quiz 2 Flashcards
(149 cards)
1
Q
what is hypersensitivity?
A
inflammation due to exaggerated, inappropriate or ineffective immune response to antigens that, in the absence of immunity, are usually innocuous
2
Q
what are the types of anti-body mediated sensitivity? what are the characteristics of this type of sensitivity? how long can it last?
A
types I, II, and III
characterized by a reaction that frequently develops rapidly over minutes or hours but which can continue for months if the reactants remain available, by antibodies being present in body fluids or on cell surfaces, and by the ability to be passively transferred by serum containing the appropriate antibody
3
Q
immediate hypersensitivity (type I)
What are the target organs?
What is the mechanism?
What are the clinical manifestations?
A
target organs: respiratory tract, GI tract, skin
mechanism: IgE (usually), other immunoglobulins (eg IgG4)
clinical manifestations: rhinitis, asthma, urticaria, atopic dermatitis, GI allergy
occurs after prior sensitization and within minutes
only need a very small amount of antigen
4
Q
cytolytic hypersensitivity (type II) What are the target organs? What are the components of the mechanisms? What are the clinical manifestations? Explain the mechanism steps.
A
target organs: circulating blood elements inc. red cells, white cells, platelets
mechanisms: IgG, IgM and complement; ingestion of phagocytes of opsonized target cells; ADCC
clinical manifestations: blood transfusion reactions, hemolytic anemia, leukopenia, thrombocytopenia, hemolytic disease of newborn
IgG and IgM antibodies bind to determinants on the surface of host cells leading to host cell destruction by activated complement and/or cytolytic effector cells (NK cells, macrophages, neutrophils, eosinophils, monocytes)
engagement of IgG Fc receptors and/or receptors for activated complement components leads to phagocytosis and/or release of superoxide anion, h202, TNF or perforins
5
Q
immune complex hypersensitivity (type III) What are the target organs? What are the mechanism components? What are the clinical manifestations? Explain the mechanism.
A
target organs: blood vessels of joints, skin, kidneys, lungs
mechanism: antigen-Ab complexes (mostly IgG and IgM) and compliment
clinical manifestations: serum sickness, systemic lupus erythematosus, chronic glomerulonephritis
local destructive inflammatory lesions which result from tissue deposition of complexes containing antigen, antibody and complement
6
Q
cell-mediated hypersensitivity (type IV) What are the target organs? What is are the mechanism components? What are the clinical manifestations? Explain the mechanism.
A
target organs: skin, lungs, CNS, thyroid, other organs
mechanisms: sensitized T lymphocytes, NK cells, macrophages
clinical manifestations: contact dermatitis, TB, allergic encephalitis, thyroiditis, primary graft rejection
due to reintroduction of antigen into an individual who has t-cell immunity to that antigen - T cells release variety of inflammatory mediators (cytokines)
7
Q
mixed types I and III hypersensitivity
What are the mechanism components?
what are the clinical manifestations?
A
mechanisms: IgE and precipitating IgG
clinical manifestations: allergic bronchopulmonary aspergillosis
8
Q
mixed types III and IV hypersensitivity
What are the mechanism components?
What are the clinical manifestations?
A
mechanisms: Ag-Ab complexes and cell-mediated immunity
clinical manifestations: extrinsic allergic alveolitis
9
Q
Define atopy
A
“strange”
presence of specific IgE antibodies directed against common environmental antigens
10
Q
Define anaphylaxis.
A
severe, whole-body allergic reaction resulting from the sudden release of mast cell and basophil derived mediators into the circulation
includes dilation adn leakage of post-capillary venules (causing edema, hypotension and cardiovascular collapse) and constriction of airway smooth muscles
11
Q
IgE
What type of hypersensitivity is IgE a major component of?
Is it in high or low concentrations in affected individuals?
In what body areas is type I IgE produced?
How does IgE bind to effector cells?
A
antibody that mediates type I hypersenstivity
in low concentration in serum of normal donors but in higher concentration in atopic individuals
made predominantly in plasma cells in respiratory and GI tracts
in external secretions
Fc portion binds to Fc(epsilon)R receptors on mast cells, basophils, eosinophils, lymphocytes, and monocytes
12
Q
Fc(epsilon)R
A
receptor for the Fc region of IgE that is on mast cells, basophils, eosinophils, lymphocytes, and monocytes
13
Q
basophils
Where do these cells originate?
What do these cells respond to?
What receptors do basophils have and what influence do they have on inflammation?
A
originate in bone marrow
circulate in blood
respond to chemotactic stimuli
have H2 (histamine) receptors that probably transmit a negative feedback signal to turn off mediator response
14
Q
mast cells
Where are mast cells found in the body?
What stimulates mast cells (name 5)
What do mast cells release when stimulated?
A
around blood vessels in subcutaneous and sub mucous tissue and in peritoneal cavity
stimulated by anti-IgE, antigen, anti-mast cell antibody, anaphylotoxins (C3a and C5a), lectins (bind and crosslink sugar residues on IgE)
when activated, degranulates
15
Q
define eosinophilia
What do they target?
A
high numbers of eosinophils in the blood
hallmark of allergic disease
have IgE receptors and are important cytotoxic effectors against IgE coated targets
16
Q
crosslinking
Define the process of crosslinking.
A
mast cell and basophil IgE receptors are normally occupied by monomers of IgE
exposure to the appropriate antigen will result in crosslinking of these receptors, triggering the release of mediators (release of granule contents)
17
Q
histamine
Explain the difference between the actions of…
H1 receptors
H2 receptors
A
via H1 receptors contracts smooth muscle, increases vascular permeability, increases mucous secretion by goblet cells
via H2 receptors increases gastric secretion, feeds back to decrease mediator release by basophils and mast cells
has regulatory role in both innate and adaptive immunity
basically H1 is inflammatory. H2 is anti-inflammatory
18
Q
slow reacting substance of anaphylaxis (SRS-A)
these are aka as?
