Immunology final
6. Isotype switching and immunoglobulin gene rearrangement by somatic recombination are both recombinational processes but have very different outcomes. Give four ways in which they differ from each other.
(1) Gene rearrangements affect the variable region of immunoglobulins, whereas isotype switching affects the constant region. (2) Different recombination-signal sequences and enzymes are used for the two processes. (3) Isotype switching occurs only after antigen stimulation, whereas gene rearrangement occurs only during B-cell maturation in the bone marrow. (4) All isotype switch recombinations are productive, but not all gene rearrangements are. (5) Only heavy chains are involved in isotype switching, whereas both heavy-chain and light-chain genes are involved in somatic recombination.
8. Describe the six functionally distinct phases of B-cell development. Be sure to include location, purpose, and a brief description of the mechanism.
(1) Repertoire assembly: Bone marrow expression of diverse B-cell receptors. (2) Negative selection: Modification, elimination or inactivation of autoreactive B cells. (3) Positive selection: Selection of a small subset of immature B cells to become mature B cells in secondary lymphoid organs. (4) Searching for infection: Patrolling for infectious material by recirculating continuously between lymph, blood and secondary lymphoid organ compartments. (5) Finding infection: B cells become activated by antigen in secondary lymphoid tissues and then undergo clonal expansion. (6) Attacking infection: B cells differentiate into plasma cells and memory cells in secondary lymphoid tissues.
3. Describe three distinct mechanisms by which antibodies eradicate infection.
(i) Neutralization. By binding to the surface of a pathogen, antibodies interfere with the ability of the pathogen to grow and replicate. Antibody binding to a pathogen or a bacterial toxin can also inhibit its binding to receptors on host cells and therefore prevent its entry into cells. (ii) Opsonization. Antibody coating the surface of a pathogen or toxin can promote phagocytosis of the antibody-covered particle. Antibodies acting in this way are known as opsonins. The antibody-bound material interacts with Fc receptors on the surface of phagocytic cells such as macrophages and neutrophils, which bind the constant region (the stem) of the antibody. Stimulation of Fc receptors in this way stimulates the engulfment and degradation of antibody-coated material by the phagocyte. (iii) Complement activation. IgG or IgM antibody bound to a pathogen stimulates activation of the complement system, leading to the deposition of complement proteins on the surface of the pathogen. Certain of these act as opsonins and bind to complement receptors on phagocytic cells to stimulate the phagocytosis and destruction of the pathogen.
28. Explain the theoretical molecular process that would lead to persistent memory CAR+ T cells after adding the CD137 signaling domain to the intracellular part of the CAR.
...CD137 plays an important role in T cell proliferation and survival, particularly for T cells within the memory T cell pool.42 CD137 mediates its effects on T cell survival and proliferation through activation of the AKT/mammalian target of rapamycin pathway43 and the upregulation of the antiapoptotic genes, Bcl-xL and BFL-1.44
4. A. Review the mechanisms of each of the three pathways of complement (alternative, lectin, and classical) and point out the differences between them in terms of how they are activated. B. Distinguish which pathway(s) are considered part of an adaptive immune response and which are considered part of innate immunity, and say why.
A. (1) The classical pathway is activated in two ways, either by the presence of antibody bound to the surface of the microorganism (for example IgM bound to lipopolysaccharide of Gram-negative bacteria) or by the presence of C-reactive protein bound to a bacterium. (2) The lectin pathway requires the presence of mannose-binding lectin, an acute-phase protein made by the liver in response to interleukin-6 (secreted by activated macrophages) and which accumulates in plasma during infection. (3) The alternative pathway requires an activating surface of a pathogen, which stabilizes complement components. B. Only the classical pathway is considered part of the adaptive immune response because of the requirement for antibody. However, the classical pathway is also considered part of innate immunity because of the ability of C-reactive protein, an acute-phase protein, to activate it. The other two pathways are considered part of innate immunity because they are initiated independently of antibody.
22. A. Contrast acute rejection and chronic rejection. B. What is GVHD and what type of transplantation does it occur as a result of?
