(Pset) Mid-Term #1 Online Immunology

Immunology X110 Online

Mid-term #2 Name: MICHELLE FREED

150 points

Part I. Clearly state the meaning / function for each of the terms, abbreviations, cell types or organs listed below. Be sure to include a detailed enough answer to indicate your full understanding of the definition you provide; but limit your answer to no more than five sentences. You must use your own words. Any answers that use information derived from sources beyond the commentary and the textbook must be properly referenced. Any answers lifted word for word from the commentary or the textbook will receive no credit.

(50 points) - 5 points each

1. HAART: Highly active anti-retroviral therapy, this is the term given to the combination of antiviral medications that are used to suppress HIV viremia. The standard regimen is based on a two nucleotide/nucleoside analogue reverse transcriptase inhibitor (NRTI) with either a non-nucleotide/nucleoside revervse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (PI) or an integrase inhibitor. The goal of therapy is an undetectable viral load. Explain also why HAART is not a “cure”…

2. Perforin: This is a membrane-disrupting cytolytic protein that is found in killer immune cells such as cytotoxic T cells and natural killer cells. Perforin forms pores in the target cell membrane allowing the delivery of pro-apoptotic serine proteases, granzymes, into the cytoplasm of the target cell and initiating apoptosis.

3. Localized anaphylaxis: This is a geographically isolated immediate hypersensitivity reaction that occurs with response to antigen. Anaphylaxis reactions involve adjacent IgE antibodies bound to basophils and/or mast cells that are cross-linked by binding to antigen. This causes the release of mediators such as histamine, leukotrienes, and prostaglandins that cause inflammation. The common clinical signs include itchy and watery eyes, coughing, sneezing, and congestion. Examples: hay fever, hives, atopic dermatitis.

4. Antigenic variation: This is a process by which mutation of the proteins can cause modifications in the antigens that are important for the generation of neutralizing antibodies.There are two kinds: antigenic drift, comprising minor amino acid changes such as those that necessitate a new influenza vaccine each year, and antigenic shift. The latter involves acquisition of new structural proteins and a major change in antigenic properties such that antibodies in the population no longer recognize the antigen. Not limited to influenza, more general phenomenon…not limited to Ab recognition… hint: consider memory B and T cells 5. M cells: These are also known as microfold cells and are key to the mucosal immunity in the gut. They are associated with the follicle in the Peyer’s patch and transport foreign material from the gut lumen to immune cells. They are able to take up antigen, by endocytosis or phagocytosis, from the lumen of the gut and transcytose to antigen presenting cells in the circulation. They do not directly participate in antigen processing or presentation.

6. Primary immunodeficiency: As opposed to a secondary immunodeficiency, which is acquired, a primary immunodeficiency is one that an individual is born with. These are often genetic and characterized by specific deficits in different aspects of the immune system, i.e. T cell deficiency, B cell deficiency. PI diseases can go undetected because they do not have unique symptoms of their own. Rather, they appear as "ordinary" infections, often of the sinuses, ears, or lungs.

What are other possible consequences of immunodeficiency? Hint: see figure 11.9

7. Seroconversion: This is the process by which an individual generates antibodies to a specific antigen. This is carried out either by immunization or infection. For example, during acute HIV, an individual does not generate antibodies to HIV until several weeks after exposure. The time from which an individual goes from a negative Ab test to a positive Ab test marks their seroconversion.

8. Herd immunity: This is the concept that vaccinating a critical mass of a population will essentially eliminate a disease from a community, making it not necessary to vaccinate every single individual in the community. If more people are immune to a certain virus, either through vaccination or through already having the disease, then more people in the population, even if they themselves aren’t immune, are protected from the disease.

9. ITAM: Immunoreceptor tyrosine-based activation motif on CD3 is very important for T cell receptor signaling. This region is phosphorylated, which allows it to become activated by binding an enzyme known as ZAP70 (zeta associated protein), and this enzyme turns on downstream T cell signaling. ITAM are defined by two YxxL/I sequences separated by a six-eight amino acid long spacer.

10. Commensal microorganism: This is an organism that lives in symbiosis with a host organism without providing any specific benefit and without inflicting any harm. These are like the organisms that live in the human gut. They are not harmful or hurtful.

Part II: Decide whether each of these statements is true or false, and then briefly explain why. Be sure to include a detailed enough answer to indicate your full understanding of the definition you provide; but limit your answer to no more than five sentences. You must use your own words. Any answers that use information derived from sources beyond the commentary and the textbook must be properly referenced. Any answers lifted word for word from the commentary or the textbook will receive no credit.

(50 points) – 5 points each (2 points for T/F and 3 points for explanation)

1. Celiac disease and the tuberculin test are good examples of type III hypersensitivity reactions. FALSE. These would be good examples of Type IV hypersensitivity reactions. Type IV are mediated by immune cells, not antibodies, and are often called delayed type because the reaction takes two to three days to develop. Th1 effector cells secrete pro- inflammatory cytokines and chemokines directed at macrophages because often persisting antigens, like M. tuberculosis, are microorganisms existing within a macrophage. Granulomas form to wall-off the antigen but cause tissue damage. A Type IV response to gluten is likely to be the major cause of the gut lesions and increased permeability to gluten and other foods in Celiac disease.

