Immunology Final Flashcards
(115 cards)
1
Q
Be able to describe where (the anatomical location) and from what cell type a naïve B cell acquires cognate antigen.
A
In the secondary lymphoid tissue from the FDC
2
Q
Describe the molecules that comprise the BCR (Heavy and light chains, Ig alpha/beta).
A
heavy chain on bottom then light chains we have light chains on further right and variable heavy inside
3
Q
The strength of BCR signaling depends on what factor?
A
BCR cross linking
1) Antigen -> multivalent will send strong signal on BCR.
2) BCR -> affinity high affinity BCR engagement of BCR can be done with lower amount of antigen. Can detect small amount of antigen and low affinity BCR may not send signal at all. IMPORTANT IF WE THINK ABOUT DIFF BETWEEN MEMORY AND PRIMARY HUMORAL RESPONSES. Memory B cell has more sensitive BCR versus a naïve b cell. They can detect lower amounts of antigen so that they will be activated sooner.
4
Q
Characteristics of thymus independent antigens
A
signals generated are sufficient to activate the B cell in the absence of additional signals. dense clustering of b cell receptors and co receptors which produces sufficient signaling to stimulate b cell proliferation. these antigens do not require help from t cells
they are repetitive, high density, cross link bars, elicit primarily low affinity IgM…IgM activate complement
Thymus-independent antigens induce IgM synthesis by B cells without cooperation by T cells. INDUCE IGM
5
Q
Role of follicular dendritic cells (FDCs) in B cell responses. Positive selection of B cells
A
Provide survival signals to immature B cells, heavy and light chain rearrangement, negative selection non self reaction, leave bone marrow need surveil signal from FDC.
store intact antigen, interrogated by mature b cells.
6
Q
Antigen repository for activation of naïve B cells
A
know that antigen is not phagocytosed, remains on FDC surface for months to years
7
Q
Linked recognition
A
a process by which a B cell is optimally activated by a helper T cell that responds to the same, or physically associated, antigen but not necessarily the same epitope.
8
Q
There are two waves of B cell proliferation/antibody production in a primary humoral response
explain the timecourse/characteristics of these waves
primary focus
A
Primary focus of clonal expansion. this cellular proliferation lasts several days and gives rise to diving B lymphoblasts secreting IgM. Antibody leaves the node in the efferent lymph and is delivered to the blood, which rapidly carries it to the site of infection
cognate pairs of mutually activated antigen specific b and tfh cells move from the boundary region to the medullary cords, where they proliferate to form large clones of identical cognate pairs
response.
Primary response reflects that initially IgM is produced quickly (3 days) T dependent responses first wave – represents b cells in medullary cords b cell that meets with tfh reconifnzes the same antigen but diff epitopes. They can come together and form stable assocaitation. Travel to medullary cords and the B cell expands and some become plasma cells that produce IgM. (low affinity)
Switching of cosntatnt heay region to igQ or ige , ceontroblasts become centrocytes compete for antigen with germinal center reaction we see maturation. Decline represents death of short lived plasma cells. Some anitbodies remain (long lived plasma cells) this period is a period of memory)
And the switching where the infection has been cleared with high level antibody = protective humoral immunity. This period is important because you possibly have given it to someone else and you are contiously being exposed to pathogen because you have high level of antibody.
If reexposed with memory response and dramatic expansion of antibody is switching because it is high affinity peak represents memory B cells. Memory b cells will go through second germinal center reaction and they will produce more antibody the first time and higher affinity. Protective immunity and immunological memory. Acquire more memory more plasma and each time there is subsequent germinal center reaction.
9
Q
Secondary focus of clonal expansion
A
produces a germinal center source of high quality antibody. 2nd priority antibody quality. create antibody of same specificity remaining b and t cell pairs will go back and form germinal center reaction. differentiate to give plasma cells secreting antigen specific IgM. mitotic division
10
Q
How do rare pathogen specific B cells find rare Tfh cells specific for the same pathogen? Why is this important for effective humoral responses?
A
they screen the antigens teh b cells put on the mhc class ii …….
11
Q
What types of cells are found at a primary focus?
A
conjugate b and t cell pair. b lymphoblasts differentiate into plasma cells.
12
Q
Where in the lymph node is the primary focus?
A
medullary cords
13
Q
What type of antibody is produced there? primary focus
A
B lymphoblasts that secrete IgM and differentiate int plasma cells
14
Q
Where in the lymph node is the secondary focus?
A
primary follicle
15
Q
What structure does the secondary focus form?
A
germinal center is formed by the expanding population of antigen specific b cells, and this is where b cells undergo affinity natural and isotope switching of their antibodies
16
Q
What types of antibodies are produced there? secondary
A
B cell expansion, antigen specific b cells
17
Q
Describe the events that occur in the germinal center.
What types of cells are involved (I can think of three)?
