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Explain the difference between thymus dependent and thymus independent antigens.
- Thymus dependent: only induce generation of antibodies by B cells when T cell help is available (they induce memory as well as affinity maturation after somatic hypermutation). (peptide epitope)
- Thymus independent:
induce antibodies even in the absence of T cell help. They do not induce isotype switching or somatic hypermutation, and no memory is produced. (LPS or Bacteria DNA)
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T or F
a) Plasma cells produce secreted antibody, proliferate and undergo somatic hypermutation to produce antibodies with a higher affinity for antigen.
b) An immunodeficiency called hyper IgM syndrome is characterized by lack of CD40 ligand expression on T cells.
c) Antibody-dependent cell-mediated cytotoxicity (ADCC) is mediated by NK cells, which use their Fc receptors to bind to antibody-coated target cells, which they kill through inducing apoptosis.
d) TI-2 polysaccharide antigens are commonly used in vaccines administered to infants because they stimulate strong antibody responses.
- a) FALSE, B plasma cell is terminally differentiated B cell that is not dividing and cannot change its antibody specificity. Somatic hypermutation occurs before B-cells differentiate into plasma cells.
- b) TRUE
- c) TRUE
- d) FALSE, TI-2 polysaccharides activate only mature B cells, which are not fully acquired till age 5.
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(a)Why is CD40 ligand expression on T cell important?
and (b) what is the effect of no CD40 signaling in germinal center formation?
- (a) CD40 ligand binds to CD40 on B cells, signaling B cells to activate NFkB, a transcription factor that upregulates the expression of ICAM-1, an adhesion molecule, on the surface of B cells.
- (b) Hyper-IgM syndrome and no germinal centers.
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Which of the following is a characteristic of follicular dendritic cells in the primary follicles of secondary lymphoid tissues?
a) they are bone marrow derived hematopoietic cells.
b) they provide a stable depository of intact antigens able to bind to BCRs.
c) they internalize immune complexes through CR2 receptor cross-linking.
d) they bear bundles of immune complexes called iccosomes that are passed on to antigen-specific B cells.
e) they produce cytokines that induce B cells to proliferate and become centroblasts.
b,c
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What is the main effector function of the IgM antibody?
complement activation (it can also neutralize pathogens and toxins)
IgM is the first antibody to be produced by the plasma cells during a primary antibody response and is secreted as a pentamer that circulates in the blood. Because of the large size of pentameric IgM, it does not penetrate effectively into infected tissues and is most effective against pathogens in the bloodstream.
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IgM: Inhibits
IgG3: Inhibits
IgG2a: Inhibits
IgE: Induces
IgG1: Induces
IL-4
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Augments production of IgA
IL-5
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IgM: inhibits
IgG1: Inhibits
IgE: Inhibits
IgG3: Induces
IgG2a: Induces
IFN-gamma
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IgM: Inhibits
IgG3: inhibits
IgG2b: induces
IgA: induces
TGF-beta
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Describe the course of events that results in the swollen lymph nodes characteristic of many infections.
B-cells that have bound specific antigen and encountered their cognate T-cells in the lymph nods are activated and start to proliferate. These activated B-cells move into primary follicles. The primary follicle enlarges and morphologically changes into a germinal center. The activated B-cells undergo somatic hypermutation while dividing in the germinal center, producing activated B-cells with mutated surface immunoglobulin. Only cells that take up antigen efficiently are present it to helper T cells will be selected to differentiate into plasma cells or memory cells. Antigen will be encountered at the surface of follicular dendritic cells as an immune complex. If B cells do not encounter their specific antigen they will undergo apoptosis and be ingested and cleared by macrophages. This takes about 7 days after an infection begins, and the increase in cell numbers accounts for the swollen lymph nodes.
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Explain what passive transfer is and how it occurs via placental transfer and through breast milk.
- Passive transfer of immunity refers to the process of transferring preformed immunity from an immune subject to a nonimmune subject. This can be achieved by transferring whole serum purified antibody, monoclonal antibody, or intact effector or memory lymphocytes.
- IgG antibodies are transported transplacentally to provide passive protection in the bloodstream and extracellular spaces of tissues until the baby can begin making its own antibodies. IgA is transferred into the infant's GI tract in breast milk and protects the GI epithelia from colonization and invasion by ingested microorganisms.
