Test 2, deck 2 Flashcards
(86 cards)
1
Q
what is an exaggerated or misdirected immune response called, and what are the 4 types
A
"hypersensitivity disease" type 1: allergies/asthma (IgE) type 2: diseases caused by antibodies directed against tissue antigens (hemolytic anemia) type 3: immune complex diseases (lupus) type 4: TMMI problems
2
Q
what is an immune complex? what is its role?
A
binding of an antibody to its antigen; role= facilitation & amplification of both humoral and cellular defenses to pathogens
3
Q
what does the formation of an IC depend on?
A
- intensity of antigen stimulus, including:
1) type of antigen
2) length of host exposure
3) route/site of exposure
4
Q
what influences the rate of IC formation?
A
- rate of antibody formation
- antibody avidity (how well it sticks)
- valence of antigen
- complement & Fc/FcR interactions
5
Q
what does the vigor of an immune response depend on?
A
- gender (women= huge response to B cell antigens)
- age
- MHC
- immune related genetic loci
- polymorphisms of Fc receptor genes
6
Q
most important inflammatory reaction
A
binding of (antigen+IgG) to FcgammaR on monocytes and neutrophils; aggregation of ICs on surface of bacteria allows for cross-linking of receptors
7
Q
what two inflammatory amplifying systems can an IC activate?
A
1) FcR crosslinking
2) complement (classic or direct)
8
Q
how is IC mediated inflammation controlled?
A
- antigen exposure is reduced (antibiotics)
- catabolization of Ics by neutrophils/macs after binding FC receptor
- free IC bound RBC and transported to liver
9
Q
describe the erythrocyte transport of ICs
A
- IC-C3b form complexes
- C3b can bind to the CR1 (on all peripheral blood cells except platelets)
- C3b converted to iC3b (inactive)
- goes to liver and is removed by fixed macrophages (kupffer cells) OR
- goes to spleen to activate B cells
10
Q
what happens if formation of IC> destruction?
A
“Free” IC will activate multiple inflammatory amplifying systems locally & systemically
(especially Fc activation and complement)
11
Q
what happens to circulating ICs not on RBCs?
A
- activates local neuts and macs in endothelium (commonly kidney/skin/synovium)
- releases Il8 which recruit more neuts to area & activates complement pathway
- destroys vasculature & tissues
12
Q
how is IC mediated inflammation controlled?
A
- antigen exposure is reduced (antibiotics, drainage)
- catabolization of Ics by neutrophils/macs after binding FC receptor
- free IC bound RBC and transported to liver
13
Q
what is an Arthus reaction?
A
- occurs when there are high levels of pre-existing antibodies to the antigen introduced under the skin (e.g. repeated immunization)
- get rapid accumulation of immune complexes, lots of neutrophil activation
- get pain, swelling, redness at site of antigen infection
14
Q
what is acute serum sickness?
A
- give foreign serum to treat rattle snack venom
- body starts making antibody against serum
- formation of serum proteins + anti-serum antibodies exceeds disposal
- get fever, vasculitis, nephritis, arthritis (depending on site of IC deposition) and reduced complement levels (high IC formation)
15
Q
what is the problem diagnosing IC disease? what can be used?
A
- wide variation in complexes
- typically diagnosed clinically
- newer assays try to look for activated C3
16
Q
3 treatments for IC disease
A
- eliminate antigen (drain, take antibiotics)
- inhibit antibody formation
- suppress inflammation
17
Q
what happens when IC goes to the spleen (via RBC receptors) or lymph nodes (via lymph)
A
- not efficient site for disposal
- extremely potent stimuli for antibody production
18
Q
describe immunoregulation by Fcgamma receptors on APCs
A
- only recognize antibody with something in FAB
- cross-linking by antibodies activates ITAM
- cell is prompted to phagocytose the complex
- receptor affinity is high, can be activated by small amount of IC
19
Q
describe immunoregulation by Fcgamma receptors on b-cells
A
- receptor affinity is low, needs lots of IC
- complexes cross link Fcgamma receptors and activate ITIM
- ITIM is a negative signal, shuts down further B-cell proliferation
20
Q
how is the Rh problem prevented?
