Exam 1 Prep

Short answer: Dendritic cells, also called 'antigen-presenting-cells' are considered the bridge between the innate and the adaptive immune responses. Describe two key features of dendritic cells that are essential for them to provide this bridging function.

1. Dendritic cells respond to infections using innate pattern recognition receptors (PRRs) that recognize PAMPs. 2.Once triggered by PRR stimulation, dendritic cells are induced to migrate from the infected tissue to the regional draining lymph node. 3. Following stimulation of the PRRs on a dendritic cell, dendritic cells up-regulate co- stimulatory molecules that are required to activate T lymphocytes. 4. Following pathogen uptake by the dendritic cell, the pathogen is degraded and peptides of the pathogen are displayed on the dendritic cell surface for recognition by the antigen receptors on T lymphocytes.

Short answer: A common characteristic of a site of infection, such as a pimple on the skin, is pus. What is responsible for the white color of pus?

1.11: White blood cells, primarily neutrophils.Pus is an inflammatory response to a bacterial infection of the skin. The inflammatory response recruits neutrophils from the blood into the site of infection, along with some monocytes.

Short answer: In the 1970s, immunologists discovered the genetic mechanism allowing a population of B cells to produce an enormous diversity of different antibodies. At the time, this discovery shocked the field of biology, as it called into question the 'immutable' nature of DNA, which was known to be the genetic material transmitted from generation to generation during the propagation of the species. Briefly describe this startling mechanism.

1.18: Antibody diversity is generated when each developing B cell undergoes a DNA rearrangement process. This process involves the combination of small gene segments, encoded as separate elements in the genome, to form a complete coding sequence for the antibody protein. As a result of this process, the DNA of the B cell is irrevocably altered, and would no longer be able to transmit all the genetic information to the next generation.

True/False: For cells of the innate immune system, each individual cell has multiple pattern recognition receptors, and can recognize many different pathogens. In contrast, cells of the adaptive immune system each express only a single antigen receptor, and have a single specificity for pathogen recognition.

1.19: True.Cells of the innate immune system generally express multiple pattern recognition receptors. Each of these receptors recognizes a conserved feature of a class of pathogens. Therefore, a single innate immune cell can respond to a multitude of different pathogens. In contrast, the antigen receptor on B and T lymphocytes is clonally distributed; each single cell expresses only one version of this receptor, and has a single binding specificity.

Multiple choice: The clonal selection theory was first proposed in the 1950s, decades before the molecular details of B and T lymphocyte development and lymphocyte antigen recognition responses were elucidated. Nonetheless, Burnet, who proposed this theory, correctly inferred several key aspects of adaptive immune responses. One key postulate that Burnet proposed was that: Cells of the innate immune system are distinct from those of the adaptive immune system. Cells of the adaptive immune system are generated from a pluripotent hematopoietic stem cell that resides in the bone marrow. B and T lymphocytes are closely related cells that have distinct properties from myeloid cells.

1.20: D.Clonal selection theory was original developed to explain the production of antibodies, as T lymphocytes were not known at that time. A key postulate of the theory was that the body contains a heterogeneous population of lymphocytes, each of which is programmed to produce a single type of antibody. Burnet proposed that each lymphocyte expressed a membrane-bound form of the antibody on its surface as a receptor. Following antigen binding, he proposed that this receptor would induce the proliferative expansion of that lymphocyte into a clone of cells. Each member of this clone of cells would express the identical antibody to the original cell, and all of them would then secrete this antibody.

Multiple choice: The clonal selection theory was first proposed in the 1950s, decades before the molecular details of B and T lymphocyte development and lymphocyte antigen recognition responses were elucidated. Nonetheless, Burnet, who proposed this theory, correctly inferred several key aspects of adaptive immune responses. One key postulate that Burnet proposed was that: Some antigen receptors might recognize the individuals on cells or antigens Many lymphocytes might generate antigen receptors that don't recognize anything Many lymphocytes might generate antigen receptors that recognize multiple different pathogens Some antigen receptors might recognize foreign tissues and lead to graft rejection during organ transplantation Some lymphocytes might not generate functional antigen receptor proteins

1.21: A.The random process that generates lymphocyte antigen receptors can create antigen receptors that are self-reactive. Many of these potentially self-reactive lymphocytes are eliminated during lymphocyte development, a process known as clonal deletion. Other self-reactive lymphocytes are functionally inactivated or inhibited from responding to their self-antigen. Altogether, these mechanisms ensure that the individual's lymphocytes remain tolerant to self.

Multiple choice: Secondary (or peripheral) lymphoid organs are sites for initiation of adaptive immune responses. Given the rarity of lymphocytes specific for any given antigen and the vast amount of body tissue that must be protected, the system of secondary lymphoid tissues is efficient because:

1.22: A.The system of secondary lymphoid organs is important in promoting interactions between rare antigen-specific lymphocytes and their antigens. Instead of requiring each naive lymphocyte to traffic into every nook and cranny of the body, the pathogens and their products are brought to centralized locations and concentrated there. This allows the naive T and B lymphocytes to spend their time traveling from lymph node to lymph node looking for their antigen, making the encounters between lymphocytes and antigens much more efficient.

One factor that contributes to the enhanced secondary response to an antigen is the increased number of antigen-specific lymphocytes present after the primary response; these are known as memory cells.

1.29: True.Several factors contribute to the enhanced secondary response to an antigen. One of these is the clonal expansion of antigen-specific lymphocytes that occurs during the primary response. While many of these cells die after the antigen is cleared, a subset of them remain as long-lived memory cells.

1.36 True/False: TH1, TH2, TH17, and T follicular helper (TFH) cells represent four different subsets of CD4 effector cells. Each of these subsets produces a distinct set of cytokines when stimulated, that in turn, act to mobilize distinct immune effector mechanisms. While TH1, TH2, and TH17 cells recruit and activate innate immune cells, TFH cells act to amplify the adaptive immune response.

1.36: True.Most CD4 effector cells produce cytokines that act on innate immune cells, For instance, TH1 cells activate macrophages, TH2 cells recruit and activate mast cells, basophils, and eosinophils, and TH17 cells recruit neutrophils. Unlike these subsets, TFH cells function to promote B cell activation and antibody responses, and thus help amplify the adaptive immune response.

Short answer: A common mechanism by which sensor cells in the host detect micro- organisms relies on the production of unique microbial components not found in the host. Propose a strategy by which a clever microbe could evade this type of response.

1.5: Sensor cells commonly recognize unique microbial components, such as bacterial lipopolysaccharide or other cell wall constituents. A clever microbe could evade this response by altering its membrane or cell wall components so that they are no longer recognized by the sensor cell receptors.

Multiple choice: The classical complement pathway is initiated by C1q binding to the surface of a pathogen. In some cases, C1q can directly bind the pathogen, for instance by recognizing proteins of bacterial cell walls, but in most cases C1q binds to IgM antibodies that are bound to the pathogen surface. How does this IgM-binding feature of C1q contribute to rapid, innate immune responses rather than to slow, adaptive responses?

2.14: B.Natural antibody, which is primarily of the IgM class, is produced in the body prior to pathogen exposure. These antibodies are widely reactive with many microbial pathogens, although they generally have low affinity for the pathogen. However, since IgM is a pentamer of IgM monomers, each IgM pentamer has 10 binding sites for antigen, allowing even low affinity antibodies to bind, due to the increased avidity of multiple binding sites. This natural antibody will then recruit C1q, leading to complement activation. Since the natural antibody pre-exists prior to pathogen exposure, this response is rapid and is considered part of the innate immune response.