A. Acute rejection occurs within a few days of transplantation and is mediated by an alloreactive CD4 and CD8 T cell-mediated adaptive immune response by the recipient against the 'foreign' HLA molecules on the graft and involves the direct pathway of recognition. In contrast, chronic rejection occurs months to years after transplantation; it is mediated by anti-HLA class I and anti-HLA class II alloantibodies and involves the indirect pathway of recognition. CD4 T cells are first activated by recipient dendritic cells presenting donor-derived HLA class II allotypes of the recipient. These activated CD4 T cells in turn activate B cells, which are also presenting donor-derived allogeneic HLA peptides. This cognate interaction results in the production of anti-HLA class I (and also anti-HLA class II) antibodies. B. Graft-versus-host disease (GVHD) is a severe adverse immunologic reaction following allogeneic bone marrow transplantation, induced by the reaction of donor T cells to recipient histoincompatible antigens. immune cells from the donor attack the recipient patients tissues.
17. A. Explain the difference between antigenic drift and antigenic shift in the influenza virus. B. Which is most likely to lead to a major worldwide pandemic? C. What is the role of the phenomenon of 'original antigenic sin' in immunity to this virus? D. In the Kamlangdee et al. paper describing the broad protection of a mosaic hemagglutinin vaccine, what were the important aspects taken into consideration while constructing the mosaic hemagglutinin gene?
A. Antigenic drift is a term used to describe one of the ways that influenza (flu) viruses change and mutate. It describes a minor change in the flu virus. Antigenic shift is a more major change in the influenza virus. This shift occurs typically when a human flu virus crosses with a flu virus that usually affects animals (such as birds or pigs). B. Antigenic shift is an abrupt, major change in the influenza A viruses, resulting in new hemagglutinin and/or new hemagglutinin and neuraminidase proteins in influenza viruses that infect humans. Shift results in a new influenza A subtype or a virus with a hemagglutinin or a hemagglutinin and neuraminidase combination that has emerged from an animal population that is so different from the same subtype in humans that most people do not have immunity to the new (e.g. novel) virus. Such a "shift" occurred in the spring of 2009, when an H1N1 virus with a new combination of genes emerged to infect people and quickly spread, causing a pandemic. When shift happens, most people have little or no protection against the new virus. C. The 'original antigenic sin' concept refers to the impact of the first influenza virus variant encounter on lifelong immunity. Although this model has been challenged since its discovery, past exposure, and likely one's first exposure, clearly affects the epitopes targeted in subsequent responses. Understanding how previous exposure to influenza virus shapes antibody responses to vaccination and infection is critical, especially with the prospect of future pandemics and for the effective development of a universal influenza vaccine. D.e mosaic method chooses the most frequent T-cell epitopes and combines them to form a synthetic antigen. ). Highly pathogenic avian influenza (HPAI) H5N1viruses have spread as far as Eurasia and Africa since their first emer-gence in 1996. These viruses infect a range of domestic and wild avianspecies as well as mammals (2) and pose a pandemic threat (3). Cur-rent prevention and treatment strategies for H5N1 virus either areantiviral or vaccine based or involve nonpharmaceutical measures,such as patient isolation or hand sanitation (4,5). However, theseapproaches have flaw
12. Virus-infected cells attacked and killed by effector cytotoxic T cells are often surrounded by healthy tissue, which is spared from destruction. A. Explain the mechanism that ensures that cytotoxic T cells kill only the virus-infected cells (the target cells). B. What cytotoxins do cytotoxic T cells produce?
A. Cytotoxic T cells focus their killing machinery on target cells through a process called polarization. The cytoskeleton and the cytoplasmic vesicles containing lytic granules are oriented toward the area on the target cell where peptide:MHC class I complexes are engaging T-cell receptors. In the T cell, the microtubule-organizing center, Golgi apparatus, and lytic granules, which contain cytotoxins, align toward the target cells. The lytic granules then fuse with the cell membrane, releasing their contents into the small gap between the T cell and the target cell, resulting in the deposition of cytotoxins on the surface of the target cell. The cytotoxic T cell is not killed in this process and will continue to make cytotoxins for release onto other target cells, thereby killing numerous target cells in a localized area in succession. B. The cytotoxins include perforin, granzymes, and granulysin, molecules that induce apoptosis (programmed cell death) of the target cell.
