Immunology

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: A. In vitro experiments showing that very few species of bacteria are susceptible to lysis by the membrane attack complex B. Experiments indicating that only bacteria, but not viruses or fungi, are susceptible to lysis by the membrane attack complex C. The very low levels of terminal complement components in the serum D. The fact that other mammalian species lack the terminal components of the complement pathway needed to form the membrane attack complex E. The limited susceptibility to infections of patients with deficiencies in terminal complement components

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.

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. Two of the three pathways for complement activation are initiated by constitutively produced recognition molecules that directly interact with microbial surfaces. B. When the complement cascade leads to the formation of a membrane-attack complex, the pathogen is killed. C. Several of the soluble products generated by complement activation lead promote the inflammatory response. D. Complement proteins bound to the pathogen promote uptake and destruction by phagocytic cells. E. The C3 convertase is only produced when complement activation is initiated by antibody binding to a pathogen.

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.

RIG-I like receptors (RLRs) such as RIG-I, MDA-5, and STING are cytoplasmic nucleic acid sensors. Give two examples of how such innate sensors distinguish between the RNA/DNA of the host from that of an infecting pathogen.

1. Unique structure: RIG-I recognizes single-stranded RNA that lacks the 5′-cap structure found on mammalian mRNA. A second example is MDA-5, which recognizes double-stranded RNA, a form of RNA not generally found in healthy host cells. A third example is STING, which recognizes cyclic dinucleotides made by bacteria, but not by host cells. 2. Localization: Innate DNA sensors recognize double-stranded DNA found in the cytosol; in contrast, host DNA is generally localized to the nucleus. An example is cGAS, which binds to cytosolic DNA and stimulates the production of cyclic GMP-AMP (cGAMP) that, in turn, activates STING.

Signaling through the Drosophila Toll pathway is initiated when pathogen recognition receptors (PRRs) bind to microbial products, such as bacterial peptidoglycan. Aspects of this pathway share similarity to the mammalian complement cascade as well as to the innate recognition system based on TLRs. One feature of Toll signaling that resembles the complement pathway is: A. The activation of an extracellular proteolytic cascade involving cleavage of self-proteins B. The deposition of Toll signaling proteins onto the microbial surface C. The release of soluble fragments of Toll that induce inflammation D. The assembly of a membrane attack complex in the microbial membrane following Toll activation E. The presence of receptors for Toll cleavage products on phagocytic cells to promote pathogen ingestion

A. Like the complement cascade in mammals, Toll signaling is initiated by pathogen recognition receptors that activate the first step of a proteolytic cascade following recognition of microbial products. This extracellular proteolytic cascade ultimately ends with the cleavage of the Drosophila protein Spätzle. Cleavage of Spätzle changes its conformation, enabling it to bind to Toll and induce Toll dimerization, thereby initiating Toll signaling.

NK cells can be activated following recognition of a virus-infected cell, if that cell has down-regulated expression of MHC class I proteins on its surface. However, NK cells can also recognize infected cells or tumor cells, even if they still express MHC class I proteins. In this latter case, activating receptors on NK cells are recognizing: A. Molecules on the target cell up-regulated by cellular or metabolic stress B. Cytokines secreted by the virus-infected or tumor cell C. MHC class I-like decoy molecules encoded by the virus D. Mutated self-proteins expressed by the tumor cell E. Double-stranded DNA in the cytoplasm of the infected or tumor cell

A. One important receptor on NK cells is NKG2D, which forms a homodimer on the NK cell surface. This activating receptor binds to ligands that are MHC class I-like molecules induced by various types of cellular stress. For example, the ligands for NKG2D are expressed in response to cellular or metabolic stress, and so are up-regulated on cells infected with intracellular bacteria and most viruses, as well as on incipient tumor cells that have become malignantly transformed. Thus, recognition by NKG2D acts as a generalized 'danger' signal to the immune system.

Septic shock is a serious, often fatal response to an infection in the bloodstream. This response can be elicited in mice by intravenous injection of bacterial LPS. However, it was found that one strain of mice, C3H/HeJ, is resistant to LPS-induced shock. This fact was used to clone the gene for TLR-4 based on positional cloning from C3H/HeJ mice. Another example of a strain of mice that is resistant to LPS-induced septic shock is: A. TNF-receptor-deficient mice B. TLR-2-deficient mice. C. LFA-1-deficient mice D. Neutrophil-deficient mice E. Complement receptor-deficient mice

A. Septic shock is caused by a massive release of TNF-α into the bloodstream, which causes systemic vasodilation leading to a loss of blood pressure, and increased vascular permeability, which leads to a loss of plasma volume. TNF-α also causes blood clotting in small vessels throughout the body, leading to compromised blood perfusion of many organs and thus to organ failure. Mice with defects in TNF-α receptors or in which the ADAM17 gene (encoding TACE, the TNF-α-converting enzyme) has been inactivated in myeloid cells, are resistant to septic shock. TACE is needed to release TNF-α from the cell membrane of myeloid cells, generating soluble TNF-α that enters the bloodstream.

When stimulated by binding to bacterial products, the fMet-Leu-Phe (fMLF) receptor triggers multiple responses by phagocytes, including migration and induction of antimicrobial activities. Most of these responses are activated by small GTPases of the Rac and Rho families that are indirectly activated by fMLF receptor stimulation. The fMLF receptor can initiate multiple downstream signaling pathways because: A. It couples to a heterotrimeric G protein that has α and βγ subunits with independent activities. B. It couples directly to two different guanine nucleotide exchange factors (GEFs). C. It binds to Rac, Rho, and cdc42 directly. D. It promotes fusion of phagosomes with lysosomes, initiating multiple signals. E. It induces assembly of multiple enzymes from individual cytosolic components.

