Immuno

Identify the correct pairing of recombination signal sequences (RSSs) during somatic recombination at a light-chain locus for the J segment shown. Sequences are shown in the 5′ to 3′ direction from V to J.

(V) 7-23-9 9-12-7 (J) Recombination is possible only between two different types of RSSs and must follow the 12/23 rule. The first type contains a conserved heptamer sequence (7) and a conserved nonamer sequence (9) separated by a 12-bp spacer. The second type also contains the conserved heptamer and nonamer sequences, but they are separated by a 23-bp spacer. The heptamer sequence always flanks the gene segment undergoing recombination. Therefore, the heptamers must flank the 3′ end of the V segment and the 5′ end of the J segment.

Where does the degradation of extracellular pathogens occur? A. in endocytic vesicles and lysosomes B. on the cell surface by MHC molecules C. in the cytoplasm D. in the extracellular spaces of infected tissue

A. in endocytic vesicles and lysosomes Pathogens present outside human cells are first phagocytosed and then degraded by proteases in the endocytic vesicles and lysosomes of the phagocyte.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which damage to small blood vessels occurs when immune complexes of self antigens and autoreactive antibodies form and deposit there. The self antigens include DNA, RNA, and components of nucleoprotein particles. Which of the following explains why self-reactive B cells in SLE have escaped immunological tolerance? XIncorrect choiceIndividuals with SLE have an immunodeficiency that disrupts self-tolerance.Self-tolerance operates only in the early years of one's lifetime. √Correct choiceSelf-tolerance is readily induced to accessible self antigens, but not to inaccessible self antigens.Self-tolerance is not efficient when self antigens are abundant and systemically distributed.

Accessible self antigens, such as those expressed on the cell surface or circulating in the blood plasma, mediate efficient self-tolerance. Inaccessible self antigens, including those sequestered inside plasma or nuclear membranes, are not normally available to purge self-reactive B cells.

A B cell is undergoing a test for reactivity to self antigen. The two potential outcomes of this test are shown. Drag the labels to the panel where the listed event is occurring.

Allelic exclusion occurs after a functional antigen receptor has been generated. During receptor editing, allelic exclusion occurs only on the light-chain gene that produces a functional light-chain protein.Central and peripheral tolerance work in concert to ensure that self-reactive B cells are eliminated and only self-tolerant B cells are able to perform effector functions. When these mechanisms fail, autoimmunity can arise leading to diseases like systemic lupus erythematosus.

Which of the following describes the location of the T-cell receptor δ-chain gene? A. on chromosome 14, but distant from the α-chain locus B. within the α-chain locus on chromosome 14 between the Vα and Jα gene segments C. within the β-chain locus on chromosome 7 between the Dβ1 and Jβ1 gene segments D. within the γ-chain locus between the Jγ and Cγ gene segments on chromosome 7

B. within the α-chain locus on chromosome 14 between the Vα and Jα gene segments Chromosome 14 contains the loci for the T-cell receptor α-chain and δ-chain genes. The δ-chain locus is embedded between the V and J segments of the α-chain locus.

Which of the following is associated with a loss-of-function defect in Bruton's tyrosine kinase (BTK)?

BTK is encoded on the X chromosome and when deficient causes X-linked agammaglobulinemia (XLA). Carrier females are able to make B cells. Therefore, XLA is an X-linked recessive disease more prevalent in males.BTK is essential for the development of B cells. In individuals with X-linked agammaglobulinemia (XLA), the B cells arrest their development at the pre-B-cell stage. As these cells are unable to continue through development, they die via apoptosis.

Page 1395.4. Contrast the intracellular loading compartments and the features of the peptides bound by MHC class I and MHC class II molecules. What is the reason why MHC molecules are able to bind a variety of peptides? √Correct choiceA small number of amino acids in the peptide bind specifically to complementary pockets in the MHC molecule's peptide-binding groove.XIncorrect choiceThe peptide-binding groove of a given MHC molecule can bind to several peptides simultaneously. XIncorrect choiceThey bind very loosely and transiently to peptide antigens, so that a very large array of peptides can bind to any given MHC molecule.The MHC genes undergo somatic recombination to produce thousands of different MHC molecule variants.

Because only a couple of amino acids specifically anchor the peptide to the MHC molecule through stable noncovalent forces, the rest of the peptide sequence can vary. Therefore, a given MHC molecule can bind thousands of different peptides. This property is known as promiscuous specificity.

Page 1395.3. Explain the structure and function of the two classes of MHC molecules in antigen recognition by T cells. What best describes the binding of the CD4 and CD8 co-receptors to MHC molecules? The CD4 and CD8 co-receptors compete with the T-cell receptor for access to the peptide-binding site.The CD8 co-receptor can bind to either MHC class I or MHC class II. √Correct choiceThe CD4 and CD8 co-receptors bind at locations distinct from the peptide-binding site.XIncorrect choiceThe CD4 co-receptor is expressed on antigen-presenting cells and binds to the T-cell receptor of helper T cells.