18. A. Explain the mechanism by which human immunodeficiency virus (HIV) enters a host cell. B. Explain the cellular tropism of HIV, discussing the difference between macrophage-tropic and lymphocyte-tropic HIV. C. Some people seem to be resistant to HIV infection because a primary infection cannot be established in macrophages. What is the reason for this?
A. Human immunodeficiency virus (HIV) infects cells bearing CD4 molecules on their surface. These include TH1 and TH2 cells, macrophages, and dendritic cells. CD4 acts as a receptor involved in binding the gp120 envelope glycoprotein of HIV. A co-receptor is also required for virus entry. Two are used by HIV: the chemokine receptors CCR5 and CXCR4. CCR5 is expressed on all CD4+ cells, whereas CXCR4 is restricted to T cells. After binding to the co-receptor, another viral envelope glycoprotein, gp41, facilitates fusion between the host cell's plasma membrane and viral envelope with the release of viral components into the cytoplasm. B. The cell tropism of HIV depends on which co-receptor is used for entry. Macrophage-tropic HIV, associated with early infection, uses the CCR5 co-receptor. Lymphocyte-tropic HIV, associated with a phenotypic change in late infection in about 50% of cases, uses CXCR4. C. About 1% of the caucasoid population is homozygous for a mutant form of CCR5 that cannot be used by HIV as a co-receptor. The mutation involves a 32-nucleotide deletion called CCR5-δ32, which alters the reading frame and results in a nonfunctional CCR5 protein. This renders such individuals resistant to primary infection by macrophage-tropic variants of HIV but still susceptible to lymphocyte-tropic strains that use the CXCR4 co-receptor.
20. A. Describe in detail the mechanism responsible for mast-cell activation during a type I hypersensitivity reaction. B. What are the similarities between the activation of mast cells and NK cells via FcRI and FcRIII, respectively? Be specific. C. What are the differences? Again, be specific.
A. If an individual becomes sensitized to antigen by making antibodies of the IgE isotype during first exposure, then a type I hypersensitivity reaction may result if antigen is encountered again. The IgE made initially binds stably via its Fc region to very high-affinity FcεRI receptors on mast-cell surfaces. When antigen binds to this IgE, cross-linking of FcεRI occurs, delivering an intracellular signal that activates the mast cell. B.
16. B cells are activated by CD4 TH2 cells only if both cell types recognize the same antigen. The same epitope, however, does not need to be shared for recognition. A. Discuss why this characteristic is important in vaccine design. B. Provide an example of a conjugate vaccine used to stimulate the synthesis of IgG antibody against Haemophilus influenzae B polysaccharide.
A. Many bacteria are surrounded by a polysaccharide capsule. In some cases, antibodies against the capsular polysaccharides give protective immunity against the pathogen. Antibodies produced against polysaccharide antigens are generally restricted to the IgM isotype, because the help needed to switch isotypes to IgG is provided by T cells, which recognize only peptide antigens. Adult humans make effective immune responses to polysaccharides alone and thus can be protected by subunit vaccines made from the capsular polysaccharides of encapsulated bacteria. Their antibody responses are polysaccharide-specific, T-cell independent, and involve antibodies of the IgM isotype. In contrast, children do not make effective immune responses to polysaccharides alone and thus cannot be immunized with such vaccines. However, if the polysaccharide is conjugated to a protein, peptides from the protein part of the molecule can activate specific TH2 cells. B cells specific for polysaccharide will bind and internalize the whole antigen via their antigen receptors, process it, and then present peptides from the protein part on their surface. T cells specific for these peptides will interact with the B cell, delivering the necessary cytokines (such as IL-4) and the CD40-CD40-ligand signal required for isotype switching. The B cell will then produce IgG anti-polysaccharide antibodies. This type of vaccine can be used to immunize children so as to induce protective anti-polysaccharide antigens. B. A vaccine of this type has been produced against Haemophilus influenzae B (HiBC), which can cause pneumonia and meningitis. The conjugate vaccine is composed of a capsular polysaccharide of H. influenzae conjugated to tetanus or diphtheria toxoid (a protein). The antibody response is polysaccharide-specific, T-cell dependent, and comprises IgG that protects children from the meningitis caused by this microorganism.
