Haematology, coagulation and immune Flashcards
1
Q
what does thrombin activate ?
A
platelets and activating factors V, VIII, IX
2
Q
What is haegerman factor
A
XII
3
Q
What is Von Willembrands factor
A
VIII
4
Q
What are the vitamin K dependent pathways in the clotting cascade ?
A
- IX -> IXa
- X -> Xa
- II -> IIa
- VII -> VIIa
5
Q
What are Ca dependent pathways in the clotting cascade ?
A
Aids in the activation of;
- IX -> IXa (forms a complex with activating factor XIa)
- X -> Xa (form a compelx with IXa and VIIIa in the intrinsic pathway) and IIIa and VIIa in the extrinsic pathway
- Va and Xa to activate II ->IIa
- XIIIa + Ia + Ca helps stabilise the fibrin clot
6
Q
What are activators of the intrinsic pathway
A
Exposure of collagen, kallibrein and heigh molecular weight kininogen (HMWK)
7
Q
What are activators of the extrinsic pathway?
A
Release of tissue factor (III) from endothelial famage
8
Q
What pathways of the clotting cascade are affected in haemophila A?
A
Conversion of VIII by thrombin to VIIIa
9
Q
What pathways of the clotting cascade are affected in haemophila B?
A
Conversion of IX->IXa via XIa and Ca
10
Q
What pathways of the clotting cascade are affected in haemophila C?
A
activation of XI to XIa (via XIa)
11
Q
What are the 3 components of Virchows triad;
A
- Hypercoagulability
- Hemodynamic changes (stasis and turbulence)
- Endothelial injury/dysfunction
12
Q
What are risk factors associated with hypercoagulability ?
A
hyperviscosity, coagulation factor V Leiden mutation, coagulation factor II mutation, deficiency of antithrombin III, protein C or S deficiency, nephrotic syndrome, changes after severe trauma or burn, cancer, late pregnancy and delivery, breed, advanced age, cigarette smoking (possibly secondary exposure), hormonal contraceptives, obesity, DIC
13
Q
what are risk factors associated with clot formation when there is stasis and/or blood tubulence
A
venous stasis due to poor cardiac output, atrial dilation, long surgical operations, prolonged immobility (e.g. bed bound during hospitalization), varicose veins, aneurysms
14
Q
What are risk factors associated with endothelial injury dysfunction and clot formation?
A
vessel injury, damages arising from shear stress or hypertension on the blood vessel. Additionally, this category is ruled by surface phenomena and contact with procoagulant surfaces, such as bacteria, shards of foreign materials, biomaterials of implants or medical devices, membranes of activated platelets, and membranes of monocytes in chronic inflammation.
15
Q
What are pros and cons of TEG?
A
Pro; induces cells in the evaluation of clotting
Con; poor reproducibility without strong tissue factor or contact activator, and interpretatin difficult in animals with altered HCT and platelets
16
Q
What are pros and cons of thrombin-antithrombin complexes?
A
Pro: use of plasma eliminates Hct and platelet effects
Cons: expensive, must be batched
17
Q
what are pros and cons of measuring D-dimers?
A
Pro: Specific for breakdown of cross-linked fibrin (clot breakdown)
Con: Not available in all labs
18
Q
What are pros and cons of measuring fibrin[ogen] degradation products?
A
Pros: inexpensive, simple to run
Con: Not specific: can indicate lysis of fibrinogen,
fibrin, or cross-linked fibrin
19
Q
what are disorders that platelet and the vascular wall ?
A
thrombocytopenia, thrombocytopathia, abnormalities of von Willebrand factor (vWF), and vasculitis
20
Q
when does thrombocytopaenoa lead to petechia?
A
when the PLT count is <20,000/mcl
21
Q
mucosal bleeding and bruising is more common in which coagulation disorders?
A
thrombocytopathia, von Willebrand disease (vWD), and vasculitis
22
Q
Coagulation FACTOR deficiencies most commonly result in what symptoms ?
A
ecchymoses, hematomas, and/or muscle, joint, or body cavity bleeding
23
Q
PLATELET deficiencies or defects most commonly result in what issues?
A
Mucosal bleeding, petechia, echymosis
24
Q
what factors my affect the results during testing of coagulation factors?
A
sampling errors (not clean stick, did not get a continous laminar collection flow, innapropriate tube used for collection or causing haemolysis during sampling) but also patient specific factors such as having recently consumed a fatty meal, being icteric or undergoing haemolysis
25
what is the presfered anticoagulant for CBC and platelet count? Why?