Multiple choice: B cells express a complement receptor that binds to C3b cleavage products, such as iC3b and C3dg. When a B cell with an antigen receptor that specifically recognizes that pathogen also has its complement receptor stimulated because the pathogen is opsonized with these C3 fragments, B cell activation is greatly enhanced. Due to this mechanism, B cells can be activated by much lower concentrations of antigen (in this case, the pathogen) than if the antigen is devoid of complement components. This mechanism functions to:

: A.The complement receptor on B cells, CD21, is often referred to as the B cell co-receptor. When this receptor is engaged together with the B cell antigen receptor, the B cell can be activated by much lower concentrations of antigen compared to antigen lacking ligands for CD21. Experiments have indicated that CD21 stimulation can reduce the concentration of antigen needed to activate the B cell by 100-1000-fold. This allows B cells to detect small numbers of infecting pathogens, to initiate an adaptive response prior to the occurrence of a high pathogen load in the host.

Multiple choice: Lymph nodes function as meeting points between antigen-bearing dendritic cells arriving from the tissue and recirculating B and T lymphocytes. Whereas the dendritic cells coming from the tissue enter the lymph node via the afferent lymphatic vessels, the recirculating lymphocytes enter the lymph node: Also from the lymph fluid draining the tissue Directly from their primary lymphoid organ where they develop From the blood by crossing the high endothelial venules By being trapped in the lymphoid follicle by resident macrophages By being carried there by dendritic cells

: C.Recirculating lymphocytes are in the blood, and are attracted by chemokines to enter the lymph node. They do this by binding to adhesion molecules and the chemokines posted at high endothelial venules, which are the regions of the blood vessel wall that are in the lymph node. The lymphocytes squeeze themselves through the blood vessel wall to leave the blood and enter the lymph node

Multiple choice: Given the enormous heterogeneity of antigen receptors expressed on the populations of naive B and T lymphocytes, the adaptive immune response relies on a process whereby the rare lymphocyte that binds to the antigen is first induced to proliferate, before it can perform its effector function. For B cells, there is a clever mechanism that ensures that the specificity of the antibody secreted by the plasma cell will recognize the same pathogen that initially stimulated the B cell antigen receptor and induced B cell proliferation. This mechanism is:

: E.The B cell antigen receptor includes a membrane-bound form of the antibody protein, along with two transmembrane subunits that provide receptor signaling functions. When a given B cell binds to a pathogen using its B cell antigen receptor, the B cell is stimulated to proliferate and differentiate into a plasma cell. As a plasma cell, this B cell generates a secreted form of this same antibody protein by eliminating the transmembrane domains that anchor the antibody protein into the B cell membrane.

Synthesis question: One major difference between the innate and adaptive immune responses is in the mechanism by which pathogens are recognized. Innate immune cells use pattern recognition receptors (PRRs) to recognize conserved determinants shared by all the members of a category of pathogens, whereas adaptive immune cells (B and T lymphocytes) have highly specific antigen receptors. a) Which of the patterns of receptor expression in Figure Q1.44 represent innate immune cells?

A. Innate immune cells express multiple different receptors for recognizing PAMPs; however, all cells of the same innate subset express the same receptors

he majority of vaccines work by eliciting pathogen-specific antibodies that circulate in our bodies and protect us in the event that we are later exposed to that specific pathogen. For most viruses and bacterial toxins that we are vaccinated against, these pre-existing antibodies are protective because: They neutralize the virus or toxin, preventing it from attaching to and entering our cells. They bind to the virus or toxin and carry it to the liver where it can be degraded. They bind to the virus or toxin and directly induce lysis. They induce mucus production that helps flush the toxin or virus out of the body. They bind to epithelial cells and induce the production of antimicrobial peptides.

A.Most vaccines against virus infections or bacterial toxins function by eliciting neutralizing antibodies. These antibodies bind to the virus or toxin immediately after entry (for the virus) or production by the bacteria (for the toxin) and prevent them from binding to and entering our cells.

Multiple choice: The importance of complement activation as an innate immune defense against infections is illustrated by:

A.One of the best indicators of the importance of an immune protective mechanism is the development by pathogens of strategies to evade that mechanism. In the case of the complement pathway, many pathogens have evolved strategies to avoid complement activation on their surface. These include the expression of proteins that attract complement regulatory proteins to their surface, in an effort to mimic host cell surfaces that can inactivate complement. An additional strategy is to secrete proteins that directly inhibit components of the complement pathway.

Multiple choice: When macrophages in a tissue encounter bacteria, they release cytokines that induce an inflammatory response. These cytokines act on other immune cells, to recruit them to the site of infection and to enhance their activities. In addition, these cytokines act on the endothelial cells of the blood vessel wall to: Increase their permeability, allowing fluid and proteins to leak into the tissue Solidify the tight junctions to prevent the bacteria from entering the blood Proliferate, allowing the blood vessel to enlarge Up-regulate microbicidal mechanisms, so they can kill bacteria Secrete anti-microbial peptides

A.The inflammatory response induced by macrophage-derived cytokines leads to the recruitment of cells, fluid, and soluble mediators into the tissue at the site of an infection. A key aspect of this response is the action of inflammatory cytokines on the blood vessel endothelial cells. These cells up-regulate adhesion molecules, allowing circulating white blood cells to stick to the blood vessel wall near the site of infection. In addition, the junctions between the endothelial cells loosen, allowing fluid and cells to leak out of the vessel into the tissue. In the fluid are soluble mediators, such as antimicrobial peptides, complement proteins, and antibodies.

Multiple choice: One surprising aspect of the immune system is that individuals make responses to human tissues from a different individual, causing serious problems for organ and tissue transplantation. The basis for this immune response is: The extensive polymorphism of MHC genes in the human population The fact that transplanted tissues often carry infectious microbes into the recipient The fact that individuals may differ in their blood group antigens (i.e., their blood type) The presence of many antigen-presenting-cells in the transplanted tissue The presence of many B and T lymphocytes in the transplanted tissue

A.The major component of the graft rejection response is due to recognition of the 'foreign' MHC proteins on the graft by the recipient's T lymphocytes. This occurs because of the extensive polymorphism of MHC genes in the human population. As a result, two different individuals nearly always express different MHC molecules from each other. Since MHC molecules are efficiently recognized by T cells, the T cells in the recipient will respond to the donor's tissue and destroy it, just as if it were a pathogen.

choice: Opsonization of pathogens by both antibodies and complement proteins (C3b) leads to uptake and destruction of the pathogen by phagocytic cells that express both Fc receptors and complement receptors. Which of the following in Figure Q2.16 is the most efficient form of dual opsonization of the pathogen by antibody and C3b to maximize phagocytosis?

A.The most efficient form of opsonization by antibody plus C3b is when the complement protein is covalently linked to the antibody molecule. This leads to efficient engagement of both Fc receptors and complement receptors on phagocytic cells.