What are they derived from?
What is their action?
A
aka cysteinyl leukotrienes (LTC4, LTD4, LTE4)
derived from membrane FA
constrictors of peripheral airways, cause dilation and increased permeability of micro vessels (resulting in edema)
enhanced airway mucous secretion, constriction of coronary and cerebral arteries, decreased myocardial contractility, increased gastric acidity
19
Q
What is leukotriene B4?
What is its action?
A
binds to a different receptor than SRS-A
causes neutrophil chemotaxis, adhesion of neutrophils to endothelium of post capillary venules, and neutrophil degranulation
induces leakage of post capillary venules resulting in edema
20
Q
prostaglandin D2
What is the action?
A
brochoconstrictor, peripheral vasodilator, coronary and pulmonary vasoconstrictor, inhibitor of platelet aggregation, neutrophil chemoattractant
21
Q
platelet activating factor (PAF) Action on platelets? Action on blood vessels and lungs? Action on skin? Action on eosinophils and neutrophils?
A
low molecular weight lipid
produced by varitety of cells including mast cells
causes platelet aggregation with release of vasoactive mediators such as serotonin
vasodilator and bronchoconstrictor - contracts nonvascular SM directly
induces wheal and flare reactions even in absence of platelets
chemotaxis and degranulation in eosinophils and neutrophils
increases vascular permeability
22
Q
neutral proteases
What is their action?
A
activate kinins (ie bradykinin) and complement to cause …
increased vascular permeability
decreased blood pressure
and contraction of SM
23
Q
mediators of hypersensitivity with pharmacologic effects on SM and mucous glands (list)
A
histamine SRS-A Leukotrine B4 Prostaglandin D2 PAF neutral proteases
see other cards for details on these
24
Q
mediators of hypersensitivity that are pro-inflammatory by chemotactic properties (list)
A
leukotriene B4 interleukin 8 complement factor C5a PAF rantes eotaxins
25
leukotriene B4 (LTB4)
What is the precursor?
is this slowly or rapidly released?
What is the action on other immune cells?
derived from membrane FA
rapidly released
chemotactic factor for polymorphonuclear cells, eosinophils, and macrophages
26
mediators of hypersensitivity that cause tissue destruction
Name cell types and effector compounds that they release
toxic oxygen radicals (superoxide) released from neutrophils, macrophages, and mast cells
acid hyrolases and neutral proteases from mast cells
major basic protein from eosinophils
27
major basic protein
| Released by what cells?
mediator released by eosinophils
| can damage airway epithelium
28
NSAIDS
What effect can these have on prostaglandins and the immune system?
can induce anaphylactic reactions independent of adaptive immune mechanisms
29
drugs for type I hypersenstivity
1: inhibitors of mediator action - benadryl etc. that inhibit H1 so block histamine activity, synthetic steroids for inflammatory mediators, epinephrine and long acting beta-2 receptor agonists for low blood pressure and bronchospasm
2: inhibitors of the production and release of inflammatory mediators - inhibit cytokine production, histamine release, antibodies to IgE
30
```
subcutaneous immunotherapy (SCIT)
What is this used for?
how does this work?
```
identify offending antigen (allergen) and give gradually increasing doses subcutaneously
activates allergen-specific t-reg cells by hyposensitization protocols and increasing levels of allergen-specific IgG and IgA generally coincide with decreases allergic symptoms - may be due to removal of allergen-antibody complexes by mononuclear phagocytes with less mediator-release than is triggered by IgE allergen complexes
31
blood transfusion reactions
Which type of hypersensitivity do blood transfusions cause?
Explain ABO reactions.
type of type II hypersensitivity
antibodies to A and B antigens (isohemagglutnins) occur naturally without transfusion of human red cells - sensitivity probably due to intestinal microorganisms that express identical antigenic determinants
if abo mismatched rbcs are infused serum antibodies will agglutinate the RBCs or cause destruction by compliment mediated lysis or by phagocytosis by macrophages in the liver and spleen
32
hemolytic disease of the newborn (HDN) aka erythroblastosis fetalis
What is this?
Why does an ABO mismatch cause less severe symptoms?
active immunization by exposure to mismatched RBCs
mother who is RH- had a fetus who is RH+
mother makes anti-D antibodies and in subsequent pregnancy with an RH+ fetus maternal IgG and antiD antibodies can cross placenta and destroy the fetal RBCs
much less common when there's an ABO mismatch as well- because when ABO mismatch fetal RBCs are rapidly destroyed by naturally occurring ABO antibodies, eliminating the source of D antigen so mother never develops anti RH+ antigens
use Rhesus prophylaxis to prevent - inject anti RhD antibodies perinatally into Rh- mothers who have an Rh+ fetus
33
autoimmune blood dyscrasias
What type of hypersensitivity is this?
What are the effects/symptoms?
What is an iatrogenic cause of this illness?
hypersensitivity type II
autoantibodies produced that recognize ones own RBCs, platelets, lymphocytes, or neutrophils
results in their elimination and anemia, thrombocytopenia, lymphocytopenia or neutropenia
antibodies to drugs or drug metabolites can also be produced- haptens associate with the host cell membrane and Fc and compliment systems eliminate any host cell that particular drug or metabolite is attached to
34
coombs' test
test for detection of antibodies bound to RBCs (type of type II hypersensitivity)
add anti-human antibody and if there are antibodies on the RBCs this will result in agglutination, resulting in a positive test
35
hyperacute graft rejection
What type of hypersensitivity is this?
What is the cause?
What specific transplanted organs cause this to occur?