Binding of CD4 to the β2 domain of MHC class II and binding of CD8 to the α3domain of MHC class I allow MHC molecules to simultaneously engage with a T-cell receptor and co-receptor.

What best describes the binding of the CD4 and CD8 co-receptors to MHC molecules? A. The CD4 co-receptor is expressed on antigen-presenting cells and binds to the T-cell receptor of helper T cells. B. The CD4 and CD8 co-receptors compete with the T-cell receptor for access to the peptide-binding site. C. The CD8 co-receptor can bind to either MHC class I or MHC class II. D. The CD4 and CD8 co-receptors bind at locations distinct from the peptide-binding site.

C. The CD8 co-receptor can bind to either MHC class I or MHC class II.√Correct choice Binding of CD4 to the β2 domain of MHC class II and binding of CD8 to the α3 domain of MHC class I allow MHC molecules to simultaneously engage with a T-cell receptor and co-receptor.

Within light-chain V domains of different antibodies, sequence differences can be found in V gene segments and at the junction between V and J gene segments. Which of the following contribute to sequence differences only in V gene segments?

CDR1 and CDR2 are two of the hypervariable regions in light-chain V domains that contribute to the specificity of antigen-binding sites and their diversity. They are both encoded within the selected V gene segment. The third hypervariable region, CDR3, also contributes to antibody specificity, but CDR3 diversity is generated at the junction between V and J segments in the light chain.

Page 1545.7. Describe the organization of and genes found within the HLA complex. Individuals with aberrant CIITA function do not express which of the following? √Correct choiceHLA class II moleculesTAP peptide transporter HLA class I heavy chainsthe immunoproteasome

CIITA is a transcriptional activator called the MHC class II transactivator. It is induced by IFN-γ and is required for the expression of all MHC class II isotypes in addition to the invariant chain. In its absence, HLA class II molecules are not produced, and helper T cells are unable to be stimulated.

Which of the following are correct statements regarding antigen processing? A. Pathogen proteins must be degraded to simpler forms to generate antigens for T-cell recognition. B. Antigen processing is restricted to material taken into the cell from extracellular locations C. T-cell receptors interact with pathogen proteins that retain their three-dimensional structure D. Phagocytic cells generate antigens from extracellular pathogens for T-cell recognition.

Correct: A. Pathogen proteins must be degraded to simpler forms to generate antigens for T-cell recognition. D. Phagocytic cells generate antigens from extracellular pathogens for T-cell recognition. Protein degradation by proteases produces the peptides that are recognized by T-cell receptors. Phagocytic cells such as macrophages and dendritic cells provide a major source of antigenic peptides following the uptake of pathogens and the breakdown of their proteins. Incorrect: C. T-cell receptors interact with pathogen proteins that retain their three-dimensional structure B. Antigen processing is restricted to material taken into the cell from extracellular locations Antigenic peptides are small linear protein fragments. The three-dimensional structure of a protein is lost when it is degraded during antigen processing. Proteins associated with both extracellular and intracellular infectious agents are subject to antigen processing. (both viral from interior and bacterial from exterior)

Which of the following statements explain why immunodeficiency is observed in individuals lacking either CD3δ or CD3ε? A. Their T cells fail to undergo somatic recombination. B. Their T cells make many fewer T-cell receptors compared with normal T cells. C. The efficiency of T-cell signal transduction is compromised. D. Their T-cell receptors are unable to bind antigen.

Correct: B. Their T cells make many fewer T-cell receptors compared with normal T cells. C. The efficiency of T-cell signal transduction is compromised. CD3δ and CD3ε help to transport T-cell receptors to the cell surface. In their absence, fewer T-cell receptors make it to the surface. CD3δ and CD3ε are part of the T-cell receptor complex and are required for efficient transduction of signals to the cytoplasm following antigen binding to the T-cell receptor. Incorrect: D. Their T-cell receptors are unable to bind antigen. A. Their T cells fail to undergo somatic recombination. Their T-cell receptors make it to the cell surface, albeit in much lower numbers compared with normal T cells, and they retain their ability to bind antigen. CD3δ and CD3ε associate with the T-cell receptor after somatic recombination has occurred.

T-cell receptors have many properties in common with immunoglobulins. Which of the following are properties shared with immunoglobulins?

Correct: The T-cell receptor resembles a membrane-bound Fab fragment of an immunoglobulin; each chain has a V region and a C region. Immunoglobulins and T-cell receptors are both antigen-binding receptors. They both contain an antigen-binding site in the variable region (V region). The T-cell receptor α- and β-chain loci have a germline configuration similar to that of the immunoglobulin heavy- and light-chain genes; they undergo recombination during T-cell development to produce functional genes. Incorrect: Unlike immunoglobulins, which consist of four polypeptide chains, T-cell receptors have only two. Unlike immunoglobulins, which have a membrane-bound form (the B-cell receptor) and a secreted form (antibody), T-cell receptors are always bound to the T-cell surface.