A. Signaling by the fMLF receptor induces cell motility, metabolism, gene expression, and cell division through activation of several Rac and Rho family small GTPase proteins. To accomplish this, the fMLF receptor, a member of the G-protein-coupled receptor family, activates a heterotrimeric G protein consisting of Gα, Gβ, and Gγ subunits. After receptor stimulation, the heterotrimeric G protein undergoes a conformational change, leading to the exchange of GDP for GTP by the Gα subunit. This causes dissociation of the trimer into two components, Gα and Gβγ, each of which has separate activities. The α subunit of the activated G protein indirectly activates Rac and Rho, while the βγ subunit indirectly activates the small GTPase Cdc42. Activation of these small GTPases is dependent on the activation of guanine nucleotide exchange factors (GEFs), one for each specific GTPase.

Stimulation of the nucleic acid sensing TLRs that reside in endosomal membranes induces the production of a different cytokine response than is produced by stimulation of the plasma membrane TLRs. In part, this distinction is based on the different adapter proteins used by the nucleic acid sensing TLRs, leading to the activation of IRF factors. The cytokine response following stimulation of nucleic acid-sensing TLRs is characterized by production of: A. The antiviral cytokine, type I interferon B. TNF-α, which induces increased vascular permeability C. Antimicrobial peptides by macrophages D. Chemokines that recruit neutrophils E. The inflammatory complement fragments, C3a and C5a

A. The nucleic acid sensing TLRs, such as TLR-3 and TLR-7, induce the activation of IRF transcription factors, leading to the secretion of antiviral type I interferons. Each of these two endosomal receptors uses a distinct signaling pathway, starting with the binding of distinct adapter proteins to induce IRF factor phosphorylation. However, consistent with their importance in innate responses to virus infections, these TLRs both induce transcription of type I interferon genes when they are stimulated.

The 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: A. They neutralize the virus or toxin, preventing it from attaching to and entering our cells. B. They bind to the virus or toxin and carry it to the liver where it can be degraded. C. They bind to the virus or toxin and directly induce lysis. D. They induce mucus production that helps flush the toxin or virus out of the body. E. 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.

The importance of complement activation as an innate immune defense against infections is illustrated by: A. The evolution of complement avoidance strategies by many pathogens B. The large number of proteins involved in the complement pathway C. The large number of complement regulatory pathways expressed by the host D. The existence of three different mechanisms for initiating complement activation E. The ability of the membrane attack complex to lyse some pathogens

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.

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. Ensure that pathogens are readily detected by the adaptive immune system before they replicate to high levels in the host B. Prevent B cells from being activated in response to antigens that are not pathogens C. Allow B cells to phagocytose the pathogen and help destroy it D. Induce increased rounds of B cell replication to make more pathogen-specific B cells E. Allow the B cell to block pathogen replication by interfering with multiple pathogen surface functions

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.

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: A. Increase their permeability, allowing fluid and proteins to leak into the tissue B. Solidify the tight junctions to prevent the bacteria from entering the blood C. Proliferate, allowing the blood vessel to enlarge D. Up-regulate microbicidal mechanisms, so they can kill bacteria E. 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.

The pattern recognition receptors on cells of the innate immune system are genetically encoded, meaning that their sequences and specificities are determined prior to the development of the individual. In contrast, the antigen receptors of B and T lymphocytes arise from a random rearrangement process that occurs differently in each lymphocyte as it develops. One potential problem entailed by the random process that generates lymphocyte antigen receptors is the possibility that: A. Some antigen receptors might recognize the individuals on cells or antigens B. Many lymphocytes might generate antigen receptors that don't recognize anything C. Many lymphocytes might generate antigen receptors that recognize multiple different pathogens D. Some antigen receptors might recognize foreign tissues and lead to graft rejection during organ transplantation E. Some lymphocytes might not generate functional antigen receptor proteins

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.

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: A. It concentrates antigens in centralized locations for rare lymphocytes to encounter B. It provides the optimal environment for the rapid proliferation of lymphocytes C. It traps the pathogens and antigens in a contained environment so they cannot spread to other tissues in the body D. It helps the innate immune cells eliminate the infection by using lymphatic fluid to drain pathogens from the infected tissue E. It filters the lymph fluid and removes pathogenic organisms before they can enter the bloodstream

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 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: A. The extensive polymorphism of MHC genes in the human population B. The fact that transplanted tissues often carry infectious microbes into the recipient C. The fact that individuals may differ in their blood group antigens (i.e., their blood type) D. The presence of many antigen-presenting-cells in the transplanted tissue E. The presence of many B and T lymphocytes in the transplanted tissue

A. 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.

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: A. Vaccines B. Antibiotics C. Systemic shock D. Complement activation E. Phagocytosis

A. 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 completely protected from infection, when exposed to the pathogen at a later time.

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: A. Viruses like HIV and Influenza undergo antigenic variation to evade previous immune responses. B. Viruses like HIV and Influenza spread too rapidly in the population for a vaccine to be effective. C. Viruses like HIV and Influenza have RNA, rather than DNA genomes, and are resistant to current vaccine strategies. D. Viruses like HIV and Influenza infect via mucosal surfaces, a route that is not well protected by current vaccine strategies. E. Viruses like HIV and Influenza are transmitted vertically (from mother to child) during fetal development, so babies are infected before they can be vaccinated.

A. 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.

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.