KEDTA. This caelates calcium preventing the activation of ;
- IX -> IXa of the intrinsic pathway
- Factor VIIIa (intrinsic) and VIIa (Extrinsice) activation of X to Xa in the common pathway
- Factor II to IIa in the common pathway
26
What is the anticoafulant of choice for most coagulation assays?
NaCitrate
27
When should a bucal mucosal bleeding time not be performed?
when there is thrombocypaenia - only perform when there are normal platelet counts
28
What tests exist to determine platelet function for diseases such as thrombocytopathia ?
- WBA; whole blood platelet agregometry
- PFA-100; platelet funciton analyser
-TEG; adapted protocos.
29
Summarise the what the following are used for; PT, APTT and ACT ?
PT; evaluates the tissue factor pathway (extrinsic; FVII) and the common pathway (FX, FV, prothrombin, fibrinogen)
APTT; contact pathway (prekallikrein, FXII, FXI); the intrinsic pathway (VIII, IX); and the common pathway (FX, FV, prothrombin, fibrinogen).
ACT; similar to the aPTT (evaluating all factors except FVII and FXIII) except that it uses whole blood.
30
Prolonged PT with noromal APTT suggests;
FVII deficiency.
31
Why does factor VII deficiency, result in long PT, but no bleeding?
Due to the short half-life of FVII, PT prolongation in vitamin K deficiency initially is due to FVII deficiency (not associated with bleeding), but the clinical bleeding occurs with development of prothrombin deficiency
32
What does APTT measure?
aPTT is the time from recalcification until formation of the first fibrin strands.
Citrated plasma is incubated with a contact activator (e.g., celite, kaolin) and lipids to allow for the generation of FXIIa and FXIa, then recalcified to allow for downstream coagulation steps.
33
Prolongation of APTT and normal PT suggests?
consistent with deficiency of FXII, FXI (hemophilia C), FVIII (hemophilia A), FIX (hemophilia B), or with heparin therapy
34
What does factor XII deficiency in cats cause clinically?
Nothing - not associated with bleeding
35
What are conditions associated with the prolongation of both PT and aPTT?
anticoagulant rodenticide exposure (vitamin K deficiency), liver disease, disseminated intravascular coagulation (DIC), and hypo- or dysfibrinogenemia.
36
How does heparin affect PT?
Heparin does not generally prolong the PT due to the inclusion of heparin antagonists in commercial PT reagents.
37
what can the ACT screen for?
rodenticide intoxication, hemophilia, hepatopathy-associated coagulopathies, and DIC
38
what tests allow for the detection of fibrinogen and fibrinolysis?
Fibrinogen, Thrombin Time, Fibrin[onegen] degration products (FDPs), D-dimer, antibrombin (AT) assay
38
what does the fibrinogen defects can be classified as?
- qualitative;(dysfibrinogenemia)
- quantitative (hypo- or afibrinogenemia)
- acquired vs. congenital (consumption, decreased hepatic synthesis, or inhibitory antibodies)
- acute phase protein; strong acute phase reactant in dogs, with increases (hyperfibrinogenemia) occurring during inflammation and infection
39
Dogs with systemic infection or inflammatory disorders may have what changes in their fibrinogen?
increases as fibrinogen is a strong acute phase reactant in dogs, with hyperfibrinogenemia occurring during inflammation and infection
40
what does the Thrombin time test for ? what is the test used for ?
time from recalcification until formation of the first fibrin strands. The TT is an indicator of fibrinogen concentration and/or function.
41
What does Fibrin[ogen] Degradation Products (FDPs) test for ?
DPs are created when plasmin lyses fibrinogen, soluble fibrin monomers, insoluble fibrin, and/or cross- linked fibrin. The presence of excess FDPs merely indicates plasmin activity
42
What conditions can cause increased FDPs ?
variety of disorders, such as DIC, anticoagulant rodenticide intoxication, hepatic disease, thrombosis, IMHA, neoplasia, pancreatitis, gastric dilation-volvulus, heatstroke, and others
43
what are D-Dimers?
D-dimers are a form of fibrin degradation product (FDP) that can only be generated from cross-linked fibrin.
44
what are 16 common diseases which cause hypercoagulability?
1) Immune-mediated hemolytic anemia
2) Systemic inflammation
* Acute pancreatitis
* Trauma
* Immune-mediated disease
3) Sepsis
4) Cardiomyopathy (hypertrophic, restrictive/unclassified, dilated)
5) Infective endocarditis
6) Heartworm disease
7) Protein-losing nephropathy
8) Protein-losing enteropathy
9) Neoplasia
10) Hypothyroidism
11) Hyperadrenocorticism
14) Corticosteroid therapy
15) Diabetes mellitus
16) Disseminated intravascular coagulation (initial phase)
45
what are the 6 common causes of hypocoagulability?