What reactions occur leading to the problem/symptoms?
type of type II hypersensitivity
when a transplant recipient has been previously sensitized to antigenic determinants in the graft tissue so that there are antibodies to the tissue present in the host - obviously results in rejection of the graft
occurs only in grafts that are revascularized directly during transplantation (like kidney grafts)
get influx of neutrophils followed by damage to glomerular capillaries, hemorrhage, platelet aggregation, and thrombus formation - blocks flow of blood to the tissues and tissues become anoxic and necrotic
very rare and should not happen clinically due to pre-screening
36
serum sickness
What type of hypersensitivity is this?
What are the mechanisms leading to symptoms?
type III hypersensitivity
serum from immunized animals was injected into humans to provide passive immunity to certain toxins or pathogens (before antibiotics)
now usually due to allergic reaction to antibiotics
antibodies to the antigen (horse immunoglobulin for example) are formed in result in immune complexes large enough to be eliminated by macrophages - removes immune complexes from the circulation but get fever, hives, inflamed lymph nodes, arthritis, inflamed kidneys and heart and nervous tissue due to local inflammatory response and mediator release
soluble immune complexes get into sub-endothelial basement membrane and attract neutrophils due to C5a generation and B4 and IL8 release - get more leukotriene release and lysosomal enzymes
discontinue serum and inflammatory disease will subside
37
elements of immune complex reactions (in type III hypersensitivity)
What are the mechanisms involved?
(its a long list)
1: IgG or IgM antibody synthesized in response to large amounts of antigen and soluble complexes form
2: some of these complexes are small and escape phagocytosis and get into the capillaries, bifurcation's of arterioles or on filtering membranes
3: complement is fixed by the complexes
4: anaphylatoxins (C3a and C5a) are generated and bind to C' receptors on mast cells and endothelial cells
5: this results in blood vessel leakage and edema
6: IgG immune complexes cross-link Fc(gamma) receptors and induce neutrophils to release leukotrine B4 and IL-8 and induce macrophages, neutrophils, and mast cells to release neutrotrienes C4, D4, E4 and TNF, and also trigger release of lysosomal enzymes and superoxide anion from neutrophils
7: B4 and SRS-A and prostaglandins and histamine cause increased vascular permeability - results in localization of immune complexes on vessel basement membrane (step in development of vasculitis)
8: platelet and leukocyte thrombi form, fibrin deposition, vessel necrosis
38
arthus reaction
Define.
What is this used for?
prototype of the immune complex reaction when Ab is in gross excess
soluble Ag is injected intradermally and combines with Ab to form immune complexes that induce localized symptoms of serum sickness including local erythema and edema
TB test.
39
anaphylatoxins
What is the basic mechanism that causes anaphylaxis?
complement factors C3a and C5a
bind to C' receptors on mast cells and endothelial cells
create blood vessel leakage and edema
C5a is also chemotactic for neutrophils
40
mechanisms of immune complex clearance (5)
1: mononuclear phagocyte system - mononucelar phagocytes ingest immune complexes via Fc and C3b receptors (esp macrophages in liver and spleen)
2: C3b receptors on erythrocytes - immune complex binds to type I complement receptors (CR1) on erythrocytes - sequesters complex and shuttles it to liver and spleen - as passes through liver complexes and CR1stripped from erythrocyte surface by macrophages
3: compliment: alternate complement pathway mediates dissolution of complexes
4: polymorphonuclear phagocytes - polymorphonuclear neutrophils have C3b and Fc receptors - probably play a role
5: other mechanisms - platelets, lymphocytes, mast cells and renal and placental epithelia also have C3b and Fc receptors
41
C1q binding
What is this diagnostic technique used for?
assay for detecting immune complexes (type III hypersensitivity)
purified C1q binds to immune complexes stoichiometrically - use labeled or solid phase C1q - immobilizes immune complexes and then use labelled rabbit anti-human immunoglobulin to detect
42
CH50 (total hemolytic complement) of serum
Why is this measurement useful in diagnosing hypersensitivity?
What type of hypersensitivity is it used to diagnose?
method for detecting immune complexes (type III hypersensitivity)
measure serum complement because activation of compliment in vivo will result in decreased serum complement
43
immunohistology
What type of hypersensitivity is this used to diagnose?
method for detecting immune complexes (type III hypersensitivity)
use both immunoflorescence and immuno-electron microscopy to identify tissue deposits of complexes
44
treatment for immune complex hypersensitivity (type III)
withdraw culprit agent
symptomatic treatment - antihistamines, nonsteroidal and antiinflammatory agents, analgesics
glucocorticoids - for fever, severe arthritis, rashes
45
tuberculin type hypersensitivity
This tuberculis test exploits what type of hypersensitivity?
type of type IV hypersensitivity
PPD test best example of cutaneous delayed hypersensitivity
only get positive result if individual previously exposed to antigen
response reaches maximum 1-2 days after exposure - response due to infiltrates of mononuclear cells (lymphocytes and macrophages)
46
# Define contact hypersensitivity
What type of hypersensitivity is this?
| What is the course of events in contact hypersensitivity?
type of type IV hypersensitivity
due to small molecules that can form covalent or non-covalent interactions with skin proteins - results in contact dermatitis
eg catechols from poison ivy or poison oak
haptens interact with the self proteins that are taken up by the langerhan's cells
langerhan's cells migrate to lymph nodes and stimulate hapten/protein-specific T cells
these expand and circulate around the body to site of contact
reintroduction of antigen results in lymphocyte proliferation, lymphokine and chemokine production, and macrophage activation
predominately due to CD4+ lymphocytes but CD8+ also involved
47
granulomatous hypersensitivity
What type of hypersensitivity?
What is granulomatous hypersensitivity?
What is the body's mechanism for containing the infection?
