Question 1

A 4-year-old girl stepped on a rusty nail in her backyard.Two days later,she is taken to the pediatrician because her heel is painful,red,and swollen and is warm to the touch.All of the following are mechanisms of innate immunity that may be protecting the patient against pathogenic microbes in the heel wound EXCEPT:

Accepted Answer

Secreted antibodies against protein antigens are effectors of humoral immunity,a component of the adaptive immune system.All other mechanisms listed are part of the innate immune system.Intact epithelial surfaces prevent microbial entry,and epithelial cells express anti-microbial factors,such as defensins.Neutrophils are effector cells that function in early phagocytosis and killing of microbes.Cytokines that mediate inflammation (e.g. ,tumor necrosis factor,interleukin-1,chemokines)are components of innate immunity.Intraepithe-lial T lymphocytes present in the epidermis and mucosal epithelia express a limited diversity of antigen receptors;as such,they are considered effector cells of innate immunity and function in host defense by secreting cytokines,activating phagocytes,and killing infected cells.

Question 2

Toll-like receptors (TLRs)are a family of homologous receptors expressed on many cell types and are involved in innate immune responses.Ten different mammalian TLRs have been identified,and several ligands for many of these receptors are known.Which of the following is a TLR ligand?

Accepted Answer

More than 10 mammalian Toll-like receptors (TLRs)have been identified,and each appears to recognize a different set of structures that are found in pathogenic microbes but not in mammalian cells.Such structures are called pathogen-associated molecular patterns (PAMPs).Unmethylated cytosine guanosine (CpG)motifs are typical of bacterial and protozoan DNA,but not mammalian DNA,and are therefore PAMPs.TLR9 binds CpG DNA.Transfer RNA,single-stranded RNA,double-stranded DNA,and heterochromatin are all normal components of mammalian cells and are not recognized by TLRs.Double-stranded RNA is produced by some viruses but not by mammalian cells and is recognized by TLR3.

Question 3

Toll-like receptors and other receptors are potent activators of various components of the innate immune system.All of the following proteins are expressed in response to signaling by these receptors EXCEPT:

Accepted Answer

CD28,the activating receptor for B7-1 and B7-2 costimulatory molecules,is constitutively expressed on the surface of many T cells and is not induced by Toll-like receptor (TLR)signaling.TLR signaling does induce expression of B7-1 and B7-2 on antigen-presenting cells.Other genes expressed in response to TLR signaling encode proteins important in many different components of innate immune responses.These include inflammatory cytokines such as tumor necrosis factor-F1F1F1S1F1F1F10 (TNF-F1F1F1S1F1F1F10),interleukin-1 (IL-1),and IL-12;endothelial adhesion molecules such as E-selectin;and proteins involved in microbial killing mechanisms,including inducible nitric oxide synthase (iNOS).The specific genes expressed depend on the cell type of the responding cell.

Question 4

Macrophages and neutrophils express several enzymes that are involved in biochemical mechanisms that kill ingested microbes.Which of the following is NOT an enzyme expressed by these cells?

Accepted Answer

Granzyme B,a proteolytic enzyme component of cytolytic T lymphocyte (CTL)and natural killer (NK)cell granules,is involved in initiating caspase-dependent CTL killing of target cells.Granzyme B is not involved in phagocyte killing of ingested microbes.Inducible nitric oxide synthase (iNOS)generates NO in macrophages,and NO is toxic to microbes.Phagocyte oxidase and myeloperoxidase are involved in generating free radical species that kill ingested microbes in phagocytes.Lysozyme is a proteolytic enzyme in neutrophil granules that contributes to microbial killing.

Question 5

A 43-year-old man with a history of kidney transplantation is on immunosuppressive drugs.He presents to the emergency department 84 days after transplantation with a slight fever,accompanied by violent shaking chills,rapid heart rate,and dangerously low blood pressure.Blood cultures are positive for gram-negative bacteria,including Klebsiella and Pseudomonas.Although the patient was initially alert and responsive to fluids and antibiotic therapy,his condition rapidly deteriorates into disseminated intravascular coagulation (DIC),hypoglycemia,and cardiovascular failure.Which of the following is an essential mediator of this patient's condition?

Accepted Answer

This patient is suffering from septic shock,characterized by the clinical triad of disseminated intravascular coagulation (DIC),hypoglycemia,and cardiovascular failure.This condition is most often initiated by endotoxin,also known as lipopolysaccharide (LPS),a component of the outer cell walls of gram-negative bacteria.LPS is a potent stimulus for tumor necrosis factor (TNF)-$\alpha$ secretion by mononuclear phagocytes and other cell types.Most of the biologic effects of LPS are mediated through TNF-$\alpha$.Transforming growth factor-$\beta$ (TGF-$\beta$)and interleukin (IL)-10 are anti-inflammatory cytokines,IL-2 is a T cell growth factor,and IL-3 is a hematopoietic cytokine.These cytokines are not mediators of septic shock.

Question 6

Which one of the following comparisons between neutrophils and macrophages is true?