1) Vitamin K1 antagonist ingestion (anticoagulant rodenticide)
2) Vitamin K1 deficiency
* Marked hepatic disease
* Decreased synthesis by intestinal microflora
* Severe fat malabsorption (secondary to extrahepatic biliary obstruction, exocrine pancreatic insufficiency, lymphangiectasia)
3) Hepatic dysfunction
4) Acute hepatotoxicosis (e.g., Amanita ingestion) * Cirrhosis
5) Hepatic lipidosis
6) Disseminated intravascular coagulation (late phase)
7) Acquired anticoagulants (e.g., antiphospholipid antibodies, acquired factor VIII inhibition)
8) Neoplasia
46
what is the most common coagulation disorder seen in IMHA?
Both venous and arterial thromboemboli have been reported in dogs with IMHA, although pulmonary thromboembolism appears to be most common
47
What is the most common cause of death in IMHA and what is the mortality rate?
80% - thromboembolism of major organs is the most common cause
48
what are the suspected mechanisms of hypercoagulability in IMHA?
IMHA causes a systemic inflammatory effect
which provides a bed fro procoagulant stimuli. Other causes include; increased platelet reactivity, increased tissue factor expression on monocytes and endothelial cells, exposure of red blood cell membrane phosphatidylserine, circulating procoagulant microparticles, and diminished endogenous anticoagulant activity
49
What is the ATE incidence in cats? and what is the survival rate?
33% occurance, 35% survival
50
what are the factors that are thought to promote ATE formation in HCM?
LA enlargement -> stasis
Endothelial injury and platelet hyperactivity are thought to be involved
51
What are causes of thrombus formation in cardiac disease?
1) HCM and LA enlargement
2) Heartworm infection
3) Endocarditis
4) myocarditis
52
How is heartworm thought to promote clot formation?
1) blood stasis (around the worms)
2) endothelial injury
3) heartworms have shown to increase platelet activity
53
What is thought to be the primary mechanism of thrombosis in PLN?
PRimary; Glomerular diseases leads to decreased filtration ability of the bowmans capsule. Albumin and ANTI-THROMBIN are lost in the urine.
Seconday; increased platelet reactivity, hyperfibrinogenemia and decreased fibrinolysis
54
What kind of thromboembolism is the most common in PLN and what is the incidence rate?
Arterial thromboemlism is the most common. Incidence is 14-27%
55
what is a marker of increased risk of thromboembolism formation in PLN?
Hypoalbuminemia may be a marker, although even dogs with normal albumin leves are hyperoagulable.
56
In protein loosing enteropathy, what mechanism is thought to be behind the formation of thrombi?
There are marginally low antithrombin levels in some studies, however, inflammation is thought to be a predisposer to clot formation
57
Are clots common in PLE?
No
58
why are neoplastic diseases thought to lead to hypercoagulable states?
hypothesized to be secondary to multiple factors, such as increased soluble or cellular expression of tissue factor, platelet hyperactivity, inflammation, and tumor disruption of vascular endothelium. Other risk factors for hemostatic abnormalities in cancer patients are cytotoxic drug therapy and development of disseminated intravascular coagulation (DIC).
59
How common is hypocoagulability in dogs with neoplasia?
TEG documented in 17% of dogs with neoplasia in one study
60
What is the most common form of hypocoagulability in neoplasia?
chemotherapy mediated bone marrow suppression
61
How common is DIC in cancer patients ? what cancers are most commonly associated with DIC?
9.6% and thought to be most common in hemangiosarcoma, mammary carcinoma, and lung adenocarcinoma.
62
What endocrinopathies are thought to be most associated with thrombosis?
Hyperadrenocorticism, hypothyroidism, and diabetes mellitus
63
what is the mechanism of hypercoagulabilty in endocrinopathies?
It is unknown.
64
what are the most common pro-inflammatory conditions which lead to thrombdosis ?
acute pancreatitis, sepsis, trauma, and immune- mediated disease
65
How does inflammation result in thrombosis?
Proinflammatory cytokines stimulate the production of platelets, and platelet reactivity is enhanced in inflammatory states. Proinflammatory cytokines stimulate the production of platelets, and platelet reactivity is enhanced in inflammatory states. Anticoagulant activity is diminished in inflammatory states, as is fibrinolysis.