Antibody diversity is generated when each developing B cell undergoes a DNA rearrangement process (to differentiate into plasma cells). 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.

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 each express a unique antigen receptor, so only a small number of them will respond to any particular pathogenic infection. The majority of these cells won''t encounter their corresponding pathogen that binds to their antigen receptor, so they remain in an inactive state.

Many of the inflammatory mediators produced by tissue macrophages at sites of infection act on the endothelial cells lining the blood vessel walls. An exception to this is (are) the: A. Cytokines that induce increased vascular permeability B. Chemokines that induce directed migration of blood monocytes C. Cytokines that induce increased expression of adhesion molecules D. TNF produced by tissue-resident sensor cells E. Bradykinin produced that causes pain

B. Most of the inflammatory mediators produced by tissue-resident macrophages in response to infection act on vascular endothelial cells to cause blood vessel dilation, leakiness of endothelial junctions allowing fluid and proteins to leak out of the blood, and induce increased expression of adhesion molecules on endothelial cells. In contrast, the chemokines that are produced act on the white blood cells adhering to the endothelium. These chemokines induce the blood cells, such as monocytes, to migrate across the endothelium into the tissue and then direct the cells toward the site of infection in the tissue.

Antibodies, complement proteins, and phagocytic cells provide effective protection against all of the following types of infections except: A. Fungi B. Virus-infected cell C. Worms D. Bacteria C. Viruses

B. All extracellular forms of pathogens are targets for antibodies, complement, phagocytic cells and antibody-dependent immune clearance mechanisms. Once a pathogen, such as a virus or intracellular protozoan, invades a cell and begins replicating in the cell, these mechanisms are no longer able to clear the infection. These intracellular stages of pathogenic infection require cellular responses, such as those mediated by T cells or NK cells.

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 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: A. Complement regulatory proteins have dual functions in inhibiting and promoting complement activation. B. Uncontrolled complement activation leads to the depletion of serum complement proteins. C. The inhibition of the membrane attack complex by complement regulatory proteins normally leads to enhanced activation of the early steps of the complement pathway. D. Complement regulatory proteins normally cause the rapid depletion of plasma complement factors. E. Uncontrolled complement activation recruits the majority of phagocytic cells, leaving few remaining to fight infections in the tissues.

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.

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? A. C1q induces B lymphocytes to begin secreting antibody within hours of pathogen exposure. B. Natural antibody that binds to many microbial pathogens is produced prior to pathogen exposure. C. C1q binds to C-reactive protein which then binds to IgM on the pathogen surface. D. C1q directly induces inflammation, recruiting phagocytes and antibodies from the blood into the infected tissue. E. C1q binds to dendritic cells in the infected tissue, inducing them to secrete inflammatory cytokines.

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.

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: A. Large helminthic parasites in the gastrointestinal tract B. Intracellular pathogens, such as viruses and some protozoa C. Extracellular bacteria that colonize the lungs D. Fungi that form hyphae in the bronchial airways E. Fungal infections in the skin epithelium

B. T cells can only interact with host cells, so they can only affect pathogens inside the cell.

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: A. ILCs cannot kill the pathogen, whereas the antigen-specific T cells can kill the pathogen. B. The early response of ILCs that reside at the site of infection is followed by the later more robust response of pathogen-specific T cells that migrate to the site of infection. C. The ILCs activate B cells to induce antibody responses whereas the T cells are able to directly eliminate the pathogen. D. The ILCs are induced to migrate from the site of infection to the draining lymph nodes where they activate the antigen-specific T cells. E. The ILCs are activated to secrete antimicrobial compounds which cause them to lyse, releasing RNA and DNA that act on T cells to stimulate T cell cytotoxic activities.

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.

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: A. The subcellular location of the RNA B. The presence of adenosine residues in viral RNA C. The methylation state of the DNA D. Unique structures found on viral RNA E. The subcellular location of the DNA

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

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: A. Which type of antibiotics each patient should be given B. The essential immune mechanism required for resistance to each category of pathogen C. Whether the disease is a genetically inherited or an acquired form of immunodeficiency D. Whether the immunodeficiency disease is likely to be transmitted to another individual E. 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.

Cytokine receptors of the hematopoietin superfamily engage signaling pathways that begin with JAK kinases and lead to activation of STAT-family transcription factors. Each receptor subunit in this superfamily binds a specific JAK kinase (one of four members) and each receptor complex usually activates one major STAT homodimer (one of seven). The specificity for activation of one STAT homodimer by each cytokine is determined by: A. The specificity of each JAK kinase for only phosphorylating one or two out of the seven possible STAT members B. The specificity of each cytokine receptor complex to only activate one of the four Jak kinase members, which then homodimerizes C. The amino acid sequence surrounding the phosphorylated tyrosine on each cytokine receptor subunit's cytoplasmic tail D. The expression of only one STAT member in each type of immune cell, depending on which cytokine receptors are expressed E. The inhibition of all but one STAT protein by the inhibitor SOCS proteins expressed in each cell type

C. Following cytokine binding, the subunits of the cytokine receptor are induced to dimerize, bringing the associated JAK kinases (one on each subunit, in general) together. These kinases then phosphorylate each other, leading to kinase activation. The activated kinases then phosphorylate tyrosine residues on the cytoplasmic tail of one subunit, usually the subunit that is unique to each cytokine. This phosphorylated sequence on the receptor subunit tail is recognized by a specific STAT protein, which binds to the phosphorylated receptor. This brings the STAT protein into proximity with the activated JAK kinase, leading to STAT protein phosphorylation, dimerization, and migration into the nucleus.