Accepted Answer

Neutrophils and macrophages can both actively phagocytose and kill microbes,and both express opsonin receptors,such as Fc$\gamma$RI or complement receptors that enhance phagocytosis.Neutrophils are short lived,whereas macrophages can survive for days or weeks.Macrophages are not terminally differentiated and can undergo cell division at inflammatory sites,but neutrophils cannot.Only neutrophils have cytoplasmic granules filled with enzymes,including lysozyme,collagenase,and elastases;these are called specific granules.

Question 7

The signaling pathways triggered by Toll-like receptors typically result in activation of which of the following pairs of transcription factors?

Accepted Answer

The predominant signaling pathway used by Toll-like receptors (TLRs)results in the activation of the NF-F$\kappa$B transcription factor.Ligand binding to the TLR at the cell surface leads to recruitment of several cytoplasmic signaling molecules through specific domain-domain interactions,resulting in degradation of I$\kappa$B and subsequent activation of NF$\kappa$B.In some cell types,certain TLRs also engage other signaling pathways,such as the MAP kinase cascade,leading to activation of the AP-1 transcription factor.T-bet and GATA-3 are transcriptional regulators involved in helper T cell differentiation.Fos is a component of AP-1,and STAT-6 is a transcription factor activated by IL-4 binding to cells.Lck is not a transcription factor,but rather a tyrosine protein kinase involved in antigen-receptor signaling in T cells.

Question 8

All of the following molecules are opsonins that facilitate efficient phagocytosis of microbes by neutrophils and macrophages EXCEPT:

Accepted Answer

C5a is a peptide released after cleavage of C5 protein during the complement cascade.It stimulates the influx of neutrophils to the site of infection,thus acting as a chemoattractant,not as an opsonin.C3b (covalently bound to microbes on which complement activation has taken place)and IgG bound to antigen,are particularly potent opsonins,because phagocytes have receptors for both C3b and the Fc region of IgG.C-reactive protein and mannose-binding lectin also can coat microbes and be recognized by phagocyte receptors;thus they serve as opsonins.

Question 9

A 4-year-old-girl sees her physician because of a severe necrotizing,oropharyngeal herpes simplex viral (HSV)infection.She has a past medical history of cytomegalovirus (CMV)pneumonitis and cutaneous HSV infection.Phenotypic analysis of her blood cells shows an absence of CD56⁺ and CD16⁺ cells.There are normal numbers of CD4⁺ and CD8⁺ cells in the blood,and serum antibody titers are normal.The patient's CD8⁺ T cells were able to kill virally infected target cells in vitro.Which of the following is NOT characteristic of this girl's immunodeficiency disease?

Accepted Answer

The presence of normal numbers of CD8⁺ T cells and the ability of these cells to kill virally infected target cells indicates that the class I major histocompatibility complex (MHC)pathway of viral peptide antigen presentation is intact.The patient's immunodeficiency is due to a lack of natural killer (NK)cells.NK cells express CD56 and/or CD16.NK cells are activated by interleukin-15 (IL-15)and IL-12,are normally inhibited by recognizing class I MHC on other cells,kill target cells with altered class I MHC expression through a granzyme B-dependent mechanisms (similar to cytolytic T lymphocyte killing),and produce interferon-$\gamma$ as part of the early innate response to viral infection.

Question 10

Which of the following is a receptor on macrophages that is specific for a structure produced by bacteria but not by mammalian cells?

Accepted Answer

The macrophage mannose receptor binds to terminal mannose and fucose residues on bacterial glycoproteins and glycolipids.Mammalian cells do not typically contain these residues.CD36 binds many different ligands,including microbial and self molecules.Fc receptors,complement receptors,and ICAM-1 are receptors for mammalian complement fragments,Ig,and LFA-1,respectively.

Question 11

Which one of the following statements about inhibitory receptors on natural killer (NK)cells is true?

Accepted Answer

Natural killing (NK)inhibitory receptors recognize class I MHC molecules that are normally and constitutively expressed,including various alleles of HLA-A and HLA-C.The cytoplasmic tails of NK inhibitory receptors contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs),but not immunoreceptor tyrosine-based activation motifs (ITAMs).Some inhibitory receptors on NK cells are members of the Ig superfamily,but not the integrin or TLR families.NK cells usually express both activating and inhibitory receptors,and activation is regulated by a balance between signals generated from both types of receptors.The inhibitory receptors on NK cells bind to self class I MHC molecules,which are expressed on most normal cells.When activating and inhibitory receptors are simultaneously engaged,the inhibitory receptor signals dominate and the NK cell is not activated.

Question 12

Complement activation in the innate immune system can be initiated in the absence of antibody.Which of the following molecular components of the complement system is involved in initiation of antibody-independent complement activation?

Accepted Answer

Mannose-binding lectin (MBL)is a soluble serum component that is structurally similar to C1 of the classical complement pathway.MBL binds to mannan residues on microbial surfaces and triggers proteolytic cleavage and activation of downstream components of the complement system.C9 is not involved in initiation of complement activation but is part of the common final membrane attack complex (MAC)pathway.CR2 is a cell surface receptor for complement fragments.A mannose receptor is a cell surface receptor on phagocytes that binds mannan residues and promotes phagocytosis of microbes.