25. In the context of autoimmunity: (A) define molecular mimicry; and (B) describe in detail how HCV infection can lead to thrombocytopenia.
A. Molecular mimicry refers to the phenomenon in which a pathogen expresses an antigen that bears a chemical similarity to a host-cell antigen. Once pathogen-specific antibodies or effector T cells are generated, they have the potential to cross-react with self antigen. B. The autoantibody is anti-GPIIIa49-66 Ab When this anti-GPIIIa49-66 Ab reacts with the epitope it fragments the platelet and forms immune complexes with them Via a complement-independent platelet fragmentation by reactive oxidative platelet fragmentation The antibody against GPIIIa49-66 suggest an antigen-driven B cell clonal expansion that positively selects for the autoantibody PHC09
27. Explain how the immune mechanisms for the detection of cancer cells are (A) similar to and (B) different from those that detect virus-infected cells.
A. NK cells and cytotoxic T cells detect cancer cells and virus-infected cells through the alteration of MHC class I. B. Unlike virus detection, which involves inflammatory responses that stimulate immediate innate immune responses, cancer cells can often grow for long periods before they induce an inflammatory state and a consequent immune response.
10. A. At which anatomical sites do naive T cells encounter antigen? B. In which sites specifically would a pathogen or its antigens end up, and how would they be transported to these sites, if they (i) entered the body through a small wound in the skin, (ii) entered the body from the gut, or (iii) got into the bloodstream? C. How do naive T cells arrive at these sites? D. Do all T cells leave these locations after priming, and if so, how?
A. Naive T cells encounter antigen, and start the primary immune response, in a secondary lymphoid tissue (for example lymph nodes, spleen, Peyer's patches, tonsils). B. (i) Lymph nodes. The pathogen, and dendritic cells that have ingested the pathogen, are carried to the nearest lymph node in the afferent lymph. (ii) Gut-associated lymphoid tissues (GALT) such as Peyer's patches. Pathogens enter GALT via specialized cells (M cells) in the gut epithelium. (iii) Spleen. Pathogens circulating in the blood enter the spleen directly from the blood vessels that feed it. C. Naive T cells are delivered to all secondary lymphoid organs from the blood. They can also pass from one lymph node to another via a lymphatic. D. After differentiation, CD8 effector cells and CD4 TH1, TH2, TH17, and regulatory T cells exit from the lymphoid tissue (via efferent lymph, which delivers them eventually into the blood) in search of infected tissues. Antigen-activated CD4 TFH cells remain in the lymphoid tissue where they provide help to antigen-specific B cells
7. A. Describe in chronological order the steps of the antigen-processing and antigen-presentation pathways for intracellular, cytosolic pathogens. B. (i) What would be the outcome if a mutant MHC class I chain could not associate with 2-microglobulin, and (ii) what would happen if the TAP transporter were lacking as a result of mutation? Explain your answers.
A. Proteins derived from pathogens located in the cytosol are broken down into small peptide fragments in proteasomes. The peptides are transported into the lumen of the endoplasmic reticulum (ER) using the transporter associated with antigen processing (TAP), which is a heterodimer of TAP-1 and TAP-2 proteins anchored in the ER membrane. Meanwhile, MHC class I molecules are assembling and folding in the ER with the assistance of other proteins. Initially, the MHC class I α chain binds calnexin through an asparagine-linked oligosaccharide on the α1 domain. After folding and forming its disulfide bonds, the α chain binds to β2-microglobulin, forming the MHC class I heterodimer. At this stage, calnexin is released and the heterodimer joins the peptide-loading complex composed of tapasin, calreticulin, and ERp57, which position the heterodimer near TAP, stabilize the peptide-loading complex, and render the heterodimer in an open conformation until a high-affinity peptide binds to the heterodimer through a process known as peptide editing. The heterodimer consequently changes its conformation, is released from the peptide-loading complex, and leaves the ER as a vesicle. Arrival at the Golgi apparatus induces final glycosylation, and finally the peptide:MHC class I heterodimer complex is transported in vesicles to the plasma membrane, where it presents peptide to CD8 T cells. B. (i) If an MHC class I α chain is unable to bind β2-microglobulin, it will be retained in the ER and will not be transported to the cell surface. It will remain bound to calnexin and will not fold into the conformation needed to bind to peptide. Thus, antigens will not be presented using that particular MHC class I molecule. (ii) If TAP-1 or TAP-2 proteins are mutated and not expressed, peptides will not be transported into the lumen of the ER. Without peptide, an MHC class I molecule cannot complete its assembly and will not leave the ER. A rare immunodeficiency disease called bare lymphocyte syndrome (MHC class I immunodeficiency) is characterized by a defective TAP protein, causing less than 1% of MHC class I molecules to be expressed on the cell surface in comparison with normal. Thus, T-cell responses to all pathogen antigens that would normally be recognized on MHC class I molecules will be impaired.