66
what are antiplatelet agents ?
clopidogrel and aspirin
67
what are examples of anticoagulats ?
warfarin, heparin and and the Xa inhibitors
68
what are potential side effects of thrombolytic therapy?
Hemorrhage, reperfusion injury, and embolism
69
what are the mechanisms by which a patient can develop hypovitaminosis-K?
1) rodenticide with vit-K antagonist
2) decreased vitamin K synthesis from the intestinal microflora
3) decreased vitamin K absorption
70
what is the role of vitamin K in the coagulation cascade?
important cofactor in production and activation of the vitamin K–dependent coagulation factors II, VII, IX, and X, and the endogenous anticoagulant proteins C and S. Vitamin K in the reduced form is essential for carboxylation of the glutamic acid residues of these coagulation factors
71
Draw the vitamin K depend epoxidase cycle illustriating the carboxylation of clotting factors and the site of wafarin inhibition.
72
how does rodenticide affect the coagulation cascade ?
Anticoagulant rodenticides antagonize vitamin K epoxide reductase, causing rapid depletion of the vitamin K–dependent coagulation factors. Factors II, VII, IX, and XI have relatively short half-lives (42, 6.2, 13.9, and 16.5 hours, respectively), and decreased factor levels can be detected shortly after anticoagulant rodenticide ingestion.
(Reduced vitamin K is cofactor for converstion clotting factor precursors into carboxylated clotting factors)
73
How long does it take for rodenticide to reach peak plasma concentration and how long does it take for PT will prolongation to occur?
when does PT normalisaition start to occur by?
peak concentration in a few hours, vitamin K dependent porotein sysntheiss starts to drop in 12h, and PT starts to prolong in 36-72h. PT normalises 14-36 hours after starting vitamin K1 therapy at sufficient levels.
74
what are second generation anticoagulants and hwat is the half life?
What is the recomended treatment timeframe?
bromadiolone, brodifacoum, and diphacinone. Half life is 5-6 days; therefore, oral vitamin K1 treatment is recommended for 2-4 weeks
75
when should PT be rechecked post stopping Vit K therapy ?
36-48 hours after discontinuing vitamin K1 therapy to ensure normal coagulation status and sufficient treatment duration.
76
Why does liver disease result in changes to the coagulation cascade?
liver is responsible for synthesizing most pro- and anticoagulant factor. Most patients with liver disease have a parallel decline in pro- and anticoagulant proteins, resulting in a relatively balanced hemostatic system in vivo in initial disease stages.
77
in people with liver disease, what are common reported causes of hypocoagulability? ?
thrombocytopenia, thrombocytopathia, and vessel wall interaction, decreased levels of coagulation factors II, V, VII, IX, X, XI, dysfibrinogenemia, and decreased alpha2-antiplasmin
78
in people with liver disease, what are common reported causes of thrombosis?
elevated levels of factor VIII and von Willebrand factor and decreased levels of proteins C and S, antithrombin, and plasminogen
79
define DIC?
systemic activation of coagulation, leading to intravascular fibrin deposition, thrombosis, and organ dysfunction. DIC is a consumptive coagulopathy that can result from many systemic diseases including widespread inflammation, sepsis, and neoplasia
80
what is the primary mediator of DIC?
Explain how this causes variable hypercoagulable and hypocoagulable states?
Tissue factor. Normally, tissue factor is not exposed to the circulating blood. However, in states of inflammation and other diseases, pro-inflammatory cytokines and endotoxins induce tissue factor expression and release. High concentrations of tissue factor can be found on circulating monocytes, endothelial cells, neoplastic cells, microparticles, and other sources. Once in circulation, tissue factor forms a complex with activated factor VII, a potent stimulus for thrombin formation. Excess circulating thrombin cleaves fibrinogen, leaving behind multiple fibrin clots that can lead to microvascular and macrovascular thrombosis. Coagulation inhibitors are consumed in the process, further promoting coagulation. As clots form, platelets become entrapped and thrombocytopenia is identified. Simultaneously, excess circulating thrombin results in the conversion of plasminogen to plasmin, leading to fibrinolysis. Fibrinolysis results in excess amounts of fibrinogen degradation products (FDPs), which have anticoagulant properties, possibly contributing to hemorrhage.
81
How does DIC result in shock, hypotension and increased vascular permeability?
Excess plasmin also activates the complement and kinin systems, leading to clinical signs such as shock, hypotension, and increased vascular permeability
82
what are the stages of DIC and how do these relate to coagulation ?
initial (nonovert, or compensated) stages of DIC, patients are in a hypercoagulable phase. However, procoagulant factors progressively become consumed, leading to a hypocoagulable (overt, or uncompensated) phase. Prolonged coagulation times accompanied by clinical signs of bleeding may be apparent in the hypocoagulable phase. Patients in acute, fulminant DIC present with bleeding; however, in more chronic forms, patients might show signs only related to the underlying disorder.
