various repair processes lead to different mutational outcomes.

mismatch repair; base-excision repair

(sum) Antibodies can defend the body against extracellular pathogens and their toxic products in several ways. The simplest is by direct interactions with pathogens or their products, for example, by binding to the active sites of toxins and _________ them or by blocking their ability to bind to host cells through specific receptors. When antibodies of the appropriate isotype bind to antigens, they can activate the classical pathway of complement, which leads to the elimination of the pathogen by the various mechanisms described in Chapter 2. Soluble immune complexes of antigen and antibody also fix complement and are cleared from the circulation via complement receptors on red blood cells.

neutralizing

To affect cells, many toxins consist of separate domains for exerting toxicity and for binding to specific cell-surface receptors by which they enter cells. Antibodies that bind a toxin's receptor-binding site can prevent cell entry and protect cells from attack. Antibodies that act in this way to neutralize toxins are referred to as _________.

neutralizing antibodies.

(chapter sum) Antibodies that coat pathogens bind to Fc receptors on phagocytes, which are thereby triggered to engulf and destroy the pathogen. Binding of antibody C regions to Fc receptors on other cells leads to the exocytosis of stored mediators; this is particularly important in parasite infections, in which Fc-epsilon-expressing mast cells are triggered by the binding of antigen to IgE antibody to release inflammatory mediators directly onto parasite surfaces. Antibodies can also initiate the destruction of pathogens by activating the complement system. Complement components can ________ pathogens for uptake by phagocytes, and recruit phagocytes to sites of infection. Receptors for complement components and Fc receptors often synergize in activating the uptake and destruction of pathogens and immune complexes. Thus, the humoral immune response is targeted to the infecting pathogen through the production of specific antibody; however, the effector actions of that antibody are determined by its heavy-chain isotype.

opsonize

(sum) -IgM antibodies are found mainly in blood; they are ______ in structure. IgM is specialized to activate complement efficiently upon binding antigen and to compensate for the low affinity of a typical IgM antigen-binding site. -IgG antibodies are usually of higher affinity and are found in blood and in extracellular fluid, where they can neutralize toxins, viruses, and bacteria, opsonize them for phagocytosis, and activate the complement system. -IgA antibodies are synthesized as monomers, which enter blood and extracellular fluids, or they are secreted as dimeric molecules by plasma cells in the lamina propria of various mucosal tissues. IgA dimers are selectively transported across the epithelial layer into sites such as the lumen of the gut, where they neutralize toxins and viruses and block the entry of bacteria across the intestinal epithelium. -Most IgE antibody is bound to the surface of mast cells that reside mainly just below the body surface; antigen binding to this IgE triggers local defense reactions.

pentameric

Each globular head of a C1q molecule can bind to one Fc region, and binding of two or more heads activates the C1 complex. In plasma, the ________ molecule has a planar conformation that does not bind C1q; however, binding to the surface of a pathogen deforms the IgM pen- tamer so that it looks like a staple, and this distortion exposes binding sites for the C1q heads.

pentameric IgM

Neisseria gonorrhoeae, the causative agent of the sexually transmitted disease gonorrhea, has a cell-surface protein known as _______ that enables the bacterium to adhere to the epithelial cells of the urinary and reproductive tracts and is essential to its infectivity. Antibodies against " can inhibit this adhesive reaction and prevent infection.

pilin

(chapter sum) The production of antibody usually requires the action of helper T cells specific for a peptide fragment of the antigen recognized by the B cell, a phenomenon called linked recognition. An activated B cell first moves to the T-zone-B-zone boundary in secondary lymphoid tissues, where it may encounter its cognate T cell and begin to proliferate. Some B cells become _________, while others move to the germinal center, where somatic hypermutation and class switch recombination take place. B cells that bind antigen with the highest affinity are selected for survival and further differentiation, leading to affinity maturation of the antibody response. Cytokines made by helper T cells direct class switching, leading to the production of antibody of various classes that can be distributed to various body compartments.