A
centroblasts , AID induced by tfh..cytokines and cd40L induce . express mutated/switched cell surface Ig. increases IgE and increases affinity. centrocyytes perform this
18
Q
Centroblasts
A
Proliferation: Centroblasts (proliferating B cells)- directed by Tfh ( cytokines, CD40L), upregulate AID = iso switch, somatic hypermutation
19
Q
Competition for survival: Centrocytes
A
are no longer proliferating, Ig is a range of affinities, undergo affinity maturation (Centrocyte with high affinity acquires antigen from FDC, presents to Tfh to receive CD40L survival signal)
20
Q
Two types of cells produced by germinal center reaction
A
plasma cells (IL 10) or memory B cells (IL 4) depending on the cytokines secreted by their cognate Tfh
21
Q
At what point during the course of an infection are B cells more likely to differentiate into plasma cells
A
at the height of the adaptive immune response, the main need is for large quantities of antibodies to find infection, the centrocytes leave germinal center and differentiate under influence of IL 10 to produce plasma cells
22
Q
At what point during the course of an infection are B cells more likely to differentiate into memory b cells
A
as the infection subsides and under the influence of IL 4 the centrocytes turn into long lived memory b cells that now possess isotope switching, high affinity antigen receptors.
23
Q
Describe the role of the Tfh cell in various stages of the humoral response (medullary cord B cells, centroblasts, centrocytes). Especially focus on the role of CD40L.
A
tfh provides the critical survival signal, they have linked recognition of t and b cells. in the primary focus before the GC the cytokines and CD40L drive b cell proliferation and differeitanteion to plasma cells (IgM)
24
Q
role of tfh on humoral response during germinal center reaction
A
centroblasts cytokines and cd40L AID induced
competition for antigen. must become effector cell to either differentiate into plasma or b cell. promote survival of centrocytes and present to TFH cells. promotion and inducing AID will lead to somatic hypermutation and isotope switching CD40L is a potent activator of B cells and is able to induce proliferation and, in combination with cytokines, isotype switching and differentiation of B cells.
25
What enzyme is only expressed in germinal centers?
AID- essential for both somatic hypermutation and isotope switching
26
In what types of infections are IgG most useful?
CD40L and Cytokines control isotype switching in B cells. In humans IFN gamma induces production of opsonizing antibody (IgG1 and IgG3) while IL-4 induces production of IgE.
IgG - bacterial and viral
27
in waht types of infections are IgE most useful?
allergic reactions
28
What signal guides isotype switching in germinal center B cells?
AID
29
Which isotypes protect the blood, lymph, and extracellular spaces of the body?
IgM, IgG and monomeric IgA
30
Which isotypes are especially good at: Activating complement, neutralization, activating granulocytes, protecting mucosal surfaces?
IgM...mucosal surfaces = dimeric IgA
31
The anatomical location of mast cells provides protection throughout the body. Describe the locations of mast cells and how they protect against invading pathogens.
Mast cells are found in most tissues of the body, particularly in locations that are in close contact with the external environment, such as skin, airways, and intestines and blood. Mast cells can modulate host innate immune responses through the release of granular and secreted mediators (reviewed in [1], [2]). The release of histamine and other vasoactive mediators increases vascular permeability and local blood flow, and can act on smooth muscle to increase the expulsion of mucosal parasites.
32
Describe bacterial exotoxins
released when the bacterium dies. they cause disease by disrupting normal function of human cells.
33
What type of immune response is most effective against these molecules... bacterial exotoxins
antigen antibody mediated immunity ... acquired
34
How are vaccines formulated to generate this type of immune response
neutralizing antibodies are made against receptor binding chain of the bacteria , high affinity neturalizing IgG cover up the binding site in the toxins module
35
what are toxoids?
antibodies that bind to the receptor binding polypeptide can be sufficient to neutralize a taxon and the vaccines and tetanus work on this principle. they are modified toxin molecules, in which the toxic chain has been denatured to remove its toxicity .. ELICIT NEUT ANTIBODY
36
Fc epsilon-R I
High affinity IgE receptor. this is specific to myeloid cells...mast cells - tissue resident.. activation of esonophils mucosal surfaces and basophils circulation
Fc receptor that is expressed on granulocytes when cross linked it will cause the granulocyte to release granules. High affinity receptors levels of IgE quite low, it is bound to granulocytes (sensitization)
37
Fc gamma-R I
High affinity Fc receptor for IgG, constitutive on macrophages, DCs, monocytes, induced on neutrophils and eosinophils -> myeloid cells. facilitates uptake and destruction of pathogens..after pathogen has been tethered to the phagocyte, interactions between antibody Fc regions and the fc gamma RI send signals that induce the phagocyte to engulf the antibody coated pathogen ...becomes full engullfed
Major phagocytic receptor, macrophages express this when they see opsonized IgE will release this.
38
Fc gamma receptor IIB
inhibitory factor and beat ITIMS, which associate with intracellular proteins that develop inhibitory signals.
Inhibitory receptor – when engaged will send inhibitory signal to cell that expresses it on a naïve b cell. Prevents or inhibits naïve b cell responses during a secondary response. B cell will be getting a specific signal in BCR and inihibitory signal with this receptor so it doesn’t expand or differentiate.
39
Fc gamma-R III
activating receptor for IgG and is the only Fc receptor expressed by NK cells. they have been studied in the context of killing by NK cells. antibody dependent cell mediated cytotoxicity is the way in which the therapeutic anti cd20 monoclonal antibody eliminates types of b cell tumor. this has a low affinity for Fc. they ae used for IgG activation and cancer, autoimmunity and transplantation
macrophage naeutroophil eosinophil nk cells
Expressed on NK cells and the ADCC. Virus infected cell , viral proteins will be produced. These will be expressed on surface of infected host cell. Antibodies will recognize the foreign vira protein and the effector mechanism is phagocytic cell or NK cells can use this receptor to bind to the Fc regions on this virus infected cell. It will form a stable pairing and NK cells will secrete its cytotoxic variable into this. Good example of adapted immunity makes for mores specific killing of virus infected cell. Recognition mechanism is different.
