Brock Biology of Microorganisms (15th Edition)
15th Edition
ISBN: 9780134261928
Author: Michael T. Madigan, Kelly S. Bender, Daniel H. Buckley, W. Matthew Sattley, David A. Stahl
Publisher: PEARSON
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Chapter 27, Problem 3AQ
Polymorphism implies that each different MHC protein binds a different peptide motif. However, for the MHC class I proteins, only 6 peptide motifs can be recognized in an individual, whereas over 6000 motifs can be recognized by the entire human population. What advantage does recognition of multiple motifs have for the individual? What potential advantage does recognition of the extremely large number of motifs have for the population? Can everyone process and present the same antigens?
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The adaptive immune system uses multiple strategies to generate diversity in our ability to mount responses to a wide array of infectious microorganisms. These strategies include the generation of diverse repertoires of B-cell and T-cell antigen receptors, as well as polymorphism of MHC genes. The polymorphism of MHC genes differs from the diversity of lymphocyte antigen receptors in that:
It involves DNA rearrangements at multiple gene segments in the MHC locus.
It requires different enzymes than the RAG1/RAG2 recombinase required for antigen receptor rearrangements.
It results in a diverse repertoire of clonally distributed receptors on dendritic cells, rather than on lymphocytes.
It creates diversity between individuals in the population rather than within a single individual.
It does not contribute to the transplant rejection responses that occur after organ transplantation between unrelated individuals.
In the 1980s, a mutant strain of mice was identified, carrying amino acid changes in the MHC class II gene. This mutant strain was derived from C57Bl/6 mice, which carry the H-2b haplotype. Inbred H-2b mice express only one MHC class II protein, called Ab. The mutant strain, called ‘bm12’ was found to have 3 amino acid changes in the Ab protein, at positions 67, 70, and 71 of the Aβ chain. The positions of these amino acid changes on the MHC class II structure are shown below by the red circles in Figure Q6.30A. On the right, the side view diagram of MHC class II shows the direction of these three amino acid side chains.
Initial experiments with wild-type C57Bl/6 mice and bm12 mice showed that the wild-type mice made a robust CD4 T cell response after immunization with the insulin protein isolated from a cow; in contrast, the bm12 mice failed to make any detectable response to this foreign protein. Epitope mapping studies identified amino acid residues 1–14 of the bovine insulin A…
MHC polymorphism at individual MHC genes appears to have been strongly selected by evolutionary pressures. In other words, there appears to be selection for maintaining hundreds to thousands of different alleles of each MHC gene in the population. This notion is based on the observation that nucleotide differences between alleles that lead to amino acid substitutions are more frequent than those that are silent substitutions (i.e., not changing the amino acid sequence of the protein). In addition, the positions within the MHC protein where most of the allelic sequence variation occurs are not randomly distributed, but are concentrated in certain regions of the MHC protein. This latter point indicates:
That some nucleotide sequences within the MHC genes are hot-spots for mutation
That MHC genes are more susceptible to point mutations than to larger nucleotide deletions
That MHC allelic polymorphism has been driven by selection for diversity in peptide binding specificity
That MHC genes…
Chapter 27 Solutions
Brock Biology of Microorganisms (15th Edition)
Ch. 27.1 - Prob. 1MQCh. 27.1 - Prob. 2MQCh. 27.1 - Distinguish between clonal deletion and clonal...Ch. 27.1 - QWhy is it necessary that all three defining...Ch. 27.2 - Identify the intrinsic and extrinsic properties of...Ch. 27.2 - Describe an epitope recognized by an antibody, and...Ch. 27.2 - Give an example for each: natural and artificial...Ch. 27.2 - QWhat properties are required for a vaccine to...Ch. 27.3 - Summarize antibody production starting with...Ch. 27.3 - Differentiate among antibody classes using...
Ch. 27.3 - Prob. 3MQCh. 27.3 - QDescribe the structural and functional...Ch. 27.4 - Draw a complete Ig molecule and identify...Ch. 27.4 - Describe antigen binding to the CDR1, 2, and 3...Ch. 27.4 - Describe the recombination events that produce a...Ch. 27.4 - QWhich Ig chains are used to construct a complete...Ch. 27.5 - Identify the cells that display MHC class I and...Ch. 27.5 - Compare the MHC I and MHC II protein structures...Ch. 27.5 - Define the sequence of events for processing and...Ch. 27.5 - QDescribe the basic structure of class I and class...Ch. 27.6 - Define polymorphism and polygeny as they apply to...Ch. 27.6 - How does a single MHC protein present many...Ch. 27.6 - QPolymorphism implies that each different MHC...Ch. 27.7 - Prob. 1MQCh. 27.7 - Identify diversity-generating mechanisms unique to...Ch. 27.7 - Describe and compare the structural features of Ig...Ch. 27.7 - QWhat diversity-generating mechanisms function to...Ch. 27.8 - Describe the mechanism used by Tc cells to...Ch. 27.8 - Describe the effector system (the cell-killing...Ch. 27.8 - Compare and contrast the roles and activities of...Ch. 27.8 - QWhat mechanism do Tc cells use to identify and...Ch. 27.9 - Discriminate between immediate hypersensitivity...Ch. 27.9 - Provide examples and mechanisms for an...Ch. 27.9 - QHow do immediate and delayed-type...Ch. 27.10 - Describe the binding site for superantigens on T...Ch. 27.10 - Compare and contrast the immunodeficiency observed...Ch. 27.10 - Prob. 3MQCh. 27.10 - Prob. 1CRCh. 27 - Antibodies of the IgA class are probably more...Ch. 27 - Prob. 2AQCh. 27 - Polymorphism implies that each different MHC...Ch. 27 - What problems would arise if a person had a...