Multiple choice: Although the complement cascade can be initiated by antibodies bound to the surface of a pathogen, complement activation is generally considered to be an innate immune response. This is because

A.There are three pathways for initiating complement activation. One of them, known as the classical pathway, occurs when the pathogen has antibodies bound to its surface, leading to recruitment of C1q. The other two pathways, the lectin pathway and the alternative pathway, are initiated by mechanisms that do not require antibodies directed against the pathogen surface. These latter two pathways are dependent on constitutively produced, and therefore 'innate' recognition molecules that directly bind to pathogen surfaces, initiating complement activation.

Short answer: Most B and T lymphocytes in the circulation appear as small, inactive cells, with little cytoplasm, few cytoplasmic organelles, and nuclei containing condensed inactive chromatin. Yet these cells comprise the adaptive immune response, without which individuals die in infancy. What is the explanation for this apparent dichotomy?

B and T lymphocytes are a heterogeneous population, comprised of cells that each express a unique antigen receptor. As a consequence, only a small number of B and T lymphocytes will respond to any particular pathogenic infection. The vast majority of the circulating cells will never encounter the pathogen that binds to their antigen receptor; hence these cells remain in a naive, inactive state.

Multiple choice: Epithelial surfaces provide the first line of defense against infection by the use of several types of mechanisms. One of the chemical mechanisms used by epithelia is: A. Joining of epithelial cells by tight junctions B. Secretion of antimicrobial peptides by epithelial cells C. Production of mucus, tears, or saliva in the nose, eyes, and oral cavity d. Movement of mucus by cilia e. Peristalsis in the gastrointestinal tract

B.Anti-microbial peptides are produced by epithelia at all mucosal and epidermal surfaces. These chemicals are important in immune protection against microbial pathogens. All other choices are mechanical mechanisms by which surface epithelia protect against infections, not chemical mechanisms.

Multiple choice: Multiple pathways for regulating complement activation limit the potential damage caused by complement deposition on host cells or caused by the spontaneous activation of complement proteins in the plasma. Genetic deficiencies in these mechanisms often lead to chronic inflammatory diseases, but in some cases can paradoxically lead to increased susceptibility to bacterial infections. This latter outcome may occur because:

B.Individuals with a genetic defect in factor I are subject to recurrent infections with pyogenic (pus- forming) extracellular bacterial infections. This occurs because, in the absence of factor I, uncontrolled complement activation ends up depleting the complement proteins from the plasma. This leads to impaired complement activation on these bacteria, and therefore, to diminished clearance of these infections.

Short answer: The antibody protein is often depicted as an uppercase letter Y, with the two variable regions (antigen-binding domains) pointing up, and the stem consisting of the Fc region (constant domain). An analogy has been made between an antibody protein and a guided missile, with one type of antibody domain functioning as the guidance system, and the other type of domain as the 'payload.' Which antibody domain serves as the guidance system, and which as the payload? Explain your answer.

B.Intracellular pathogens, such as viruses and some protozoa, cannot be eliminated by antibody- based mechanisms once they have begun replicating in host cells. In order to detect these intracellular pathogens, a system that surveils the intracellular status of host cells is needed. T cells fulfill this function by recognizing peptides on cell surface MHC receptors. The MHC receptors can pick up pathogen-derived peptides from within the infected cell and display them on the cell surface for T cells to 'see.'

Multiple choice: Several subsets of innate lymphoid cells (ILCs) have been identified that share their patterns of cytokine production with the known subsets of T cells. The combined activity of related ILC and T cell subsets is effective in eradicating pathogenic infections because:

B.The ILCs are components of the innate response, as they respond rapidly following encounter with pathogens, and in most cases, these cells are resident in mucosal tissues. In contrast, T cells are slow to respond and are found recirculating through the blood and secondary lymphoid organs prior to their activation by specific antigen. The ILCs are thus positioned for rapid responses to pathogens that breach the barrier, and the cytokines they produce help control the infection, allowing time for the adaptive response to be initiated. The T cell response is more robust, owing to the clonal expansion of antigen-specific T cells, and these cells then migrate to the site of infection. Once there, the T cells produce cytokines that amplify the response started by the ILCs.

1.38 Multiple choice: Inherited immunodeficiency diseases result from a single gene defect in one component of the immune system. By identifying the class of microbial pathogens a given immunodeficient individual becomes susceptible to, studies of these diseases indicate: Which type of antibiotics each patient should be given The essential immune mechanism required for resistance to each category of pathogen Whether the disease is a genetically inherited or an acquired form of immunodeficiency Whether the immunodeficiency disease is likely to be transmitted to another individual Whether the disease is likely to be life-threatening or not

B.The study of immunodeficiency diseases has been extremely informative about the essential mechanisms required for immune protection against different classes of pathogens. For instance, these studies have shown that individuals lacking B cells or antibodies are highly susceptible to extracellular bacterial infections, but have normal responses to most viral infections.

Multiple choice: The skin and bodily secretions provide the first line of defense against infection. One response in this category that is common during upper respiratory virus infections is: Production of antibodies Infiltration by white blood cells Mucus production Increased saliva production Fever

Based on common experience, students should know that mucus production is a common response to upper respiratory virus infection. Other responses may also occur, such as fever, production of antibodies, or infiltration of white blood cells, but these are not 'bodily secretions.' Increased saliva is not a symptom common to upper respiratory infections.

Synthesis question: One major difference between the innate and adaptive immune responses is in the mechanism by which pathogens are recognized. Innate immune cells use pattern recognition receptors (PRRs) to recognize conserved determinants shared by all the members of a category of pathogens, whereas adaptive immune cells (B and T lymphocytes) have highly specific antigen receptors. Which of the patterns of receptor expression represent B and T lymphocytes?

C. B and T lymphocytes each express only a single specificity of antigen receptor; however, each B or T cell expresses a different receptor from the other cells of the same subset

Multiple choice: The formation of the C3 convertase is a key step in complement activation that occurs in all three complement pathways. This enzyme cleaves C3 in blood plasma, leading to a conformational change in the C3b fragment that exposes its reactive thioester group. The activated C3b is potentially harmful to the host, if it becomes covalently attached to a host cell, rather than to the surface of a pathogen. This deleterious outcome is largely avoided by:

C.Active C3b is highly labile, and is rapidly inactivated by hydrolysis. This prevents the C3b from remaining active should it diffuse away from the pathogen surface where it was activated by the C3 convertase.

Multiple choice: Patients with recurrent infections of Neisseria meningitidis, an extracellular bacterial pathogen that causes meningitis, were examined to determine the underlying cause of their immunodeficiency. A subset of these patients were found to have defects in complement activation on the bacterial surface, a process that for this bacterium is dominated by alternative complement activation leading to C3b deposition on the pathogen surface. When neutrophils from these patients were examined in vitro, the results in Figure Q2.19 were obtained. Based on these data, the identity of the green neutrophil mediator in Figure Q2.19 is likely to be:

C.Factor P (properdin) is made by neutrophils and stored in their granules. When neutrophils are activated by the presence of pathogens, factor P is released. Factor P binds to and stabilizes the reactive form of C3 (C3-H20) and the C3 convertase C3bBb. In the absence of factor P, the alternative complement pathway is inefficient, due to the rapid spontaneous inactivation of C3- H20 and C3bBb. This pathway is particularly important in protection against Neisseria meningitidis, and patients that are deficient in producing factor P are highly susceptible to infections with this pathogen.