40
FcRn
IgG receptor diverts the IgG away from the lysosomes and takes it to the basolateral surface of the cell, where the basic pH of the extracellular fluid induced the receptor to release IgG. this transport receptor is FcRn. this is the brambell receptor. two molecules bind to the Fc region of one IgG molecules. this selectivity protects IgG from the processes of degradation to which other plasma proteins are subject
Transcytosis of IgG. Carrying a molecule across a cell layer. This will be carrying IgG across placenta -> mothers blood stream into fetal blood stream.
41
Describe the type of passive immunity that an infant receives form its mother.
the transfer of preformed IgG from mother to child in breast milk is passive transfer of immunity. another is intravenous immunoglobulin given to pattens with genetic defects.
42
Why are infants especially susceptible to infection from the age of 3-12 months?
IgG levels are lowest in infants aged 3-12 months , and this is when they are most susceptible to infection. can take longer to attain immune competence after birth.
43
Describe the role of FcεRI in parasitic infection. What cell types are involved in killing parasites?
binds to IgE antibodies. IgE is secreted un small amounts by plasma cells and become attached to the surfaces of mast cells resident in tissue, activated eosinophils at mucosal surfaces, and circulation basophils, where these cells are ready to bind to pathogens and antigens. IgE is specialized in causing physical ejection of pathogens and toxic substances. this receptor carries a variety of IgE molecules that are specific of different antigens. mast cells with large granules are deposited that contain histamine and other molecules that contribute to inflammation. cross link generates signals to release granules. increase permeability of flood and vasodilation recruits cells and proteins to defend the site of infection.
Mast cell that is sensitized with parasitic IgE. After humoral response initiated after . Binding to Fc episolon receptor 1further exposure will cause them to degranulate and degranulation involves release of multiple molecules and most potent is histamines. Histamine in parasite responses induces parastalsis in the GI tract that will expel in the tract, vomiting. Induce mucosal and reduce parasites trhough sneezing and blowing nose. Recreuit more granulocytes to site of parasitic infection. To get IgE it is all mediated by the CD4 TH2 response. Humoral response afain parasite needed for the sesnsitization. IL 4 AND IL5 are major players. IL 4 drives IgE isotype switching. IL5 activates granulocytes. Lower levels tend to induce Th2. In general TH2 is what you see with parasitic infection.
44
Describe how the humoral response enhances the ability of phagocytes to fight infection. (Mention FcγRI)
facilitate the uptake and degradation of pathogens by phagocytes. in adaptive immune response, antibodies made against surface antigens will coat the pathogen tith their Fc regions pointing outward and free to bind the Fc RI expressed on myeloid cell surfaces. this induces the phagocyte engulfing of pathogens
45
For what type of bacteria is this antibody effector function critical (See asplenia case study)?
they must be osponised for efficient phagocytosis ... ecanpuulation is harder, they must be opsonized because they are resistant to phagocytosis, resistant to complement fixation
46
Describe how the humoral response enhances the ability of NK cells to fight infection. (Mention FcγRIII, ADCC).
NK cells can recognize and kill humans cells that have been coated with IgG1 and IgG3 antibodies. the antibody dependent cell mediated cytotoxicity (ADCC) signals from FC RIII activated the NK cell to kill the tumor cell. the ADCC can kill healthy B cells that express CD20. NK cells are major contributors to the innate immune response to infection, in which they use mechanisms other than ADCC. in the primary adaptive immune, ADCC will only come into play as a mechanism of NK cell killing once pathogen specific IgG antibodies are available.
47
primary adaptive immune response
is first infection 1-3 weeks peak of antibodies and effector t cells. they are secreted by plasma cells residing in the bone marrow.
48
provide protective immunity
high levels are sustained for months. these antibodies ensuring that a subsequent invasion will not occur. this decreases antibody and effector t cells. antibody persisted after effector t cells inactivated to prevent reinfection.
49
immunological memory
lasts 1 - 2 years (decades).
50
second infection
a much faster and stronger secondary immune response made, eliminated the pathogen before to could disrupt tissue. this is mediated by long lived, pathogen specific f cells and t cells that had been made during primmer immune response. LONG LIVED MEMORY T CELLS AD B CELLS
51
How do pathogens establish chronic infections (we discussed two ways)
CONTINOUS ANTIGEN EXPOSURE - MEMORRY CELLS...EFFECTOR CD8 T CELLS CAN IVE RISE
1) High mutation rate
2) They can become latent
Latency production of pathogen proteins is turned off. Invisible to CD8 t cells.
52
• Loss of adaptive immunity typically results in an increase in levels of chronic infection (Ex. HCMV). What does this tell us about the normal role of adaptive immunity in the context of chronic infection?
increase in viral load that occurs whenen the virus is reactivated triggers a rapid increase in the numbers of virus specific effector CD8 t cells. this falls back ones the virus has been brought under control..low level of link lived virus specific memory T cells.
53
• Loss of adaptive immunity typically results in an increase in levels of chronic infection (Ex. HCMV). What does this tell us about the normal role of adaptive immunity in the context of chronic infection?
increase in viral load that occurs whenen the virus is reactivated triggers a rapid increase in the numbers of virus specific effector CD8 t cells. this falls back ones the virus has been brought under control..low level of link lived virus specific memory T cells.