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Complement activation
IgM
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Fc receptor-dependent phagocyte responses: complement activation; neonatal immunity (placental transfer)
IgG (1,3)
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Immunity against helminths
Mast cell degranulation (immediate hypersensitivity)
IgE
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Mucosal immunity (transported through epithelia)
IgA
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1. Understand the organization of the germinal center, cell constituents, and flow of events of T and B cell activation
Germinal centers are formed when activated B cells enter lymphoid follicles. The germinal center is a specialized microenvironment in which B-cell proliferation, somatic hypermutation, and selection for antigen binding all occur. Rapidly proliferating B cells in germinal centers are called centroblasts. Closely packed centroblasts form the so-called ‘dark zone’ of the germinal center. As these cells mature, they stop dividing and become small centrocytes, moving out into an area of the germinal center called the ‘light zone’, where the centrocytes make contact with a dense network of follicular dendritic cell processes.
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How are IgG antibodies transported across cell monolayers?
The receptor FcRn transports IgG from the bloodstream into the extracellular spaces. At the luminal side of the endothelial cell, IgG and other serum proteins are actively taken up by fluid-phase pinocytosis. In the endocytic vesicle the pH becomes acidic and each IgG molecule associates w/ 2 molecules of FcRn. At the basal side of the cell, the basic pH dissociates the complex of IgG and FcRn is released into the extracellular space.
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How does IgA get from one side of the luminal surface to the other?
and where does it's final destination?
IgA is made in mucosa-associated lymphoid tissue (MALT) and is transported across the barrier of the mucosal epithelium. First, IgA binds to the poly-Ig receptor on the basolateral surface of an epithelial cell, followed by uptake through receptor-mediated endocytosis into an endocytic vesicle. On reaching the opposite face of the cell, the apical surface, the vesicle fuses w/ the membrane. Here the poly-Ig receptor is celaved proteolytically between the membrane-anchoring and the IgA-binding regions, thus releasing IgA into the mucous layer on the surface of the epithelium. IgA remains attached to a small piece of the poly-Ig receptor, called the secretory component, which holds the IgA at the epithelial surface through interactions with molecules in the mucus. The rest of the poly-Ig receptor is degraded and serves no further purpose.
IgA is released into the lumen of the GI, urogenital, and resp. tracts, onto surface of the eyes, into the nose and throat, and into breast milk (which is the route by which newborn babies receive protective maternal IgA.
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Babies have the lowest Ig levels at months 3-12 months, and are most vulnerable to infection at this time. So why not immunize at 0-3 months?
Since babies still have so much maternal IgG, any vaccine will be recognized and killed by the mothers IgG, so you will never have a memory event.
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Flow of affinity maturation in germinal centers
- Activation of B cels and migration into germinal center =>
- B cell proliferation =>
- Somatic Hypermutation of Ig V genes =>
- B cell recognition of antigen on follicular dendritic cells; selection of high-affinity B cells =>
- Death of B cells that do not bind antigen =>
- Generation of memory (5-10%) and antibody secreting cells (plasma cell)
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Resting B cells express surface Ig and MHC class II, they can be induced to grow, undergo somatic hyper-mutation and isotype switch. Do plasma cells have any of these properties? Do plasma cells have any properties that resting B cells don't have?
No they don't have any of those properties of resting B cells.
They secrete Ig, which resting B cells are not capable of doing.
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Q: What are the cytokines that influence the innate immune system?
A: (1) interferon alpha/beta (type one interferon) (2) TNF (3) IL-1 (4) IL-6 (5) Chemokines
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Q: What are the cytokines that regulate lymphocyte activation and differentiation?
A: IL-2; IL-4; TGF-beta; INF-gamma; IL-10; IL-12 (all discussed individually)
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Q: What cytokine induces a TH1 T-cell and what does this helper cell do?
A: IL-12 and IFN-gamma. TH1 cells (1) activate macrophages (2) Induce more T cells (TH1) (3) increase MHC expression on APC's (4) Induce B cells to release opsonins (help macrophages).
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Q: What cytokine induces TH2 T-cells and what does this helper cell do?
A: IL-2 and IL-4; TH2 cells (1) inhibit macrophage activation (2) induce more T cells (TH2) (3) Induce B cells to produce IgE and IgG4.
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Q: What makes IL-2 and what are its actions?
A: Made by most helper T-cells upon activation. It is a T-cell growth factor. (2) it can also act on NK cells increasing killing capacity.
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Q: What makes IL-4 and what are its functions?
A: Product of TH2 T cells and sometimes mast cells. (1) Induce production of IgE (2) block macrophages (anti-iflammatory) (3) mast cell growth factor (4) stim. Expression of adhesion receptors.
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Q: What does TGF-beta do?