Multiple choice: Naive B and T lymphocytes are small, quiescent cells with little cytoplasm and low metabolic activity. Yet within hours after being activated following encounter with their antigen, these cells enlarge and up-regulate many biosynthetic and metabolic pathways. Approximately one day later, the cells begin dividing, and for several days they are the most rapidly dividing cells in the body, undergoing 2-4 rounds of cell division every day. In order to maintain this phenomenal rate of cell division, lymphoblasts must:

C.Lymphoblasts up-regulate many biosynthetic and metabolic pathways to produce macromolecules and energy used for rapid cell division. Many of these processes require new mRNA and protein synthesis by the activated lymphocyte. For the purpose of energy production,lymphoblasts up-regulate glucose transporters and enzymes that are used in the glycolytic pathway

Multiple choice: Pathogenic infections induce damage to the host by a variety of mechanisms. While many mechanisms are direct effects of the pathogen, some damaging mechanisms result from the immune response to the infection, as illustrated in Figure Q2.2. Examples of damage caused by the host immune response are:

C.Pathogens cause direct tissue damage by the production of exotoxins or endotoxins, as well as by direct cytopathic effects. Tissue damage caused by the host immune response include damage caused by cell-mediated immunity and by the accumulation of immune complexes.

Multiple choice: Even when the complement cascade fails to proceed beyond generating the C3 convertase, complement activation is effective at inducing pathogen uptake and destruction. This process of immune protection is mediated by: Activation of complement inhibitory receptors on phagocytes that promote pathogen uptake Activation of soluble proteases in the serum that disrupt pathogen membranes Engagement of complement receptors on phagocytes by C3b and its cleavage products which promotes phagocytosis Engagement of complement receptors on B cells that promotes antibody production Stimulation of antimicrobial peptide secretion by phagocytes

C.Phagocytes have a variety of receptors that recognize C3b and fragments of C3b, such as iC3b. Engagement of these complement receptors stimulates phagocytosis of the C3b-coated pathogen, leading to pathogen destruction.

Multiple choice: Streptococcus pneumoniae is a Gram-positive bacterium that colonizes the mucosal surface of the upper respiratory tract in humans. The presence of this bacterium in the nose and throat is widespread in the population, and in most people, colonization with Strep. pneumoniae is asymptomatic. Figure Q2.7 shows a comparison of in vitro growth curves of the wild-type strain of Strep. pneumoniae, as well as a Strep. pneumoniae mutant strain with a defect in one bacterial gene. The graph on the right shows the growth curve following addition of lysozyme during the logarithmic phase of bacterial growth. Which statement could account for the data in these graphs?

C.Strep. pneumoniae is a Gram-positive bacterium that readily colonizes the human nose and mouth, due to the resistance of its peptidoglycan to degradation by lysozyme, an enzyme that is abundant in tears, saliva, and mucus. Wild-type Strep. pneumoniae is naturally lysozyme- resistant because a substantial proportion of GlcNAc residues in its peptidoglycan are deacetylated, and no longer substrates for lysozyme-mediated hydrolysis. This accounts for the prevalence of Strep. pneumoniae in the upper respiratory tract of healthy humans, where lysozyme is present at high concentrations. When one of these enzymes is missing, as in strain B, the bacteria become lysozyme-sensitive, and are killed by the lysozyme.fungi.

ultiple choice: Unlike B lymphocytes, T lymphocytes do not generate a secreted form of their antigen receptor after they are activated and proliferate. This is because the effector functions of T cells are restricted to: Responses important in protozoan infections, but not other types of infections Interactions with large helminthic parasites, which cannot be phagocytosed Interactions with other cells, such as virus-infected cells or other immune cells Responses important in mucosal surfaces (e.g., the lung), where antibodies cannot go Stimulating B cells and not any other types of cells

C.The effector functions of T cells are all restricted to interactions with other host cells, and not with the pathogen directly. These effector functions include killing of cells infected with intracellular pathogens (cytotoxic T cells), activation of B cells and macrophages (helper T cells), and suppressing the activity of other lymphocytes (regulatory T cells).

1.35 Short answer: T cells expressing the co-receptor CD8 are generally cytotoxic cells, with an important function in eliminating virus infections that can occur in many different cell types and tissues. In contrast, CD4 T cells directly interact with a very restricted set of cells, such as dendritic cells, macrophages, and B cells. Describe one important mechanism that accounts for this division of labor between CD8 and CD4 T cells.

CD8 T cells recognize antigenic peptides bound to MHC class I molecules, which are expressed on nearly all cells of the body. Therefore, any cell type that becomes virus-infected would be able to present viral peptides on MHC class I molecules for recognition by CD8 T cells. In contrast, CD4 T cells recognize antigenic peptides bound to MHC class II molecules. MHC class II proteins are expressed only on other cells of the immune system, such as dendritic cells, macrophages, and B cells. Due to the restricted expression of MHC class II proteins, CD4 T cells are restricted to interacting with these cells of the immune system.

Multiple choice: One form of anemia results when individuals have a deficiency in the enzyme phosphatidylinositol glycan A (PIGA). This enzyme is required for the membrane attachment of proteins anchored by glycolipids to the plasma membrane, using what is called a 'GPI-linkage.' Included in the group of GPI-linked cell surface proteins is DAF/CD55. These individuals become anemic because:

D.Host cells express several complement-regulatory proteins on their surface. These proteins function to rapidly inactivate any C3bBb (active C3 convertase) that may form on the host cell membrane. Several of these complement regulatory proteins use GPI-linkages to attach to the host cell membrane. Included in this group is DAF/CD55, which competes with factor B for binding to C3b on the cell surface, and displaces Bb from any active C3 convertase that has already formed. The absence of DAF/CD55 makes host cells susceptible to complement-mediated lysis. For reasons that are not entirely clear, red blood cells are particularly susceptible to complement-mediated lysis and the absence of the GPI-linked subset of complement regulatory proteins is sufficient to cause red blood cell lysis leading to anemia.

Multiple choice: Mannose binding lectins (MBL) and ficolins are the two classes of proteins that can initiate the lectin pathway of complement activation. These proteins are selective for activating complement on the surfaces of microbial pathogens rather than host cells because:

D.MBL and ficolins have binding specificity for carbohydrate side chains and oligosaccharide modifications that are unique to microbial pathogens, and not found on host cells. MBL binds to mannose, fucose, and GlcNac residues, which are common on microbial glycans; in contrast, MBL does not bind to sialic residues, which terminate vertebrate glycans. Ficolins have specificity for binding to oligosaccharides containing acetylated sugars, a structure also only found on pathogen surfaces, not on host cells.

Short answer: Dendritic cells are phagocytic, but also capable of ingesting large amounts of extracellular fluid and its contents, a process known as macropinocytosis. What specialized function do dendritic cells have in immunity that might account for their need to perform macropinocytosis?

Dendritic cells are essential in activating T lymphocytes. Therefore, it is important that dendritic cells acquire all possible categories of threats. While many intact microorganisms can be taken up by phagocytosis, small toxins produced by pathogens are more efficiently ingested by macropinocytosis.