54
Reasons why memory responses are more effective than primary responses:
1) Memory B and T cells outnumber naïve pathogen-specific lymphocytes
2) Antibody produced during a memory response is higher quality- due to somatic hypermutation and affinity maturation the antibodies are higher affinity. Due to isotype switching the antibodies gain access to additional anatomical sites and can engage Fc receptors on various WBCs
3) Memory lymphocytes are more quickly activated, their receptors are more sensitive to activation
4) Memory T cells are not sequestered in lymphoid tissues (except Tfh), in fact they have lost expression of the chemokine receptor that directs them to lymphoid tissue and circulate in the blood only. Upon reinfection, they can quickly gain access to the site of infection and exert their effector function
55
After a primary response, pathogen-specific antibody levels remain fairly high in the blood for several months. There is a special term for the type of immunity that this antibody providing, what is it?
protective immunity .... antibodies are secreted by plasma cells residing in bone marrow..high levels for month after infection cleared.
56
Pathogen-specific antibody levels then decline to a lower but steady level. What explains this decline?
antibody level dropped and pathogen would now be more likely to establish an infection. a much faster immune response can occur now cduring secondary adaptive immune response. IMMUNOLOGICAL MEMORY
57
What is the fate of most effector cells produced during a primary adaptive response?
they will be inactivated
58
How are pathogen-specific antibody levels maintained for decades?
memory lymphocytes populations are long live, antibody levels maintained at a steady state, memory lymphocyte populations are replenished via cell division..antigen dindependent ..cytokine drive...IL-7 and IL-5 (survival of t cells)
antibody level must be maintained by memory plasma cells making vaccinia specific antibody throughout a person life time. vaccination of small pox
Pathogen specific antibody can be maintained for 80 plus years for small pox. Certain path life for several weeks, must be continual production of antibody. That is the responsibility of long lived plasma cells (bone marrow) don’t require antigen
Memory lymphocyte include memory b cell and memory t cell and antigen is not required and a lot of this data is from studying people vaccinated against small pox. Whats driving their survival are cytokines.
59
How are memory lymphocyte numbers maintained long term?
sustained by populations of long lived lymphocytes that were induced on exposure to antigen but then persist in its absence. individual memory cells have limited life span. a small fraction are dividing and replenishing. antigen indeiependt activation and proliferation is driven by signals delivered by cytokines via their receptors on emery cells. the surveil and proliferation of memory cd4 and cd8 t cells depends on signals from il 7 and il 15. renewal and replenishment of member b cells and their memory t cells is believed to occur in bone marrow and be driven by cytokine thy produce.
60
Explain how pathogen-specific antibodies change throughout a primary immune response.
most plasma cells made in the primary response are short live.
61
Compare the characteristics of antibodies from a primary immune response to a secondary immune response.
in primary response, low affinity IgM antibodies are made first, but then somatic hypermutation, affinity maturation, and isotope swathing give rise to high affinity IgG, IgA, and IgE. memory b cells are derived from the clones of b cells making antibodies with teh highest affinity for antigen. to ensure that low affinity antobodies and IgM are no made in the secondary response, the activation of naive pathogen specific v cells is suppressed. in primary pathogen binding to the antigen receptor of a naive b cell delivers a signal that activates the cell to become an antibody producing plasma cel.. in secondary the antigen receptor and inhibitory F c receptor cross link by a pathogen coated with IgG this delivers a negative signal that prevents activation of the cell.
Constant heavy region involves isotype switching.
Change through effecting variable heavy and variable light. -> involves somatic hypermutation
(bOTH HAPPEN IN GERMINAL CENTER)
Driven by AID….particular cell type would be centroblasts. (B cell when it gets to B cell area it is forming germinal center first cell involved is centroblasts. When it interacts with Tfh it provides signals to centroblasts in the form of cytokines and CD40L!!!!!!! on T cell binding to CD40 on centroblasts important interaction because it induces AID. Without interaction and AID induction, there is only IgM no isotype switching and no high affinity antibody.
Part 2 of germinal center reaction would be centrocyte (these are the cells that are competing) there is a range of affinities. They compete for antigen which is held by FDC , whatever has highest affinity cell surface receptor will strip antigen off FDC and process through CLASS II pathway. Present this to Tfh. This provides survival signals. As adaptive response moves along we get affinity maturation where
62
Under what conditions will a secondary adaptive response be initiated?
when human is exposed to same infection
63
Explain why in a secondary response, memory B cells are activated but naïve B cells specific for the same epitope are not (Hint, Fc gamma-R IIB, Figure 11.5).
the antigen receptor and the inhibitory Fc receptor Fc RIIB1 on a naive B cell can be cross linked by a pathogen coated with IgG, this delivers a negative signal that prevents the activation of the cell. memory b cells do not express Fc RIIB1 and area activated by the pathogen binding to the IgG B cell receptor.
64
How are anti-Rh responses against an Rh+ fetus prevented in an Rh- woman?
infused with purified human anti-RhS IgG antibody called RhoGAM, during the 28th week of pure. this is sufficient to coat all teh fetal red cells that cross the placenta. activation of mothers RhD specific naive B cells is prevented. source = bloodtype
65
Compare/contrast the two categories (Tem vs T cm) of memory T cells in terms of their location, response to infection, role in memory responses, which subsets( CD4, CD8, etc) are included in these two categories.