Page 1676.2. Relate the rearrangement of immunoglobulin heavy-chain and light-chain genes to the stages of B-cell development and the two developmental checkpoints. Assume that an early pro-B cell has productively rearranged D to J segments on both chromosomes. What happens if there is then a nonproductive V-DJ rearrangement of the heavy-chain locus on the first chromosome? The pro-B cell is signaled to die by apoptosis.Terminal deoxynucleotidyl transferase (TdT) adds additional nucleotides at the junctions between V and D. XIncorrect choiceA second rearrangement occurs on the first chromosome involving only V and J segments.√Correct choiceRearrangement of V-DJ occurs on the second chromosome.

D-J rearrangements occur first on both chromosomes in early pro-B cells. Then V-DJ rearrangement occurs on only one chromosome in late pro-B cells. If the V-DJ rearrangement is nonproductive, then the second chromosome undergoes V-DJ rearrangement. Productive V-DJ rearrangement on either chromosome signals survival to the pre-B-cell stage. Nonproductive rearrangements on both chromosomes signal apoptosis.

Where do MHC class I molecules bind to peptide antigens? A. in lysosomes B. on the surface of cytotoxic T cells C. after traveling to the cell surface of antigen-presenting cells D. in the endoplasmic reticulum

D. in the endoplasmic reticulum Peptides generated by cytosolic proteases bind to MHC class I molecules after they are delivered to the endoplasmic reticulum. Only after binding to peptide can MHC class I molecules progress to the cell surface.

Which component of MHC molecules is soluble? A. MHC class II β chain B. MHC class I α chain C. MHC class II α chain D. β2-microglobulin

D. β2-microglobulin β2-microglobulin is not membrane bound but forms a noncovalent association with MHC class I α chain to allow for stable expression of peptide-bearing MHC class I molecules on the cell surface.

Match each item with either HLA-A or HLA-DQ.

HLA-A is an MHC class I molecule consisting of a highly polymorphicheavy chain called α, and a monomorphic β chain called β2-microglobulin. HLA-DQ is an MHC class II molecule containing two polymorphic chains, α and β.

Which domains exhibit the highest degree of polymorphism between members of the HLA-B isotype? α2 and α3α1 and β1 β1 and β2√Correct choiceα1 and α2

HLA-B is a highly polymorphic MHC class I molecule, made up of a nonvariant β2-microglobulin chain and a variant α chain containing three domains, α1, α2, and α3. The peptide-binding groove is composed of α1 and α2 domains, and allotype variability is clustered in this location. The amino acid substitutions affect interaction with peptide and T-cell receptors.

Which of the following are correct statements regarding antigen presentation? Correct Answer(s) An MHC molecule, like an immunoglobulin, is able to bind to more than one antigen simultaneously.Press Space to openCorrect AnswerIncorrect Answer Antigen-specific T-cell receptors require antigenic peptides to be presented by MHC molecules on the cell surface.Press Space to openCorrect AnswerIncorrect Answer MHC molecules are delivered to the cell surface first, and then bind antigenic peptides.Press Space to openCorrect AnswerIncorrect Answer MHC molecules on the cell surface have peptide bound to them.Press Space to openCorrect AnswerIncorrect Answer Incorrect Answer(s)

If MHC molecules are present on the cell surface, they must be bound to peptide antigens. This is because an MHC molecule can travel to the cell surface only after binding to a peptide. Unlike a B-cell receptor, which binds directly to its soluble or cell bound-specific antigens, a T-cell receptor can recognize and bind to only a complex of a peptide antigen and an MHC molecule presented to it on the surface of an antigen-presenting cell. An MHC molecule can bind only one peptide antigen at a time.

Which of the following are correct statements about anergic immature B cells?

IgD expression remains and is found on the cell surface in anergic cells. While the IgM protein is still expressed, it primarily remains in the cell and not on the surface Anergic cells have a half-life of 1-5 days compared to the 40-day half-life of a non-anergic, mature B cell.In response to monovalent self antigens and following the induction of an anergic state, immature B cells are signaled to make IgD and express it on the cell surface; however, IgM fails to assemble a functional B-cell receptor and is largely retained in the cell. These cells have short half-lives and are inactive. Anergic cells are inactivated and nonresponsive. They will not activate at this point.

Which of the following are present on the surface of naive B cells?

IgG is not found on the surface of naive B cells.Coexpression of IgM and IgD on naive B cells is the result of RNA processing. The Cμ and Cδ genes are the nearest to the rearranged VDJ region, and transcription initiated at the VH promoter extends through both of them. Differential cleavage, polyadenylation, and alternative splicing of this long primary transcript gives rise to the messenger RNAs for μ and δ heavy chains.