What can reactivate the infection?
type of type IV hypersensitivity
due to persistent antigens associated with an organism difficult to remove (like leprosy or TB)
with TB, T cells and activated macrophages in outer margins of granulomas appear and keep teh TB contained and prevent systemic infection
anti TNF therapies such as that for RA can result in increased risk of reactivation of latent TB
48
diseases associated with Delayed Type Hypersensitivity?
What type of hypersensitivity?
What is delayed type hypersensitivity?
What are diseases associated with hypersensitivity?
types of type IV hypersensitivity diseases
when immune response itself is destructive in the process of trying to remove the infecting agent
examples: TB, leprosy, toxoplasmosis, leishmaniasis, schistrosomiasis
49
autoimmunity
define.
any immune response in which the processing and elimination of antigen leads to inappropriate destruction of host tissues
can result from interactions with either foreign or autoantigens
50
cross reactive epitopes
Define with regard to autoimmunity.
What disease is an example?
foreign antigen that could induce autoimmunity
active response generated against an epitope common to both a microbe and host tissue so that the host tissue is also attacked
eg rheumatic heart disease - group a streptococci express epitopes common to heart muscle
51
foreign antigens and host cell surfaces
How can this cause autoimmunity?
What is a common resulting symptom of this type of occurance?
foreign antigen that could induce autoimmunity
when microbial antigens are expressed on the surfaces of infected or transformed host cells, esp. with viral infections
foreign antigens can also be adsorbed onto surfaces of cells or react chemically with surface antigens in hapten-like manner to alter specificity - commonly results in thrombocytopenia (low platelet levels) and anemia
52
autoantigens
define.
What are theories that induce autoimmunity from autoantigens?
foreign and unrecognized self antigen that could induce autoimmunity
reactivity to auto antigens in normally suppressed but can be induced
theories for induction include sequestered antigen theory and immunologic deficiency theory (see other cards)
53
sequestered antigen theory
explain
theory regarding how immune response to auto antigens could stop being suppressed
antigens absent or anatomically separated during fetal development are not recognized as self since tolerance induction occurs during development
exposure through trauma or infection to these antigens can result in autoimmune disease
54
immunologic deficiency theory
explain this theory of activation of autoimmunity
theory regarding how immune response to auto antigens could stop being suppressed
deficient immune response allows persistence of infection or inflammation which leads to modified auto-antigens or uncovering of sequestered antigens
55
autoimmune hemolytic anemia (AIHA)
Immune Thrombocytopenia Purpura (ITP)
What are these?
What is the mechanism?
What is an indication of successful therapy?
diseases in which autoantibodies mediate cell destruction
IgG autoantibodies bind to RBCs (in AIHA) or platelets (in ITP) and this results in their destruction via complement receptor or Fc receptor mediated clearance
successful therapy coincides with decreased Fc receptors on monocytes and macrophages
56
myasthenia gravis (MG)
What is this illness?
disease in which autoantibodies interfere with receptor function
weakened and easily tired muscles
antibodies to acetylcholine receptor - may be compliment activiating (IgM, IgG1, IgG2, IgG3) or non-activating (IgG4, IgA)
either block Ach binding sites or destroy cell by cross-linking receptor so that it becomes non-functional or internalized
seems to be due to only a small population of B cells being activated so a very small subset of B or T cells may be involved
57
graves disease
autoantibodies block or stimulate thyroid receptors
get either growth stimulating immunoglobulin (TGSI) or thryotropin binding-inhibitory immunoglobulin (TBII)
seems to be due to only a small population of B cells being activated so a very small subset of B or T cells may be involved
abs to receptor on thyroid gland that recognizes TSH bind to the receptor and stimulate excessive thyroid hormone
IgG can cross placenta and cause hyperthyroidism in newborns of women with this disease
58
systemic lupus erythematosus (SLE)
form of autoimmune disorder where autoantibodies form precipitating immune complexes
autoantibodies damage target tissue by direct interactions by formation of toxic immune complexes which damage organs indirectly
suspected to be due to a generalized defect in a suppressor mechanism
commonly also autoantibodies to Treg cells
59
autoimmune thyroid disease
form of autoimmunity that causes endocrine dysfunction
affects 1% of us population
Graves' disease
Hashimoto's thyroiditis
60
Hashimoto's thyroiditis
type of autoimmune disease in which endocrine system is stimulated
autoantibodies inhibit thyroid function
61
contributing factors to autoimmune diseases
1: genetics - strong association between HLA type and incidence
2: sex - much more common in women than in men - likely due to neuroendocrine and immune system interactoins
3: age - more prevalent in older adults - likely due to less stringent immunoregulation by the aging immune system
4: infections - can initiate disease
5: drugs
62
treatments for autoimmune diseases
subdue inflamation thorugh NSAIDS, glucocorticoids and TNF blockers
cytotoxic drugs or lymphoid irradiation in sever classes
bcell depleting antibody for RA
plasmapheresis (removal of plasma) for antibody-mediated diseases (MG)
intravenous immunoglobulin for some by modulating function of Fc receptors and interfering with complement activation and cytokine networks
63
MHC in transplantation
```
function as strong antigens in transplant situations
MHC has three classes (I, II, and III) of genes closely linked on chromosome 6 in humans
only match class I and II gene products for donors
these genes are highly polymorphic but not inherited completely randomly - variable distribution of determinants among ethnic groups
haplotypes (combination of alleles at each of the loci within the MHC on the same chromosome) are usually inherited intact
```
64
histocompatibility (H) antigens
antigens on the graft that elicit the hosts immune system to reject the graft
when genetically matched grafts are histocompatible and when not matched are histoincompatible
65
autograft
donor and recipient are the same individual
| no genetic basis for rejection
66
syngenic graft
between two individuals who are genetically identical in all respects (monozygotic twins)
these grafts are accepted
67
allograft
between two genetically unlike individuals of the same species
usually rejected in the absence of immunosuppressive therapy
histocompatibility antigens are called alloantigens
68
xenograft
between individuals of different species
| rejected due to genetic disparity
69
bone marrow
What is unique about a bone marrow transplant?