26. A. What are the two main classes of gene that, if not expressed correctly, can lead to malignant transformation? B. What are the gene products made by each class?
A. Proto-oncogenes and tumor suppressor genes. B. Proto-oncogenes encode proteins that participate in cell division, such as growth factors, growth factor receptors, signal transduction proteins, and activators of gene expression. Tumor suppressor genes encode proteins that inhibit the division of mutant cells; examples are p53, APC, and DCC.
15. A. What is the difference between the Salk and Sabin polio vaccines? B. Which one should be used for an individual who has an immunodeficiency disease, and why?
A. The Salk polio vaccine is an inactivated virus vaccine, whereas the Sabin polio vaccine is a live-attenuated virus vaccine. B. The Salk vaccine should be used for immunocompromised individuals. Live attenuated vaccines carry a risk of mutational reversion in an immunocompromised host to a more virulent, disease-causing strain. This occurs because the virus is able to replicate at higher levels and acquire a significant number of mutations, some of which may lead to reversion to a pathogenic strain.
14. A. Explain why the DTP vaccine stimulates a much stronger protective immunity than does the DT vaccine. B. Relate this to the use of adjuvants in vaccines. When would they be used? Why are they used? C. In Figure 4B of the Knudsen et al. paper, it shows that CAF01 was better at protecting mice from Mycobacterium tuberculosis challenge than alum. Using the data from Figure 4A and previous research on effective immune responses to M. tuberculosis, describe why it is thought that CAF01 has better protective efficacy.
A. The diphtheria (D) and tetanus (T) toxoids are purified proteins that on their own do not stimulate Toll-like receptors or other receptors of the innate immune response. Hence, an inflammatory response is not initiated by the DT vaccine, which consequently results in the failure to initiate an adaptive immune response. When inactivated Bordetella pertussis is added to make the tripartite vaccine (DTP), it efficiently activates the innate immune response by acting as an adjuvant and inducing inflammation. It also provides additional pathogenic antigens to which the host responds. B Adjuvants in immunology are often used to modify or augment the effects of a vaccine by stimulating the immune system to respond to the vaccine more vigorously, and thus providing increased immunity to a particular disease. no adjuvents in live-attenuated vaccines, adjuvents are used in sububit or protein vaccines. C.. It is possible that CAF01-based vaccines are also able to induce IL-17 in humans but at a very low and un-detectable level and that the response only becomes apparent after infection. CAF01-based TB vaccines were also capable of inducing long-term protective responses with a high frequency of vaccine-induced CD4 T-cells retrieved more than one year after vaccination in mic
5. A. Describe the two different domains of TLRs and their respective functions. B. What is NFB and what is its role in mediating signals through TLRs?
A. The first domain of the TLR is an extracellular domain, also known as the pathogen-recognition domain, which contains a hydrophobic, leucine-rich repeat region (LRR) forming a horseshoe-shaped structure that binds specifically to arrays on microbial surfaces. The second domain of the TLR is the cytoplasmic signaling domain, also known as the Toll interleukin receptor (TIR) domain, which facilitates the transmission of information to the interior of the cell. B. NF\kappaB is a transcription factor, and some TLRs signal through an intracellular pathway that involves the activation of NF\kappaB. In the absence of stimulation of the TLR, NF\kappaB is found in an inactive form in the cytoplasm. Signaling through the TLR results in a phosphorylation cascade that converts NF\kappaB to its active form, which is then able to translocate into the nucleus and direct the transcription of specific genes that promote the cell's response to the infection.