Multiple choice: Women with urinary tract infections caused by E. coli are generally treated with a course of antibiotics. A common complication of the antibiotic treatment is the occurrence of a vaginal yeast infection caused by Candida albicans, an organism that is normally present in very low numbers in the human vaginal tract. This complication occurs because:

E.Commensal organisms associated with all epithelial surfaces provide protection against colonization by pathogenic microbes. One mechanism is by competition for nutrients as well as for attachment sites on epithelial surfaces. Another mechanism is by producing metabolites that are toxic to other organisms. When these commensal microorganisms are eliminated by antibiotic treatment, pathogenic microbes are able to step into the void and establish an infection.

When complement proteins are covalently deposited onto the surface of a bacterium, this can sometimes lead to direct lysis of the bacterium. However, more commonly, the deposition of complement proteins onto the bacterial surface does not directly harm the bacterium. Instead, these complement proteins aid in bacterial elimination by: Recruiting antibodies to the bacterial surface, leading the antibody-dependent neutralization Providing a mechanism for phagocytes to use their Fc receptors to recognize and ingest the bacterium Cross-linking carbohydrate structures on the bacterial surface, thereby preventing the bacterium from replicating Stimulating B lymphocytes to produce more antibodies against the bacterium Providing a mechanism for phagocytes bearing complement receptors to recognize and ingest the bacterium

E.In most cases, the protective immune response elicited by a complement-tagged bacterium is the uptake and degradation of the bacterium by phagocytes expressing complement receptors. This includes both macrophages and neutrophils, both of which express complement receptors. In addition to aiding in bacterial engulfment, binding of the complement proteins on the bacterium to the complement receptors on the phagocyte can also enhance the production of microbicidal effector functions in the phagocyte.

2.26 Multiple choice: The terminal components of the complement pathway assemble to form a membrane attack complex that can induce pathogen lysis and death. Yet, evidence indicates that this feature of complement is less important than the earlier steps that promote pathogen opsonization and induce inflammation. This conclusion is based on:

E.Patients with genetic deficiencies in terminal complement components show only a limited increase in susceptibility to infection. These individuals are more susceptible to infection by Neisseria species that cause gonorrhea or meningitis. Otherwise, these individuals show no other increased susceptibility to infection, indicating that formation of the membrane attack complex is a less important aspect of complement activation compared to the earlier steps that lead to opsonization of the pathogen as well as inducing inflammation.

Multiple choice: Individuals with defects in T cell development have a severe immunodeficiency disease called SCID (severe combined immunodeficiency disease). In these individuals, the absence of all T cells causes defects in both cell-mediated (T cell- based) and humoral (antibody-based) immune responses. The defect in antibody responses in SCID patients is due to: The important role of T cells in regulating B cell development in the bone marrow The inter-dependence of T cells and B cells for the normal development of secondary lymphoid organs. The absence of phagocytic cells needed for antibody-dependent pathogen clearance in SCID patients The poor survival of B cells in patients with defects in their T cells The important role of T follicular helper cells in generating protective antibody responses

E.T follicular helper cells are a subset of CD4 T cell that provide signals needed for B cell activation and the generation of protective antibody responses to most infections. In the absence of T cells, antibody responses are poor and generally not sufficient for pathogen clearance.

Multiple choice: The alternative pathway of complement activation has an important role in innate immunity, due to its ability to greatly amplify the amount of C3b deposited onto the pathogen surface. This amplification occurs because:

E.The C3 convertase (C3bBb) of the alternative pathway contains C3b, allowing it to generate more of itself and amplify the overall level of C3b formed. Once additional molecules of C3b are made by C3bBb, these can recruit additional molecules of factor B and the plasma protease factor D. Factor D cleaves factor B, and one of the products, Bb, remains associated with C3b, forming more active C3 convertase.

Multiple choice: The production of antimicrobial peptides is one of the most evolutionarily ancient mechanisms of defense for multicellular organisms, and most eukaryotic species make many different forms of these proteins. For instance, human paneth cells in the gastrointestinal epithelium make 21 different defensins. The reason for this diversity of antimicrobial peptides i:

E.The diversity of antimicrobial peptides is a reflection of the diversity of microbial pathogens that they attack. Some antimicrobial peptides are active against Gram-negative bacteria, while others are only active against Gram-positive bacteria. Other antimicrobial peptides are only active against fungal pathogens, and some are able to disrupt the membrane envelopes of some viruses.

ynthesis question: The immune system uses several types of effector modules to protect us against different categories of pathogens. Which of these categories might be effectively eliminated by innate immune responses that include antimicrobial peptides and phagocytic cells such as neutrophils and macrophages? Explain your answer.

Extracellular bacteria and fungi. These pathogenic microbes are often efficiently cleared by the innate immune response. The pathogens express PAMPs that stimulate PRR on innate cells in the infected tissue, such as macrophages and dendritic cells. These activated macrophages and dendritic cells induce an inflammatory response. The inflammatory response leads to the influx of fluid and phagocytic cells into the site of infection. The fluid contains some preexisting antibodies and complement proteins, that will 'tag' the microbes. The inflammatory response also recruits neutrophils and monocytes from the blood, which will phagocytose and destroy the bacteria or fungi. In many cases, this response is sufficient to eliminate the infection, without the necessity for an adaptive immune response.

ynthesis question: The immune system uses several types of effector modules to protect us against different categories of pathogens. b) Which of these categories of pathogenic organisms might be most effectively dealt with by antibodies, if the innate response is insufficient for their eradication?

Extracellular bacteria and fungi; helminthic parasites. These extracellular pathogens will elicit antibody responses, if they are able to avoid clearance by innate immune responses. Antibodies will coat the pathogens, leading to activation of innate immune cells that ultimately do the 'dirty work' of eliminating the pathogen. In the case of extracellular bacteria and fungi, the antibody-coated microbes are readily engulfed by phagocytic cells and destroyed. In the case of helminthic parasites, antibody-coated parasites will elicit activation of basophils and eosinophils that deposit toxic compounds onto the parasite surface.

2.3 True/False: Mucosal surfaces and external epithelia are major routes of pathogenic infection. Mucosal surfaces are found in tissues such as the gastrointestinal tract, the reproductive tract and the mouth and respiratory tract. While the mouth and respiratory tract are routes of virus but not bacterial infections, the gastrointestinal tract is the route for bacterial but not virus infections.

False.Both bacterial and virus infections can use both the mouth and respiratory tract and the gastrointestinal tract. There is no route of infection that is specific for a single category of pathogen.

True/False: Our immune system efficiently kills all categories of microbes that attempt to colonize our bodies.

False.Not all microbes are pathogens, and our immune system does not attempt to eliminate all non- pathogenic microbes. Consequently, many body surfaces are colonized by large numbers of non-pathogenic microbes. These are called commensal micro-organisms, and they are found in places like the gastrointestinal tract, the skin, and the oral mucosa.

True/False: The C3 convertase amplifies the process of complement activation by generating large amounts of C3b and cleaving large numbers of C5 molecules.

False.The C3 convertase does generate large numbers of C3b molecules which become attached to the pathogen surface in the vicinity of the convertase. This enzyme can only cleave C5 when bound to a molecule of C3b, generating the C5 convertase. The generation of the C5 convertase occurs at a much lower level than the C3 convertase, and many fewer molecules of C5 than C3 are cleaved.

True/False: The classical and lectin pathways of complement activation converge at the step of C3 activation. However, the initiating steps of each pathway use protein components and enzymatic mechanisms that share no similarity with each other.