What are the risks?
unique graft type comprised of immune cells
| risk of graft rejection and also of graft versus host disease
70
graft versus host disease
What is this with regard to bone marrow transplant?
when bone marrow is transplanted and the donor immune cells mount an immune response against the host tissues
71
allogenic histocompatibility antigens
What are major histocompatibility antigens?
What are minor histocompatibility antigens?
histocompatibility antigens involved in allografts
classified as major or minor based on the strength of the graft rejection they cause
major difference will cause more dramatic and faster response
major ones are coded for by HLA complex while minor ones are in many genetic loci and are still not well characterized
72
acute rejection
What is the time period?
What is the mechanism?
What are the preventive measures?
1 of 3 types of graft rejection
within the first weeks or months following transplantation
graft has infiltrates of activated lymphocytes and monocytes
effector mechanism through cytotoxic T cells or helper/delayed type hypersenstivity T cells and monocytes and macrophages
clinically mitigated by matching MHC molecules between donor and host and by administration of immunosuppressive drugs
73
chronic rejection
What is the time period?
What is the symptom?
note: mechanism is not yet clear.
1 of 3 types of graft rejection
takes months to years - gradual loss of function of the graft
mechanism not clear
lesion is proliferation of cells lining arterial walls that may be associated with IgM deposits but also infiltration with mononuclear cells, esp T cells
not always controlled by immunosuppressive drugs
74
immune response leading to graft rejection
What areas of the body do not experience graft rejection?
What type of immune cells are usually mediate (as in cause) graft rejection?
Are MHCII or MHCI mismatches more severe?
lymphatic channels are important and so regions without access to these do not reject grafts (such as anterior chamber of eye, interior of brain, fetus)
cell-mediated rejection involving t-cells and macrophages is most common
predominately mediated by CD4 T cells but CD8 T cells are involved - mismatches at MHCII are more deleterious than those at MHCI
T cell receptor recognizes foreign mhc molecules via direct or indirect allorecognition
75
What is direct allorecognition?
When does this occur?
TCR binds directly to the foreign MHC molecule and elicits t-cell activation regardless of the peptide presented on MHC
way that T cells recognize donor tissue in grafts
only occurs if graft contains donor derived APCs (eg dendritic cells) - this stimulates the development of alloreactive T cells that recognize and attack graft cells
76
What is indirect allorecognition?
What is the mechanism?
way that T cells recognize donor tissue in grafts
host professional APCs ingest graft cells and present antigens from these on MHC molecules
TCR recognizes peptide derived from foreign MHC molecule that is cross presented by the normal host APCs on normal host MHC molecules
77
immunosuppression
What are somethings that cause?
generalized intentional depression of the immune response
four techniques:
1: drugs - cytotoxic, corticosteroids, some antibiotics
2: radiation
3: ablation (usually surgical) of lymphoid tissue
4: biologic agents, such as anitlymphocyte globulin and anti CD3
78
tolerance
depression of an immune response to an antigen or a limited number of antigens
79
tumor immune surveillance
Define.
How does immunosuppression effect?
when the adaptive immune system prevents the outgrowth of transformed cells or destroys them before they become harmful
patients that are immunosuppressed have elevated risk of developing cancers
80
What is "immune editing?"
What are the three steps in cancer progression with regard to immune editing?
new term for immune surveillance
three steps:
elimination - NK cells and T cells infiltrate early microscopic tumors and eliminate or fail to eliminate the cancer
equilibrium - tumor may remain dormant for many years under pressure of constant immune attack by CD8 T cells and NK cells
escape - if tumor subsequently mutates and evades host immune response
81
tumor antigens
which immune cells target tumors?
How do the recognize tumors?
```
T cells (particualry CD8) and antiboies are most effective against cancer due to specificity and longlevity
tumors may express tumor specific antigens (TSAs) or tumor associated antigens (TAAs) which are also found on some normal cells
antigens can also be classified as viral, mutations, oncofetal, and self antigens
```
82
viral tumor antigens
Are these antigenic?
What percentage of cancers are caused by virus?
strongly antigenic because they're foriegn
estimated that 60% of cancers caused by viruses
shared by all tumors induced by the same virus and good targets for vaccines
83
mutation induced tumor antigens
Are these antigenic?
some mutations that are causing the cancer can be recognized by the immune system
since these mutated proteins are not identified as normal self proteins, the t and B cells that recognize them are not eliminated from the host
84
oncofetal antigens in tumors
What are these?
many tumors express proteins that are only present during fetal development (since many tumor cells take on stem-cell-like characteristics)
self-antigens and so are TAAs (tumor associated antigens)
85
self antigens in tumors
Are these antigenic?
What are the causes of vitiligo?
normal cellular antigens are expressed at specific stages of cell differentiation
these differentiation antigens are on tumor cells
must first overcome mechanisms of immune tolerance to target these
vitiligo is caused by treatment of melanoma inducing autoimmunity against melanocytes because melanomas express the same antigens as mature melanocytes
86
ways tumors can evade immune system
1: body develops tolerance to tumor antigens - if majority of tumor antigens are TAA or if for some reason T cells are unresponsive to the antigens
2: selection for tumor antigen negative variants - survival of the fittest among tumor cells - those with recognizable antigens die
3: tumor immunosuppresses patient - releases molecules such as TGFb or IL-10 that immunosuppress
4: tumor has low immunogenticity - has little or no class I MHC on surface
5: induce immunosuppressive Treg cells and myeloid derived suppressor cells - tumor cells good at recruiting these
87
antigen specific immunotherapy
What immune cells are used?