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- Some species, like camels, alpacas, and llamas, have evolved variant forms of immunoglobulin proteins that retain the ability to bind to antigens. While overall the antibodies made by these animals are simpler than human or mouse antibodies, an important feature conserved among all of these antibodies is: The presence of both heavy and light chain polypeptides Antigen-binding sites comprised of VH and VL sequences The presence of exactly three constant region domains The presence of two antigen-binding sites per antibody The presence of multiple disulfide bonds linking antibody light chains to heavy chainsarrow_forwardAntibody diversity is generated by multiple mechanisms, each of which contributes to the generation of antibodies with up to 1011 different amino acid sequences in their antigen-binding sites. Several of these mechanisms involve changes in the DNA sequences encoding the antibody heavy and light chain proteins. One mechanism that does not rely on changes to the DNA within the immunoglobulin heavy and light chain gene loci is, instead, dependent on: The contributions of amino acids from both the heavy chain and the light chain to form the antigen-binding site The random usage of V, D, and J gene segments to form the heavy chain V region sequence The random usage of k light chains versus l light chains to pair with the heavy chain The activity of TdT to add random nucleotides at the junctions between the V, J, and D region sequences The fact that heavy chain V regions contain an extra gene segment encoded by the D region compared to light chain V regionsarrow_forwardSecondary lymphoid organs (SLOs) are important sites for the initiation of T cell responses via immune priming. Once an antigen-presenting cell (APC) presenting peptide-MHC arrives at a secondary lymphoid organ, it must find a relatively rare T cell clone with a TCR that recognizes its presented peptide-MHC complex. Which of the following features of SLOs increases the likelihood of this APC finding its cognate T cell? Activated APCs are captured by SLO-resident macrophages once they enter via afferent lymphatics, allowing them to be interrogated by T cells Concentrate high densities of T cells within specific zones to enable efficient APC browsing Drain pathogens from infected tissues through the lymphatics, bringing them to secondary lymphoid organs where they can be killed by B cells Contain specialized nutrients that are required for productive TCR signaling following interactions with a cognate APCarrow_forward
- Three major cell types, dendritic cells, macrophages, and B cells, present peptides bound to MHC class II molecules for recognition by CD4 T cells. In general, these peptides are derived from proteins or pathogens taken up by the cell by endocytosis, phagocytosis, or macropinocytosis. Based on these pathways of antigen uptake, some of the enzymes that degrade proteins to generate peptides for MHC class II presentation are: Ubiquitin ligases that tag proteins for degradation by the proteasome ATP transporter proteins that deliver endocytic proteins into the cytosol for degradation Cysteine proteases like cathepsins that function at acidic pH The lysosomal thiol reductase found in the endosomes The lysosome-associated membrane trafficking protein, LAMP-2arrow_forwardOne strategy for vaccine development currently under investigation is the use of pathogen-derived T cell epitopes as a component of the vaccine. For viral pathogens, implementing this strategy involves scanning the predicted amino acid sequences of the viral proteins for likely peptide epitopes that would bind to MHC class I and MHC class II molecules. In addition to the complication of MHC sequence polymorphism in the human population, another complication of this strategy for peptide epitopes that would bind to MHC class II proteins is: The importance of viral proteins containing peptides that are cleaved into 8–10 amino acid long fragments. The ability of viruses to mutate their proteins to avoid MHC anchor residue sequences. The fact that long peptides (>13 amino acids) are rapidly degraded in cells. The fact that MHC class II proteins are intrinsically stable, even in the absence of binding to a peptide. The absence of defined sequence motifs that predict peptide binding to…arrow_forwardPeptides are stably bound to MHC molecules, and also serve to stabilize the MHC molecule on the cell surface. Once expressed on the surface of host cells, an MHC protein remains stably associated with its bound peptide for several days. This highly stable peptide binding behavior is important because: a) It prevents peptide exchanges on the cell surface, ensuring that peptide:MHC complexes are reliable indicators of the proteins present inside that host cell. b) If the MHC protein lost its peptide it would become unstable, and would be rapidly internalized and degraded. c) Pathogens would otherwise evade the immune response by making decoy peptides that mimic host cell peptides. d) Pathogens would be able to evade the T cell response by making proteases that cleave MHC proteins inducing peptide release. e) Immune responses to infection often induce noxious chemicals that damage surface MHC proteins, and might result in peptide loss.arrow_forward