A: suppresses the effect of other cytokines (anti-inflamm
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Q: What produces INF-gamma and what is its function?
A: Prod. by TH1 T-cells. (1) anti-viral and anti-proliferative (2) activates macrophages (3) upregulate NK and neutrophil function (4) shifts TH0 cells to TH1 upon activation
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Q: What makes IL-12 and what are its functions?
A: B- cells and monocytes. The receptor is express by NK and T-cells. (TNF-alpha induces IL-12 prod. by macrophages. (1) activates NK (2) commits TH0 to TH1 pathway (3) increases activity/proliferation of CD8 T cells.
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Q: What are the two regions of an antibody structure and what terminal are they (N or C terminal)?
A: FAB region is the N terminal (bound with light chain), and Fc region (C term) in membrane if membrane bound.
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Q: What holds the different chains of an antibody structure together?
A: Disulfide bonds
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Q: What are the 5 different antibody classes?
A: Alpha=IgA; Delta=IgD; Epsilon=IgE; Gamma=IgG; Mu=IgM
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Q: What region of an antibody molecule determines the specificity of antigen binding?
A: The Hypervariable regions.
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Q: What does CDR stand for and what is it?
A: Complementary Determining Regions. They are complementary to the bound antigen. The most hypervariable regions.
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Q: What tissue are the immunoglobulins found in?
A: 80% of M is in blood. G found in fluids, tissues, and blood. D is not secreted (on B cells), A in the mucus (lining of endothelium)
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Q: List some functions of IgM, including where it is found.
A: Major Ig on B cells. Membrane bound as monomer, acts as primary antigen receptor. Secreted as pentamer and functions as blood group antibodies (ABO), Opsonins, complement activation, early polysaccharide antibody, and rheumatoid factor is usually IgM against IgG.
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Q: What are some overall functions IgG provides?
A: Complement activation (G3>G1>G2; not G4). Opsonins for bacteria. Anti-viral neutralizing activity. Neutralizes diphtheria, and tetanus toxin.
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Q: What are the relative amount of each antibody?
A: IgM = 10%. IgG = 75%. IgA= 15%. IgD=0.2%. IgE=not mentions, must be very few unless allergic reaction.
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Q: What are general properties of IgA?
A: Coats resp. and GI tract. Anti-viral, polio, RSV, rubella, etc. Prevents antigen absorption and allergies (immune exclusion) ( his example was it preventing absorption of ragweed and thus not making IgE).
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Q: What are general properties of IgE?
A: Allergens crosslink IgE and trigger release of histamine, leukotrienes, cytokines, and mediators of allergy. Immunity against parasites (directs eosinophils, monocytes, NK cells to parasites (if kids get a lot of parasites, they have fewer allergies because the IgE is busy).
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Q: What are general functions of IgD?
A: NONE. It is an antigen receptor (on 50% of B cells) but it's not secreted and function in serum is unknown.
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Q: Which antibodies have subclasses and what are the subclasses?
A: IgG has 4 subclasses and A has 2. G1, G2, G3, G4. A1 and A2.
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Q: What are the jobs of the 4 IgG subclasses?
A: G1= antiprotein to toxins (eg. Diphtheria, tetanus, H. flu vaccine) G2= mainly antipolysaccharide. Pneumovax for S. pneumonia, and meningitis (infants don't make this) G3= short half life, viral antibodies, flu, and MMR. G4=unknown
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Q: What various proteins and receptors are found on a B cell?
A: Ig monomers of all classes, receptors for Fc portions of antibodies, receptors for C3b (called CR2) activation by complement, CD19 is signal transducer for complement activation, MHC class II proteins.
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Q: What cell is the primary antibody producer?
A: Plasma cells.
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Q: What are conditions associated with polyclonal hypergammaglobulinemia?
A: Chronic infections, Chronic inflammation (lupus, RA, collagen vascular diseases etc), liver disease (alters metabolism of Ig).
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What are the Fc receptors (those that bind antibody proteins) and what do they do?
- There are various receptors for the Fc regions of IgG. The subunit structure, relative binding strengths for different IgG isotypes, and effect upon ligation (activating or inhibiting) vary from type to type.
- Antibody-coated bacterium bind to Fc receptors on the cell surface of phagocytes, trigging phagocytosis of the antibody.
- Fc-gamma receptors on myeloid cells are Fc receptor that bind with high affinity to IgG, FcgR1 binds the tightest and is activating upon ligation (RIIa, RIIIa,b also are activators, but bind with lower affinity). FcgRIIB2/1 are inhibitors (via ITIM) upon ligation. Regulating the activity of phagocytes.