A
give mother IgG antibody to bind with fetal red cells, turns off B-cells that are anti-fetal RBC by tricking them into thinking they’ve made enough, CD4 and B memory cells are not generated
21
Q
describe the Rh problem
A
- 1st pregnancy: Rh- mother exposed to Rh+ antigen from baby, forms anti-Rh antibodies, has primary response
- 2nd pregnancy: maternal IgG (including anti-Rh) crosses placenta and destroys fetal red cells, has secondary, more intense response
22
Q
what happens if you get Rh- mom IgM anti-Rh?
A
won’t work, because you want to be targeting the Fcgamma response; IgM will stimulate more IgG
23
Q
an allergic response is a type ___hypersensitivity reaction
A
type 1
24
Q
define atopy
A
the ability to transfer reactivity to allergens by means of
serum; genetic predisposition to develop IgE antibodies upon exposure to environmental allergens
25
what cells express high affinity for IgE FcE receptors constitutively? what are they full of?
- mast cells and basophils
| - vasoactive mediators like histamine and leukotrienes
26
how are mast cells categorized and where are they found?
2 major subtypes:
- tryptase (MCT cells) - mucosa of respiratory & GI tracts
- tryptase and mast cell-specific chymase (MCTC cells)- connective tissues (dermis/submucosa) of GI tract, heart, conjunctivae, perivascular tissues
27
how is IgE induced? common component of environmental antigens?
- by environmental proteins ("allergens") found in insects, worms, shellfish and foods and fungi that can induce hypersensitivity responses in atopic individuals
- MHCII D genes, in concert with other non-MHC genes, promote IgE production over IgG responses by influencing the type of TLR activated, type of T-helper cell and cytokine milieu present during allergen presentation by APC
- chitin ( a polysaccharide not found in mammals)
28
how do genetics influence allergies?
- 50% of individuals with two allergic parents will also be allergic
- multiple genes act together to produce an allergic response
29
describe the context of antigen exposure required to develop an allergy?
- high level of exposure early in life coupled to a lack of exposure to other infectious disease antigens
- route- delivery of antigens in small amounts to mucosal surfaces
30
sequence of an allergic response
1. contact allergen (usually mucosal)
2. uptake of allergen by DC w/ "allergic" TLR; get production of IL-4
3. allergen presented in MHC Class II
4. Th-2 activation occurs
5. IL-4 is dominant cytokine, allergen-specific B-cells activated (lots of IL4 & 13)
6. Promotion of IgE class switch by upregulating Cd-23
31
T/F FC on IgE can bind FCRs on mast cells and basophils without antigen
TRUE- STRONG (20,000 x stronger than IgG binding its FC receptor)
32
what is the immediate phase of the type 1 hypersensitivity reaction?
- occurs within 15 minutes of allergen exposure (MUST be exposed before)
- allergen binds IgEs already on mast cells/basophils
- vasoactive mediators are released
- prostaglandins and leukotrienes are synthesized/released
- complement activation by tryptase released from mast cells
33
what is the late phase of the type 1 hypersensitivity reaction?
- occurs within hours of allergen contact
- completely dependent on Th2 activation
- characterized by infiltration of the site by eosinophils, neutrophils, mast cells, basophils, lymphocytes
34
what cytokine increases FcER display, augmenting the IgE reaction?