plasmablasts

B cells proliferate in the primary focus for several days, and this constitutes the first phase of the primary humoral immune response. Some of these proliferating B cells differentiate into antibody-synthesizing _______ in the primary focus. Not all B cells activated by the initial interaction with TFH cells will move into the primary focus. Some will migrate into the lymphoid follicle, where they may eventually differentiate into plasma cells, as described below. " are cells that have begun to secrete antibody, yet are still dividing and express many of the characteristics of activated B cells that allow their interaction with T cells. After a few more days, the " in the primary focus stop dividing and may eventually die.

plasmablasts

(sum) Somatic hypermutation diversifies the V region through the introduction of __________ that are selected for providing greater affinity for the antigen as the immune response proceeds. Class switching does not affect the V region but increases the functional diversity of immunoglobulins by replacing the C-mu region in the immunoglobulin gene, which is first expressed with another heavy-chain C region to produce IgG, IgA, or IgE antibodies. Class switching provides antibodies with the same antigen specificity but distinct effector capacities. The switching to different antibody isotypes is regulated by cytokines released from helper T cells.

point mutations

Sn consists of about 150 repeats of the sequence (GAGCT)n(GGGGGT), where n is usually 3 but can be as many as 7. The sequences of the other switch regions (S-gamma, S-alpha, and S-epsilon) differ in exact sequence but all contain repeats of the GAGCT and GGGGGT sequences. It appears that movement of RNA polymerase through this highly repetitive region is occasionally halted—called _________. This may be caused by bubble-like structures, called _________, that form when the transcribed RNA displaces the non-template strand of the DNA double helix due to having many G residues in tandem on one strand.

polymerase stalling; R-loops

IgA antibody synthesized in the lamina propria is secreted as a dimeric IgA molecule associated with a single J chain. This polymeric form of IgA binds specifically to a receptor called the ___________, which is present on the basolateral surfaces of the overlying epithelial cells. When the " has bound a molecule of dimeric IgA, the complex is internalized and carried in a transport vesicle through the cytoplasm of the epithelial cell to its luminal surface. This process is called transcytosis.

polymeric immunoglobulin receptor (pIgR)

Some bacterial pathogens have _________, a large structure that lies outside the bacterial cell membrane and resists direct engulfment by phagocytes. Such pathogens become susceptible to phagocytosis only when they are coated with antibodies and complement that engage the Fc-y or Fc-a receptors and the complement receptor CR1 on phagocytic cells, triggering bacterial uptake

polysaccharide capsules

At a region between the T-cell area and red pulp, B cells will form an emerging aggregate of differentiating B cells called the ________, which in lymph nodes is located in the medullary cords, where lymph drains out of the node, and in the spleen can be seen as extrafollicular foci in the splenic red pulp.

primary focus

IgM also binds to the pIgR and can be secreted into the gut by the same mechanism. Upon reaching the luminal surface of the enterocyte, the antibody is released into the mucous layer covering the gut lining by proteolytic cleavage of the extracellular domain of the pIgR. The cleaved extracellular domain of the pIgR is known as _________ (frequently abbreviated to SC) and remains associated with the antibody. " is bound to the part of the Fc region of IgA that contains the binding site for the Fc-alpha receptor I, which is why secretory IgA does not bind to this receptor. " serves several physiological roles. It binds to mucins in mucus, acting as 'glue' to bind secreted IgA to the mucous layer on the luminal surface of the gut epithelium, where the antibody binds and neutralizes gut pathogens and their toxins. " also protects the antibodies against cleavage by gut enzymes.

secretory component

In the base-excision repair pathway, the enzyme ________ removes the uracil base from the uridine to create an abasic site in the DNA. If no further modification is made, this will result at the next round of DNA replication in the random insertion of a nucleotide opposite the abasic site by DNA polymerase, leading to mutation. The action of UNG may, however, be followed by the action of another enzyme, ________, which excises the abasic residue to create a single-strand discontinuity (known as a single-strand nick) in the DNA at the site of the original cytidine.