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Inactivated virus vaccine
are made of virus particles that are not able to replicate because they have been chemically or physically treated in a way that inactivates the nucleic acid. Examples are Salk polio vaccine, rabies vaccine, and influenza vaccine.
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Live-attenuated virus vaccines
are made of viruses that have lost their pathogenicity and ability to reproduce efficiently in human cells through mutations accumulated as a result of growing the virus in non-human cells. (polio, measles, vaccine, mumps, yellow fever, rubella, varicella.
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_____ vaccines are composed only of particular antigenic pathogen componenets known to induce protective immune responses. Recombinant DNA technology enables the production of antigenic proteins in the absence of other pathogen gene products. (Hep A,b, and pertussis)
Subunit
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Why are adjuvants used in experimental immunology?
and which ones are used in humans?
when mixed with an antigen, and adjuvant increases its immunogenicity. Adjuvants work by inducing a nonspecific antigen-independent inflammation, which helps to drive the immune response forward. Adjuvants delay the release of antigen at the injection site and prevent its rapid clearance from the body by converting the soluble antigen into particulate material.
aluminum, MF59 and bacterial components.
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Bacterial vaccines differ from viral vaccines in that only in bacterial vaccines are _________ used. (select all that apply)
a. subunit components
b. toxoid
c. whole infectious components
d. capsular polysaccharides
e. capsule:carrier protein conjugates
b,d,e
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Reasons complicating the development of vaccines to combat chronic dz's include ______. (select all that apply)
a. evasion of the host's immune system by the pathogen
b. the polymorphic diversity of MHC class I and class II molecules.
c. the generation of inappropriate immune responses that do not eradicate the pathogen
d. survival of the infectious agent for long periods inside the host
e. high mutation rates in the pathogen
a,b,c,d,e (all)
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What is the risk to a population that reduces its use of particular vaccines over a period of time?
as the number of susceptible individuals increases to a particular threshold, herd immunity is no longer effective in protecting individuals who have never been vaccinated. The outcome is the resurgence of the dz and an epidemic. (has happened in whooping cough, and measles)
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Name the vaccination strategy
When it was first done it was best done in a rate tongue. You inject the ____ into muscles and the dendritic cells bind the ___ (E coli ___), takes it up and turns on a transient gene. The dendritic cell then synthesizes the novel protein => vaccine.
DNA vaccination strategy
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________ vaccines are made by covalently coupling antigenic polysaccharide found in bacterial capsules to a carrier protein (often a toxoid). This converts the otherwise T-independent bacterial polysaccharide antigen into a T-dependent antigen. T cells respond to an epitope on the protein carrier, wheras B cells respond to epitopes on polysaccharide portion of the conjugate. This ensures that T-cell help is provided to B cells making anti-capsule antibodies. (Hib vaccine_
Conjugate
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How can we test serum/mucus swabs for the presence of antigen-specific antibodies?
ELIZA: Enzyme-linked immunosorbent assay
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What is the difference between the Rotarix and Rotateq vaccines?
- Rotarix: a live attenuated single human rotavirus strain that expresses the G1 variant V7 and the P8 variant VP4. Both variable proteins are common in disease-causing strains.
- Rotateq: is a mixture of 5 different non-pathogenic cattle rotaviruses engineered to express VP4P8, VP7G1, VP7G2, VP7G3 and VP7G4 variants from common human pathogenic strains, in addition to cattle-specific variable proteins. Rotateq protects against a broader range of variable proteins than Rotarix.
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Explain how immunological memory operates in (a) the shot term and (b) the long term.
- (a) Short-term operates shortly after an adaptive immune response has cleared the infection in an individual and while the pathogen is still present in the community. If the individual is reexposed and reinfected, antibodies generated in the first round of infection can bind immediately to the pathogen, blocking its action by neutralization and mediating its removal and destruction by complement fixation and phagocytosis, In addition, any remaining effector T-cells or activated B cells can respond straight away to the presence of antige. These activities ensure that the infection does not reestablish itself and also generate a fresh supply of antibodies and effector cells.
- (b) Long-term: is mediated through long-lived memory lymphocytes that are generated in the primary immune response. These are cells that can be rapidly stimulated by reexposure to the same antigen to produce a strong and effective immune response that rapidly clears the pathogen.
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What is the best way to measure memory function of T-cells?
Test levels of CD45 (CD45RA = naive T-cell, CD45RO = memory/effector T cell)
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