Immunobiology-Chapter 10, 11, 13, and 14

CXCR5 is the receptor for the chemokine CXCL13, secreted by follicular stromal cells and follicular dendritic cells in the B cell zones (i.e., lymphoid follicles) of secondary lymphoid organs. A conditional knockout mouse in which CXCR5 was specifically deleted only in T cells would have:

A defect in T cell-dependent antibody responses

Patients with the disease X-linked lymphoproliferative syndrome (XLP) lack expression of the small adapter protein SAP, which associates with receptors of the SLAM family. One characteristic of this disease is an inability of cytotoxic T cells to control infections with a virus, Epstein-Barr virus (EBV), that replicates in B cells. This defect in control of EBV results from:

A defect in adhesion of cytotoxic T cells to EBV-infected B cells

Viruses utilize many different strategies to evade the immune response after infection. One strategy, illustrated in Figure Q13.25, is an effect on virus-infected cells. The virus used in this experiment is most likely:

A large DNA virus

In this experiment, the anti-'X' antibody was shown to inhibit the response of the TH2 cells, and therefore is likely to be:

A neutralizing antibody to TSLP

If one examined a skin biopsy from a patient with tuberculoid leprosy, one would expect to see:

A substantial number of granulomas

Given these data, the most likely identity for the gene that is defective in Mutant-X mice is:

CD40-ligand

The immune mechanism that correlates with protection based on these data is:

ADCC induced by NK cells

Which antibodies were depleted from the serum in the final experiment shown above:

All IgE antibodies

Malaria is caused by protozoan parasites, Plasmodium falciparum and Plasmodium vivax. These pathogens are transmitted when an individual is bitten by a Plasmodium-infected mosquito. This route of transmission:

Allows the parasite to avoid the normal mechanisms blocking infections at barrier surfaces

Multiple choice: The vaccine to Haemophilus influenzae type b is called a conjugate vaccine. It is composed of the tetanus toxoid protein conjugated to the capsular polysaccharide of the H. influenzae type b bacteria. When used to vaccinate infants, the antibody response generated by this vaccine would include:

Antibodies to the bacterial polysaccharide and the tetanus toxoid

In germinal centers, proliferating B cells undergo a process called somatic hypermutation, in which mutations are introduced into the V regions of the antibody heavy and light chain genes. When this process is complete after several weeks, the overall affinities of the antibodies produced are greatly increased compared to those present early in the primary response. The somatic hypermutation process leads to increased antibody affinity because:

B cells making higher affinity antibodies receive more help from TFH cells.

Important information can be learned by studying the immune system of female carriers of the XLA disease gene. These individuals, identified as mothers of boys with XLA, show non-random X chromosome inactivation in their B cells, but random X chromosome inactivation in all of their other cells, including their T cells and macrophages. This finding indicates that:

B cells require the BTK protein for normal development.

When mixed together in culture together with a conjugate antigen of the tetanus toxoid protein linked to the to H. influenzae type b polysaccharide, which combination of spleen cells would generate a memory B cell response?

B lymphocytes from mouse C plus T lymphocytes from mouse A

Some individuals with repetitive exposure to high doses of Schistosoma mansoni develop resistance to re-infection by this helminthic parasite. In contrast, other individuals remain highly susceptible. Population studies showed that resistant individuals had increased numbers of circulating eosinophils in their blood compared to susceptible individuals, and further, that these eosinophils had increased levels of:

FcεRII, the low affinity IgE receptor

Studies show that about 50-100 different B cells initially seed each germinal center (d7 post-infection). These different B cells are represented by different colored circles in a white oval (germinal center) in Figure Q10.9. Which of the choices shown best represents the B cell population that would be found in the same germinal center approximately two weeks later?