uracil-DNA glycosylase (UNG); apurinic/apyrimidinic endonuclease 1 (APE1)

B cells begin to emerge during the first 4-5 days of an immune response. Plasmablasts in primary foci primarily secrete antibodies of the IgM isotype that offer some immediate protection. In contrast, B cells in the germinal center reaction undergo several processes that produce antibodies that are more effective in eliminating infections. These processes include _________, which alters the V regions of immunoglobulin genes (see below), and which enables a process called __________, which selects for the survival of mutated B cells that have a high affinity for the antigen.

somatic hypermutation; affinity maturation

Naive T cells and B cells express the ___________, which they use to egress from the peripheral lymphoid tissues.

sphingosine 1-phosphate receptor, S1PR1

Opsonized particulate antigens can also be taken up by specialized macrophages residing in the _______ of lymph nodes and the ________ of the spleen, regions that are both adjacent to the B-cell follicles. These macrophages seem to retain the antigen on their surface rather than ingesting and degrading it. These antigens can then be sampled and carried by antigen-specific follicular B cells.

subcapsular sinus (SCS); marginal sinus

(sum) Helper T cells recognize peptide fragments derived from the antigen internalized by the B cells and displayed by the B cells as peptide:MHC class II complexes. ____________ stimulate B cells by conjugation in germinal centers, with binding of CD40 ligand on the T cell to CD40 on the B cell, and by their release of cytokines, such as IL-21. Activated B cells also express molecules, such as ICOSL, that can stimulate T cells.

Follicular helper T cells

This RNA is processed to generate an RNA structure, called a _________, that is based on the G-rich repetitive element of the switch region. This G-quadruplex serves a dual purpose, both binding to AID and also associating with the switch region from which it was transcribed, based on its sequence complementarity.

G-quadruplex

Activated B cells express ________, a member of the B7 family of co-stimulatory molecules and a ligand for ________ (inducible co-stimulatory protein), which is expressed by T cells. This T- and B-cell interaction, provided by linked recognition, activates "" signaling in T cells and is important for the completion of TFH differentiation, leading to induction of the transcription factors Bcl-6 and c-Maf. These transcription factors are required for SAP production and the consequent sustained contact between B and TFH cells.

ICOSL; ICOS

TFH cells also secrete several cytokines that regulate B-cell proliferation and antibody production. Primary among these is ______, which is produced early in immune responses by TFH cells and which activates the transcription factor ______ in B cells to support proliferation and differentiation. IL-21 exerts similar autocrine effects on TFH cells.

IL-21; STAT3

(sum) The T-cell-dependent antibody response begins with _____ secretion but quickly progresses to the production of additional antibody classes. Each class is specialized both in its localization in the body and in the functions it can perform.

IgM

class switching involves recombination between specific swithc signals

Last two steps: 4. DSBR machinery joins the two switch regions and excises intervening sequences 5. The selected constant region is now located adjacent to the VDJ region

In the mismatch repair pathway, the presence of uridine is detected by the mismatch repair proteins _________. They recruit nucleases that remove the complete uridine nucleotide along with several adjacent nucleotides from the damaged DNA strand. This is followed by a all-in 'patch repair' by a DNA polymerase; unlike the process in all other cells, in B cells this DNA synthesis is error-prone and tends to introduce mutations at nearby A:T base pairs.

MSH2 and MSH6 (MSH2/6)

_______ have relatively fewer mutations than usual at A:T, but not at C:G, in their hypermutated immunoglobulin V regions. This fact suggests that " is the repair polymerase involved in this pathway of somatic hypermutation. These individuals also have a form of ________, a condition resulting from the inability of their cells to repair DNA damage caused by UV radiation.

Poln; xeroderma pigmentosum

Polymerase stalling seems closely connected with the recruitment of AID to specific switch regions being transcribed. A multisubunit RNA processing/degradation complex, the ________, associates with AID and accumulates on transcribed switch regions, and the protein _____ associates with the stalled polymerase; both are necessary for AID to generate double-stranded breaks.