relies on B or T cells or antibodies to target specific antigens on tumors
88
What is nonspecific immunotherapy in cancer?
do not target specific antigens but rather induce overall immune activation
89
what is active immunotherapy in cancer?
elicits a host immune response
90
what is passive immunotherapy in cancer?
involves direct administration of immune effector cells or molecules
91
nonspecific biological response modifiers
What are common non-specific modifiers used to treat melanoma?
type of nonspecific active immunotherapy
uses nonspecific immunostimulants that induce strong immune responses and some tumor cell killing
tumor cell lysis probably occurs as a result of of the production of cytokines that activated immune effector cells
enhances non-specific activation of immune cells
IFN-a and IL-2 are commonly used to treat melanoma
92
antibodies to tumor antigens
specific passive immunotherapy for cancer
search for monoclonal antibodies to tumor cells
use mutant form of epidermal growth factor receptor (EGF-R) taht has a deletion of an extracellular domain or idiotype region of a Bcell or T cell tumor
causes tumor cell lysis via complement activation by targeting ADCC or via phagocytosis by effector cells or by inducing apoptosis
93
immune stimulatory antibodies
example of nonspecific active type of immunotherapy for cancer
MAbs (monoclonal antibodies) used to target immune-stimulatory pathways or to block immune inhibitory pathways
94
tumor vaccines
type of specific active treatment for tumor
try to use vaccines to induce immunity to viruses know to be associated with the development of tumors (HPV) or to induce effective immunity to a patient's specific tumor cells
95
adoptive T cell therapy
type of specific passive immunotherapy for cancer
patient tumor-infiltrating lymphocytes can be expanded, activated with cytokines, and re-infused into patients to eliminate large established tumor burdens
96
What is primary immunodeficiency?
result of a failure of proper development of the humoral or cellular immune system
97
What is secondary immunodeficiency?
acquired - consequence of other diseases and treatments such as chemotherapy
98
antibody deficiencies
What types of infections are susceptible?
mainly result from abnormal B cell development - any steps in development may be blocked or abnormal
overall lack of antibodies means that patients have recurrent bacterial infections, mostly pneumococcus, sterptococcus and hemophilus
99
Bruton's disease
few or no B cells so few if any antibodies
| unable to coat the surface of bacteria
100
common variable immunodeficiency (CVID)
various forms of primary immunodeficienies
some due to defective regulation by T cells so absence of T helper activity
some due to B cells that don't respond to signals from other cells
antigen presentation or other cytokine abnormalities may also be involved
have low IgG and often also low IgA with impaired specific antibody production in response to vaccines and infections
problems with IgA most common
get recurrent sinus and lung infections
101
x-linked agammaglobulinaemia (XLA)
type of B cell deficiency
B cell precursors fail to develop due to defective gene for btk thats involved in activation of the pre-b cell to immature B cell
get low levels of mature B cells and low Ig serum levels
T cells are normal
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hyper IgM syndrome
type of B cell deficiency
increased IgM but little or no subclasses from IgG in the circulation due to defective gene coding for either CD40 on B cells or CD40L on activated T cells
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IgA in immunodeficiency
IgA is the most common primary immunodeficiency
most patients don't present with significant disease but have increased rate of respiratory infections
(deficiencies in IgG often asymptomatic but also increased respiratory infections)
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DiGeorge syndrome
due to an absent or very small thymus
severity depends on amount of thymus present
results in T cell deficiency
get severe fungal, protozal infections and tetany due to hypocalcemia
105
bare lymphocyte syndrome
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defects in genes needed for MHC class II expression lead to a lack of CD4+ T cells
results in severe SCID phenotype
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Wiskott-Aldrich syndrome (WAS)
mutation in WAS protein
connects T cell signaling pathways to cytoskeletal mechanisms that are important for T cell activation - results in defective T cells
symptoms: eczema, decreased blood platelets and small platelets and leukocytes so that they don't migrate properly
x-linked
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ataxia-telangiectasia
due to mutations in the ATM protein
ATM is involved in DNA repair and is a normal checkpoint if DNA is damaged
results in impaired lymphocyte development and function
and vascular malformations
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severe combined immunodeficiency (SCID)
affects B cell and T cell development or function
50% of patients have defect in common cytokine gamma chain used by many cytokine receptors so lymphocytes dependent on these cytokines do not develop properly in these individuals
10% have adenosine deaminase (ADA) enzyme deficiency or thymocytes purine nucleoside phosphorylase deficiency - leads to toxicity in lymphocytes due to a buildup of purine metabolites which inhibit DNA synthesis
30% have defects in enzymes involved in recombination - cannot produce function immunoglobulin or T cell receptors - don't get any functional B or T cells
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phagocytic cell deficiencies
intrinsic - related to the inherent properties of the phagocyte
extrinsic - due to other factors (such as deficiency of antibody or compliment, suppression of phagocytic activity)
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cyclic neutropenia
too few neutrophils due to problems in stem cell differentiation and neutropenia
autosomal dominant
only have the low neutrophil count for 3-6 days of the 21 day neutrophil cycle
111
leukocyte adhesion deficiency (LAD)
lack of adhesion to endothelium
LAD1 due to absence of beta-integrin - results in absence of LFA-1 expression
LAD2 is due to a defect in GDP-fucose transporter and results in so sialyl-Lewis X, which is the ligand for E-selectin, which is involved in the initial attachment to the endothelium at sites of infection so leukocytes aren't recruited to the site of infection
autosomal recessive
get lots of pyogenic infections
112
chediak-higashi syndrome
phagosomes don't fuse with the lysosomes in phagosytic cells
| also affects functions of macrophages and NK cells
113
chronic granulomatous disease (CGD)
defect in genes for NADPH oxidase - results in defective intracellular killing of bacteria because neutrophils and macrophages can't kill phagocytosed microbes