Many different NOD-like receptors, including several with pyrin domains and several with HIN domains, can function to trigger inflammasome assembly leading to the activation of caspase-1. The reason for many different sensors in this innate response system is that: A. Each NOD-like receptor is expressed in a different set of phagocytic cells, depending on its tissue location. B. Each NOD-like receptor resides in a different intracellular compartment. C. Each NOD-like receptor performs a different step in the multi-step cascade leading to inflammasome activation. D. Each NOD-like receptor binds to a different adapter protein and triggers a different form of the inflammasome. E. Each NOD-like receptor recognizes different PAMPs and is activated by different pathogens.

C. IL-1 secretion by dendritic cells requires two signals. One signal is needed to induce the transcription of the IL-1 mRNA by the cells. This signal is often provided by stimulation of a TLR expressed on the dendritic cells. In this example, the S. aureus membrane prep or the live S. aureus bacteria would provide the ligand for TLR stimulation. The second signal needed for IL-1 secretion is the activation of the inflammasome, leading to caspase-1-mediated cleavage of the pro-IL-1 protein. This second signal is provided by the S. aureus toxin or by the live bacteria, which would be producing the toxin. Without both of these signals, no IL-1 is secreted by the dendritic cells.

The first pattern recognition receptor (PRR) important in innate immune responses was discovered in the fruit fly Drosophila melanogaster. Stimulation of this receptor, called Toll, induces: A. The synthesis of prostaglandins and leukotrienes B. The inflammatory response in Drosophila hemolymph vessels C. The production of antimicrobial peptides D. The recruitment of phagocytic cells to the site of infection E. The activation of Drosophila complement

C. In response to activation of Toll by Gram-positive bacteria and some fungi, transcription factors related to mammalian NFκB are activated. This pathway leads to the expression of host defense proteins, including several antimicrobial peptides.

NK cells express receptors from several families, each of which has multiple members. Some of these receptors are activating and others are inhibitory, and NK cell activation is dependent on the balance of signaling overall. The individual NK cells in an individual: A. Always express a majority of activating versus inhibitory receptors B. Are more potent effectors of cytotoxicity than of cytokine-production C. Each express only a subset of all possible NK receptors D. Are not considered members of the innate lymphoid cell lineage E. Undergo massive proliferation in response to infection, similar to T lymphocytes

C. NK receptors belong to several different families, including the killer cell immunoglobulin-like receptor family (KIRs), the killer cell lectin-like receptors (KLRs), and in mice, the Ly49 receptors. Within each family, individual receptors can be activating or inhibitory, and are highly polymorphic between different strains of mice. An important feature of the NK-cell population is that any given NK cell expresses only a subset of the receptors in its potential repertoire, and so not all NK cells in the individual are identical.

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: A. The inability of active C3b to diffuse away in the blood plasma. B. The inability of active C3b to covalently attach to the membranes of eukaryotic cells. C. The rapid hydrolysis of active C3b in solution, rendering it inactive. D. The tight binding of active C3b to the C3 convertase. E. The ability of active C3b to recruit phagocytic cells.

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.

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: A. Use the large energy stores accumulated by them when they were naive quiescent cells prior to their activation B. Engulf their neighboring small quiescent lymphocytes in order to take their lipids and proteins for raw material C. Up-regulate synthesis of mRNA and proteins, some of which encode for glucose transporters and enzymes used for glycolysis D. Phagocytose extracellular proteins and lipids and degrade them for energy production E. Macropinocytose metabolites and sugars from the blood for use in glycolysis

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.

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: A. Production of antibodies B. Infiltration by white blood cells C. Mucus production D. Increased saliva production E. Fever

C. 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.

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. Examples of damage caused by the host immune response are: A. Exotoxin production --> Endotoxin B. Cell-mediated immunity --> Direct cytopathic effect C. Endotoxin --> Immune complexes D. Direct cytopathic effect --> Endotoxin E. Cell-mediated immunity --> Immune complexes

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.

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: A. Activation of complement inhibitory receptors on phagocytes that promote pathogen uptake B. Activation of soluble proteases in the serum that disrupt pathogen membranes C. Engagement of complement receptors on phagocytes by C3b and its cleavage products which promotes phagocytosis D. Engagement of complement receptors on B cells that promotes antibody production E. 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.

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: A. Also from the lymph fluid draining the tissue B. Directly from their primary lymphoid organ where they develop C. From the blood by crossing the high endothelial venules D. By being trapped in the lymphoid follicle by resident macrophages E. 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.

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: A. Responses important in protozoan infections, but not other types of infections B. Interactions with large helminthic parasites, which cannot be phagocytosed C. Interactions with other cells, such as virus-infected cells or other immune cells D. Responses important in mucosal surfaces (e.g., the lung), where antibodies cannot go E. Stimulating B cells and not any other types of cells

C. The effector functions of T cells can only interact with other host cells, and not with the pathogen directly. These effector functions include killing of cells infected with intracellular pathogens activation of B cells and macrophages and suppressing the activity of other lymphocytes.

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

C. 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.

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 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 I molecules for recognition by CD8 T cells. In contrast, CD4 T cells recognize antigenic peptides bound to MHC II molecules. MHC 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.