CENTRAL MEMORY
L selection positive...function more like a naive t cell would, undergo mitotic cell division. CCR7 positive, circulate in lymphoid organs, stem like cell, can ba activated by antigen and cytokines. don't require signal 2 just signal 1. activated by antigens presented by dendritic cells.
Tcm will expand in lymphoid tissue upon antigen reencounter. Will kill of infected cell and this will go to draingn lymph node where it will be presented against dendritic cells. Tcm once expanded they will differentiate. CD4 Tcm. Tcm is a reserve to be called upon to increase numbers of effector cells. Cd4 will produce more of that and cd8 will produce more of the other. KNOW GENERAL FUNCTION LOCATION AND WHY IMPORTANT TO HAVE TWO DIFFERENT.
Important to have tcm because tem effector cells will die and become inactivated. So Tcm expand and maintain pool of memory cells.
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EFFECTOR MEMORY T CELLS
naive t cells attach to HEV to get into secondary lymphoid tissues. L selection negative. CCR7 negative, circulate in non lymphoid tissue, already differentiated , have high levels of effector molecules. mucosal or inflamed tissues because they dont have l selection and ccr7 to allow them to enter secondary lymphoid tissue. can respond immediately to infection
Effector memory migrates through various tissues. These are similar to effector t cell during a response. They don’t stay in lymphoid tissues must go to site of infection and they can immediately exert their function with signal 1. Can have cd8 t effector memory cell. Utility is that they are ideally position and they are ready to go and can kill pathogen. Often you don’t have enough of these Tem to do what is needed. Need some kind of expansion and this is where t cm come in
67
EFFECTOR MEMORY T CELLS
naive t cells attach to HEV to get into secondary lymphoid tissues. L selection negative. CCR7 negative, circulate in non lymphoid tissue, already differentiated , have high levels of effector molecules. mucosal or inflamed tissues because they dont have l selection and ccr7 to allow them to enter secondary lymphoid tissue. can respond immediately to infection
Tcm will expand in lymphoid tissue upon antigen reencounter. Will kill of infected cell and this will go to draingn lymph node where it will be presented against dendritic cells. Tcm once expanded they will differentiate. CD4 Tcm. Tcm is a reserve to be called upon to increase numbers of effector cells. Cd4 will produce more of that and cd8 will produce more of the other. KNOW GENERAL FUNCTION LOCATION AND WHY IMPORTANT TO HAVE TWO DIFFERENT.
Important to have tcm because tem effector cells will die and become inactivated. So Tcm expand and maintain pool of memory cells.
68
What is the easiest way to distinguish a naïve vs a memory B cell?
Naive B cells have not yet been trained by the immune system to recognize specific antigens -therefore the term "naive". Prior to antigen exposure, they must be trained in the bone marrow to recognize certain antigens.
Naïve B cells have IgM on surface and memory B cell does not. One reason why memory humoral response than primary humoral response because right away isotype switching antibody produced without anything needing to be done. Fc gamma receptor II B inhibitory receptor is on naïve and not memory cells.
Memory B cells, on the other hand, are formed after antigen exposure and clonal selection. As stated above, they have specific receptors for antigens and can produce antibodies.
69
Be able to describe the various types of vaccines (killed/inactivated)
the poliovirus vaccine can be either killed (Salk) or live attenuated (Sabin)........
virus particles that cannot replicate because they have been treated chemically with formalin or physically with heat or irradiation. for influenza and rabies are this type. one work if the viral nucleic acid can be completely and reliably inactivated.
need multiple doses
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, live attenuated vaccine
mutant form of live virus that grows poorly in human cells, usually elicit a better protective immunity than killed virus. they can infect cells and replicate, and thus mimics a real infection. to attenuate a pathogenic human virus, it is grown in cells from another anima species. such donations sleet for variant viruses that grow faster in non humans, the measles, mumps and yellow fever are live attenuated.
71
subunit vaccines
need multiple doses. only one component or subunit of the virus is used for vaccination. surface proteins are purified from the plasma. concern was that infectious particles of HBV should be completely removed. they ere not, vaccination could infect people and give diseases. abc SUBUNIT VACCINE BEING ONE OF THE FIRST MADE USING RECOMBINANT dana TECH. YEAST AND PURFIIED IN LARGE QUANTITY.
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problems with live attenuated vaccines
a mutation in viral genome can occur during manufacturinge of vaccine
revertance in live attenuated can become pathogenic while in killed vaccine as long as its completely killed there is no problem
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toxoid vaccines
to avoid these, infected individuals need mohave supplies of high affinity neutralizing antibodies. toxin molecules and inhibit its toxic activity. in the presence of antibodies, the toxin molecules neutralized for secretion. the inactivated protein retains sufficient antigenic activity to provide against disease.
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conjugate vaccine
Why are these especially useful in generating immunity in children to encapsulated bacteria? In your answer use the term “linked recognition”
different epitopes recognized b B cells and T cells are synthetically linked together.
effects young childrenn protection agains thee infection is provided by high affinity IG antibodies that bind to the polysaccharides on the outhrr surface of the capsule and trigger complement-mediated killing of the bacteria.
Conjugate correlate = polysaccaridhe covalently linked to protein..conjugate vaccine. Idea is that netutralizing antibody response against poly saccharide capsule of bacterial cell must be linked to protein…because just poly there is no t depedent antigen
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combination vaccine
provides protection against more than one pathogenic organism and disease. one function is to be adjuvant that triggers innate and other is to provide the antigens that will stimulate a specific adaptive response. inflammation induced by bacteria provide strong adaptive immune responses.