83
What are the subdivisions of the immune system;
1) innate - rapid intial response
2) adaptive - delayed but prolonged immunity
- Antibodies (antibacterial)
- Cell-mediated immunity (antiviral)
84
How does the immune system recognise invading pathogens?
- PAMPS: pathogen associated molecular patterns -> ie surface molecules or nucleic acid of an invading pathogen is recognised by the immune sustem.
- DAMPS; damage associated molecular patterns (or Alarmins); molecules released from damaged tissues and broken cells.
85
How do PAMPS and DAMPS trigger an immune response?
PAMS and/or DAMPS bind to pattern recognition receptors (PRR) on surface or within sentinel cells (most important PRR are Toll like receptors). The most important sentinel cells are macrophages, dendritic cells and mast cells.
86
what is the most important family of pattern recognition receptors ?
Toll like receptors (TLR)
87
List the location of binding, the ligans and surface of ligand for TLR 1 through 13
all are found on the cell surface except TLLR3 and 7->10
They can all bind bacteria except 3, 10 and 11. They all bind viruses except 1, 5, 10, 11
88
what happens when sentinel cell PRR's are bound (like TOll) ?
Inflammatory process is initiated. Cytokines are released which turn on the inflammatory process recruiting more cells to the site, increasing blood flow, vessel permeability and allowing antimicrobial cells to flood affected tissues
89
What are the 3 major pro-inflammatory cytokines produced by sentinel cells ?
1) TNF-a
2) Interlukin-1 (IL1)
3) Interlukin-6 (IL6)
90
Tissue redness, swelling, pain and heat is most commonly caused by which pro-inflammatory cytokine?
TNF-a
91
what are chemokines?
Pro-inflammatory molecules which coordinate cell migration
92
list the biological ativities of TNF-a
93
List the biological activities of IL-1
94
List the mediator, major source and function of the main vasoactive moelcules produced during acute inflammation
95
Give an example of a vasoactive amine?
Histamine
96
Give an example of a vasocative peptide?
bradykininn
97
what are the 3 vasoactive substancs produced by COX-1 and COX-2?
Prostaglandin, thromboxanes, prostacyclins
98
What are leukotrines produced by ?
lipoxygenases
99
Once PRR's are bountd, and we have acute inflammation, which is the first cell population recruited to a site?
Neutrophils
100
How are neutrophils atracted towards an invading pathogene?
Cytokines activate vascular endothelial cells so that neutrophils in the bloodstream will stop, attach, and then migrate toward sites of microbial invasion and tissue damage.
101
What is the role of cytokines?
To phagocytose invading pathogens.
102
What is opsonization?
What are the most effective opsonins?
Microorganisms must usually be opsonized before they can be efficiently ingested and killed. The most effective opsonins are antibodies (CD32) and complement (CD35)
103
what is the respiratory burst and what causes it?
Ingested microorganisms are killed by potent oxidants through a process called the respiratory burst, by antibacterial proteins called defensins and by lytic enzymes.
104
How long lived are neutrophils and how common are they?
Neutrophils are short-lived cells that cannot undertake prolonged or multiple phagocytosis.
Neutrophils make up 60-75% of WBC’s in carnivores
105
what regulates the production and loss of neutrophils?
The production of neutrophils is regulated by a cytokine called granulocyte colony-stimulating factor (G-CSF) and their loss by their rate of apoptosis.
106
what is the role of macrophages
1) Macrophages clear dead neutrophils and produce IL-23, which stimulates IL-17 production from Th17 cells -> IL-17 stimulates G-CSF (granulocyte colony stimulating factorr) production which increases neutrophil synthesis
2) macrophages are activated by PAMPS and DAMPS and phagocytose invading pathogens not taken care of by neutrophils (esp intracellular ones)
3) Macrophages produce IL-12 which activates NK cells
4) Macrophages also eat dead and dying neutrophils and thus prevent damage caused by escaping neutrophil enzymes.
107
What are P-selectin and Integrin?
- P-selectin cause neutrophils to stop and roll on endothelial cells
- Integrin signals neutrophils to completely stop on endothelial cells
108
what molecules induce the neutrophils to bind to endothelial cells?
- P-selectin cause neutrophils to stop and roll on endothelial cells
- Integrin signals neutrophils to completely stop on endothelial cells
109
what is a key chemotractant for neutrophils?