Most normal tissues contain resident macrophages, and connective tissue sites in the gastrointestinal tract and the lung contain large numbers of these cells. Yet the blood also contains a high number of circulating 'classical' monocytes that can differentiate into macrophages after entering tissues. These circulating monocytes function to: A. Phagocytose and kill pathogens in the blood B. Line the endothelial surfaces of the blood vessels with phagocytic cells C. Enter lymph nodes and patrol for infecting microbes in these organs D. Amplify the local innate immune response by entering tissues that are infected E. Differentiate into dendritic cells during an inflammatory response

D. Circulating 'classical' monocytes are recruited to enter tissues by the release of cytokines and chemokines resulting from an infection. Once they enter the tissues, the cells differentiate into activated inflammatory monocytes or macrophages, where they can function to phagocytose and destroy pathogens, as well as to produce additional cytokines and chemokines to amplify the local immune response.

Innate lymphoid cells (ILCs) are effector cells that generally reside in barrier tissues, such as the skin, the gut, and the lung. These cells closely resemble subsets of T lymphocytes, but lack a T cell antigen-receptor. Instead, these cells produce their effector molecules following stimulation by: A. Microbial PAMPs that stimulate pattern recognition receptors on ILCs B. TNF-α, which is produced during the inflammatory response C. Acute phase response proteins produced in the liver during an infection D. Cytokines made by other innate cells, such as macrophages or dendritic cells E. Antimicrobial peptides made by epithelial cells in response to infection

D. ILCs function as effector cells that amplify signals produced by innate sensor cells. They are stimulated by cytokines produced by cells such as macrophages and dendritic cells when the macrophages or dendritic cells have been activated by innate sensors of microbial infection or tissue damage.

Mycobacteria are intracellular pathogens that have adapted to life inside phagocytic cells, such as macrophages. These intracellular bacteria are taken up by phagocytosis, similar to other pathogens, but the bacteria are not killed. One possible mechanism that could account for this immune evasion by mycobacteria is their ability to: A. Prevent induction of nitric oxide production in the phagosome B. Prevent the acidification of phagosomes C. Prevent the expression of antimicrobial peptides in the phagosome D. Prevent fusion of phagosomes with lysosomes E. Kill the macrophage before it kills them

D. Once a microbe is phagocytosed by a macrophage, it is sequestered in an intracellular vesicle known as a phagosome. The phagosome then fuses with one or more lysosomes, to form the phagolysosome. The phagolysosome is the compartment which has the capacity to expose the ingested pathogen to acidification, antimicrobial peptides, and reactive oxygen species. These events do not occur in the phagosome prior to its fusion to lysosomes. Mycobacteria have evolved mechanisms to prevent phagosome-lysosome fusion as an immune evasion strategy.

In recent years, several new vaccines have been developed that are made from purified viral surface proteins, rather than intact or live viruses. They are referred to as subunit vaccines. In order to generate a protective adaptive immune response to a subunit vaccine, the viral protein(s) must be mixed with an adjuvant. The adjuvant functions to: A. Mimic the process of normal virus entry by binding to the host receptor and inducing receptor-mediated endocytosis B. Induce vascular permeability to promote the accumulation of fluid and serum proteins at the vaccine injection site C. Induce the production of chemotactic proteins that recruit neutrophils and then monocytes to the site of vaccine injection D. Stimulate dendritic cells to up-regulate co-stimulatory molecules and migrate to the regional lymph node E. Promote the activation of the complement cascade to induce complement deposition on the viral subunit proteins

D. Adjuvants are substances that are mixed with protein antigens to promote their 'immunogenicity' in generating adaptive immune responses. Historically, it was found that adjuvants containing microbial components were the most effective. These compounds stimulate tissue macrophages and dendritic cells to express co-stimulatory molecules. They also stimulate tissue dendritic cells to migrate out of the tissue into the lymph, and traffic to the regional lymph node. These features are essential in generating an adaptive immune response, which is initiated in a lymph node, not in the tissue site. Current efforts to develop new adjuvants for use in subunit vaccines have taken advantage of our knowledge of PAMPs, and which ones are effective at stimulating innate sensors (PRRs) in dendritic cells.

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: A. Red blood cells B. Macrophages C. Lymphocytes D. Endothelial cells E. Granulocytes

D. Hematopoietic stem cells in the bone marrow give rise to all the blood cell lineages, including erythrocytes (red blood cells), myeloid cells (macrophages and granulocytes), and lymphocytes. Endothelial cells, which comprise the blood vessel walls, are not derived from hematopoietic stem cells.

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: A. DAF/CD55 prevents the lysis of red blood cells by infecting pathogens. B. DAF/CD55 normally prevents the spleen from clearing healthy red blood cells from the circulation. C. In the absence of PIGA, the red blood cell membrane is bare of proteins allowing increased access of complement activating proteins to attach to the cell membrane. D. DAF/CD55 is a complement inhibitory protein that inactivates any C3 convertase that may form on host cell surfaces. E. In the absence of PIGA, red blood cells are unable to synthesize high levels of hemoglobin.

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.

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: A. Their higher-order oligomeric structure can be assembled only after the monomers first bind to pathogen membranes. B. They only recruit MASP (MBL-associated serine proteases) proteins when bound to pathogen surfaces and not when bound to host cells. C. They only undergo the conformational change needed to activate MASP proteins when bound to a pathogen and not when bound to a host cell. D. They only bind to carbohydrate side chains and oligosaccharide modifications found on pathogen surfaces but not on host cell membranes. E. The activated MASP proteins are rapidly inactivated by hydrolysis when present on the surface of a host cell.

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.

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: A. The mucous layer lining mucosal surfaces makes it difficult for normal antigen-presenting cells to function. B. The epithelial surfaces that line the gut, lungs, and nasal passages prevent antigen-presenting cells from accessing microbes and microbial products. C. The epithelial cells found in mucosal tissues are distinct from those that provide barrier functions to the skin. D. Mucosal sites, where most pathogens access the body, are exposed to vast numbers of diverse microbes. E. Mucosal tissues lack innate sensor cells that can respond to PAMPs and provide short-term innate immune protection.