Figure D

Studies have shown that secondary lymphoid tissues are a major reservoir of HIV in infected individuals. In part, this is due to the high numbers of viral target cells expressing CD4, such as T cells, macrophages, and dendritic cells. Surprisingly, secondary lymphoid tissues were also found to contain large numbers of infectious virus particles in the form of immune complexes. A comparison of the viral species found in these immune complexes indicates that they include virus particles that have been retained for over a year. The cells responsible for this reservoir of infectious HIV are:

Follicular dendritic cells

A common misconception is that our immune system fails to make a productive immune response to HIV infection, thereby leading to chronic infection. In fact, following a primary HIV infection, our immune system:

Generates a response that efficiently controls viral replication

HAART therapy is widely used in the US to treat HIV-infected individuals. This treatment is quite effective at inhibiting HIV replication, thereby preventing the progression to AIDS. However, HAART treatment is unable to completely eradicate all viral stores; consequently, patients must remain on this treatment indefinitely, as cessation of treatment leads to a rapid rebound in viral replication. One additional important side benefit of HAART treatment is its ability to:

Greatly reduce HIV transmission

The first drug treatment for HIV licensed in the US was zidovudine (AZT), a reverse transcriptase inhibitor. However, AZT has now been completely replaced by HAART as the recommended treatment for HIV-infected individuals. The use of HAART, rather than AZT, is preferred because:

HAART is a combination therapy that reduces the possibility of viral escape

In the late 1990s, a group of individuals was discovered that remained uninfected with HIV, in spite of multiple exposures to the virus. Analysis indicated that these HIV-resistant individuals had a homozygous deficiency caused by a 32-bp deletion in a single gene, and furthermore, that this mutation was present at a frequency of ~10% (in heterozygous form) in individuals of European descent. These data provided clear evidence indicating that:

HIV infection requires a co-receptor in addition to CD4.

Neutralizing antibodies are effective at preventing infection or toxicity mediated by pathogens or their toxic products. In fact, nearly all vaccines currently in use function by eliciting neutralizing antibodies. One example is the tetanus vaccine, in which neutralizing antibodies are generated against an inactivated form of the tetanus toxin (i.e., the tetanus toxoid). The most important feature of a neutralizing antibody is:

Having high affinity for the antigen

In 1918, a worldwide epidemic of influenza A resulted in the deaths of 40-50 million people. This strain of influenza A, known as H1N1—referring to the genotypes of the viral surface proteins, hemagglutinin (H) and neuraminidase (N)—was shown to be derived from an avian virus that adapted to infect and grow in human cells. Interestingly, by 1957, the H1N1 strains of Influenza A had completely disappeared from the human population, to be replaced by new strains (H2N2) that contained three gene segments from avian origin. The most likely explanation for the disappearance of the early twentieth century form of H1N1 Influenza A virus is:

High levels of existing immunity in the human population to the H1N1 surface antigens

Toxoplasma gondii is a single-celled parasitic protozoan that infects and replicates in macrophages. It is common in the environment, and is transmitted to humans by the ingestion of undercooked meat or by accidental ingestion of the parasite's oocytes from contaminated water or cat litter. Infected individuals with healthy immune systems are generally asymptomatic, and rapidly clear the infection. However, in AIDS patients, infections of Toxoplasma gondii can lead to severe disease and even death. To investigate the immune mechanisms important in controlling Toxoplasma gondii, a mouse model of the infection was developed. Mice were infected with the protozoa at a dose where the majority of the mice survive the infection, and at the same time, were injected with a neutralizing antibody to a cytokine made by T cells (anti-'X' IgG). A second group of mice received the protozoa plus a control IgG antibody, as shown in Figure Q11.10. The most likely candidate for cytokine 'X' is:

IFN-γ

While innate immune responses to all types of infections induce local inflammatory responses due to activation of blood vessel endothelial cells, some components of the innate response differ depending on the nature of the pathogen. In the case of intracellular bacterial or protozoan infections, tissue-resident dendritic cells and macrophages produce a cytokine that stimulates ILC cells to produce:

IFN-γ

Salmonella typhimurium is a Gram-negative bacterial pathogen that infects its host via the gastrointestinal (GI) tract. Early in infection, the bacteria enter and replicate in gut epithelial cells, where the infection provokes a type 3 response, including the development of TH17 cells, in the GI tract. However, this type 3 response in the GI tract does not eradicate the pathogen, as S. typhimurium has evolved strategies to evade the TH17 response and to spread systemically by infecting and replicating in macrophages. Therefore, a second phase of the immune response is required to completely eliminate the pathogen from the body, as has been demonstrated in mouse models of S. typhimurium infection. These experiments in mouse models likely showed that:

IFN-γ is required to clear S. typhimurium from the body.