C5a
110
what are key differences in what macrophages and neutrophils target?
* Neutrophils focus on destroying extracellular bacteria
* Macrophages predominately fight off intracellular pathogens
111
when do macrophages migrate to the site of infection and what do they do there?
Macrophages migrate to sites of inflammation after neutrophils. They eat and kill any surviving microbial invaders.
Macrophages also eat dead and dying neutrophils and thus prevent damage caused by escaping neutrophil enzymes.
112
What molecular pathways attract macrophages to a tissue?
Neutrophils produce monocyte chemoattractant protein-1 under influence of IL-6 which attracts macrophages.
Macrophages and neutrophils interact via CD31 - healthy neutrophils send signal to be released
Macrophages are activated by PAMP’s and DAMP’s
113
What are the positive feedback systems that allow Macrophages and NK cells to activate one another?
Macrophages produce IL-12 which activates NK cells. NK cells in turn produce INF-𝛄 which activates macrophages further
114
M1 macrophages produce which powerful oxidising agent?
nitric oxide
115
List the classical and alternative macrophage activation pathways
116
What is the difference between M1 and M2 macropahges?
M1 are activated by INF-𝛄 through the classical activation pathway
M2 are when resting macrophages are activated by IL-4, IL13 and IL-10
117
what are key functional differences between M1 and M2 macrophages?
The M1 (classical) cells show increased;
- size, phagocytosis, MHC III expression, antibacterial activity, lysosomal enzyme production and NO production
The M2 (alternative); by increased tissue repair, increased MHC class II expression and reduced mucrobial killing
118
Which cells are repsonsibe for a grunaloma fromation and what are they activated by.
M2 cells.
IL-4, IL-10, IL-13 are important for inducing M2 activation
M2 cells are responsible for “walling-off” chronic infection/inflammation (Granuloma formation)
119
What are the main cytokines produced by the body that are responsibel for animals feeling sick?
IL-1, IL-6, TNF-a and HMGB1
120
what receptors are bound by the following on macrophages
- PAMPs
- Transferrim
-IL-2
PAMP-> TLR2 and TLR4
Transferin -> CD71
Interlukin 2 -> CD25
121
List the main receptors and their binding agent on macrophages;
122
What are the most important iron-binding molecules in the immune system?
Transferrin, lactoferrin, hepcidin, siderocalin, haptoglobin, and ferritin
123
What do iron binding molecules bind and why?
iron, as Salmonella and Mycobacteria need iron for growth
124
what are the roles of Hepcidin and ferroportin and why do they do what they do?
They prevent iron release from cells. Salmonella and mycobacterium need high iron levels for growth
125
What is the complement?
roup of proteins in the blood that work together to protect the body from infection. It's part of the innate immune system but also plays a role in the addaptive immune systme
126
Where is the complement found and how is activated?
Complement proteins are found in normal serum.
The complement system may be activated through three different pathways: two innate pathways , the alternative pathway (via PAMPS) and the lectin pathway, and one adaptive pathway, the classical pathway (via antibodies bount to antigens) .
127
How are the complement innate pathways activated ?
Via PAMPS.
128
what is a key opsonizing agent in the complement pathway?
C3b
129
What is the terminal complement complex?
Complement components, especially C3b, bind covalently to invading microbes and opsonize them.
* Complement components may form a terminal complement complex and punch holes in microbes.
130
How does the complement trigger inflammation ?
The complement system triggers inflammation through the release of the potent chemoattractant C5a.
131
How does the alternative pathway of the complement activate, and how do normal cells protect themselves from the complement?
Alternative pathway relies on binding to C3 on cell surface – on normal cells factor H and factor I cause degradation of C3 – on abnormal cells Factor H and I cannot bind and complement is activated
132
How is the lectin pathway of the innate complement pathway target abnormal cells
Lectin pathway relies on soluble lectin molecules that are pattern recognition molecules to bind to abnormal cells
133
what triggers the classical component pathway?
Classical pathway starts when C1 binds groups of antibodies that have attached to a cell
134
what is the amplification pathway of the complement system ?
Amplification pathway leads to formation of terminal complement complex -> punches holes into the cell causing osmotic lysis
135
How important is the terminal attach complex in the oeveral immune system?
TCC effects likely less important than inflammatory effects of complement cascade
136
Draw the lectin pathway of the complement system?
137
Draw the antibody + antigen pathway of C5a activation
138
Describe the roles of the following chemotactants ?
C1, C2a, C3a, C3b, C5a, C5ab67
139
describe the amplification pathway of the complement system?