Which of the following are correct statements regarding the synthesis of Igα and Igβ polypeptides

Igα and Igβ combine with the surrogate light-chain components (VpreB and λ5) to form the pre-B-cell receptor, and with the regular light-chain component (κ or λ) to form the B-cell receptor. Unlike the surrogate light-chain components, which are no longer made after the pro-B-cell stage, Igα and Igβ are made at all stages of B-cell development.Igα/Igβ are part of the signaling complex that allows a B-cell receptor to transmit signals to the nucleus.

Which of the following are correct statements about antigen processing in the absence of infection?

MHC class I and class II molecules traffic continuously to the cell surface though the Golgi apparatus whether an infection is present or not. If pathogens are not present, the peptides presented derive from self proteins. The peptides of incorrectly folded human (self) proteins undergoing cytosolic degradation are pumped into the lumen of the endoplasmic reticulum, where they bind to MHC class I molecules. This process operates whether an intracellular infection is ongoing or not. Likewise, MHC class II molecules bind self peptides in the absence of extracellular infection. For MHC class II, peptide binding occurs in a compartment that connects the endocytic and exocytic pathways.

Page 1515.6. Explain how human MHC diversity is achieved. Complete the passage with the terms provided. MHC gene products encoded by the multiple genes belonging to the MHC class I or class II gene families are called -Press Space to openoligomorphichighly polymorphicisotypesallotypes, whereas alternative versions of particular MHC genes are called -Press Space to openoligomorphichighly polymorphicisotypesallotypes. For instances where there are many versions of a particular MHC gene, that gene is considered -Press Space to openoligomorphichighly polymorphicisotypesallotypes, whereas when only one version of a particular MHC gene exists, it is called monomorphicmonomorphic.

MHC gene products encoded by the multiple genes belonging to the MHC class I or class II gene families are called isotypes, whereas alternative versions of particular MHC genes are called allotypes. For instances where there are many versions of a particular MHC gene, that gene is considered highly polymorphic, whereas when only one version of a particular MHC gene exists, it is called monomorphic. An isotype describes an MHC gene product encoded at a particular locus on chromosome 6 within the MHC. Humans have six MHC class I isotypes and five MHC class II isotypes. Many, but not all, isotypes are highly polymorphic with numerous alleles encoding different allotypes. For example, the MHC class I heavy chains of HLA-A, B, and C are highly polymorphic, but the MHC class I heavy chainof HLA-F is monomorphic.

Which of the following are correct statements regarding T lymphocytes?

MHC molecules are bound to the plasma membrane of antigen-presenting cells. They are not secreted. Immunoglobulins can bind to epitopes of proteins, carbohydrates, and lipids, whereas T-cell receptors bind primarily to peptide antigens bound to an MHC molecule.

Page 1796.6. Describe the mechanisms that ensure self-tolerance of B cells. An immature B cell will continue to rearrange its light-chain loci until which of the following occurs?

Once a B-cell receptor is expressed that does not have specificity for multimeric self antigens, rearrangement of the light-chain locus stops, and then the immature B cell moves out of the bone marrow to continue its maturation.Once a B-cell receptor is expressed that does not have specificity for multimeric self antigens, rearrangement of the light-chain locus stops, and then the immature B cell moves out of the bone marrow to continue its maturation. Only immature B cells bearing non-self-reactive receptors are permitted to leave the bone marrow. Therefore, light-chain gene rearrangement stops prior to cells' arrival at secondary lymphoid organs. IgM is made from the second checkpoint onward at the small pre-B-cell stage. IgD, produced by alternative splicing of the heavy-chain mRNA, appears at the immature B-cell stage after functional μ chains have been assessed for their inability to react with a multivalent self antigen.Receptor editing allows B cells a chance to rearrange their light chains in order to become self-tolerant and avoid being deleted. Once a self-tolerant antigen receptor is successfully made, the B cell ceases the receptor-editing process and moves into the periphery. The B cell can retry this process until it has exhausted its V and J segments on the genome. When all V and J segments have been used and the B cell is still self-reactive, the B cell dies through apoptosis.

What is the main difference between the additional P nucleotides and N nucleotides during the antibody gene segment recombination process?

P nucleotides are templated, whereas N nucleotides are not (they are random). P nucleotides rely on the unequal opening of hairpin loops in the DNA, giving a bit of DNA template to read and match as the overhang is repaired.

Why are the immunoglobulin loci in non-B cells transcriptionally silent? Antigen recognition by and signal transduction through the B-cell receptor does not occur.Gene rearrangement of these loci has not occurred. Non-B cells do not express components of the surrogate light chain.√Correct choicePax-5 is not made in those cells.