RNA exosome; Spt5

The cytoplasmic regions of these SLAM family receptors all interact with an adaptor protein, ________, which is expressed highly by TFH cells and which is necessary for prolonging cell-cell contact mediated by these receptors. The " gene is inactivated in _________, which is associated with a T-cell and NK-cell lymphoproliferative disorder and with a defect in antibody production due to failed interactions between TFH cells and B cells in the germinal center. The regulated migration of activated B cells and TFH cells to the same location in the peripheral lymphoid organ increases the chance that linked recognition will occur and deliver appropriate help for B-cell differentiation.

SAP (SLAM-associated protein); X-linked lymphoproliferative syndrome

The ability of TFH cells to successfully deliver these signals to B cells depends on intimate contact between these cells. Specific adhesion molecules, including several Ig superfamily receptors of the _________ family, are involved that prolong and stabilize cell-cell contact. TFH cells and B cells both express SLAM (CD150), CD84, and Ly108, which promote cell adhesion through homotypic binding interactions

SLAM (signaling lymphocyte activation molecule)

In the example of class switching shown when transcription through the Sİ regions caused the rearrangement between the S-mu and S-epsilon regions, making the IgE isotype antibody. This results because IL-4 signaling activates the transcription factor ________, which initiates transcription of the Iİ promoter upstream of the Sİ region. Other cytokines activate other promoters upstream of other switch regions to produce other antibody classes. TFH cells also produce IL-21, which promotes switching to IgG1 and IgG3.

STAT6

Protein antigens alone are unable to induce antibody responses in animals or humans who lack T cells, and they are therefore known as _____________, and typically involve antigen-specific T-cell help. The T cells involved are TFH cells that reside in the lymphoid tissues and are not fully differentiated TH1, TH2, or TH17 effector cells. These signals include the activation of CD40 on B cells by TFH expression of its ligand, CD40L (CD154), and production of various cytokines by TFH cells, including IL-21. CD40 signaling activates the non-canonical NFkB pathway and enhances B-cell survival by inducing the expression of anti-apoptotic molecules such as Bcl-2.

thymus-dependent/TD antigens

(sum) Some nonprotein antigens stimulate B cells in the absence of linked recognition by peptide-specific helper T cells. Responses to these __________ antigens are accompanied by only limited class switching and do not induce memory B cells. However, such responses have a crucial role in host defense against pathogens whose surface antigens cannot elicit peptide-specific T-cell responses.

thymus-independent

Some microbial antigens can provoke antibody production with- out T-cell help, but activation of naive B cells by antigens usually involves help from _________. Activated B cells then differentiate into antibody-secreting ________ and ________.

T follicular helper (TFH) cells; plasma cells; memory B cells

Before B and T cells exit the peripheral lymphoid tissues, they are retained and initially occupy two distinct zones, the _______ and the ________ (or B-cell areas or B-cell zones), respectively. These zones are established by different patterns of chemokine receptor expression and chemokine production.

T-cell areas; primary lymphoid follicles

Thymus-independent antigens fall into two classes, TI-1 and TI-2, which activate B cells by two different mechanisms. TI-1 antigens rely on activity that can directly induce B-cell division without T-cell help. We now understand that _____ contain molecules that cause the proliferation and differentiation of most B cells regardless of their antigen specificity; this is known as _________. TI-1 antigens are therefore often called _________, a mitogen being a substance that induces cells to undergo mitosis.

TI-1 antigens; polyclonal activation; B-cell mitogens

Antibody-coated viruses that enter the cytoplasm are cleared by a system that employs a novel class of Fc receptor called ________ that is expressed by a variety of immune and nonimmune cell types. " is a cytosolic IgG receptor that has a higher affinity for IgG than any other Fc receptor, and it also has E3 ligase activity. When a virus that has bound IgG enters the cytoplasm, " attaches to the antibody and uses its E3 ligase activity to ubiquitinate viral proteins. This leads to proteasomal degradation of virions in the cytosol before translation of virally encoded genes can occur.