Il-5
35
describe the hygiene hypothesis?
early exposure to childhood
illnesses “sets” normal Th1 and Th2 responses to subsequent environmental antigen exposure; lack of early exposure is associated with lack of Tregs
36
What is the most important factor for arriving at a correct allergy diagnosis?
a careful clinical history
37
what happens to your cardiovascular system with anaphylaxis?
heart rate spike, blood pressure drops- die b/c of hypotension
38
describe the RAST assay
- patients serum added to cellulose disc with bound antigen
- IgE present in serum binds to antigen
- wash, add radio labeled anti-IgE, radioactivity counted with a gamma counte
39
autograft, isograft, allograft, xenograft
- self-to-self, accepted
- identical twin to twin, accepted
- person to person, variable degrees of rejection ("allogenic graft")
- species to species, strong rejection
40
3 types of donors
living-related
living- nonrelated
cadaver
41
describe the complement-dependent cytotoxicity assay and what its used to tests
- tests for recipient's antibodies to donor
- take patients serum and incubate with a panel of lymphocytes of known HLA specificity
- if there are antibodies, they will bind to MHC antigen on lymphocyte cell surface
- add complement, which lyses known pairs (bad
42
describe the mixed lymphocyte culture
- assess recipients T-cell proliferation against donor
- mix recipient's lymphocytes with irradiated donor lymphocytes (only role is to display MHC)
- cells incubated for 5 days, add radioactive precursor of DNA
- if recipient's t-cells don't proliferate, get no radioactive uptake= no interactions = OK for donation
43
what does the intensity of rejection depend on?
1) differences in MHC (especially class 2)
2) the host's immune response genes
3) physician intervention (drugs)
44
what is the difference between direct and indirect alloregulation?
direct- recipient's APC takes up antigen, presents it in MHCII, presents to T cell
indirect- donor's APC migrate to lymph node, recipient's T cells recognizes MHCII as antigen
45
what's a passenger leukocyte?
leukocytes present in donor tissue (E.G. dendritic cell) migrate to spleen, activate T cells, which migrate to graft and kill it
46
what can be the trigger for specific rejection?
1) antigen picked up by host B cells
2) donor dendritic cells presenting self-peptide which looks like antigen
3) antigen picked up by host dendritic cells
47
what happens after specific rejection has been triggered?
1) activated macrophage mediated graft destruction
2) CD8 specific graft cytolysis
3) Th17 mediated inflammation ** if dominant, will be more destructive (more neuts)
4) antibody mediated graft destruction
48
what are some reasons hyperacute rejection occurs?
- (often) occurs immediately after graft placement, recipient has alloantibody before transplantation (mis-match in blood type)
- can be sensitized by multiple pregnancies, blood transfusions
49
what happens with hyperacute rejection?
- get rapid binding of antibodies to antigens on transplant epithelium, platelets aggregate at site of damage
- platelets secrete mediators for coagulation cascade, graft becomes ischemic
- neutrophils attracted to ischemia , cause clotting
- complement escalates whole clotting situation
- graft turns pale
50
what happens with acute rejection?
- immune cells appear in graft during the first 3 weeks after grafting
- CD4 t-cells react with antigens and mediate TMMI response
- antigen-specific T cells attack graft
- Th17 promotes inflammation
- B cell antibody appears `
51
what is the hallmark of chronic rejection?
repeated episodes of rejection; diffuse, widespread arteriolar narrowing, fibrosis; eventually leading to graft ischemia
52
how do gene arrays help with rejection diagnosis?
take biopsy of organ, distinguishes between acute & chronic rejection & drug toxicity
53
when does graft-vs-host disease occur?
- when bone marrow is transplanted and the T cells attack recipient's tissue
- or when immunoincompetent host recieves a transfusion
- to test, use reversed mixed lymphocyte culture
54
what gene prevents xenotransplantation?
alpha-1,3-galactosyl; get hyperacute rejection
55
what does fetal tissue at the materal-fetal interface down regulate? what does it up-regulate, and what does that do?
down-regulates normal MHC complexes (I and II)
| up regulates MHC-G, inhibits cytotoxicity of NK cells
56
what do placental NK cells produce?
* are special NK cells*
- TGF-B and IL-10 (for regulatory effects)
- angiogenic factors
57
what do you find in high concentrations in uterine wall?