D. 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.

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: A. Bacteria and fungi do not require B cell or T cell responses for their clearance. B. Bacteria and fungi are not efficiently transported to draining lymph nodes to initiate adaptive immune responses. C. Systemic infections of bacteria and fungi are usually cleared by the spleen. D. The defective immune response occurs too rapidly following infection to be due to a defect in B or T lymphocytes responses. E. Adaptive immune responses require dendritic cells to take up and degrade pathogens.

D. 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.

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.

In healthy adults, neutrophils represent approximately half of their white blood cells. During a bacterial infection, this number often rises to >80%. One factor contributing to this rise is: A. Recruitment of neutrophils from tissues into the blood B. Proliferation of neutrophils at the site of infection C. Proliferation of neutrophils in the blood D. Differentiation of blood monocytes into neutrophils E. Release of neutrophils into the blood from the bone marrow

E. Cytokines produced by macrophages in response to a bacterial infection induce leukocytosis, referring to an increase in the numbers of neutrophils circulating in the blood. These neutrophils come from two sources. First, increased numbers of neutrophils are released from the bone marrow, their normal site of maturation. Second, neutrophils are released from sites in blood vessels, where they are loosely attached to endothelial cells.

Many different viruses encode proteins that function to down-regulate MHC class I expression on host cells following infection with the virus. This immune evasion mechanism allows the virus to hide from CD8 T lymphocytes that normally detect virus-infected cells by using their T cell antigen receptor to recognize viral peptides bound to MHC class I proteins on the surface of the infected cell. To counteract this immune evasion strategy, NK cells have: A. Activating receptors that recognize MHC class I proteins B. A mechanism to secrete antiviral peptides C. Inhibitory receptors that recognize viral capsid proteins D. Activating receptors that recognize viral capsid proteins E. Inhibitory receptors that recognize MHC class I proteins

E. NK cells express both activating and inhibitory receptors, and it is believed that their decision to kill a target cell depends on the relative balance of these two types of signals. When the activating signals are dominant over the inhibitory signals, the NK cell will kill that target cell. Normal host cells constitutively express high levels of MHC class I molecules, and therefore are poor targets for NK cells. However, when a virus infection causes down-regulation of MHC class I proteins on the infected cells, the engagement of inhibitory receptors for MHC class I proteins is lost, tipping the balance in favor of the activating signals. This leads to NK cell killing of the virus-infected target cell.

An infection in the skin, such as a pimple, often produces pus. The major component of pus is: A. Toxic oxygen molecules released by macrophages B. Toxic nitrogen molecules released by macrophages C. NETs released by neutrophils D. Dead epithelial cells killed by lysozyme E. Dead and dying neutrophils

E. Neutrophils are recruited in large numbers to sites of infection. These cells are short-lived (<1 day) and die shortly after a round of phagocytosis when they have used up their primary and secondary granules. Infections of extracellular encapsulated bacteria, such as streptococci and staphylococci, recruit large numbers of neutrophils, and are known as pus-forming bacteria.

A key feature of TLR signaling is the ability to induce inflammatory cytokine gene expression extremely rapidly following TLR stimulation. This is accomplished by signaling pathways using several mechanisms to activate transcription factors that are already present in the cell prior to TLR stimulation, but are kept in an inactive state. These signaling pathways use all of the following mechanisms EXCEPT: A. Induced ubiquitination leading to protein degradation B. Induced ubiquitination inducing protein-protein interactions C. Induced phosphorylation leading to nuclear translocation D. Induced phosphorylation leading to kinase activation E. Induced phosphorylation preventing protein degradation

E. TLR signaling pathways lead to the activation of NFκB and of IRF family transcription factors. Each pathway has multiple steps, beginning with the adapter proteins MyD88, MAL, TRAM, and TRIF in various combinations. These steps include both K48-linked and K63-linked ubiquitination, resulting in protein degradation or protein-protein interactions, respectively. Also included are steps of protein phosphorylation, leading to nuclear localization of the IRF factors, and leading to kinase activation for TAK1. None of these steps include a process whereby protein phosphorylation stabilizes protein turnover by preventing degradation.

Macrophages express multiple types of receptors on their surface that stimulate phagocytosis of microbes, leading to pathogen internalization and destruction. Many of these receptors, such as Dectin-1, rely on direct recognition of a PAMP on the pathogen surface. However, some receptors that stimulate phagocytosis rely on soluble factors (not associated with the phagocyte membrane) to identify and mark the pathogen for uptake by the phagocyte. One such receptor is: A. The mannose receptor B. The class A scavenger receptor C. The lipid receptor D. The macrophage C-type lectin receptor E. The complement receptor

E. The complement receptor expressed on phagocytes binds to complement-coated pathogens. A pathogen becomes opsonized with complement proteins when it is first recognized by an initiating member of the complement pathway, such as MBL, other collectins or ficolins, or by antibody. Another example of a receptor on phagocytes that stimulates phagocytosis but does not directly recognize the pathogen surface is one of the Fc receptors.

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: A. The E. coli infection damages the reproductive epithelium, causing a breach in the tight junctions and allowing invasion by the Candida albicans. B. The E. coli infection induces adhesion molecule expression on the reproductive epithelium, allowing attachment of the yeast. C. The antibiotic treatment kills all strains of fungi present in the reproductive tract, except the Candida albicans. D. The E. coli infection causes gastrointestinal distress leading to diarrhea. E. The antibiotics kill many of the commensal organisms in the reproductive tract, allowing overgrowth of the fungus.