this results in the recruitment of more and more macrophages and activates T cells, resulting in granulomas
several genetic defects cause it - many x-linked
get lots of bacterial and fungal infections
114
interferon-gamma receptor deficiency
defects in IFN-gamma or IL-12
| results in atypical mycobacterial infections
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Job's syndrome
hyper IgE syndrome
failure to produce IFN-gamma by Th cells resulting in reduced killing of bacteria by macrophages
get recurrent colds, staph infections, skeletal defects
high IgE levels result in histamine release which blocks the inflammatory response and inhibits neutrophil chemotaxis
116
hereditary angioedema
C1q deficiency - the C1q is an inhibitor of C1 - if it's not working, C1 continues to act on C4, which activates C4a, which activates C3a and C5a, which increase capillary permeability and edema in organs
basically the compliment system can't be shut off properly
due to continuous compliment activation and consumption
autosomal dominant
117
paroxysmal nocturnal haemoglobulinuria
due to decay accelerating factor (DAF) deficiency
results in lysis of RBC precursors because of defect in the anchoring of DAF to the cell membrane - this results in increased activation of the compliment system
get brownish urine due to compliment mediated hemolysis
118
HIV/AIDS
secondary immunodeficiency
| retrovirus that has trophism for T cells, esp the CD4+ t-helpers
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immune senescence
immune capacities decrease during aging - reduced responses to vaccines and increased risk of infection
thymus involves so T cell education is all but lost
number of memory T cells increases so limited numbers of naive T cells entering pool
older cells have limited ability to expand
also age-related reductions in humoral immunity including shifts in antibody specificities from foreign to autoantigens, shifts in antibody isotypes from IgG to IgM, and shifts in antibody affinities from high to low
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steps of hypersenstivity reaction
sensitization phase:
exposure to antigen
antigen activates Th2 cells
Th2 cells stimulate B cells to class switch to IgE
B cells release IgE antibodies
IgE binds to Fc(epsilon)RI on mast cells
effector phase:
mast cells are armed and ready to respond
after second exposure the mast cells are activated
mast cells release mediators (degranulation)
note: mast cells can reform their granules in about 48 hours
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live attenuated vaccines
based on mutations of the pathogens genome due to growth in alternate hosts (viruses) or long term culture (bacteria)
problem: when you manipulate these bacteria and viruses so much to make sure that they're not deadly you lose a lot of the antigens that they would be making
in bacteria, delete the virulence gene and gene for horizontal transfer to make it safer
advantage: the body will make more diverse antibodies to these vaccines than to dead ones because the injected virus or bacteria will be accessing its genome and replicating which will result in a greater diversity of proteins being expressed
live vaccines also give "shedding and herd immunity" to viruses, which apparently we'll hear about in the virology section
Only get both IgA and IgG and CD8+ T cell response with live vaccine - for antibodies, needs to be administered the way that the disease would be contracted (ie for polio it should be oral administration)
live vaccines also give longer lasting protection
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inactivated (killed) vaccines
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cannot cause infection so good for diseases that are deadly such as rabies but not as effective, especially with just one dose, which is problematic in places where getting access to doctors is difficult (since its hard to get patients to come back for their second shot)
don't get IgA response or CD8+ T cells with a killed vaccine because there's no replication so no viral epitopes are presented in the class I MHC of infected cells, as there would be with a live virus
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123
types of flu vaccine
the inactivated vaccine is the shot that is most commonly used
the live attenuated vaccine is the flu mist commonly used in children - this is advantageous because it's easier to give to children than a shot and because it allows them better protection, which children need since they have not been exposed to lots of other forms of the flu yet like adults have
the live flu vaccine is temperature sensitive so that it only replicates in the cooler nasal passages but is killed in the warmer lungs where it would infect the individual so you get the IgA production without risk of infection - this prevents infection (not in their lecture, but I thought it was cool)
124
concerns about live vaccines
(not in their notes, but probably good to know)
1) if it's composed of attenuated viral mutants, it can sometimes revert to virulence (this has only happened with the polio vaccine)
it can also still cause disease even if it doesn't revert in those with weak immune systems
2) it can be excreted (spread to others) - usually this is good, as it immunizes others, but if theres a mutant form of the virus that spreads it can be dangerous - happened with polio also
3) a second virus can infect the vaccine during the manufacturing process
125
vaccination
innate immunity has to hold the line until the adaptive immune system can be stepped up and reach levels of effectiveness
vaccines give us a controlled means to eliminate the waiting time for protective responses to be developed and deployed
126
active immunity
induced by live virus whose pathogeneity has been attenuated or by a killed virus
127
subunit vaccines
like the hep B vaccine
contain purified viral proteins
features resemble those of a killed vaccine
easy to make large amounts of them and very safe but unlikely to stimulate cytotoxic T cell response (so not as effective)
128
conjugate vaccines
these mix of a B cell epitope and a T cell epitope
the B cell epitope is often a carbohydrate that wouldn't do anything on its own but when the T cell is activated by its epitope the B cell is activated by the T cell and you get an immune response
"conjugate vaccines use t cell antigen with b cell antigen to provide a more robust response in children. Children don't have a very good B cell response for some reason." - bharat
129
DNA vaccines
these are currently experimental but show promise
for them, DNA for viral proteins is purified and inserted into a vector which is then this vector is used as the vaccine
this results in antibody and cytotoxic T cell response, though has only been tried in animals
130
passive immunity