The most likely identity of the cytokine that is missing in these knockout mice is:

IL-15

Once an individual becomes sensitized to an allergen, such as an inhaled antigen, the allergic response can become self-amplifying upon each re-exposure to the allergen. Thus, even in the absence of CD4 TH2 cell activation, increases in IgE secretion by mucosal-resident plasma cells can be induced by:

IL-4 secretion and CD40-ligand expression by mast cells and basophils

Studies using mouse models of allergic asthma have provided information about the cell types and soluble mediators that contribute to this disease. One common experimental model uses airway exposure to protease allergens, such as papain from papaya or the house dust mite allergen. Interestingly, papain is able to induce allergic lung inflammation even in RAG-deficient mice. In this system, the type 2 cytokines, IL-5, IL-9, and IL-13, are likely coming from:

ILC2 cells

Individuals with a genetic polymorphism in the Fcγ receptor, FcγRIIa (CD32), have an increased susceptibility to bacterial meningitis (inflammation of the membranes (meninges) surrounding the brain and spinal cord) caused by the encapsulated bacterium, Neisseria meningitidis. This polymorphism reduces the efficiency with which the phagocytes expressing FcγRIIa bind to the constant region of this receptor's target antibody. The reason this FcγRIIa-dependent response it the major form of protection against Neisseria meningitidis is because:

IgG antibodies are the major isotype able to diffuse into tissues.

On occasion, individuals on antibiotics such as Minomycin have an allergic response to the antibiotic. Symptoms often include an urticarial rash on the skin, and swelling (edema) of the legs and ankles. When this occurs, patients are advised to stop taking the antibiotic, and are treated with corticosteroids. During follow-up visits to their physician, patients are often given a skin test for hypersensitivity to the drug. This skin test involves intradermal injection of a small amount of Minomycin, and 15 minutes later the site of injection is examined for redness and swelling. In cases where this skin test is negative, the patient most likely generated:

IgG antibodies to the Minomycin

NRF2 is a transcription factor that is required to induce anti-oxidant genes, such as glutathione-S-transferase genes, in response to reactive oxygen and reactive nitrogen species released by inflammatory cells in the airways following phagocytosis of inhaled particles. Mice deficient in Nrf2 were tested for their allergic airway response to inhaled allergens in comparison to wild-type controls. Compared to wild type mice, the Nrf2-/- mice would be expected to show:

Increased levels of IL-4 and IL-13 in the airway

A small group of HIV-infected individuals are known as 'elite controllers.' These individuals have HIV viral RNA copy numbers that persistently remain <50 copies/ml of plasma. Studies examining the immune response to the virus in these individuals would likely reveal:

Increased numbers of virus-specific CD4 and CD8 T cells secreting IFN-γ compared to individuals with high viral titers

Yersinia pestis, the causative agent of the bubonic plague, has multiple mechanisms of immune evasion. This Gram-negative bacterium is transmitted from fleas (body temperature, 26°C) to humans (body temperature, 37°C) by flea bites. Studies have shown that the lipopolysaccharide (LPS) produced by Y. pestis grown at 37°C is about 10-fold less potent at stimulating TLR4 signaling than is the Y. pestis LPS from bacteria grown at 26°C. When these two forms of Y. pestis LPS are compared for their abilities to induce responses from human macrophages, one would expect that the 26°C Y. pestis LPS would result in:

Increased production of TNF-α and IL-6

Infections of intracellular pathogens (e.g., mycobacteria, listeria, toxoplasma, viruses, etc.) cause a rise in the numbers of monocytes in the blood, a symptom known as monocytosis. In the cases of these infections, monocytosis is likely caused by:

Increased production of monocytes in the bone marrow induced by TH1 cytokines

The 'hygiene hypothesis' has been proposed as an explanation for the rapid increase in allergies and asthma incidence in Western countries over the last half century. One line of evidence supporting this hypothesis is:

Individuals of African descent have much higher incidence of atopic disease when living in Western countries.

HIV encodes several proteins that function to promote viral replication, packaging, and budding from host CD4 T cells. In addition to inhibiting cell-intrinsic antiviral mechanisms and down-regulating surface expression of MHC class I and class II molecules, these proteins function to:

Induce robust, sustained CD4 T cell activation

Allergic responses to inhaled antigens occur when an individual is first sensitized to the antigen (i.e., the allergen), inducing an immune response, and then has a subsequent exposure to the same antigen. The sensitization phase is characterized by:

Induction of a CD4 T cell type II immune response

One vaccine, PPSV23, is a mixture of polysaccharides isolated from 23 different serotypes of S. pneumoniae. The second vaccine, PCV13, is a conjugate vaccine made from polysaccharides of 13 different serotypes of the bacteria conjugated to diphtheria toxoid (inactivated toxin protein). The PPSV23 vaccine is only given to adults, whereas infants and small children are given PCV13. This is because:

Infant B cells are immature and don't respond to TI-2 antigens.