11. A. Identify three types of professional antigen-presenting cell. B. How are they distributed in secondary lymphoid tissue? C. Which kinds of antigen do they present efficiently to T cells? D. Why are dendritic cells so important in adaptive immune responses? Explain what they do.
A. The three types of professional antigen-presenting cells are dendritic cells, macrophages, and B cells. B. Dendritic cells are found in T-cell-rich areas of secondary lymphoid tissue; macrophages are distributed throughout the tissue; B cells are localized in lymphoid follicles. C. Dendritic cells present all types of antigen but present viral antigens particularly efficiently. Macrophages present bacterial antigens well because they bear generalized receptors that can bind and internalize many different bacteria. B cells present peptides of soluble protein antigens, such as protein toxins, that they have internalized via their antigen receptors. D. Dendritic cells engulf, process and then transport antigens to a nearby secondary lymphoid tissue, such as lymph nodes, where they then encounter antigen-specific T cells, which then differentiate into effector T cells. Effector T cells are then able to leave the secondary lymphoid tissue and travel to the site of infection and perform their particular effector response to eradicate the infection.
19. Below is an example of flow cytometry data. A. Based on what you know about flow cytometry, describe the process involved in obtaining this data. B. Based on the information given, analyze the results in terms of types of cells present and changes between the left and right panels. C. The left sample was obtained from a patient in 2010 while the right was obtained from the same patient in 2016. What type of infection might the data indicate?
A.Flow cytometry is a technology that is used to analyse the physical and chemical characteristics of particles in a fluid as it passes through at least one laser. Cell components are fluorescently labelled and then excited by the laser to emit light at varying wavelengths. The fluorescence can be measured to determine various properties of single particles, which are usually cells B.
21. Explain the results from Figure 2B and C in the Karisola et al. paper. Why were these experiments performed? What do the data show? What are the implications in AHR treatment?
CD1d-deficient mice had more macrophages in theirBALF than the other strains but their amount decreased when treated withα-GalCer (Fig 2B).In contrast, onlyα-GalCer-treated WT mice displayed a significant increase in the numbers ofneutrophils in BALF, this response was absent in both iNKT cell deficient strains (Fig 2B).We next examined whether iNKT cells are required for the development of the Th2-type en-vironment in the lungs. Only in the WT mice, didα-GalCer increase the production of theTh2-type cytokines IL-4 and IL-13, Th1-type IFN-γand regulatory IL-10 and again, this effectwas not present in the iNKT cell deficient mice
. In the Ianni et al. paper, Treg's were favorable, but in the Kalos et al. paper, they did not want them induced. Describe T regulatory cells and how they function and then describe why they are wanted in some situations, but not others using these two papers as examples.
CD4+ T cells are commonly divided into regulatory T (Treg) cells and conventional T helper (Th) cells. Th cells control adaptive immunity against pathogens and cancer by activating other effector immune cells. Treg cells are defined as CD4+ T cells in charge of suppressing potentially deleterious activities of Th cells.
2. Describe what clonal selection and clonal expansion are in the context of an adaptive immune response? Describe how and where they occur in detail.
During the Antigen Independent period, stem cells produce many immature lymphocytes which get receps specific to antigens. Clones that respond to self antigens are eliminated during "clonal deletion." From the "repertoire" of lymphocytes a single clone which responds to a particular antigen will be activated and will proliferate and differentiate. In an adaptive immune response to a pathogen, the term clonal selection describes the fact that only those lymphocytes that can recognize that particular pathogen and respond to it are selected to participate in the immune response. Clonal expansion describes the proliferation and subsequent differentiation of these few original lymphocytes to provide large numbers of effector lymphocytes. Clonal selection ensures that the adaptive response will be tailored specifically for the particular type of pathogen involved in the infection. Clonal expansion ensures that the few original lymphocytes specific for the pathogen produce a large population of effector lymphocytes that can make an effective immune response against the pathogen.