140
what cells are responsible for triggering the addaptive immune response?
TCC effects likely less important than inflammatory effects of complement cascade . Dendritic cells are the most efficient of these antigen-processing cells. Only dendritic cells can effectively stimulate naïve T cells.
141
What are the key innate immune cells involved in triggering Naive T-cells
Dendritic cells are the only ones that can effectively stimulate naive T cells
142
where are dendridic cells found?
Immature dendritic cells are found throughout the body.
143
what happens to dendritic cells when they come into contact with foreign material?
* Once stimulated by antigens, dendritic cells mature and become highly effective in presenting these processed antigens to T cells. They express high levels of antigen receptors called major histocompatibility complex (MHC) class II molecules on their surface.
* Dendritic cells ingest antigens, break them into small fragments, and then present them on their surface MHC molecules, where they can be recognized by T cells.
144
Are macrophages antigen presenting cells?
Macrophages also act as antigen-presenting cells, but since they also destroy ingested antigens, they are much less efficient than dendritic cells.
145
what is the role of IL-12 in the adaptive immune response?
IL-12 is a key cytokine that determines T-helper (Th) Th1/Th2 polarization. Th1 cells develop when it is present. Th2 cells develop when it is absent.
146
In addition to macrophages and dendritic cells, what is a 3rd antigen presenting cell?
B cells can act as antigen-presenting cells and are especially effective during secondary immune responses
147
What allows antigen presenting cells to present antigens to T Cells and how are they able to communicate the large varierty of structural differences different pathogens may possess?
*Antigen-presenting cells use receptors called MHC molecules to bind and present antigens.
* MHC molecules are encoded by genes located within the major histocompatibility complex.
* The classical MHC molecules are highly polymorphic. That is, they show an enormous variety of inherited structural variations that permit each individual animal to respond to a different set of antigens.
148
What are differences between Class I MHC, Class II MHC and Class III MHC?
* Class I MHC molecules are found on all nucleated cells. Their function is to present endogenous antigens to CD8+ T cells.
* Class II MHC molecules are largely restricted to professional antigen-presenting cells such as dendritic cells, macrophages, and B cells. Their function is to present exogenous antigens to CD4+ T cells.
* The class III region of the MHC contains a mixture of genes, some of which encode complement components.
149
Where are lymphocytes found?
found mainly within lymphoid organs
* Lymphocytes arise from stem cells in the bone marrow.
* Lymphocytes mature within primary lymphoid organs. There are two types of lymphocyte: T cells and B cells.
* T cells mature within the thymus.
* B cells mature within gastrointestinal lymphoid tissues, the bone marrow, or the bursa of Fabricius, depending on species.
150
what happens to lymphocytes which have self antigens ?
If newly developed lymphocytes have receptors for self-antigens that could potentially cause tissue damage, they are killed before they can leave primary lymphoid organs.
151
what are the major secondary lymphoid organs?
Lymph nodes, spleen, bone marrow, and some Peyer’s patches within the intestine.
152
what are primary lymphoid vs secondary lymphoid organs ?
primary - site of development and maturation
Secondary - where mature lymphocytes migrate to and reside until needed
153
What are lymphocytes and how can they be distinguished from one another?
* Lymphocytes are the cells that can recognize and respond to foreign antigens.
* Lymphocytes all look the same but can be differentiated by their characteristic cell surface molecules.
* These cell surface molecules are classified by the CD (cluster of differentiation) system.
154
What receptors do lymphocytes possess ?
*Lymphocytes possess antigen receptors plus the signal transducing molecules required to activate the cell. * They also possess receptors for cytokines, immunoglobulins, and complement.
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what is immunophenotype?
collection of cell surface molecules on a lymphocyte is called its immunophenotype
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what receptors are used by NK cells to detected targets?
NK cells do not have antigen receptors (CD4 or CD8), they have receptors that can bind molecules expressed on healthy normal cells but not on diseased, abnormal cells. NK cells thus recognize and kill target cells that fail to express these surface molecules
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What is the cluster of differentiation ?
cell surface molecules used to differentiate various lymphocytes (eg CD4 and CD8). The collection of cell surface molecules on lymphocytes is called immunophenotype
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What are the roles of CD3, CD4, CD8, CD25, CD118, CD120, CD210, CD58
* CD3 used for signaling – found on all T cells
* CD4 binds to MHC II and is only found on T helper cells
* CD8 binds to MHC I and is found on cytotoxic T cells
* CD25 - the interleukin-2 (IL-2) receptor
* CD118 - an interferon (IFN) receptor
* CD120 - the tumor necrosis factor (TNF) receptor
* CD210 - the IL-10 receptor
* CD58 is the ligand for CD2. CD2 is found only on T cells, whereas CD58 is widely distributed on many cell types. When cytotoxic T cells encounter their target cells, CD2 and CD58 bind them together. It is likely that CD58 facilitates T cell binding to any cell undergoing surveillance
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what is the rile of CD58
When cytotoxic T cells encounter their target cells, CD2 and CD58 bind them together. It is likely that CD58 facilitates T cell binding to any cell undergoing surveillance
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what are the major complement receptors on lymphocytes
CR1, CR2, CR3 and CR4
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What are the roles of the different complement receptors?