Within minutes after encounter with an allergen, individuals with allergic rhinitis show symptoms of nasal itching, nasal congestion, sneezing, and a runny nose. These symptoms generally subside within 30 minutes, but reappear several hours later. Analysis of the nasal epithelium in such an individual 6 hours after allergen encounter would show:

Infiltration of eosinophils, basophils, neutrophils, T cells, and macrophages

One important feature of retroviruses such as HIV is their generation of a provirus, a copy of the viral genome that is inserted into the host cell chromosome. In addition to providing a template for viral mRNA transcription, the proviral genome:

Is maintained long-term and transmitted to all of the cell's progeny

'Compound X' is most likely:

Leptin

Listeria monocytogenes is a bacterial pathogen that causes a variety of diseases including gastroenteritis, encephalitis, and sepsis. The bacterium has evolved a strategy to replicate in the cytosol of macrophages, and to spread from one macrophage to another using the host's actin machinery to facilitate direct transfer between cells, thereby avoiding the extracellular space. This unique lifestyle of L. monocytogenes is dependent on the bacteria encoding enzymes that:

Lyse the phagocytic vesicle membrane, allowing bacterial escape into the cytoplasm

It is well documented that antibody affinities for an immunizing antigen continue to increase upon successive rounds of immunization (i.e., secondary, tertiary, etc.). This is due to the fact that:

Memory B cells can re-enter germinal centers and undergo additional somatic hypermutation.

Celiac disease occurs when an individual makes an aberrant immune response to a protein in gluten, such as α-gliadin. Evidence suggests that very few proteins are able to elicit the immune response that causes celiac disease. A key piece of this evidence is that:

More than 95% of patients express the MHC class II DQ2 allele.

Individuals that lack all T cells have the most severe form of immunodeficiency (SCID) and will not survive past their first birthday without a bone marrow transplant from a healthy donor. These individuals fail to make antibody responses to the normal childhood vaccines because:

Most antibody responses require T cell help for the B cells

Antibody-dependent cell-mediated cytotoxicity (ADCC) is an important effector mechanism in immunity to virus infections. This immune pathway has also been exploited for clinical applications. For instance, patients with various disorders, including rheumatoid arthritis and some B cell lymphomas, are treated with an antibody directed at CD20, a surface receptor expressed on all B cells. This antibody leads to the depletion of B cells from the patients by the actions of:

Natural killer (NK) cells

Inflammatory bowel disease (colitis) is a CD4 T-cell mediated disease that can be transferred to naive mice by administration of effector CD4 T cells that home to the gastrointestinal tract and induce inflammation. Simultaneous administration of neutralizing antibodies to IL-12p40 can prevent the disease, as can neutralizing antibodies to IL-23p19. Disease symptoms can be exacerbated by administration of IL-23, but not of IL-12. These data strongly suggest that:

Neutralizing antibodies to IL-17 would prevent disease.

Infants born with the immunodeficiency disease X-linked agammaglobulinemia (XLA) have a block in B cell development, and fail to produce mature B cells. As a result, these infants lack the ability to produce antibodies. After birth, babies with XLA first begin to show symptoms of recurrent and persistent extracellular bacterial infections due to common environmental pathogens when they are 4-6 months of age. The reason these infants are healthy for the first 4-6 months after birth is that:

Newborn infants have high circulating levels of maternal IgG at birth.

In individuals with a peanut allergy, mild allergic responses are those that involve a single site, typically a skin reaction such as hives. More severe allergic reactions generally involve multiple tissue sites, such as the skin, oral mucosa, airway mucosa and gastrointestinal tract. Given two groups of allergic patients, one with only skin responses, and the other with 3-4 different tissue sites involved, one would expect that:

Patients with the severe allergic responses would have higher concentrations of allergen-specific IgE.