1. What are the main differences between innate immunity and adaptive immunity?
Innate immune responses are initiated almost immediately after infection, whereas adaptive immunity takes longer to develop. Innate immunity uses generalized and invariant mechanisms to recognize pathogens. Examples of these are the receptors on phagocytes that recognize surface molecules shared by many different pathogens and stimulate phagocytosis, and serum proteins such as complement. Innate immunity is often unable to eradicate the pathogen completely, and even when it does, it does not produce immunity to reinfection. An adaptive immune response, in contrast, involves specific recognition of the particular pathogen by highly specific receptor on a subset of lymphocytes, which are selected from a pool of millions of lymphocytes each bearing receptors specific for different molecules. Adaptive immunity is often powerful enough to eradicate the infection and provides long-term protective immunity through immunological memory.
13. From an immunological viewpoint, why would it be inadvisable for a mother who has recently given birth to move with her newborn to a foreign country where there are endemic diseases not prevalent in her homeland?
Newborn infants are afforded passive immunity to the pathogens in their environment through IgG and dimeric IgA. IgG is transferred transplacentally, and dimeric IgA is acquired through breast milk. If an endemic infection develops in the newborn infant, the IgG antibodies in the infant's bloodstream may not have the appropriate specificity for the foreign antigens because the mother would not have encountered these antigens previously in their homeland, and therefore the newborn infant would not have acquired them passively during fetal development. Furthermore, without maternal IgG, infants are particularly susceptible to infection for the first 6 months of their life, when their immune systems are unable to produce significant levels of IgG. In addition, infections that breach mucosal surfaces may be more likely to develop during this time because dimeric IgA against such a pathogen will not be formed in the breast milk until about a week after the mother has been exposed to the same pathogen.
9. A. Describe the negative and positive selection processes that occur in the thymus. Be sure to include an explanation of how the expression and processing of self-antigens in thymic epithelium differs from the expression and processing of self-antigens outside the thymus. B. In what way is the thymic situation advantageous for the purposes of negative selection?
Positive selection ensures MHC restriction by testing the ability of MHCI and MHCII to distinguish between self and nonself proteins. In order to pass the positive selection process, cells must be capable of binding only self-MHC molecules. If these cells bind nonself molecules instead of self-MHC molecules, they fail the positive selection process and are eliminated by apoptosis. Positive Selection 1. Thymocyte that do not recognize self MHC with a low affinity will die CD4+CD8+ thymocytes screen alphabeta TCR against mHC I: peptide and MHC II: peptide (although the peptide doesnt do anything) Negative selection tests for self tolerance. Negative selection tests the binding capabilities of CD4 and CD8 specifically. The ideal example of self tolerance is when a T cell will only bind to self-MHC molecules presenting a foreign antigen. If a T cell binds, via CD4 or CD8, a self-MHC molecule that isn't presenting an antigen, or a self-MHC molecule that presenting a self-antigen, it will fail negative selection and be eliminated by apoptosis. Negative Selection 1. The process where thymocyte that recognize self MHC with self peptide with a high affinity will be eliminated 2. Prevent autoimmune i) As well as expressing their own thymus - specific self antigens, medullary epithelial cells in the thymus produce a transcription factor called autoimmune regulator (AIRE) , which causes several hundred genes normally expressed in other tissues to be expressed in these cells. The proteins can then be processed to form self pep tides that will be presented by MHC class I molecules. (ii) The thymic epithelium uses different proteases for self- protein degradation; cathepsin L is used for peptide production instead of cathepsin S, which is used by other cell types. B.Generating a more comprehensive repertoire of self peptides in the thymus increases the types of potentially autoreactive T cell that are removed from the peripheral T cell repertoire during negative selection.
24. Explain why splenectomy is sometimes carried out in patients with persistent type II autoimmune diseases that affect leukocytes.
When autoantibodies directed toward leukocyte surface antigens bind to the cell surface, complement fixation and deposition of C3b occurs. The membrane-attack complex usually does not form on leukocytes because of complement regulatory proteins. Their elimination from the circulation, however, occurs by a different mechanism involving splenic macrophages that bear FcR and CR1, receptors for antibodies and C3b, respectively. The macrophages carry out phagocyte-mediated clearance of these leukocytes, leading to a deficiency of these cells in the circulation. Removal of the spleen spares the elimination of these leukocytes. The presence of antibody and C3b on their cell surface does not affect their ability to functional normally.