Pax-5 is a B cell-specific transcription factor that is synthesized throughout B-cell development and the lifetime of a mature B cell. When Pax-5 binds to the enhancer sequences of an immunoglobulin locus, the chromatin adopts an open configuration that permits access of additional transcription factors that initiate transcription at the locus.

Where do MHC class I molecules bind to peptide antigens? on the surface of cytotoxic T cellsafter traveling to the cell surface of antigen-presenting cells √Correct choicein the endoplasmic reticulumin lysosomes

Peptides generated by cytosolic proteases bind to MHC class I molecules after they are delivered to the endoplasmic reticulum. Only after binding to peptide can MHC class I molecules progress to the cell surface.

Page 1646.1. Describe the stages of B-cell development and the role of bone marrow stromal cells in this process. Upon reaching what stage is a developing B cell irreversibly committed to the B-cell lineage? pluripotent hematopoietic stem cell√Correct choicepro-B cell immature B cellpre-B cell

Pro-B cells mark the earliest progenitor stage of the B-cell lineage. Rearrangement of the immunoglobulin heavy-chain locus gets under way at this early stage of B-cell development.

Drag each protein to the first B-cell development stage where its expression is observed

Protein expression maintains the B-cell developmental programs and ensures that B cells undergo appropriate steps before they are allowed to enter the periphery. Some are transcription factors like Pax-5 whereas others are surrogate components like VpreB and λ5. The protein levels are coordinated and guide B cells to their mature state.

Which of the following are correct statements regarding the RAG-1 and RAG-2 proteins? Accurate Statements Regarding RAG-1/RAG-2 They are regulated to permit allelic exclusion to occur. They are expressed only at certain times during the multiple stages of B-cell development. Inaccurate Statements Regarding RAG-1/RAG-2 They are not essential for rearrangement of heavy- and light-chain loci. They are expressed coordinately with terminal deoxynucleotidyl transferase (TdT).

RAG-1 and RAG-2 proteins are components of the V(D)J recombinase complex required to facilitate rearrangement of V, D, and J segments in lymphocytes. The RAG1 and RAG2 genes are regulated by transcription factors that drive expression of these genes at certain stages of B-cell development when rearrangement of the heavy-chain locus (early and late pre-B-cell stages) and the light-chain locus (small pre-B-cell stage) is taking place. Levels of RAG-1 and RAG-2 proteins diminish after a productive heavy chain is made, and then accumulate again during light-chain gene rearrangement.RAG-1 and RAG-2 are required proteins for rearrangement of immunoglobulin genes during B-cell and T-cell development. They are highly regulated to control rearrangement and allow allelic exclusion.

In contrast to peripheral tolerance, central tolerance has what result? √Correct choiceIt signals continuation of light-chain gene rearrangement.It induces a stage of anergy in self-reactive B cells. It occurs in the circulation.It causes death of self-reactive B cells by apoptosis.

Receptor editing is permitted only while the immature B cell is in the bone marrow when the components required for gene rearrangement are expressed (a central tolerance mechanism). The components are silenced after immature B cells leave the bone marrow and enter the periphery. At this stage they are subjected to peripheral tolerance mechanisms.

Page 1716.2. Relate the rearrangement of immunoglobulin heavy-chain and light-chain genes to the stages of B-cell development and the two developmental checkpoints. The second checkpoint in B-cell development that tests the quality of the light chain occurs at what stage? early pro-B cell√Correct choicesmall pre-B cell immature B cellmature B cell

Successive rearrangement at the immunoglobulin light-chain loci occurs in small pre-B cells and provides many opportunities to make a productive rearrangement. The second checkpoint validates that this has occurred and permits survival and advancement to the immature B-cell stage. If a functional B-cell receptor is not assembled, the pre-B cell dies by apoptosis.

Analyze the figure and then enter the maximum theoretical number of times immunoglobulin gene rearrangement can occur on chromosome 22, the λ locus.

Successive rearrangements are possible only at the immunoglobulin light-chain loci on chromosomes 22 and 2. The number of rearrangements is dependent on the available J segments, not the V segments. The λ locus on chromosome 22 has four opportunities for rearrangement per locus because there are four J segments. Successive rearrangements are possible only at the immunoglobulin light-chain loci on chromosomes 22 and 2. The number of rearrangements is dependent on the available J segments, not the V segments. The κ locus on chromosome 2 has five J segments and can rearrange a maximum of five times. Successive rearrangements are possible only at the immunoglobulin light-chain loci on chromosomes 22 and 2. The number of rearrangements is dependent on the available J segments, not the V segments. The λ locus on chromosome 22 has four opportunities for rearrangement per locus because there are four J segments. Likewise, the κ locus on chromosome 2 has five J segments and can rearrange a maximum of five times. The heavy-chain locus on chromosome 14 undergoes a single rearrangement because once VDJ is brought together, all other D segments are excised.