Red blood cells are common targets of drug-induced anemia, a disorder that occurs when some drugs bind to the surface of red blood cells and trigger the development of IgG antibodies that bind to the drug-coated red blood cell and promote red blood cell destruction. Since the drug binding to the red blood cell surface does not actually harm the red blood cell, the anemia resulting in this disorder is caused by:

Phagocytosis by Fcγ-receptor-expressing macrophages in the spleen

Wild-type mice infected with one strain of Influenza A virus (PR8) by intranasal inoculation are protected from intranasal infection by a related Influenza A virus (Beijing), a phenomenon known as cross-protection. These infections are generally localized to the upper respiratory tract. Mice with a homozygous single gene defect in 'gene X' have greatly impaired cross-protection to Influenza A-Beijing following immunization with Influenza A-PR8 by the intranasal route. Gene X likely encodes:

Poly Ig receptor

Antiretroviral drugs are effective at blocking HIV replication in infected individuals, and in reducing the rate of HIV transmission. Physical barriers to transmission have also been shown to be effective at blocking HIV transmission. An additional strategy for reducing the rate of new HIV infections in high-risk populations utilizes a strategy to prevent the virus from establishing a permanent infection, once an individual has been exposed. This strategy utilizes:

Pre-exposure prophylactic treatment with antiretroviral drugs

In the late 1990s, compounds that functioned as leukotriene receptor antagonists were approved for the treatment of asthma. The first such drug, zafirlukast, inhibits the actions of a major receptor for leukotrienes, known as CYSLTR1 (cysteinyl leukotriene receptor 1). One would predict that patients on this drug would show:

Reduced bronchoconstriction

A relatively new form of therapy for IgE-mediated allergic diseases is the periodic injection of patients with anti-IgE antibody. This antibody binds to the Fc portion of IgE antibodies, and prevents the IgE antibodies from binding to both high affinity and low affinity IgE receptors on inflammatory cells. IgE bound to the high affinity IgE receptor on mast cells and basophils stimulates degranulation of these cells and their production of inflammatory mediators, following antigen encounter. In contrast, the low affinity IgE receptor is expressed on dendritic cells, and functions to trap allergen-IgE complexes for uptake, degradation, and presentation to T cells. Given these functions, individuals treated with this anti-IgE therapy would be expected to show:

Reduced symptoms upon allergen encounter and no progressive worsening of disease

Genetic variations in proteins involved in immune and inflammatory responses have been shown to be associated with the development of atopic dermatitis and other allergic diseases. However, several genes associated with these conditions do not affect the immune system directly. For example, among this latter group are genes that:

Regulate barrier function by airway and skin epithelial cells

Which of the individual relatives above would not be a potential donor for the patient's bone marrow transplant?

Sibling 1

One group of immune deficiency diseases is caused by an inability of CD8 effector T cells to kill virus-infected target cells, due to defects in cytotoxic vesicle exocytosis. Because of the inflammatory response that accompanies a normal virus infection, together with the prolongation of this response due to the inability to control the infection, patients with these disorders suffer from tissue damage caused by the infiltration of effector CD8 cells and activated macrophages into multiple organs. In addition, a subset of these patients also show increased susceptibility to extracellular and intracellular bacterial infections. This is because:

Some proteins required for cytotoxic vesicle exocytosis are required for phagosome-lysosome fusion.

IL-23 is a cytokine made by macrophages and dendritic cells in response to extracellular bacterial and fungal infections. Mice with a genetic defect in the production of IL-23 are highly susceptible to the gastrointestinal bacterial pathogen, Citrobacter rodentium. Thus, unlike wild-type mice which clear the infection, mice that fail to produce IL-23 succumb to the bacteria and die 1-2 weeks post-infection. Yet, this cytokine does not directly act on the bacteria nor does it function to recruit the granulocytes that are needed to eliminate the pathogen. Instead, IL-23:

Stimulates IL-17 and IL-22 production by ILC3 cells

Initially after an infection, the majority of the T cells present in the tissue at a site of infection are not specific for the infecting pathogen, but over the course of several days, this changes and antigen-specific T cells become enriched at this site. This is because:

T cells do not use their T-cell receptors during extravasation from blood into tissues.