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: A. Recruiting antibodies to the bacterial surface, leading the antibody-dependent neutralization B. Providing a mechanism for phagocytes to use their Fc receptors to recognize and ingest the bacterium C. Cross-linking carbohydrate structures on the bacterial surface, thereby preventing the bacterium from replicating D. Stimulating B lymphocytes to produce more antibodies against the bacterium E. 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.

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: A. The important role of T cells in regulating B cell development in the bone marrow B. The inter-dependence of T cells and B cells for the normal development of secondary lymphoid organs. C. The absence of phagocytic cells needed for antibody-dependent pathogen clearance in SCID patients D. The poor survival of B cells in patients with defects in their T cells E. 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.

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: A. The naive B cell expresses an array of different B cell antigen receptors, and randomly chooses which specificity of antibody to secrete as a plasma cell. B. The naive B cell expresses a single specificity of B cell antigen receptor, and then up-regulates the expression of this receptor so it can bind tightly to the pathogen. C. The plasma cell proliferates after it has finished secreting antibody to generate more plasma cells with specificity for the pathogen. D. The plasma cell traps secreted antibody molecules in its extracellular matrix and uses these antibodies to bind to the pathogen. E. The naive B cell expresses a membrane-bound form of the antibody as a receptor, and secretes that same antibody when it differentiates into a plasma cell.

E. The B cell antigen receptor includes a membrane-bound form of the antibody protein and two transmembrane subunits that provide receptor signaling functions. When a B cell binds to a pathogen using this receptor, the B cell divides differentiates 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.

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: A. The C3 convertase of the alternative pathway is much more active than those of the classical and lectin pathways. B. The C3 convertase of the alternative pathway works as a soluble enzyme in the plasma. C. The C3 convertase of the alternative pathway cannot be inactivated by complement regulatory factors in the host. D. The C3 convertase of the alternative pathway is more efficiently recruited to pathogen surfaces than the C3 convertases of the classical and lectin pathways. E. The C3 convertase of the alternative pathway contains C3b, and can generate more of itself.

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.

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 is: A. Epithelial cells make different forms than those made by neutrophils. B. Neutrophils make many different defensins and store them as inactive proteins in their secretory granules. C. Most of them are produced only in response to infection. D. The production of different peptides is induced following a bacterial infection versus a fungal infection. E. Each one has distinct activities against Gram-negative bacteria, Gram-positive bacteria, or fungi.

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.

True/False: Chemokines are small chemoattractant molecules made by epithelial cells, tissue macrophages, and endothelial cells in response to infection or injury. They differ slightly in sequence and structure based on the cells that secrete them, but all of them act to recruit both monocytes and neutrophils from the blood.

False. Chemokines encompass a large family of molecules that are structurally related. The different chemokines are made by distinct cell types and also act as chemoattractants for different cell types. The differences generally result from differential expression of specific chemokine receptors on different cell types. For instance the receptor for CXCL8 is expressed on neutrophils, but not on monocytes; thus, CXCL8 is a chemoattractant for neutrophils but not monocytes

True/False: All mammalian TLRs have been shown to directly bind to microbial products, leading to TLR signaling.

False. Some TLRs have been shown to make direct contact with microbial ligands based on X-ray crystal structures. However, this has not been confirmed for all TLRs. The Drosophila receptor Toll does not recognize microbial products directly, but instead, recognizes a cleaved product of a self-protein, Spätzle. This leaves open the possibility that some mammalian TLRs may function similarly to Drosophila Toll. Furthermore, TLR4 requires an accessory protein, MD-2 for binding to LPS.

True/False: The acute phase response contributes to infection control by producing molecules that promote pathogen opsonization and complement activation. This response is only induced by direct action of microbial components on hepatocytes in the liver.

False. The acute phase is induced by inflammatory cytokines (TNF-α, IL-1β, IL-6) produced by the host in response to infection. These cytokines act on hepatocytes to produce a variety of proteins, including C-reactive protein, MBL, surfactant proteins, and fibrinogen. Many of these proteins bind pathogens, but not host cells, and contribute to pathogen clearance by promoting phagocytosis and complement activation

True/False: In the sea urchin, a massive diversification of innate recognition receptors has occurred, resulting in the presence of over 200 TLR genes, over 200 NOD-like receptor genes, and over 200 scavenger receptor genes in the genome of these organisms. These receptors are unlikely to contribute to an enhanced innate immune response in sea urchins, because nearly all of these genes are pseuodgenes.

False. While some of these genes are pseudogenes, the majority encode functional proteins. It is likely that these genes have undergone rapid evolution, indicating a rapid change in receptor specificities, perhaps in response to microbial evolution and/or immune evasion. The properties of the LRR domains are consistent with the idea that these receptors represent a highly diversified pathogen recognition system.

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.

Individuals with natural killer (NK) cell deficiencies have susceptibilities to infections with herpesviruses and other DNA viruses, as well as with intracellular bacteria such as the mycobacteria that cause tuberculosis. Mycobacterium tuberculosis is a pathogen that infects macrophages and replicates in their phagocytic vesicles. Which effector function of NK cells is likely most important in promoting immunity to M. tuberculosis?