2. CD3 on T cells is functionally analogous to Igα/Igβ on B cells. TRUE. T and B cells are characterized by the surface expression of highly variable antigen receptors called the T-cell (TCR) and B-cell (BCR) receptor. The TCR consists of alpha and beta or gamma and delta chains that recognize antigen and the CD3 complex. The antigen-recognizing immunoglobulin (Ig) on the surface of B cells are associated with a protein complex of Ig-alpha and Ig-beta. In both B and T cells, binding of antigen to their respective surface receptors results in transmembrane signaling, which leads either to programmed cell death or to proliferation and differentiation.

3. Memory B cells do not require T cell help. TRUE- but are potentiated by it. When your immune system is exposed to antigen for a second time (and more times after), you already have memory B cells for that particular antigen. Plasma B cells would come across that antigen and produce antibodies against it. Interleukins aren’t needed to activate memory B cells to turn into plasma B cells. It’s only when you come across a new antigen (first exposure) that interleukins are required from activated T-cells to stimulate B cell differentiation.

Be careful here….see my commentary in topic 7.2

4. A live attenuated vaccine would not likely require addition of an adjuvant. TRUE because this is already a strong vaccine on its own without an adjuvant. Adjuvants are typically added to vaccines to enhance the immune response. Live vaccines don’t need an adjuvant because they contain a form of the organism that has reduced antigenicity – that is the vaccine is self-capable of mounting an immune response.

Need to explain how adjuvant enhances response …see my commentary in topic 7.4 5. Blocking of the Fas-Fas ligand interaction is likely to completely inhibit Tc responses. FALSE. Fas is a type I membrane protein that mediates the induction of apoptosis in selected cells when ligated either by an anti-fas antibody or by interaction with fas ligand (fasL). Fas ligand is a membrane-type cytokine belonging to the TNF family and is expressed in T cells activated by various factors including like interleukin 2 and anti- CD3. The fas-fasL interactions down-regulate immune responses through the induction of apoptosis of activated fas-positive cells during an immune response. Thus, fas-fas ligand interaction will enhance the activity of Tc receptor responses and prevent apoptosis.

Not correctly answering question. Essentially statement asks: can Tc cell still kill if the Fas pathway is disabled? Hint: is there another mechanism by which Tc cells can kill?

6. An immature B cell that readily binds to a bone marrow stromal cell will likely exit the bone marrow and migrate to a secondary lymphoid organ for further maturation. TRUE. Bone marrow stromal cells secrete cytokines such as IL-7 that signal developing B cells to divide and differentiate. While in the marrow, B cells go through Ig gene rearrangement and negative selection. The resulting immature B cells exit the bone marrow and enter the primary lymphoid follicles in order to survive. After exposure to antigen, B cells divide in secondary lymphoid follicles.

See my commentary in topic 5.1 and 5.2. Hint: What occurs during the immature phase of B cell development?

7. Our capacity to generate naïve T cells diminishes as we age. TRUE. The thymus naturally atrophies as we age and, as a result, causes T-cell production to decrease. The ratio of naive to memory T-cells in a newborn is high whereas the ratio is reversed in aged subjects. This is because most of the naive T-cells have been exposed to antigen and subsequently converted to memory cells. With the thymus tissue deteriorating as age progresses, the elderly population have almost no naive T-cells, which means they are not being replenished. Therefore, fewer T-cells are produced and the aged immune system cannot respond as well (compared to a young immune system) to a new antigen.

8. The pTα on thymocytes is functionally analogous to the surrogate light chain on pre-B cells. TRUE. Productive rearrangement of the beta chain is followed by its expression on the T cell membrane with CD3 and surrogates a chain, pTa (analogous to lambda 5 in B cells). Signaling through the preT receptor causes the cells to stop rearranging beta chain, undergo a period of proliferation, and begin to express both CD4 and CD8, becoming double positive T cells.

9. Type O individuals can accept blood from type A, type B and type AB donors. FALSE. The four blood groups are determined by their presence or absence of two antigens – A and B – on the surface of red blood cells. Group O has neither antigens but both A and B antibodies are in the plasma. Group O can donate RBCs to anybody (universal donor) but can only receive blood from group O individuals. If group O receives blood from any other group, then an agglutination reaction will occur.

10. Systemic anaphylaxis is a life-threatening allergic reaction. TRUE. Anaphylaxis is a state of severe and abnormal response of the body to allergens. It occurs when mast cells or basophils release intrinsic hypersensitivity mediators that have an effect on the body. Systemic anaphylaxis is always life threatening as it leads to shock; a sudden drop in blood pressure and narrowing of the airway, which blocks normal breathing. Common triggers of anaphylaxis include particular foods, medications, insect bites, and latex.

Explain how the allergen gets distributed so quickly around the body? Hint: see my commentary in topic 8.2

Part III: Short Answer questions. You must use your own words. Any answers that use information derived from sources beyond the commentary and the textbook must be properly referenced. Any answers lifted word for word from the commentary or the textbook will receive no credit.