The response of most individuals to contact with poison ivy includes the development of redness, swelling, blistering (edema fluid accumulation between the dermis and the epidermis), and itching. If one intended to transfer this response from a sensitized to a naive individual, one would transfer:

T cells from the skin-draining lymph nodes of the sensitized to the naive individual

In cell culture experiments, purified B cells expressing IgM can be induced to switch to producing IgE by stimulating them with an antibody to CD40 (a stimulatory antibody) plus the cytokine IL-4. In an individual undergoing an immune response, these signals would normally be provided by:

TFH cells in the germinal center

IgM antibodies are much more efficient than IgG at activating the complement cascade. However, under certain circumstances, IgG antibodies will activate the complement pathway. One example of a situation in which IgG binding to its antigen will not trigger the complement cascade is when:

The IgG antibodies are neutralizing a bacterial toxin protein by blocking the receptor-attachment site on the toxin.

Some forms of SCID are due to defects in common 'housekeeping' enzymes, such as enzymes involved in nucleotide biosynthesis pathways, that are present in all cells of the body. These genetic deficiencies cause SCID because:

The absence of these enzymes causes build-up of intermediates in the pathway that are toxic to developing lymphocytes.

Individuals with the HIV-induced immunodeficiency disease AIDS have a progressive loss in the number of CD4 T cells in their bodies. These patients have a greatly increased rate of life-threatening disease caused by the inability of their immune system to control infections of the intracellular bacterium, Mycobacterium tuberculosis (Mtb). Mtb infects macrophages and then replicates in the cell's phagosomes. The most important immune mechanism lacking in these patients that leads to their increased susceptibility to Mtb is a defect in:

The activation of macrophages by TH1 effector cells

Infants with RS-SCID generally require treatment by bone marrow transplantation from a healthy donor. In this treatment, hematopoietic stem cells from the donor will give rise to normal B and T lymphocytes, thereby restoring normal immune function. However, the bone marrow transplantation treatment does not alter the high incidence of cancer in these patients. Why not?

The bone marrow transplant restores the hematopoietic system of the patients with cells arising from the donor's stem cells. However, the genetic defect in DNA repair enzymes will still be present in all other cells of the patient, with the exception of their hematopoietic cells. These cells will retain their high susceptibility to malignant transformation due to an inability to repair double-stranded DNA breaks.

Unlike defects in antibodies or T cell functions, defects in complement components often lead to autoimmune-like symptoms, rather than to increased susceptibility to infections. This is because:

The complement pathway normally functions to clear immune complexes from the circulation.

Individuals with defects in ubiquitously expressed DNA repair proteins have a form of SCID known as RS-SCID (radiation-sensitive SCID). Studies have shown that, in addition to immune deficiencies, these patients have an increased rate of cancer. Yet, in general, they are diagnosed first based on their immunodeficiency disease, not on their susceptibility to getting cancer. This is due to the fact that:

The immune response to infections is required almost immediately after birth.

The prevention of inflammatory immune responses to inhaled antigens in healthy individuals has mechanisms in common with those that prevent inflammatory immune responses to commensal microbes in the gut. One important component of immune regulation shared by these two situations is:

The important role for CD4 regulatory T cells in suppressing inflammatory immune responses in these tissues

In the cases of some infections, such as mice infected with adenovirus, the generation of effector cytotoxic CD8 T cell responses needed to clear the infection is dependent on the antigen-presenting dendritic cells receiving stimulation through the CD40 receptor on their surface, a process known as dendritic cell 'licensing'. In this infection system, the dendritic cell would likely receive CD40 receptor stimulation from:

The interaction with a CD4 effector cell expressing CD40 ligand

Individuals with a complete absence of B cells and antibodies, such as patients with XLA, show a limited range of susceptibilities to infection rather than a global immunodeficiency to all categories of pathogens. For example, XLA patients show increased susceptibility to pyogenic bacterial infections, as antibody binding to these microbes is critical for their uptake and destruction by phagocytes. Clinicians caring for these patients are advised regarding their vaccinations, some of which could be highly dangerous to the antibody-deficient patient. In particular, XLA patients should never receive:

The live oral polio vaccine, composed of an attenuated strain of the enteric poliovirus

However, in addition to IgG, pneumococcal polysaccharides elicit robust IgA antibody responses. It was traditionally thought that these IgA antibodies functioned in neutralization, by blocking bacterial attachment to mucosal epithelial cells. It is now known that IgA antibodies, like IgG, can function as opsonins, to induce phagocytosis and killing of IgA-coated pathogens. This function of IgA antibodies depends on:

The presence of IgA-specific Fc receptors on neutrophils and macrophages

Immunological memory in humans has been examined by assessing responses in individuals who were given the vaccinia virus to induce immunity against smallpox. Antiviral CD4 and CD8 T cell responses could be detected many years after the vaccinia immunization, but declined with an estimated half-time of about 10 years. In contrast, antiviral antibody responses were maintained at a relatively constant level, with a barely detectable decline over decades. The persistence of antiviral antibodies for years after immunization is likely due to:

The presence of long-lived antibody secreting plasma cells

Individuals with peanut allergies can exhibit a variety of symptoms following exposure to the peanut allergen. These symptoms can include a runny nose, skin reactions such as hives, itching in the mouth and throat, digestive problems such as cramps, diarrhea or vomiting, and shortness of breath or wheezing. This variety of symptoms is a result of:

The presence of mast cells with pre-bound IgE in all mucosal tissues

Unlike somatic hypermutation, class switching occurs in discrete sequence regions upstream of the immunoglobulin heavy chain coding sequences (called switch regions). One key element in directing the enzyme AID to a specific switch region is the opening of the DNA duplex combined with polymerase stalling during active transcription in that region. A second key feature of directing AID to a specific switch region is:

The processed RNA from the switch region guides AID to this site in the DNA

In response to an intracellular bacterial or viral infection, effector TH1 cells, macrophages, NK cells, and CD8 cytotoxic effector cells are all recruited to the site of infection. The coordinated recruitment of all of these cell types is orchestrated by:

The shared expression of chemokine receptors on these different cell types

In the case of HIV infection by sexual transmission, a key step in the establishment of disseminated HIV infection is the replication of the virus in regional lymph nodes draining the mucosal site of initial virus entry. The ability of the virus to spread from the mucosa to the regional lymph node is made possible by:

The virus' ability to infect migratory cells that carry it from the mucosa to the lymph node

In humans, IgA is produced in copious amounts, estimated to be a rate of 3 g/day. Nearly all of the IgA secreting plasma cells are found in the gastrointestinal (GI) tract where the secreted IgA is transported across the GI epithelium into the lumen of the gut. There, this antibody protects the GI epithelium against intestinal pathogens. In contrast, none of the GI resident long-lived antibody secreting cells produce antibodies of the IgG class. The differential localization of long-lived antibody secreting cells producing IgA compared to those producing IgG is likely due to:

Their priming and differentiation in mucosal lymphoid organs

The process of somatic hypermutation of antibody V regions sequences is initiated by the enzyme AID. This enzyme targets cytidine residues in the DNA sequence that are normally part of a G:C pair in the double-stranded DNA. Yet the hypermutation process generates mutations at both G:C and A:T base pairs of the original sequence because:

There are two different pathways of repair target, one targeting G:C and one targeting A:T base pairs.

Multiple choice: A mouse is immunized with the tetanus toxoid protein (inactivated toxin) in adjuvant. One week later, the entire population of splenic B cells are isolated from the mouse and mixed with tetanus toxoid-specific CD4 TFH cells plus the purified tetanus toxoid protein. Four days later, the total number of B cells in the culture and the number of tetanus toxoid-specific B cells are determined and compared to the starting population on the day of isolation. The results are shown in Figure Q10.1. The tetanus-specific B cells preferentially survive and proliferate because:

They are the only B cells presenting the tetanus peptide to the TFH cells.

The subset of TEM cells provides an important component of protective immunity to re-infection by the same pathogen because:

They can protect against re-infection that occurs in a different site in the body than the primary infection.

In mice, an allergic response in the airways can be induced by systemic immunization with a protein antigen (chicken ovalbumin) in an adjuvant that promotes Type II immune responses, followed by several exposures to aerosolized ovalbumin administered via the airways. Mice that have a genetic deficiency in expression of the receptor c-kit are resistant to this disease because:

They lack mast cells.