Which of the following are located in the HLA complex on human chromosome 6?

TAP1 and TAP2, which make up the TAPpeptide transporter, are located between the HLA-DOA and HLA-DOB genes in the HLA class II region. Tapasin, a component of the peptide-loading complex of MHC class Iproteins, is on chromosome 6 in the HLA class II region. The inducible proteasome subunits LMP2 and LMP7, which are part of the immunoproteasome, are located between the HLA-DOA and HLA-DOB genes in the HLA class II region. β2-microglobulin is located on chromosome 15. The invariant chain is located on chromosome 5.

Which of the following is true of the HLA class III region? contains β2-microglobulin√Correct choicecontains no class I or class II genes is on a different chromosome than HLA class I and class II regions

The HLA class III region is on human chromosome 6, flanked by the HLA class I and class II regions. It does not contain any class I or class II genes. β2-microglobulin is located on human chromosome 15.

What happens if the B-cell receptor of an immature B cell does not interact with multivalent self antigens present in the bone marrow? √Correct choiceThe cell is exported to the peripheral circulation as an immature B cell.The cell arrests its developmental progression. XIncorrect choiceThe cell becomes a mature B cell and then enters the peripheral circulation.The cell alters its B-cell receptors.

The absence of an interaction with multivalent self antigens signals an immature B cell to enter the blood and coexpress IgM and IgD on the cell surface.

In V(D)J recombination, immediately following cleavage of the DNA at the junctions of gene segments and adjacent recombination signal sequences (RSSs), a hairpin is (are) formed at the ends of the gene segments, and double-strand breaks is (are) formed at the ends of RSSs. The structure formed at the end of the gene segments is then resolved by the action of DNA repair enzymes, which may open the structures in a symmetrical or asymmetrical manner.

The cleavage made by the RAG complex creates a hairpin of DNA at the ends of the gene segments. This hairpin is later cleaved by the action of DNA repair enzymes and extended by terminal deoxynucleotidyl transferase to form the coding joint. The RAG complex also creates double-strand breaks at the ends of the RSS motifs which are subsequently joined together to form the signal joint on a closed circle of DNA that is removed from the genome.

The ability of MHC molecules to bind a number of different ligands is referred to as what? peptide heterogeneity√Correct choicepromiscuous specificity polymorphismligand diversity

The constraints on which peptides can bind to an MHC molecule are limited, enabling thousands of different amino acid sequences to be accommodated by each MHC molecule. This property is also referred to as promiscuous binding specificity of MHC molecules.

Naive B cells produce IgM and IgD, both of which are bound in the plasma membrane of the cell. Why is the following statement false?To do so, naive B cells produce individual primary RNA transcripts for the µ and δ heavy chains.

The correct answer is "In naive B cells, a primary RNA transcript is produced that contains the information to produce both the µ and δ heavy chains. Post-transcriptional processing dictates how the two are produced separately from that primary RNA transcript."

Which of the following are associated with the processes of somatic recombination and the addition of junctional diversity during T-cell receptor gene rearrangement? recombination signal sequences (RSSs) switch sequencesPress Space to openCorrect AnswerIncorrect Answer 12-bp and 23-bp spacer sequencesPress Space to openCorrect AnswerIncorrect Answer somatic hypermutationPress Space to openCorrect AnswerIncorrect Answer RAG complexPress Space to openCorrect AnswerIncorrect Answer conserved heptamer and nonamer sequencesPress Space to openCorrect AnswerIncorrect Answer terminal deoxynucleotidyl transferase (TdT)Press Space to openCorrect AnswerIncorrect Answer Incorrect Answer(s)

The mechanism that generates T-cell receptor diversity is similar to the way that immunoglobulin diversity is generated before a B cell encounters antigen. The mechanisms of somatic recombination and the introduction of junctional diversity at the junctions between the V, D, and J segments in T cells are the same as in B cells. The same enzymes [V(D)J recombinase and TdT] and recognition sequences (RSSs containing heptamer/12- or 23-bp spacer/nonamer sequences) are used. Somatic hypermutation and switch sequences are specific to B-cell receptors, where they help fine-tune antibody responses. Somatic hypermutation increases antibody affinity for antigen, and switch sequences direct class-switch recombination to different heavy-chain isotypes.

Click on the last completed stage of B-cell development in a person with a deficiency in Igα.

The pre-B-cell receptor needs to assemble in order to receive a signal that allows the developing B cell to progress into the large pre-B-cell stage. Igα is part of the signaling complex of the pre-B-cell receptor. B cells that lack this protein would not progress beyond the late pro-B-cell stage.B-cell development has defined phases in which specific gene rearrangements and gene expression occurs. As the B cell is developing, it tests its rearranged immunoglobulin genes for functionality and self-reactivity. If the translated heavy-chain protein cannot receive a signal through the pre-B-cell receptor, the developing B cell will die via apoptosis.