(50 points) – 10 points each

1. Briefly answer each of the following questions:

a. What is the hygiene hypothesis? This is the idea that repeated exposure to pathogens in the environment will stimulate a Th1 response and therefore reduce allergy and result in hightened immunity later in life.

Answer lacking in more substantial explanation…what is evidence for this?

b. How might this hypothesis influence the development of new treatment strategies for type I hypersensitivities? This might result in vaccination strategies for early exposure to antigens to allow for Th1 generation to reduce hypersensitivity stimulation.

See my commentary in topic 8.3. Be sure to carefully review the hyperlinked websites…

2. T cells develop and are “educated” in the thymus where they undergo positive and negative selection. Explain what occurs during positive and negative selection; and why these selection processes are important. In your answers be sure to specifically explain what particular impact these selection processes have on T cell development. Additionally be sure to explain the role of the AIRE protein. Positive selection is the process of selecting T cells that can interact with MHC. All cells interacting with MHC are labeled to "survive" while those are killed by programmed cell death.

Need more detail here….what about CD4 and CD8? Negative selection is a process of removing T cells that bind to "self"

Explain role of thymic APCs. and the AIRE protein is an autoimmune regulator explain the mechanism by which AIRE accomplishes this… that helps to control those cells that recognize self. This is an important feature to prevent autoimmune disease.

3. Describe specific steps in the HIV life cycle to help answer the following questions:

a. Why do infected patients experience a prolonged latency period between infection and full-blown AIDS? After initial infection, the viral load acutely rises and then drops but slowly rises over time. Meanwhile, the CD4 T cells, the target of HIV, start up high and then slowly decline until the time that they drop below 200, which signifies AIDS, and individuals are susceptible to opportunistic infection. It takes between 3-7 years to progress to AIDS and during this time, individuals may be asymptomatic.

But why does this occur?

b. What are three ways that HIV evades the immune system? 1.HIV is a retrovirus that can integrate into the host genome and not be detected by antigens. 2. HIV envelope the proteins that are on the surface of the membrane that are not readily available to neutralizing antibodies because there are not many of them on the surface of the virus and they are shaped in a way that makes it difficulty for antibody to fit and bind. 3. HIV can live inside cells and be spread from cell to cell without being exposed to the outside environment.

See my commentary in topic 7.6

c. Why do patients ultimately succumb to opportunistic infections? When the CD4 count drops below 200, there is a lack of innate immunity that can protect against pathogens such as pneumocystis, toxoplasma, candida, and cryptococcus as well as bacterial pneumonias.

d. Why might individuals with mutations in the CCR5 chemokine receptor be resistant to infection by HIV? The CCR5 coreceptor facilitates entry into cells. Individuals with the delta32 mutation have been shown to have delayed progression to AIDS because cells are not able to be infected with HIV.

4. Most B cell responses require T cell help while others do not.

a. Distinguish between TD, TI-1 and TI-2 antigens and the characteristics of the humoral responses, which they induce. The thymus is responsible for TD antigens that must have direct contact with CD4 cells. The TI-1 pathway can be induced by LPS and bacterial cell wall components while TI-2 antigens are bacterial components such as flagella and cell wall polysaccharides. TI-2 antigens can activate B cells.

Review my commentary in topic 6.6

b. Describe the steps involved in TD antigen activation of B cells. Be sure to explain the roles of the various cell surface molecules involved in the activation process. T cell-dependent (thymus-dependent, TD) bind to T-helper cells to trigger a response by the B cell. Binding of thymus-dependent antigens to a B cell's membrane immunoglobulin is necessary to activate the proliferation and differentiation of B cells.

Answer needs more detailed description of the “steps”…hint: what happens after the B cell binds Ag? What happens at molecular level regarding B cell/T cell interaction? Review my commentary in topic 6.6 5. Distinguish between Th1, Th2 and Treg cells by answering the following questions:

a. What are the key effector functions of these cells? Th1 cells are account for cell-mediated immunity and antibody-mediated immunity. They control bacterial and viral pathogens through cytotoxic T lymphocyte activity. Th2 cells assist B cells and allow for IgG and other immunoglobulin subclass production.

Th1 vs Th2…intracellular vs extracellular infections…which is best for which type of infection?

Tregs serve as important regulatory elements that provide feedback.

Explain what you mean by “feedback”… b. How could these three cell types be clearly and simply distinguished from each other in an experimental laboratory? These cells can be distinguished in the laboratory because they have distinct signature markers. Th1 express IFN-γ, Th2 express IL-4,

What other cytokines do they secrete? What about the transcription factors they express?

and Treg express FoxP3 c. How and where do these different cell types differentiate to their mature functional characteristics? Th1 function involves cellular immunity, optimizing cell mediated killing of macrophages and cytotox CD8+ T cell proliferation; finally it is important in producing opsonizing antibodies. By contrast, Th2 is more important in the humoral immune system by stimulating B cell proliferation, inducing class switching, and stimulating neutralizing antibody production.

this does not answer the question being asked…

see my commentary in topic 6.3 and 6.5