76
How are live attenuated vaccines produced?
mutations are acquired during the cell culture process producing many variants. The variants that are best adapted to those particular conditions will survive and preferentially reproduce, leading to a virus strain that is well adapted to that particular cell type, etc…
FIRST ISOLATED BY GROWING IT IN CULTURED HUMAN CELLS. THIS IN ITSELF CAN CAUSE SOME ATTENUATION. TTHE VIRUS IS THEN GROWIN IN CELLS OF A DIFF SPECIEIS UNTIL IT ADAPTS TO THOSE CELLS AND GROWS ONLY POORLY IN HUMAN CELLS. ADATPATION IS A RESULT OF MUTATION, COMBINED OF SEVERAL POINT MUTATIONS GROWS POORLY IN HUMAN HOST, PRODUCES IMMUNITY.
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What are correlates of protection?
the measurable indicators that a parson has developed acquired immunity, antibody tier, antibody for a specific epitope, certain cytokines
78
Describe the concept of herd immunity and why is it important in maintaining public health?
population has herd immunity, large pop has received infection. which also indirectly protects the minority of people who have no been vaccinated. can not create an epidemic because of the low probability of finding susceptible individuals and creating a chain of infection.
79
What are combination vaccines (we talked about DTP)?
whole bacteria, very few are live attenuated. inactivated bacteria --- pertussis component of DTP. secreted toxins an capsular polysaccharides
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? What is a strong correlate of protection against a bacterium that secretes toxins? (Hint, bacterial toxins typically have two functionally distinct domains)
diphtheria taxon and tetanus toxin. to avoid contracting these, infected individuals need to have supplies of high affinity neutralizing antibodies.
81
Why are adjuvants necessary for non-live attenuated vaccines?
serves to trigger the innate immune response and establish a state of inflammation at the site of vaccination. the inflammation is necessary for intimating an adaptive immune response agains the antigens in the vaccine.
82
Know the effector functions and examples
| • Type I hypersensitivity
allergic rhinitis, asthma, systemic anaphylaxis
allergen specific IgE bound to the FcERI receptor of mast cells, basophils and eosinophils. degranulate and rerelease inflammatory mediators. varying sensitivity.
IgE driven involves sensitization of granulocytes
83
Know the effector functions and examples
| • Type II hypersensitivity
penicillin allergy
caused by an IgG response to chemically creative small molecules that become covalently bound to the of surface cells. the mediated by IgG antibodies made against new epitopes of cell surface proteins caused by chemical modification.
IgG mediated (cell surface associated antigen) (penicillin allergy with type II) when you receive penciilin it can modify the surface proteins which creates new antigen. These will induce the IgG response and then it will bind to your own cells.
Aspects of antigens involved are diff between ehse two)
Pathology is that there is IgG bound to your own cells that is opsonizing your own cells, and the activation of complement which is highly inflammatory, cells marked for phagocytosis
84
Know the effector functions and examples
| • Type III hypersensitivity
serum sickness (we didn’t cover this in lecture, please see textbook)
caused by small soluble immune complexes of antigen and specific IgG that form deposits in the walls of small blood vessels. the immune complexes activate complement and an inflammatory response. this is caused by antibody. reactions by IgG antibodies made against a soluble foreign protein, such as therapeutic mouse monoclonal antibody, form complexes deposited in tissue and become subject of fixation nd attack
IgG mediated
Soluble antigen and pathology is immune complexes. Induce humoral response and complexes of specific antibody plus the antigen. You get very large structures that are highly inflammatory because they (listen to recording)
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Know the effector functions and examples
| • Type IV hypersensitivity
contact dermatitis – nickel, poison ivy
are mediated b antigen specific effector T cells. in most instances by CD4 TH1 cells. red itchy of nickel allergy caused by infiltration of effector CD4 TH1 cells. responding to either the epitopes of foreign proteins or to peptides derived from chemically modified human proteins.
Delayed type hypersensitivity. Effector mechanisms involves a T cell response. Depending on allergen you are talking about this could be CD4 or CD8 t cell responses. Poison ivy – lipid soluble and gets into cytoplasm and it is phagocytosed going into MHC II pathways. Going through MHC I AND MHC II antigen presentation pathways. Both cytotoxic cd8 and cd4 responses. Poison ivy in skin the PDC will modify own proteins and the antigens will go to draining lymphnoid and prime them and become effectors and then migrate back to site of exposure. This si way this is delayed type response. Pathologiy just has to do with function of cd8 – killing own cells that express PDC sel proteins CD4 – driving macrophage activation that the general inflammation present at site
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Be able to describe the immune reaction to poison ivy
| What type of hypersensitivity?
delayed type hypersensitivity .. Type IV hypersensitivity
87
Be able to describe the immune reaction to poison ivy
| Against what molecule is the immune reaction directed?
urishol
88
Explain how either CD4 or CD8 responses are elicited to poison ivy.