Which of the following occurs in the subendosteum region of the bone marrow? Late pro-B cells accumulate while completing rearrangement of heavy-chain genes there.Small pre-B cells initiate the rearrangement of light-chain genes there. Immature B cells are exported to the circulation from there.√Correct choiceA high proportion of hematopoietic stem cells reside there.

The subendosteal zone of the bone marrow harbors hematopoietic stem cells, the most immature and undifferentiated form of a progenitor B cell. Developing B cells move from the subendosteum to the central axis of the bone marrow cavity, where they eventually leave the bone marrow as their dependence on stromal-cell interactions decreases.

If DNA rearrangement occurs within the α-chain locus, then which of the following will occur? Page 1335.2. Recall the two classes of T-cell receptors and the associated proteins required for their expression on the surface of T cells. If DNA rearrangement occurs within the α-chain locus, then which of the following will occur? √Correct choiceThe δ-chain locus is permanently deleted from the chromosome.The γ-chain locus is permanently deleted from the chromosome. Both α and γ chains are produced by the mature T cell.Both α and δ chains are produced by the mature T cell.

The δ-chain locus is permanently deleted from the chromosome. If any of the V regions of the α-chain locus rearrange to any of the J regions of the α-chain locus, then the region of DNA between these segments to be joined is excised as a small circle and removed from chromosome 14. The circle will contain the entire δ-chain loc

Label the HLA class II molecules shown as either polymorphic, oligomorphic, or monomorphic.

There are five MHC class II isotypes. HLA-DM and HLA-DO are involved in peptide loading into other HLA class II isotypes and are oligomorphic. HLA-DQ and HLA-DP show extensive polymorphism in both their α and β chains. HLA-DRα is monomorphic; that is, it has no polymorphism. However, HLA-DRβ is highly polymorphic, meaning that HLA-DR as a whole is a polymorphic isotype.

Page 1776.6. Describe the mechanisms that ensure self-tolerance of B cells. What is the normal situation whereby the immune system does not respond to self antigens? immunodeficiencypositive selection autotrophic responsesself-tolerance

There are negative selection mechanisms in place to ensure that self-tolerance to all constituents of a person's body is maintained. Self-tolerance is necessary to prevent reaction to self antigens, an autoimmune condition that would produce potentially harmful antibodies that could cause disease. Self-tolerance is highly specific and its effect does not impair a person's ability to respond to non-self antigens.

Page(s) 170-1716.2. Relate the rearrangement of immunoglobulin heavy-chain and light-chain genes to the stages of B-cell development and the two developmental checkpoints. In B-cell development, what is it called when the quality of the immunoglobulin chains arising from gene rearrangement is tested? XIncorrect choiceclonal expansionXIncorrect choicesuccessive rearrangement√Correct choicecheckpoint XIncorrect choiceallelic exclusionXIncorrect choicepre-B-cell editing

There are two B-cell checkpoints, testing for either a functional heavy chain (first checkpoint—when a functional pre-B-cell receptor is assembled) or a functional light chain (second checkpoint—when a functional B-cell receptor is assembled).

Following antigen-specific activation in T cells, what occurs with the genes encoding T-cell receptors? They undergo alternative mRNA splicing.They undergo somatic hypermutation. √Correct choiceThey undergo no further change.They undergo isotype switching.

They undergo no further change In contrast to immunoglobulin genes, which undergo further diversification after B cells encounter their specific antigen, the genes encoding T-cell receptors remain unchanged after T cells become stimulated with specific antigen. This is because T-cell receptors are used solely for antigen recognition, and not for mediating effector functions.

Page 1796.6. Describe the mechanisms that ensure self-tolerance of B cells. Drag the cell to the appropriate location on the image based on the following descriptions:B Cell Charlie—one functional self-reactive rearranged κ-chain gene, a germline-encoded κ-chain gene, and two germline-encoded λ-chain genesB Cell Echo—two nonfunctional λ-chain genes and two self-reactive κ-chain genesB Cell Sierra—one functional, self-tolerant κ-chain gene; one germline-encoded κ gene; and two germline-encoded λ genes

This B cell has generated a functional self-tolerant antigen receptor. This B cell can migrate into the periphery as an immature naive B cell. When it encounters its antigen, it will be able to respond with effector functions.Receptor editing allows self-reactive B cells that have gone through the majority of their development another chance to develop a self-tolerant antigen receptor. Each B cell can rearrange a total of four light-chain genes before it is condemned to die—two λ genes and two κ genes. About 85% of pre-B cells are able to generate a self-tolerant antigen receptor and migrate into the periphery.

Which of the following are correct statements about HLA genes?