TRIM21 (tripartite motif-containing 21)

While B-cell responses to protein antigens rely on help from T cells, some microbial constituents can induce antibody production in the absence of helper T cells. These microbial antigens are known as __________ because they can induce antibody responses in individuals who have no T lymphocytes. Such antigens are typically highly repetitive molecules, such as the polysaccharides of bacterial cell walls, and can cross-link the BCR on B cells. In such cases, a second signal can be derived from direct recognition of a common microbial constituent such as LPS that can activate TLR signaling in the B cell, activating the ________.

thymus-independent/TI antigens; NFkB pathway

Germinal centers are filled with apoptotic B cells that are quickly engulfed by macrophages, giving rise to the characteristic _______ macrophages. These contain dark-staining nuclear debris in their cytoplasm.

tingible body

The immunodeficiency disease ___________ is caused by defects in T cells that impair their interaction with B cells. Patients with " respond poorly to protein antigens, but, unexpectedly, also fail to make IgM and IgG antibody against polysaccharide antigens and are highly susceptible to infection with encapsulated bacteria such as H. influenzae.

Wiskott-Aldrich syndrome

A splice variant of _____________ is expressed in plasma cells and helps to regulate their secretory capacity. Plasma cells in bone marrow receive signals from stromal cells that are essential for their survival, and they can be very long lived, whereas plasma cells in the medullary cords or red pulp are not long lived.

XBP1 (X-box binding protein 1)

Diphtheria and tetanus toxins are two bacterial toxins in which the toxic and receptor-binding functions are on separate protein chains. It is therefore possible to immunize individuals, usually as infants, with modified toxin molecules in which the toxic chain has been denatured. These modified toxins, called _____, lack toxic activity but retain the receptor-binding site. Thus, immunization with the toxoid induces neutralizing antibodies that protect against the native toxin.

toxoids

Another important defense mechanism besides neutralization is the activation of a variety of __________ bearing receptors called Fc receptors because they are specific for the Fc portion of antibodies. These receptors facilitate the phagocytosis of antibody-bound extracellular pathogens by macrophages, dendritic cells, and neutrophils.

accessory effector cells

(sum) T cells induce a phase of vigorous B-cell proliferation in the germinal center reaction and direct the differentiation of clonally expanded B cells into either antibody-secreting plasma cells or memory B cells. Immunoglobulin genes expressed in B cells are diversified in the germinal center reaction by somatic hypermutation and class switching, initiated by __________. Unlike V(D)J recombination, these processes occur only in B cells.

activation-induced cytidine deaminase (AID)

The enzyme AID is important for both somatic hypermutation and class switch recombination, as mice lacking AID have defects in both processes. People with mutations in the AID gene that inactivate the enzyme—that is, have ___________—also lack both somatic hypermutation and class switching. This condition leads to the production of predominantly IgM antibodies and the absence of affinity maturation, a syndrome known as _________.

activation-induced cytidine deaminase deficiency (AID deficiency); hyper IgM type 2 immunodeficiency

Somatic hypermutation introduces mutations that change anywhere from one to a few amino acids in the immunoglobulin, producing closely related B-cell clones that differ subtly in specificity and antigen affinity. These mutations in the V genes are initiated by an enzyme called ________________, which is expressed only by germinal center B cells.

activation-induced cytidine deaminase, AID

Many bacteria have cell-surface molecules called ________ that enable them to bind to the surface of host cells. This adherence is crucial to the ability of these bacteria to cause disease, whether they subsequently enter the cell, as do Salmonella species, or remain attached to the cell surface as extracellular pathogens.

adhesins

Most antibody responses undergo a process called __________, in which antibodies of greater affinity for their target antigen are produced by the somatic hypermutation of antibody variable-region (V-region) genes.