T lymphocytes recognize the foreign substances, usually after the antigen is eaten, degraded, and presented (in pieces) by so-called antigen-presenting cells such as Langerhans cells in the skin, or macrophages. Urushiol metabolites are presented by this and other mechanisms. The T lymphocytes pour out inflammatory signal substances called cytokines. These call in armies of white blood cells called monocytes, which become macrophages. The macrophages become activated by the cytokines and attack everything in the vicinity, and can cause severe tissue damage. In addition to poision ivy, a good example is the skin reaction to injected tuberculosis antigen. In fact, when tuberculosis bacteria infect the lung, it is the delayed hypersensitivity against them which destroys the lung.
89
Describe the immune effector mechanisms that produce the symptoms of contact dermatitis (redness, swelling, itching, tissue destruction). POISON IVY
Redness - blood vessel dilate TNF alpha - local tissue destruction
Swelling - TNF alpha, activation of cytokines and macrophages
Itching - histamine not dependent on IgE
Tissue destruction - TNF alpha, cytokines, localized cell death. CD8 T cell activation happen secrete proteases decrease extracellular matrix and this will destroy skin layers
Itchiness of poinson ivy is due to histamine, granuolocytes can degranulate just int eh inflammatory environment, does not hae to be an antigen specific (DESCRIBE ALL THE SYMPTOMS OF POISON IVY EXPOSURE)…what is the molecular basis itching – histiamine relsase redness and swelling – vasoactive effect CD4 activating macorphages like tnf alpha and others they recruit more cells to the site tissue destruction – through several mechanisms are cytokine mediated TNF alpha (can kill cells) fas-ligand. Know a little about how tissues could be destroyed in a highly inflammatory environment.
90
what is hapten?
a molecule that is incapable, alone, of causing the production of antibodies but which can do so when fastened to a larger antigenic molecule called a carrier.
91
IgE/Mast cell immunity
| This type of response has evolved to eliminate what type of pathogens?
allergen and allergens specific IgE bound
92
IgE/Mast cell immunity
| What are the “key players” in responses to parasites/Type I hypersensitivity reactions?
FcERI receptor of mast cells, basophils, and eosinophils
TH2 response IL4: switch to IgE
IL5; granulocyte activationTh2 helps secrete cytokines, promote tissue repair.
93
What is the primary source of histamine and what effect does histamine have on:
o GI Tract - increase fluid secretion, increase expulsion of GI tract (vomit, diarrhea)
o Respiratory system - decrease air way diameter, congestions and blockage always wheezing sneezing, swelling and mucus secretion
o Blood vessels - increase blood flow, permeability, increase fluid in tissues causing increased flow of lymph to lymph nodes in tissues and increased effector response in tissues
As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective tissues.
Histamine increases the permeability of the capillaries to white blood cells and some proteins, to allow them to engage pathogens in the infected tissues.
94
What is atopy? What are risk factors for atopy?
meaning out of place or peculiar. atopic individuals have a genetic predisposition to allergy. epidemic of allergy higher blood level of IgE and eosinophils that non atopic people. half the risk is genetic the other half are env factors.
Predisposition to making TH2 responses and high levels of IgE. Genetic basis for this. HLA allotypes (genetic) effecting cytokines like IL 4 and IL 5. Tend to make more than these cytokines that are involved in TH2 IGE responses. If you are atopic that would mean you have high levels of IL 4 upon exposure so it would be difficult to switch to TH1 type of response because we know TH2 are directly inhibitory on development of TH1 responses. Signal 3 is what casues to be TH1 or TH2 responses. More likely will differentiate in TH2.
One of the therapies for allergies is desensitization – (allergy shots) this goes from low dose allergen -> high dose. Attempt to move from Th2 response and induce Tregs. This will supprsse activity of Th2 cells and mast cells responsible for pathology. Because there is a swich away from Th2 you see IgE production moving to IgG4 specific for allogen itsel.
95
If you are atopic, why is it difficult for the immune system to be redirected to a non-TH2 response such as TH1 dominated responses?
this complexity reflects the fact that allergic disease is caused by slight but significant perturbation of the balance between Th1 and Th2 response, which can be caused by man diff combinations of gene polymorphisms as well as env factors.
96
Systemic- systemic anaphylaxis
Why is systemic release of histamine potentially life-threatening? Under what conditions might systemic release of histamine occur?
allergen enters the bloodstream it can cause widespread activation of the connective tissue mast cells associated with blood vessels. this causes systemic anaphylaxis. disseminated mast cell activation casques both an increase in vascular permeability and a widespread contraction of smooth muscle.
blood moves slower and blood pressure may drop because of permeability
97
• Desensitization- what is it, how does it work?
modulate the antibody response so that it shifts away from one dominated by IgE to one dominated by IgG. patents are given a series of allergen injections in which the dose is initially small and gradually increased. sometimes anaphylaxis may occur, because the patient is being exposed to the allergen to which they are sensitized.
98
What observations led to the hygiene hypothesis? What is the hygiene hypothesis?
inverse correlation between the incidence of parasitic infection and the incidence of allergic disease. proposed that the epidemic of allergy was caused by improved hygiene, widespread vaccination to prevent infection, and increased used of antibiotic drugs to terminate infection.
This mechanism was one proposed to explain why kids that suffer through infections early in life are resistant to allergen. Hygiene hypothesis – stating that prior infection seems effective against allergen.
This mechanism was proposed against viral infection induces th1 responses. Directly antagonistic against th2 and this drives allergic reactions. In this individuals. T reg phenonmen where lfe styles and being exposed to farm animals and being outside more will induce t reg that suppress allergic responses. More westernized life style there tens to be poor treg induction.