False.The initiating steps of the classical and lectin pathways of complement activation are remarkably conserved in their mechanisms. The pathogen recognition component of the classical pathway, C1q, has structural similarity to MBL and the ficolins. The C1r and C1s components of the classical pathway, that are activated to form the serine protease, are closely related to the MASP proteins of the lectin pathway.

Short answer: Infants and young children with deficiencies in specific complement components present with recurrent respiratory infections caused by extracellular bacteria. The peak age of susceptibility is between 6 and 12 months after birth. At this time, as shown in Figure Q2.12, maternal antibodies acquired by the child during fetal gestation are nearly gone, but the child is not yet generating robust antibody responses to new infections, as indicated by the low circulating levels of IgG and IgA. As children with this immunodeficiency get older, they outgrow this disease and show no further evidence of these recurrent infections. Based on this information, name one likely gene deficiency (in the complement system) that could cause this primary immunodeficiency, and the specific complement pathway likely to be affected. Explain your answer.

MBL or MASP.Infants and small children with defects in MBL or MASP show recurrent upper respiratory infections by extracellular bacteria. This is due to a defect in the lectin pathway of complement activation. When maternal antibodies wane and the child is not yet generating robust antibody responses on its own, complement activation cannot proceed by the classical pathway. During this time, protection against upper respiratory bacterial infections is highly dependent on the lectin pathway, initiated by MBL or collectin binding to the pathogen. The information provided rule out the alternative pathway, which is initiated by spontaneous C3 cleavage. If there was a defect in C3, or a downstream component of the complement cascade shared by all three pathways, the recurrent infections would not disappear as children age.

Multiple choice: The mucosal tissues of the body have their own unique set of immune structures that function as sites for initiating adaptive immune responses. The necessity for mucosa-associated lymphoid tissues to have unique cell types (M cells) and structures is because: The mucous layer lining mucosal surfaces makes it difficult for normal antigen- presenting cells to function. The epithelial surfaces that line the gut, lungs, and nasal passages prevent antigen-presenting cells from accessing microbes and microbial products. The epithelial cells found in mucosal tissues are distinct from those that provide barrier functions to the skin. Mucosal sites, where most pathogens access the body, are exposed to vast numbers of diverse microbes. Mucosal tissues lack innate sensor cells that can respond to PAMPs and provide short-term innate immune protection.

Mucosal sites, such as the intestine, the reproductive tract, and the lungs are the locations in the body exposed to the greatest numbers and diversities of microbes. Most of those microbes are non-pathogenic, but a subset is capable of causing disease (i.e., is pathogenic). As a consequence, these mucosal sites have developed several unique mechanisms for immune protection. One of these is the presence of M cells that sample the antigens outside the epithelial barrier for surveillance by lymphocytes. Another is the presence of multiple subsets of tissue-resident lymphocytes that provide rapid responses to pathogens that breach the barrier.

Short answer: The effector activities important in eliminating infectious organisms from our bodies can be categorized into four different groups: cytotoxicity, intracellular immunity, mucosal and barrier immunity, and extracellular immunity. Briefly describe why the immune system requires four different effector modules for maximum protection.

Pathogenic microorganisms can be divided into groups based on their lifestyle in the host. Each of these lifestyles requires a different set of effector mechanisms for pathogen eradication. Cytotoxic activity is required to eliminate virus infections, which can take place in many different cell types in the body. Intracellular immunity is required for pathogens that have evolved to live inside phagocytes. Mucosal and barrier immunity is required for large parasites that generally enter the body through mucosal sites and cannot be engulfed by phagocytes. Extracellular immunity is required for most smaller extracellular pathogens that can be engulfed and eliminated by phagocytes.

Short answer: Pathogenic organisms cause damage to the host by a variety of mechanisms, depending on the category of the pathogen and its mode of replication in the host. Give an example of two different types of pathogens that are unlikely to be dealt with by the same mechanism of immune protection.

Pathogenic organisms that are very small (viruses, intracellular bacteria, single-cell parasites) will replicate inside host cells, and often induce cell lysis. Slightly larger pathogens are usually extracellular bacteria or fungi. These extracellular microbes cause damage by releasing toxins into the circulation. The largest pathogens are the helminthic parasites, which are too large to invade host cells. These organisms damage tissues by forming cysts that promote destructive responses in the tissues. In each case, the immune mechanisms required to eliminate the pathogen are different. Most notably, the mechanisms required to eliminate intracellular pathogens are different than those needed to eliminate extracellular pathogens.

Synthesis question: Four different clinical isolates of the Gram-positive bacterium, Staphylococcus aureus, are tested for their abilities to resist innate immune defense mechanisms. For these experiments, each bacterial strain is first grown in culture to achieve log-phase replication, and then cultures are supplemented with dilutions of human serum containing normal serum proteins as well as antibodies capable of binding to S. aureus. One hour later, the cultures are analyzed and the numbers of live bacteria are quantitated. c) From these data, what is the most likely mechanism killing S. aureus strain A? What about strain C?

Since strain A is still killed following depletion of antibody, but not following depletion of C3, it is likely that strain A is susceptible to the lectin pathway of complement activation, initiated by binding of ficolin (or collectin) to the bacterial surface. Ficolins are the most likely initiators of complement activation in this case, as they are at high concentrations in the serum. Although it is theoretically possible that strain A is killed by the alternative pathway of complement activation, this possibility is unlikely. The spontaneous hydrolysis of C3 produces a fluid-phase C3 convertase that is very short-lived. This fluid- phase C3 convertase is stabilized by properdin (factor P), which is only produced by neutrophils when they are activated by pathogens. Therefore, there is unlikely to be factor P in the serum used in this study, and therefore, the alternative pathway of complement activation would be very inefficient. Strain C is no longer killed following depletion of antibody. Therefore, strain C is likely susceptible to the classical pathway of complement activation.

Multiple choice: An infant with recurrent bacterial and fungal infections is suspected to have an immunodeficiency disease. Within two days after exposure to a pathogen, the organisms have proliferated to dangerous levels requiring immediate systemic antibiotic treatment. It is unlikely that this infant has a defect in B or T lymphocyte responses to the infection because:

The adaptive immune response, consisting of responses by B and T lymphocytes, takes approximately one week to become effective and participate in controlling an infection. The defect in this infant is in the very early innate response, which controls the infection during the first several days after exposure.

Short answer: Our environment contains masses of microorganisms, many of which reside as commensal organisms on our body's mucosal and epithelial surfaces without causing disease. What two features distinguish a pathogenic microbe from these commensal microbes?

The first important feature of a pathogenic microbe is that it must establish a replicating colony of organisms in our body. This can occur by the pathogen crossing an epithelial barrier and replicating in the tissue, or by attaching to the epithelial surface and establishing a colony there. The second feature is that the pathogen needs to have special mechanisms to evade the innate immune response.

Multiple choice: The best evidence supporting the concept of immunological memory is: The increased numbers of antigen receptors expressed by lymphocytes after primary exposure to an antigen The increased levels of cytokines made by lymphocytes after primary exposure to an antigen The increased rapidity and magnitude of the secondary response to the same antigen The increased swelling of lymph nodes during the secondary response to the same antigen The long lifespan of vertebrates, which would be impossible without immunological memory

The most compelling evidence supporting the existence of immunological memory is the fact that the secondary response to an antigen is faster, of higher magnitude, and more effective than the response that occurs following an individual's first exposure to that antigen. This is the basis of vaccination.