Question 13

Which of the following statements about the innate immune system is NOT true?

Accepted Answer

Innate immunity is the first line of defense against infections,yet many pathogenic microbes have evolved strategies to resist innate immunity.Adaptive immunity,being more potent and specialized,plays a critical role in defending against these virulent microbes.Innate immunity is the phylogenetically oldest mechanism of microbial defense,and it is present in all multicellular organisms,including plants and insects.Studies have shown that hampering effector mechanisms of innate immunity renders hosts much more susceptible to infection,even with a functional adaptive immune system.It is also true that,like the adaptive response,the innate immune response consists of recognition,activation,and effector phases.Although it provides the initial,rapid response against microbes,innate immunity can influence adaptive immune responses to tailor them against particular microbes.

Question 14

A 3-year-old boy,who is small for his age,has a history of pyogenic (pus-producing)infections and cutaneous skin abscesses.Physical examination is remarkable for high fever,enlarged liver and spleen,and swollen cervical lymph nodes.A culture from an abscess on his arm reveals Staphylococcus aureus,a gram-positive bacteria that is also catalase-positive.Immunoglobulin and complement levels are normal.Results of the nitroblue tetrazolium test are consistent with a diagnosis of chronic granulomatous disease (CGD).The boy's immunodeficiency involves impaired generation of which of the following?

Accepted Answer

Chronic granulomatous disease (CGD)is a rare,inherited immunodeficiency disease associated with a defective intracellular respiratory burst in phagocytes.It consists of a group of heterogeneous disorders of oxidative metabolism in which the pathways required for generation of toxic reactive oxygen species (ROIs)are impaired.In patients with CGD,phagocytosis occurs normally,but the engulfed microbes are not killed and they multiply within the cell.In this way,patients are susceptible to recurrent infections with organisms such as Staphylococcus,which are of low virulence in normal hosts.

Question 15

Which of the following is an example of how the innate immune response stimulates or modifies adaptive immunity?

Accepted Answer

Innate immune responses are important stimulators of adaptive immunity.Increased expression of B7-1 and B7-2 on antigen-presenting cells after microbial activation of Toll-like receptors (innate immunity)is critical in providing costimulatory signals for T cell activation (adaptive immunity)via binding to CD28 receptors on T cells.T helper cell-mediated endothelial or macrophage activation is an example of adaptive immunity using the effector mechanisms of innate immunity.Neither IgG3 opsonization facilitating natural killer cytolytic activity nor double-stranded RNA stimulating interferon-$\beta$ secretion involve innate immunity enhancing adaptive immunity.

Question 16

Which of the following comparisons of the innate and adaptive immune systems is FALSE?

Accepted Answer

Innate immune system receptors are encoded by germline genes that have evolved to recognize microbial structures or molecules produced by stressed self,and therefore there is little chance of innate immune responses to normal self.Because the specificities of adaptive immune system receptors (Ig or T cell receptor molecules)are randomly generated by somatic recombination and junctional-diversity mechanisms,there is a greater chance that the adaptive immune system receptors may recognize normal self molecules,leading to autoimmunity.Mechanisms of tolerance minimize this possibility,but these mechanisms can fail.The adaptive immune system receptors can recognize nonmicrobial structures.Although most innate immune system receptors recognize microbial structures,some Toll-like receptors and activating receptors of natural killer cells do recognize nonmicrobial self proteins expressed by stressed,damaged,or infected cells.Memory is a unique property of the adaptive and not the innate immune system.

Question 17

A 67-year-old homeless man is brought to the emergency department after being found behind a neighborhood bar in freezing weather.On arrival,he has a shaking chill,fever,and cough productive of blood-tinged sputum.A chest radiograph shows lobar consolidations consistent with bacterial pneumonia.Blood cultures are positive for Streptococcus pneumoniae.Which of the following molecular patterns recognized by Toll-like receptors expressed on the surface of this patient's phagocytes is important for activating his innate immune system against this gram-positive bacterial infection?

Accepted Answer

Gram-positive bacteria contain cell walls rich in peptidoglycan.When shed by bacteria such as Streptococcus pneumoniae,peptidoglycan serves as a ligand that binds Toll-like receptor 2 (TLR2),stimulating an innate immune response.The other choices listed are also ligands that stimulate TLRs,but they are not present in gram-positive bacteria.Double-stranded RNA is found in replicating viruses,lipopolysaccharide (LPS)is a component of the outer cell wall of gram-negative bacteria,and both lipoarabinomannan and phosphatidylinositol dimannoside are present in mycobacteria.

Quiz 3: Innate Immunity

Toll-like receptors (TLRs) are a family of homologous receptors expressed on many cell types and are involved in innate immune responses.Ten different mammalian TLRs have been identified,and several ligands for many of these receptors are known.Which of the following is a TLR ligand?