administration of preformed antibodies in the form of immune globulins
this provides immediate protection and is used in combination with active immunity for disease that are treated after exposure like rabies and hep B
131
toll receptors
receptors that detect certain aspects of bacteria or viruses common to multiple species of these (Ie recognize a carbohydrate commonly used in the cell membrane of bacteria but that isn't found in humans)
when these are activated they result in the release of cytokines:
the ones mentioned in lecture are:
IL-1 induces fever by acting on the hypothalamas in the brain and also activates lymphocytes and changes the permeability of the endothelium
IL-6 also induces fever
IL-8 recruits PMNs
TNF-alpha increases the leakiness of endothelial cells
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fever
induced by IL-1 and IL-6 by actions on the hypothalamus
| advantageous because lymphocytes proliferate better at higher temperatures
133
RAGD
enzyme involved in Tcell recombination
| if deleted, have no T cells so no adaptive immunity
134
STAT1
no innate immunity if deleted
135
immunoediting
way by which immune system can adapt to mount an immune response to cancer growth
1: the immune system recognizes stroma remodeling, which results in tissue damage
2: the inflamation signals are released - IFN-gamma
3: IFN-gamma induces tumor death and promotes chemokines CXCL10, CXCL9 and CXCL11 that block vessel formation to the tumor
4: the cell debris is ingested by dendritic cells, which move to the lymph nodes and trigger the differentiation of Th1 cells, resulting in the activation of CD8+ T cells which move to the site and kill tumor cells
5: NK cells and macrophages transactivate one another via IFN-gamma and IL-12 production - they produce reactive O2 species and nitrogen intermediates and trigger the apoptosis of tumor cells
136
steps to immediate hypersensitivity reaction
IgE is made in response to the antigen (after activation of Th2)
IgE binds to Fc receptors on mast cells
crosslinking of bound IgE by reintroduced antigen results in the release of mast cell mediators
this results in:
increased vascular permeability
increased smooth muscle contractility
cytokines recruit neutrophils and eosinophils (creating an inflammatory late phase reaction)
Th2 secretes IL-4 and IL-13 to stimulate b lymphocytes to switch to IgE producing cells
production of antibody results in sensitization: IgE binds to Fc receptors on Fc(epsilon)RI on mast cells
when the antigen is present again and binds to 2 or more antibodies on these receptors the mast cell is activated (must be two or more because need crosslinking to activate)
this results in:
degranulation
secretion and synthesis of lipid mediators
synthesis of cytokines that will reduce local inflammation (TNF and IL-4) and recruit leukocytes - results in late phase reaction (IL-5 activates eosinophils)
Ig1 and Ig3 bind to neutrophil and macrophage Fc receptors and activate them, resulting in inflammation
these and IgM activate the compliment system via the classical pathway
complement byproducts recruit leukocytes and induce inflammation via reactive O2 intermediates and lysosomal enzymes
137
degranulation
when mast cells release their granules that contain:
histamine - results in dilation of small blood vessels, increased vascular permeability, stimulation of transient contraction of smooth muscle
proteases - damage local tissue
arachidonic acid metabolites (prostaglandins) - vascular dilation
leukotrienes - stimulate smooth muscle contraction
138
immunogenic tolerance
unresponsiveness to self antigens
induced by exposure of lymphocytes to these antigens because functionally inactivated or killed if they respond to them (positive and negative selection that we learned about for the last quiz)
central tolerance when developed in generative lymphoid tissue
peripheral tolerance when developed in peripheral tissue
139
central T lymphocyte tolerance
if recognize self antigens in thymus with high avidity, the t lymph cells die via apoptosis (negative selection)
antigens that induce this include plasma proteins and other protein common in most cells
transcription factor AIRE (autoimmune regulator) is responsible for regulating the expression of these in generative tissue
140
peripheral T lymphocyte tolerance
when peripheral T cells recognize a self antigen in peripheral tissues it undergoes anergy or death or is suppressed by Treg cells
141
anergy
when T lymphocyte recognizes antigens without adequat leves of costimulators
may express CD152 (CTLA-4) which is a high affinity receptor for B7 molecules that deliver inhibitory signals to T cells
problems in the CTLA-4 gene result in autoimmunity
infection may break T cell anergy, resulting in autoimmune disease
142
activation-induced cell death
way to ensure tolerance/prevent autoimmunity
1: repeated activation leads to coexpression of Fas (CD95) and Fas Ligand (FASL)
2: these activate each other or activate these ligands on nearby cells
3: caspases are activated
4: apoptosis occurs
IL-2 (a tcell growth factor) potentiates this process
antigen induced activation could also induce production of proapoptotic proteases
a fas mutation results in autoimmune disease
143
immune suppression (to prevent autoimmunity)
when encounter self antigens, some self-reactive T lymphocytes become regulatory cells and suppress the activation of other lymphocytes
most CD4+ have high levels of CD25 (the alpha chain of the IL-2 receptor)
some produce cytokines (TGF-beta and IL-10) that block the activation of lymphocytes and macrophages
144
central B cell tolerance
wehn B lympocytes interact strongly with self antigens in bone marrow they're either killed (negative selection) or they change their receptor specificity by activating the Ig gene recombination machinery, resulting in the expression of a new light chain that combines with the old heavy chain and creates a antigen receptor that is no longer sensitive for self
145
peripheral B cell tolerance
if mature B lymphocytes encounter high levels of self antigen in the peripheral lymph tissue the become anergic (they don't receive T cell help)
146
mixed lymphocyte reaction
in vitro model of T cell recognition of alloantigens
detects magnitude of MHC differences by mixing T cells from one individual with leukocytes from another
to establish practicalities of donor-host matches
147
cyclosporine
blocks T cell phosphatase required to activate transcription factor NFAT
this inhibit transcription of regulator cytokines in T cells
immunosuppressant used in graft hosts to prevent rejection of the graft
148
corticosteroids
inhibit cytokine production by macrophages and lyse certain types of T cells
block transcription factors NFK-beta and AP-1
149
B versus T cell deficiency
recurrent infections with bacteria indicate B cell deficiency whereas recurrent infections with fungi, viruses or protozoa indicate T cell deficiency