Synthesis question: One major difference between the innate and adaptive immune responses is in the mechanism by which pathogens are recognized. Innate immune cells use pattern recognition receptors (PRRs) to recognize conserved determinants shared by all the members of a category of pathogens, whereas adaptive immune cells (B and T lymphocytes) have highly specific antigen receptors. c) Following an infection, how does the population of innate cells change? Starting with the cartoon representing your answer to part (a), draw the population present at one week post-infection.

The population of innate cells is largely unchanged before and after infection.

Multiple choice: Some Pattern Recognition Receptors (PRRs) recognize nucleic acids, like RNA or DNA. Since our own cells contain human RNA and DNA, the activation of innate immune pathways by these PRRs must rely on additional criteria to discriminate self from nonself. Additional criteria include everything EXCEPT: The subcellular location of the RNA The presence of adenosine residues in viral RNA The methylation state of the DNA Unique structures found on viral RNA The subcellular location of the DNA

The presence of adenosine residues would not discriminate between viral and host RNA, as both types contain these residues.

Synthesis question: One major difference between the innate and adaptive immune responses is in the mechanism by which pathogens are recognized. Innate immune cells use pattern recognition receptors (PRRs) to recognize conserved determinants shared by all the members of a category of pathogens, whereas adaptive immune cells (B and T lymphocytes) have highly specific antigen receptors. d) Following infection, how does the population of B and T lymphocytes change? Starting with the cartoon representing your answer to part (b), draw the population present at one week post-infection.

The rare B or T lymphocyte with an antigen receptor specific for the pathogen undergoes clonal expansion. This population is therefore much more abundant after infection than before. All other lymphocytes remain unchanged.

hort answer: The immune system evolved to protect us against infections from pathogenic microorganisms. However, immune responses can also cause, rather than prevent disease. Give two examples of situations in which an immune response causes a disease, whereas the absence of a response has no consequences.

There are several cases in which immune responses can cause diseases, whereas their absence is a neutral event. One example is allergic responses to non-threatening antigens, such as food items, antibiotics, metal ions, or inhaled substances. Another example is autoimmune diseases, in which individuals make destructive immune responses to their own cells or tissues. Graft rejection in transplant patients is another possible example, although it doesn't quite fit the criterion of being 'an immune response that causes disease,' since in this case, the immune response is prevented 'the cure' rather than causing the disease.

True/False: Neutrophils regulate the production of active cathelicidins (a class of antimicrobial peptides) by segregating the inactive propeptide from the processing enzyme that cleaves and activates it in two different types of cytoplasmic granules. These two types of granules are induced to fuse with phagosomes after ingestion of microbes, bringing the processing enzyme and the propeptide together.

True.All antimicrobial peptides, including cathelicidins, are produced as inactive propeptides. The active forms of the peptides are generated following proteolytic cleavage of the propeptides. Neutrophils constitutively produce cathelicidins, which are synthesized as inactive propeptides. The inactive cathelicidin propeptides are stored in secondary granules, whereas the cleavage enzyme, neutrophil elastase, is stored in primary granules. These two types of granules are induced to fuse with phagocytic vesicles, called phagosomes, after the neutrophil has engulfed a pathogen. This fusion brings the cleavage enzyme together with the cathelicidin propeptide, leading to cathelicidin activation.

true/False: Several pathogens produce proteins, either membrane-bound or secreted, that inactivate C3b that might be deposited on the pathogen surface. C3b is specifically targeted due to its central position in all three complement pathways.

True.All three pathways of complement activation converge on the assembly of a C3 convertase that produces C3b bound to the pathogen surface. Therefore, pathogens that can inactivate bound C3b can interfere with complement activation that might be initiated by any of the three pathways. This makes C3b an ideal target for an immune evasions strategy.

True/False: Innate lymphoid cells and NK cells are effector cells that respond rapidly after encountering a pathogen. Several different subsets of innate lymphoid cells exist, and each is specialized to respond to a category of pathogen (e.g., viruses, extracellular bacteria, helminthic parasites, etc). Innate lymphoid cells reside primarily in tissues such as the lungs, the lining of the gastrointestinal tract, and the skin, because these sites represent the major routes of entry of pathogens into the body.

True.Innate lymphoid cells are tissue-resident cells found primarily in the lung epithelium, the skin, and the intestinal epithelium. Since most pathogens enter the body through one of these sites, it is important to post innate immune cells in these locations where they will readily encounter a pathogen that has breached one of the body's barriers.

True/False: The C3 convertase of the alternative complement pathway amplifies the overall magnitude of complement activation regardless of which of the three pathways initiated the complement activation initially.

True.The C3 convertase of the alternative pathway contains C3b, allowing it to generate more of itself and amplify the overall level of C3b formed. Since C3b is a common intermediate for all three pathways of complement activation, once the initial C3b is generated by any of the pathways, the recruitment of factor B, and cleavage by factor D can proceed. By this mechanism, the initial C3b generated forms an amplification loop leading to more C3b, regardless of how the initial C3b was made.

rue/False: The spleen is a secondary lymphoid organ that performs several functions. In addition to its role as a site for initiating adaptive immune responses, the spleen is important in removing dead or damaged red blood cells from the circulation. Its immune function is important because blood-borne pathogens will not be transported to draining lymph nodes via the lymph fluid.

True.The spleen is important for trapping blood-borne pathogens so they can be taken up and degraded by dendritic cells for presentation to T lymphocytes to initiate adaptive immune responses

Short answer: Although homozygous deficiencies in complement regulatory proteins cause serious diseases, more subtle alterations in the balance of complement activation versus inhibition have been found to contribute to disease susceptibility. Describe the genetic evidence linking subtle alterations in complement regulatory proteins to disease susceptibility.

Two types of genetic alterations in complement regulatory proteins have been linked to disease susceptibility. First, individuals heterozygous for mutations in one of several complement regulatory proteins (MCP, factor I, factor H). These individuals are predisposed to develop a hemolytic disease that leads to damage to platelets and red blood cells, and to kidney inflammation. Second, individuals with particular single-nucleotide polymorphisms in the gene for factor H are predisposed to macular degeneration, an age-related disease that causes blindness. Furthermore, polymorphisms in other complement genes have been found to contribute to the susceptibility to age-related macular degeneration.

ltiple choice: Adaptive immune responses are slow to develop, taking days to weeks after exposure to reach their peak. However, these responses are more specific than innate responses, and also generate immunological memory. These latter features, which provide enhanced protection upon re-infection with the same pathogen, are the basis of: Vaccines Antibiotics Systemic shock Complement activation Phagocytosis

Vaccines are designed to generate an adaptive immune response to a non-disease-causing form of a pathogen, or a pathogen product. Due to the specificity of this response, and the generation of immunological memory, vaccinated individuals make a substantially more robust response, and are often completed protected from infection, when exposed to the pathogen at a later time.