- special NK cells
- gamma delts
- paternal antigen-specific T-regs
58
what happens to maternal lymphocytes that access fetus?
converted to T regs
59
what is the clinical implication for mother during pregnancy
- progesterone + placental derived factors suppress local & systemic Th-1 responses
- lack of Th1 predisposes mom to viruses (e.g. flu, TB)
- if converted to Th1 bias, can lose fetus
60
what happens when the fetus is infected?
high presence of Tregs can lead to tolerance to the infecting pathogen, can prevent child from responding appropriately later
61
what are 4 key benefits of commensal microbiota?
1. required for development of the immune system (germ-free animals have almost no secondary lymphoid tissue)
2. provide energy by metabolizing polysaccharides
3. provide vitamins
4. protect from pathogens
62
what balance does a healthy intestinal microbiota generate?
Th1/Th17 : Tregs
63
what does dysbiosis of the gut contribute to?
inflammatory bowel disease, autoimmunity, allergy, obesity
64
what can dysbiosis be caused by?
diet, antibiotics, stress, early childhood exposure, genetics
65
what should not be given with cancer drugs?
antibiotics -killing commensals decreases chemotherapy effectiveness
66
what can IBD be treated with?
- is T-cell mediated inflammatory response
- treat in mice by giving B. fragilis, inducing an anti-inflammatory response (by inducing Tregs); shows promise with mouse MS as well
67
what is the hygiene hypothesis?
- increase in allergy due to decreased exposure to microbes during childhood
- Th1 responses down-regulate Th2 (IgE producing) responses
68
what happens if you co house mice with obesity associated microbiota and lean associated microbiota and feed them a low fat diet?
They both get lean!
69
T/F Cecarean delivery results in vaginal microbiota
FALSE- skin microbiota
70
3 ways superantigens differ
1) can react with MHCII in unprocessed form
2) activate outside the peptide binding groove- is on the side, like a TCR-MHC bridge
3) elicit an immediate primary polyclonal response in T-cells
71
what do superantigens cause?
- massive outpouring of pro-inflammatory cytokines
| - can lead to cytokine storm syndromes & systemic toxicity
72
what cytokines do you see a lot of with a superantigen response?
INF-gamma & TNF alpha
73
viruses required a living host for propagation; 3 ways they evade destruction?
1. down regulate TLRs
2. produce inhibitory signals for NK cells
3. produce soluble cytokine effectors to bind up cytokines before they act
74
factors that play role in autoimmunity
gender (females 85%), genes, environment
75
what percentage of siblings with diabetes share 2 HLA haplotypes? 1? 0? what is the normal ratio?
60: 35:5
25: 50:25
76
if a TCR reacts with an AIRE protein what happens?
- it is converted to a protective CD4, CD25 Treg
77
what is Treg function controlled by? what is it reliant on?
CTLA-4 (acts as brake); reliant on IL-2 from exogenous sources
78
things that could lead to an autoimmune disease
- inadequate display of AIRE
- loss of CTLA4 gene
- loss of FoxP3 function
79
non-T cell source of autoimmunity
- TLR over-expressed/under-expressed/mutated
| - DC function impaired
80
how could a viral infection initiate an autoimmune disease?
- infect cells (e.g. beta cells) and initiate CD8 attack against them
- display antigens that look like Beta cells so the CD8s attack
- incite collateral damage
81
if something is chronic with lots of neutrophils, which immune effector cell do you suspect?
Th17
82
what are the initiation cytokines for Th17
TGFbeta, IL23, Il6 (last 2 prevent T regs)
83
what inhibits the development of Th17s?
INFgamma, IL4
84
what does IL17 do?
recruits neutrophils
85
what normally happens to self-reactive B cells?
- checking is less stringent, normally die from neglect because no t-cell can activate them
86
T/F All autoantibodies cause disease
FALSE- if find autoantibodies in blood of women, not necessarily lupus