- A cell line carrying a mutation in a single gene is found to express very low levels of MHC class I on its surface. When infected with influenza virus, these cells are not recognized nor are they killed by a CD8 T cell line specific for an influenza peptide bound to the MHC class I protein expressed by these cells. Incubation of the mutant cell line with a large excess of this peptide in the cell culture medium overnight leads to the results shown below. What is the most likely candidate for the gene that is defective in the mutant cell line?arrow_forwardSome viruses have mechanisms to down-regulate MHC class I protein expression on the surface of cells in which the virus is replicating. This immune evasion strategy might prevent effector CD8 cytotoxic T cells from recognizing and killing the virus-infected cells. Would this immune evasion strategy also prevent the initial activation of virus-specific CD8 T cells? Yes, because no viral peptide:MHC class I complexes would form to activate CD8 T cells. No, because dendritic cells would take up infected cells and cross-present viral peptides to activate CD8 T cells. No, because some presentation of MHC class I complexes with viral peptides would occur before the virus could down-regulate all the surface MHC class I protein. Yes, because this immune evasion strategy would also function in dendritic cells, even if the virus doesn’t replicate in dendritic cells. No, because the type I interferon response induced by the virus infection will up-regulate MHC class I expression and override the…arrow_forwardThe virus shown in the diagram below is only able to infect and replicate in epithelial cells. In order for the cross-presenting dendritic cell to display viral peptides, rather than self peptides on its surface MHC class I proteins, which of the following procedures could be utilized, starting with the components shown in the figure below? Mix epithelial cells with heat-killed virus, wait 24 hrs, wash away any virus particles outside the epithelial cells, then add epithelial cells to dendritic cells. Mix epithelial cells with viral peptides, wait 24 hrs, wash away any viral peptides not bound to the epithelial cells, then add epithelial cells to dendritic cells. Mix epithelial cells with live virus particles, wait 24 hrs, wash away any virus particles outside the epithelial cells, then add epithelial cells to dendritic cells. Mix dendritic cells with viral nucleic acids and epithelial cells for 24 hrs. MIx epithelial cells will viral nucleic acids, wait 24 hrs, wash away any viral…arrow_forward
- During MHC class I synthesis and folding in the endoplasmic reticulum (ER), a process of peptide editing takes place as the newly synthesized MHC class I protein is held in a ‘peptide receptive’ state by binding to the calreticulin:ERp57:tapasin complex. Peptide editing ensures that the MHC class I molecules that reach the cell surface have stable, high affinity binding for their peptide cargo. Peptide editing is important to the immune response because it: Maintains high levels of surface MHC class I expression Ensures that MHC class I molecules are not degraded in the ER Retains the nascent MHC class I molecule in a peptide receptive state Allows surface MHC class I molecules to bind new peptides from the extracellular milieu Prevents surface MHC class I molecules from undergoing peptide exchange at the cell surfacearrow_forwardalpha:beta TCRs are membrane-bound proteins comprised of two polypeptides linked by a disulfide bond. Both polypeptide components of the alpha:beta TCR are members of the immunoglobulin superfamily, and each of their domains share structural similarity with regions of antibody proteins. However, due to the different functions of TCRs versus antibodies, the overall domain organization of the TCR is not the same as for an antibody. In the figure below, describe three features that are incorrect illustrations of the alpha:beta TCR.arrow_forwardThe extensive polymorphism of MHC genes in the population is thought to represent an evolutionary response to outflank the evasive strategies of pathogens. This polymorphism makes it difficult for pathogens to eliminate all potential MHC binding epitopes from their proteins. Based on this reasoning, it would seem advantageous for each individual to encode more than three different MHC class I and three different MHC class II genes per chromosome copy. If some individuals in the population had MHC loci that encoded 10 different MHC class I and 10 different MHC class II genes, the T cell repertoire in those individuals would likely be: Much more diverse than in the rest of the individuals of that population Much better at recognizing rare pathogens not encountered by most individuals in that population Much less diverse than the rest of the individuals in that population Much more alloreactive than the T cells found in the other individuals of that population Very reactive to bacterial…arrow_forward
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Mitochondrial mutations; Author: Useful Genetics;https://www.youtube.com/watch?v=GvgXe-3RJeU;License: CC-BY