* B cells and T cells express CR1 (CD35), which binds C3b and C4b, and CR2 (CD21), which binds C3d and C3bi.
* NK cells express CR3 and CR4
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What are natural killer cells, what do they target and how do they kill cells?
a lymphocyte able to bind to certain tumor cells and virus-infected cells without the stimulation of antigens, and kill them by the insertion of granules containing perforin.
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what are T-helper cells
Helper T cells are a type of immune cell. When they sense an infection, they activate other immune cells to fight it. They may activate cytotoxic T cells or they may activate B cells, which produce antibodies.
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what are the main receptors on T-helper cells and what dot hey interact with?
Helper T cells express antigen receptors (TCRs) consisting of paired peptide chains, either α and β or γ and δ.
* These paired chains form antigen-binding receptors whose ligands are peptides linked to major histocompatibility complex (MHC) molecules on antigen-presenting cells.
* The antigen-binding chains of the TCR connect to a complex signal transducing component called CD3.
* Each TCR is also associated with either CD4 or CD8. CD4 binds to MHC class II molecules on antigen-presenting cells. CD8 binds to MHC class I molecules expressed on all nucleated cells.
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What must occur for a T-cell to respond to an antigen?
T cells must bind to antigenic peptides linked to MHC molecules. They must also receive co stimulation from cytokines and other molecules.
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How do antigen presenting cells comunicate with a T-cell
The multiple signals sent by an antigen-presenting cell are communicated to a T cell through an immunological synapse.
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what are the subpopulations of T-cells?
There are three major subpopulations of helper T cells.
*Th1 cells are stimulated by interleukin-12 (IL-12) and secrete interferon-γ (IFN-γ) in response. They generally promote cell-mediated responses.
* Th2 cells secrete IL-4, IL-13, and IL-10. They generally promote antibody responses.
* Th17 cell development is stimulated by IL-6, TGF-β, and IL-23. They secrete IL-17 and promote neutrophil-mediated inflammation.
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what are the predominant T cells in mammals? which are the prodomint T helper cells in the human GIT and young ruminants/pigs?
α/β Helper T cells are the predominant T cells in most mammals. γ/δ Helper T cells are mainly confined to the intestinal wall in humans but are the predominant circulating T cells in young ruminants and pigs.
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Do TCR respond to free antigen?
TCR do not respond to free antigen – antigen must be bound to MHC
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What induces differentiation, , what regulates T cell response and waht are the responses of of T helper 1 cells?
* Differentiation stimulated by IL-12 and CD80
* Interferon-γ – regulates T cell responses, upregulates antigen processing
* IL-2 – stimulates cell proliferation, activates macrophages and NK cells
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what induces the differentiation of T helper 2 cells, what do they secrete
* Differentiation promoted by ABSCENCE of IL-12
* Secrete IL-4, IL-5, IL-10, IL-13 to stimulate B cell proliferation and antibody production
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what does IL4 promote and inhibit?
IL-4 promotes IgG and IgE production, inhibits interferon-γ and Th17 cell production
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what are Th0 cells?
* Have activity of both Th1 and Th2 cells
* Progenitor cells
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what are Th17 cells?
* Promoted by IL-6, TBG-beta, IL-23, and IL-21
* Secrete IL-17 (pro-inflammatory)
* Th17 cells also help stimulate B cells
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List the anti-inflammatory effects of cortisol
1) stabilise lysosomal membranes
2) decrease capillary permeability
3) decrease migration and phagocytic ability of WBC
4) decreased lymphocyte production (esp T-cell)
5) reduces fever by reducing the release of IL-1
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what is intrnsic vs aquired antimicrobial resistance ?
Intrinsic -> inherent or innate antimicrobial resistance
- Eg cephalosporin resistance in Enterococcus
Aquired -> ability to resist the activity of a particular antimicrobial agent to which bacteria was previously susceptible (gene mutation and gene transfer)
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