Multiple choice: Vaccination against many infectious diseases has provided enormous benefit in developed countries, leading to the virtual eradication of diseases such as polio, measles, smallpox, and others. However, efforts to create long-lasting vaccines against some viral infections, like Influenza and HIV, have not been successful to date because:

Viruses like HIV and influenza undergo rapid antigenic variation. Therefore, an immune response against one strain of the virus will not usually protect individuals from infection with a variant strain. Therefore, much of the current effort toward developing vaccines against these viruses aims at targeting highly conserved regions of the virus, where an immune response would be broadly reactive to many viral variants.

ynthesis question: The immune system uses several types of effector modules to protect us against different categories of pathogens. c) Which of these categories of pathogenic organisms would require T lymphocyte responses for their elimination?

Viruses; intracellular bacteria and protozoa. Microbes that replicate inside host cells cannot be eliminated by antibody-dependent mechanisms. Instead, T cells are required for eradicating these infections. In the case of viruses, cytotoxic T cells will recognize and kill virus-infected cells. In the case of intracellular bacteria and protozoa, these microbes generally infect and replicate in macrophages. Their elimination is dependent on CD4 T cells that will activate the infected macrophage to up-regulate multiple microbicidal mechanisms for killing the intracellular pathogen.

Short answer: Recent studies using mouse models of pulmonary inflammation (a model for human asthma) have found that mice deficient in the C3a receptor have greatly reduced disease symptoms when challenged with inhaled preparations containing extracts of the fungal pathogen Aspergillus fumigatus. Specifically, the C3a receptor- deficient mice showed reduced influx of granulocytes and lymphocytes into the lung and reduced fluid in the lung after challenge. What is the explanation for these findings?

When complement is activated in the lung in response to the inhaled preparations of the fungus, the C3 convertase generates C3a. C3a induces a local inflammatory response in the lung, by acting on the vascular endothelial cells. This response includes increased vascular permeability, leading to an increase of fluid in the lung, and also acts to up-regulate adhesion molecules on the local vascular endothelium. As a result, there is increased recruitment of granulocytes, monocytes, and lymphocytes into the lung.

Synthesis question: Four different clinical isolates of the Gram-positive bacterium, Staphylococcus aureus, are tested for their abilities to resist innate immune defense mechanisms. For these experiments, each bacterial strain is first grown in culture to achieve log-phase replication, and then cultures are supplemented with dilutions of human serum containing normal serum proteins as well as antibodies capable of binding to S. aureus. One hour later, the cultures are analyzed and the numbers of live bacteria are quantitated. a) From these data, what general conclusions can be reached about the four strains of S. aureus? To identify the bactericidal mechanisms killing each strain of S. aureus, the serum is depleted of complement C3 by running it over an anti-complement C3 antibody affinity column. The experiment above is then repeated and the data are shown in Figure Q2.31B.

a) Strain A and strain C are equally sensitive to a serum component (or set of components) that can kill S. aureus. Strain B is resistant to all possible serum components that can kill S. aureus. Strain D is also sensitive to a serum component(s) that can kill S. aureus, but is killed by a different mechanism than the one(s) killing strains A and C. This latter conclusion is based on the observation that the factor(s) killing strain D are no longer active when the serum is diluted 1:16, whereas the activities that kill strains A and C are still active at this dilution.

Short answer: In vertebrates, complement activation generally involves a pathogen recognition step followed by a proteolytic cascade that produces the effector proteins that function in opsonization, membrane attack, and inflammation.a) Which of these is likely to be the most evolutionarily primitive aspect of the complement system? b) Which pathway of complement initiation is likely to be the one that most recently evolved?

a) The most primitive form of a complement system is one that resembles our alternative complement pathway, with ancestral homologs of C3 and factor B that make a C3 convertase. This provides a mechanism for opsonizing infecting bacteria and increasing their phagocytosis by phagocytic cells. These ancestral homologs of C3 and factor B have been found in echinoderms, and may even have existed in even more primitive organisms such as corals and sea anemones. b) The latest evolutionary development in the complement system is the classical pathway, which makes use of antibody binding to initiate complement activation. The adaptive immune system, including the production of antibodies, is only found in vertebrates.

1.42 Synthesis question: For each of the panels A-D in Figure Q1.42, identify the most likely component(s) of the immune response indicated by the red arrow, and briefly describe your reasoning.

a. Innate immune response. The cells responding could be mast cells, dendritic cells, macrophages, or ILCs. The response initiates rapidly (<1 day) and lasts for 2-3 days, then disappears. b. Primary adaptive immune response. Upon first exposure to antigen or pathogen, the response of B cells or T cells takes approximately 1 week to arise. It lasts for two weeks or so, then wanes. c. Memory response of adaptive immune cells. Upon secondary exposure to the same antigen or pathogen, the response of B or T lymphocytes is more rapid than the primary response, and generates a response of greater magnitude than the primary response. d.Primary adaptive immune response to a different antigen. Each time the immune system encounters an antigen/pathogen for the first time, a primary response is generated. This response will look similar each time. It is only when the same antigen/pathogen is encountered for a second time that a more rapid and more robust adaptive immune response is generated.

Synthesis question: Four different clinical isolates of the Gram-positive bacterium, Staphylococcus aureus, are tested for their abilities to resist innate immune defense mechanisms. For these experiments, each bacterial strain is first grown in culture to achieve log-phase replication, and then cultures are supplemented with dilutions of human serum containing normal serum proteins as well as antibodies capable of binding to S. aureus. One hour later, the cultures are analyzed and the numbers of live bacteria are quantitated. b) What is the most likely mechanism accounting for the killing of strain D in this experiment? To determine whether strains A and C are susceptible to the same microbicidal pathway, the serum is depleted of antibody by running over an anti-human immunoglobulin affinity column. Following this treatment, it is found that strain A, but not strain C is still killed by incubation with the serum.

b) Strains A and C are no longer killed when complement C3 is depleted from the serum. This indicates that these two strains are susceptible to complement-mediated lysis. The killing of strain D is not affected by depletion of C3, indicating a distinct mechanism. Strain D is most likely being killed by defensins, or another antimicrobial peptide. It is unlikely that strain D is being killed by lysozyme in these experiments, as lysozyme is predominantly found in tears and saliva, rather than in serum.

In patients with lymphomas, the cancer cells invade the bone marrow and destroy the environment required for normal hematopoiesis. This leads to bone marrow failure, which disrupts the production of hematopoietic cell lineages. All of the following cell types would be affected by this EXCEPT:

endothelial cells

Multiple choice: The antigen receptor on a T cell recognizes a degraded fragment of a protein (i.e., a peptide) bound to a specialized cell surface peptide-binding receptor called an MHC molecule. One key aspect of this system is that the peptides displayed on MHC molecules can be derived from intracellular proteins. This mode of antigen recognition is particularly important in allowing the adaptive immune response to detect infections by:

ntibody diversity is generated when each developing B cell undergoes a DNA rearrangement process. This process involves the combination of small gene segments, encoded as separate elements in the genome, to form a complete coding sequence for the antibody protein. As a result of this process, the DNA of the B cell is irrevocably altered, and would no longer be able to transmit all the genetic information to the next generation.

True/False: In the absence of an infection, most granulocytes (neutrophils, eosinophils, basophils) are found circulating in the blood, whereas other subsets of myeloid cells reside in tissues.

true Mast cells and macrophages are both cells of the myeloid lineage. These are tissue-resident cells that are poised to respond rapidly if an infectious microbe enters their tissue of residence.

Multiple choice: Antibodies, complement proteins, and phagocytic cells provide effective protection against all of the following types of infections in Figure Q2.1, except

virus infected cells