In addition to cytolytic activity, NK cells secrete large amounts of IFN-γ when they are activated. Secretion of IFN-γ is likely the most important effector mechanism by which NK cells help protect against intracellular bacterial infections such as M. tuberculosis. IFN-γ directly activates macrophages to enhance their ability to kill pathogens, including intracellular pathogens replicating in the macrophage. IFN-γ also influences the adaptive immune response by promoting the differentiation of pro-inflammatory TH1 CD4 T cells, which are critical in controlling intracellular bacterial infections. NK cells also produce cytokines and chemokines, such as TNF-α, GM-CSF, CCL3, CCL4, and CCL5 that function to recruit and activate macrophages.

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.

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.

NOD1 and NOD2 are cytoplasmic sensors of bacterial products such as muramyl dipeptide (MDP), a constituent in the peptidoglycans of most bacteria. These sensors are highly expressed in epithelial cells that line the body surfaces that pathogens must cross to establish an infection. Interestingly, a subset of patients with an inflammatory bowel disease called 'Crohn's disease' have inactivating mutations in NOD2. Why might this deficiency in NOD2 lead to chronic inflammation in the gut?

NOD2 is highly expressed in the Paneth cells of the gut, where it regulates the expression of potent antimicrobial peptides such as the defensins. Since NOD2 recognizes bacterial components that are found in most strains of bacteria, not just pathogenic microbes, it is likely that NOD2-induced antimicrobial peptide production is occurring constitutively in response to the gut microbiota. This constitutive production of antimicrobial peptides at the intestinal epithelium is an important component of maintaining the natural barrier function of the gut epithelium. In the absence of this, barrier function is weakened, leading to an increased prevalence of microbes crossing the epithelial barrier and inducing an inflammatory response by stimulating the other innate sensors. This chronic inflammation is the hallmark of Crohn's disease.

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.

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.

Sensor cells commonly recognize unique microbial components, such as bacterial LPS or other cell wall constituents. A 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.

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.

The antibody variable domains form the antigen-binding sites on the protein, and these serve as the guidance system. The specificity of these domains determines where the antibody protein binds, for instance, directly on a pathogen, or on a protein such as a toxin, or on a cell, etc. Antibody binding alone has limited effects. In order for antibodies to function in pathogen or toxin elimination, the antibody uses its Fc region, which functions as the 'payload.' This Fc region can be recognized by receptors on phagocytic cells, aiding in pathogen/toxin uptake, or it can promote complement activation on the pathogen. Without the 'payload,' antibody proteins would merely be binding molecules, with no other effector functions.

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.

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.

The most relevant features of dendritic cells in this context are: 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.

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. 1) allergic responses to food items, antibiotics, metal ions, or inhaled substances. 2) autoimmune diseases, in which individuals make destructive immune responses to their own cells or tissues.

True/False: The extravasation of neutrophils into tissues at sites of infection or inflammation requires changes to both the endothelium and to the neutrophil that are induced by chemokines and cytokines produced in the infected tissue.

True. Both the endothelium and the neutrophils respond to cytokines and chemokines made in the tissue in response to infection. For the endothelium, the changes include vascular dilation and up-regulation of P-selectin, E-selectin, and ICAM molecules. For the neutrophil, the chemokines bound to proteoglycans on the surface of the endothelial cells induce a conformational change in the integrins on the surface of the neutrophil, converting them into high affinity binding partners for the ICAMs on the activated endothelium.

True/False: Dendritic cells are tissue resident myeloid cells that are highly phagocytic, like macrophages. However, dendritic cells do not play a major role in large-scale pathogen destruction; instead, they are important in initiating adaptive immune responses of T cells.

True. Dendritic cells are considered to be the bridge between innate and adaptive immunity. They are tissue resident cells that rapidly respond to infections, due to their expression of many PRRs. However, unlike macrophages and neutrophils, the latter of which are recruited to infected tissues, dendritic cells do not function in large-scale pathogen destruction. Instead, they phagocytose pathogens and degrade them to generate peptides for presentation and activation of T cells.

True/False: Each family of NK cell receptors has members that promote NK cell activation, and members that send inhibitory signals when engaged. The difference between activating and inhibitory receptors lies in their association with accessory proteins that promote downstream signaling, or in their ability to recruit and activate inhibitory phosphatases, respectively.

True. KIRs and KLRs are two different families of NK cell receptors. Each has members that send activating signals to the NK cell and members that send inhibitory signals. The activating receptors associate with a signaling adapter protein, called DAP12, that contains amino acid sequence motifs known as ITAMs. When phosphorylated, ITAM sequences recruit tyrosine kinases to promote NK cell activation. In contrast, inhibitory receptors generally have longer cytoplasmic tails than the activating receptors. Rather than associating with an adapter protein such as DAP12, these receptors have amino acid motifs known as ITIMs in their cytoplasmic tails. ITIM motifs recruit inhibitory phosphatases when the receptor is stimulated, and therefore, down-regulate signaling in the NK cell.

True/False: The inflammatory response is characterized by four classic symptoms: heat, redness, pain, and swelling. In some instances, this response can be triggered by stimuli that are non-infectious such as asbestos, a process known as 'sterile inflammation.' When exposure to the stimulating trigger is persistent, a state of chronic inflammation can result. This process is likely to be detrimental to the health of the host.

True. The inflammatory response is effective at promoting immunity and eradicating infections, but at the same time causes damage to the host. The influx of fluid and cells into tissues can cause damage, and the production of antimicrobial compounds, such as toxic oxygen and nitrogen species, also causes collateral damage. Inflammatory responses also induce tissue repair, a process that when chronic can also lead to tissue damage.

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: 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.

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.

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: 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.

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.

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.

True/False: 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.

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.

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

True/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.

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.

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.

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?

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.

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.