Unlike HLA class II molecules that function exclusively in adaptive immunity by presenting peptide antigen to T cells, class I and class I-like molecules have a wide variety of functions not restricted to antigen presentation including, but not limited to, regulation of iron metabolism and NK-cell function.

Which of the following are correct statements regarding the pre-B-cell receptor?

VpreB and λ5 form the surrogate light chain of the pre-B-cell receptor. They have unique amino acid sequences extending beyond their immunoglobulin-like domains that aid in the oligomerization of pre-B-cell receptors, a necessary structural configuration for transduction of signals required for pre-B-cell survival.The pre-B-cell receptor allows the B cell to receive a survival signal, which allows the B cell to continue its development. Without this signal, the B cell will die via apoptosis.

What happens when B lymphocytes become inactivated and unresponsive to their specific antigen? √Correct choiceThey enter a state of anergy.They undergo allelic exclusion. They begin the process of receptor editing.XIncorrect choiceThey die through apoptosis.

When B lymphocytes become nonresponsive to an antigen, they become developmentally arrested—a state called anergy.

What is the main difference between antibody light-chain and heavy-chain gene segments?

While both light and heavy chains will utilize V and J segments, only heavy chains utilize a D gene segment.

Other than the T-cell receptor, why is it important that the other components of the T-cell receptor complex are invariant? because polymorphisms in CD3γ, δ, or ε or the ζ chain could compromise their ability to bind to and stabilize the T-cell receptor and transduce signals to the cell's interiorbecause CD3γ, δ, ε and the ζ chain bind to conserved portions of MHC molecules and polymorphisms in these components could disrupt T-cell receptor:MHC interactionsXIncorrect choicebecause variation in these components would interfere with the transport of the T-cell receptor to the endoplasmic reticulumbecause amino acid substitutions in these components could alter the antigen-binding properties of the T-cell receptor

ecause polymorphisms in CD3γ, δ, or ε or the ζ chain could compromise their ability to bind to and stabilize the T-cell receptor and transduce signals to the cell's interior The CD3 proteins and the ζ chain interact with the constant domains of the T-cell receptor α and β chains. Amino acid conservation is needed to ensure that the electrostatic interactions in the transmembrane domains and the association with intracellular signaling molecules are preserved. The T-cell receptor has a leader peptide that directs the nascent polypeptide chains to the endoplasmic reticulum independent of the CD3 proteins or the ζ chain.

What term defines the combination of HLA alleles within a given HLA complex on chromosome 6? haplotype isotype isoform allotype

haplotype A haplotype is the linked cluster of polymorphic genes carried on a single chromosome. Each person inherits two haplotypes, one from each parent.

Virtually all nucleated cells express MHC class I on their cell surface, even in the absence of infection. In the absence of a virus infection, what is found in the peptide-binding groove of MHC class I molecules? The peptide binding groove is empty self-peptides non-self peptides viral proteins

self-peptides These are commonly derived from normal human proteins.

Somatic recombination is an essential process for the generation of immunoglobulins and T-cell receptors and requires V(D)J recombinase. Individuals homozygous for missense mutations in either of the recombinase-activating genes RAG1 or RAG2 have an immunodeficiency called Omenn syndrome, a rapidly fatal condition treatable only by bone marrow transplantation. Which of the following would be consistent with a diagnosis of Omenn syndrome?

undetectable serum IgM - Patients with Omenn syndrome present with severe combined immunodeficiency (SCID) that inhibits development of both B cells and T cells. Pathways leading to the development of other blood cells are unaffected.

A complete and functional immunoglobulin chain is made only if what circumstance occurs?

√Correct choiceA correct reading frame in the variable region is produced. Somatic recombination and the generation of junctional diversity are random and imprecise processes. There is only a 1 in 3 chance that the added nucleotides will be in frame with the initiating start codon in the leader sequence of the gene. If this occurs, it is a productive rearrangement.

Page 1786.6. Describe the mechanisms that ensure self-tolerance of B cells. Immature B cells that pass the self-tolerance test are identified by the coexpression of IgM and IgD. What process allows this to occur? √Correct choicealternative splicing of the heavy-chain mRNAthe utilization of different promoter sequences flanking either Cμ or Cδ rearrangement of the heavy-chain locus on the second chromosomeisotype switching to Cδ, providing a short window of time for both IgM and IgD to be on the cell surface simultaneously

√Correct choicealternative splicing of the heavy-chain mRNA Coexpression of IgM and IgD is regulated by RNA processing of mRNA transcripts involving the utilization of different polyadenylation signal sequences and splice sites for intron removal.

Which component of MHC molecules is soluble? MHC class II β chain MHC class I α chain MHC class II α chain β2-microglobulin

√Correct choiceβ2-microglobulin β2-microglobulin is not membrane-bound but forms a noncovalent association with the MHC class I α chain to allow for stable expression of peptide-bearing MHC class I molecules on the cell surface.