The W/Wv mouse strain is heterozygous for two different alleles of the gene encoding the growth factor receptor, c-kit, an important receptor expressed on hematopoietic progenitor cells in the bone marrow. The major defect in these mice is the absence of single lineage of hematopoietic cells. When these mice are challenged with larval Haemaphysalis longicornis ticks, they fail to become resistant to the ticks, in spite of generating high titers of anti-tick IgE antibodies. The cell type missing in the W/Wv mice is most likely:Natural Killer (NK) cells

Tissue-resident mast cells

The germinal center is a region within the secondary B cell follicle where sustained B cell proliferation and differentiation take place. The processes of B cell proliferation and differentiation, including affinity maturation and class switching, require periodic interactions of the germinal center B cells with CD4 TFH cells. These periodic interactions between the B cells and TFH cells can occur:

When B cells cycle between the dark zone and the light zone of the germinal center

These data were obtained by ELISPOT analysis, to quantify the numbers of IFN-γ-producing CD8 T cells per million peripheral blood leukocytes in response to several EBV peptides, indicated as peptide 1, 2, 3, or 4 (note: the patients and controls were matched for HLA class I molecules; Figure Q13.13). These results indicate that:

XLP patients have normal CD8 effector cell priming following EBV infection.

A variety of genetic defects can result in patients exhibiting SCID. For many of these diseases, infants with the disease are given bone marrow transplants from healthy donors to restore normal immune function. Yet, some diseases causing T cell deficiencies cannot be treated by bone marrow transplantation. Which of the diseases below is treatable by giving patients hematopoietic stem cells from a healthy donor?

XSCID

To determine the potential mechanism leading to the immune deficiency, a series of additional studies were performed. In one study, peripheral blood leukocytes from the mice were mixed with Staphylococcus aureus bacteria, and the ability of the cells to kill the bacteria was assessed. In a second study, the compound thioglycolate was injected into the peritoneal cavity of the mice, and five hours later the numbers of white blood cells were measured. This compound elicits a robust inflammatory response in the peritoneum, including the production of several inflammatory cytokines, such as TNFα, IL-1, and IL-6, as well as a number of chemokines known to recruit neutrophils and monocytes from the blood to the site of inflammation. The results of these studies are shown in Figure Q13.16B. Given these data, a likely candidate for the gene that was targeted in these knockout mice is:

p47, a component of NADPH oxidase

HIV-infected patients that progress to AIDS suffer from a variety of opportunistic infections that rarely cause disease in healthy individuals. In addition, many of these patients acquire malignancies, such as B-cell lymphomas or Kaposi's sarcoma. A common feature of these two malignancies is that they are:

Each associated with a herpesvirus infection

Herpesviruses are a class of viruses that establish life-long infections in human hosts. Estimates suggest that >90% of the population is infected with several of these viruses, including EBV, CMV, and herpes zoster, the cause of chicken pox. One herpesvirus, Herpes Simplex virus, causes recurrent cold sores in infected individuals. Thus, in spite of a robust anti-viral CD8 T cell response, these individuals still suffer from periodic virus-induced cold sores following exposure to UV light or certain hormones or other stressors. This anti-viral CD8 T cell response:

Eliminates infected epithelial cells but not infected neurons

The cell type most likely responsible for the tissue damage in this allergen-induced airway remodeling disease model is:

Eosinophils

True/False: Once B cells begin secreting antibodies, they cease dividing and have a life-span of only a few days.

False

In this example, the virus is cleared by ~day 7 post-infection, and starting at ~day 10 post-infection, the majority of the virus-specific CD8 T cells die. The death of these virus-specific CD8 T cells is caused by:

Fas-induced death or cytokine withdrawal

Patients with Wiskott-Aldrich syndrome show severely impaired responses to vaccines such as the tetanus vaccine, which is composed of the inactivated tetanus toxin (i.e., tetanus toxoid). Yet, these patients can generate normal antibody responses to bacterial polysaccharide antigens. This selective defect in antibody responses in Wiskott-Aldrich syndrome patients is due to:

Defective polarized secretion of cytokines by CD4 T cells

Helicobacter pylori is a human gastrointestinal (GI) pathogen that can lead to a state of chronic GI inflammation in some individuals, and has been linked to gastric ulcers and other diseases. Studies have shown that human mucosal gastric biopsies of infected individuals have dendritic cells producing IL-23, and that human monocytes isolated and cultured from healthy individuals produce IL-23, but not IL-12, in response to stimulation with live H. pylori. Given these findings, which of the following responses would be enhanced in the GI tract of H. pylori-infected individuals compared to uninfected individuals?

Recruitment of neutrophils