99
What is the current thinking for why people living a “Westernized” lifestyle have a higher incidence of allergy (ex. Old Friends Hypothesis, microbial dysbiosis, the mucosal epithelium as an intermediary between environmental allergens and immune cells, poor Treg induction in Westernized environments)?
creates with sanitization of food and water supplies, increase personal hygiene, medical advances, and the elimination of creatures and habitats that spawn parasitic infections.
100
What is the current thinking for why people living a “Westernized” lifestyle have a higher incidence of allergy (ex. Old Friends Hypothesis, microbial dysbiosis, the mucosal epithelium as an intermediary between environmental allergens and immune cells, poor Treg induction in Westernized environments)?
creates with sanitization of food and water supplies, increase personal hygiene, medical advances, and the elimination of creatures and habitats that spawn parasitic infections.
101
What type of reactions are involved in instances of blood transfusion mismatch?
ABO incompatibility is identical to a type II hypersensitivity reaction. these hemolytic reactions can cause fever, chills, shock, renal failure and death. cell associated antigen antigen IgG, complement activation, phagocytosis of own cells, similar mechanism drives destruction in cases of mismatch.
102
Describe the major blood group antigens in humans (ABO, Rh)
for successful blood transfusion, the recipient must be compatible for the ABO system. the molecular basis for these antigens is structural polymmorphism in teh carb component of glycilipids and of a glycoprotein. detrimental to the outcome of blood transfusion and 7 a are the Rhesus system of blood group antigens. particularly the presence and absence of RhD antigen. transfusion of repents who lack RhD with blood from a RhD positive donor induces an antibody response against RhD that makes any further transfusion with this blood dangerous.
103
What is a cross match reaction and why are these performed?
these are done to see compatibility. done for reactivity with red cells from diff donors that have been selected for transfusion on the basis of their ABO and RhD.
104
If a person receives many blood transfusions during their life, why is it increasingly difficult to find a suitable matching blood type?
it is difficult because some patients have made so many different alloantibodies that it becomes difficult to find any blood donor tow home they are not reactive. antibodies against non-ABO and non-Rhesus blood group antigens are made in patients who have had multiple blood
105
Given someone’s blood type, be able to describe which ABO-specific antibodies they will have in their blood, who they can donate to, and from whom they can receive blood.
O blood type is the dworld donor and they have antibody A and B. O can not receive from anyone but o. A has anti B antibodies and can receive from O and A. B have anti A antibodies and can received from O and b. AB has no antibodies against A or B because they can receive from anything.
106
Hyperacute rejection of solid organs
| What type of hypersensitivity reaction?
Type II hypersensitivity reaction. delayed response. t cell mediated. worse kind of rejection and the vasculature becomes thoroughly coated with antibodies. to avoid this, transplant donors and recipients are types and cross matched for the ABO blood group antigens. can cause hemorrhage of blooding graft. deoxygenated blood organ dies
107
What are alloantigens. Toward which alloantigens are these responses normally directed against?
self antigens such as MHC molecules which vary between members of same species are alloantigens and the immune responses they provoke are alloreactions.
two types of allocation can occur which is transplant rejection. the next is the graft versus host reaction.
108
What are minor histocompatibility antigens?
Minor histocompatibility antigens are normal proteins that are themselves polymorphic in a given population. Even when a transplant donor and recipient are identical with regard to MHC genes, amino acid differences in these minor proteins can lead to rejection. Minor antigens are encoded by a large number of chromosomes and are presented only as peptides in the context of recipient MHC (indirect allorecognition). Minor antigens are responsible for the need for immunosuppression after donation between HLA-matched nonidentical twin siblings.
109
What are alloantibodies?
are immune antibodies that are only produced following exposure to foreign red blood cell antigens. Produced by exposure to foreign red cell antigens which are non-self antigens but are of the same species. They react only with allogenic cells. Exposure occurs through pregnancy or transfusion.
110
why no treatments for transplant rejection?
no treatment because the organ is destroyed
111
Acute rejection-
| What type of hypersensitivity reaction?
Type IV hypersensitivity
| delayed response, t cell mediated
112
Against solid organs: Which alloantigens are involved? What are alloreactive T cells, why do they make up such a large percentage of your T cells (1-10%)?
T cells attack the transplant. Because of diversity of receptors generated during T cell development, in ever person circulation there are T cells that can respond to complexes of peptide and allogeneic MHC CLASS I AND II molecules. T cells with this property are called alloreactive T cells, those reactive against any given allogeneic cell are between 1-10 percent. cause of rejection is that alloreative t cells in the aptints circulation are activated by allogenic HLA molecules in the graft leading to an alloreaction.
113
Graft vs Host Disease: Described the type of transplant that may result in GVHD. What is the general methodology?
hematopoietic cell transplantation are due to donor T cells in the graft that respond to and attack the recipients health tissues. affects almost all patents. bone marrow transplant. must obtain hematopoietic stem cells from a donors peripheral blood. autograft is self .
114
Chronic rejection-
| What type of hypersensitivity reaction?
Type III hypersensitivity
115
what antigens are involved in chronic rejection?
caused by IgG antibodies made against the allogeneic HLA class I molecules of the graft, forming immune complexes that deposit in the blood vessels of the transplanted kidney. CD4 Thelper cells imitate the response that leads to chronic rejection of organansplants do not recognize their antigens by the direct path way but rather the indirect pathway