affinity maturation

As well as innate function, NK cells can recognize and destroy antibody-coated target cells in a process called _______________. This is triggered when antibody bound to the surface of a cell interacts with Fc receptors on the NK cell. NK cells express the receptor FcyRIII (CD16), which recognizes the IgG1 and IgG3 subclasses. The killing mechanism is analogous to that of cytotoxic T cells, involving the release of cytoplasmic granules containing perforin and granzymes.

antibody-dependent cell-mediated cytotoxicity (ADCC)

Neutralizing antibodies are generated by immunizing other species, such as horses, with insect and snake venoms to produce anti-venom antibodies, or ________. The " are injected into exposed individuals to protect them against the toxic effects of the venom. Transfer of antibodies in this way is known as _____________.

antivenins; passive immunization

Animal viruses infect cells by binding to a particular cell-surface receptor. These are often cell-type-specific proteins that determine which cells a virus can infect, or its _______.

tropism

Class switching is sometimes impaired in the disease _________, which is caused by mutations in the DNA-PKcs-family kinase ATM, a known DNA repair protein.

ataxia telangiectasia

An important class of TI-2 antigens arises during infection by _________.

capsulated bacteria

B cells in the germinal center divide rapidly, every 6-8 hours. Initially, these rapidly proliferating B cells, called _________, express the chemokine receptors CXCR4 and CXCR5 but markedly reduce their expression of surface immunoglobulin, particularly of IgD.

centroblasts

Switching from IgM to the other immunoglobulin classes occurs only after B cells have been stimulated by antigen. It is achieved through _______, which is a type of nonhomologous DNA recombination that is guided by stretches of repetitive DNA known as switch regions. Switch regions lie in the intron between the JH gene segments and the C-mu gene, and at equivalent sites upstream of the genes for each of the other heavy-chain isotypes, with the exception of the mu gene, which does not require DNA rearrangement for its expression

class switch recombination

The molecular mechanism of somatic hypermutation and its immunological consequences, as well as __________—a process that generates the different classes of antibodies that confer functional diversity on the antibody response- as well as affinity maturation occur only in B cells and require T-cell help.

class switching

Complement activation can proceed in the absence of antibody via the lectin pathway through the actions of mannose-binding lectin (MBL) and ficolins. But complement is also an important effector of antibody responses via the __________. The different pathways of complement activation converge to coat pathogen surfaces or antigen:antibody complexes with covalently attached complement fragment C3b, which acts as an opsonin to promote uptake and removal by phagocytes. In addition, the terminal complement components can form a membrane-attack complex that damages some bacteria.

classical pathway

Successful B cells will reexpress CXCR4 and return to the dark zone, where they will undergo additional rounds of division, in effect becoming centroblasts again. Germinal center B cells that fail to acquire sufficient antigen from FDCs to engage TFH cells will become apoptotic and be lost. This process of B-cell migration within the germinal center is known as the __________.

cyclic reentry model

Somatic hypermutation involves both mutation at the original cytidines targeted by AID and mutation at nearby non-cytidine nucleotides. If the original U:G mismatch is recognized by UNG, then an abasic site will be generated in the DNA. If no further modification is made to this site, it can be replicated without instructive base pairing from the template strand by a class of ________ that normally repair gross damage to DNA, such as that caused by ultraviolet (UV) radiation.

error-prone 'translesion' DNA polymerases

Naive T cells express the chemokine receptor CCR7, and localize to zones where its ligands, CCL19 and CCL21, are highly expressed by stromal cells and dendritic cells. Circulating naive B cells express CXCR5, and when they migrate into lymphoid tissues, they enter the primary lymphoid follicles, where the chemokine CXCL13 is abundant. Within the follicle, stromal cells and a specialized cell type, the _________, secrete CXCL13. The FDC is a nonphagocytic cell of nonhematopoietic origin that bears numerous long processes; it functions by trapping antigen using complement receptors on its cell surface for access by B cells in the follicle.

follicular dendritic cell (FDC)