Immunology Flashcards
1
Q
Hospital acquired infection definition
A
Infection diagnosed >48 hours after hospital admission, more specifically on or after the third day in hospital without proven prior incubation
2
Q
Independent risk factors for HAI
A
Prolonged length of hospital stay
Indwelling devices
Mechanical ventilation
Trauma
Individual patient factors/comorbidities
3
Q
Two mechanisms by which bacteria are developing antibiotic resistance
A
Extended spectrum beta lactamases (ESBLs)
Plasmid-mediated AmpC enzymes
4
Q
Factors associated with development of MDR E. coli
A
Hospitalization >6 days
Treatment with a cephalosporin prior to admission
Treatment with a cephalosporin <1 day
Treatment with metronidazole while in hospital
5
Q
Factors associated with MDR E.coli and methicillin resistant Staph. aureus (MRSA)
A
Hospitalization > 3 days
6
Q
Neutrophil behavior
A
Neuts move from circulation into the tissues by attaching first loosely then tightly to receptors in activated endothelial cells –> move between endothelial cells and pericytes into the interstitial space –> become activated when their pattern-recognition-receptors (PRRs) bind PAMPs on pathogens and DAMPs on dying cells –> once activated they begin degranulation
7
Q
Three ways neutrophils kill
A
- Degranulate to release destructive peptides and proteases into the extracellular matrix or into an intracytoplasmic phagosome containing ingested bugs
- Assemble a reactive oxygen species generator (NAPDH oxidase complex) on the membrane of a phagosome or on the outer cell membrane which produces an oxidative burst when activated by microorganisms
- They form neutrophil extracellular traps (NETs) - DNA, histones, and other nuclear material combine with destructive peptides and proteases from intracytoplasmic granules and are expelled from the cell into the extracellular space; the NETs ensnare and kill pathogens and contain destructive molecules preventing damage to regional tissues. A process called “NETosis”.
8
Q
Molecule that signals for neutrophil production
A
Cytokine granulocyte colony stimulating factor (G-CSF)
Most important cytokine for maintaining neutrophil homeostasis
9
Q
What makes G-CSF
A
Bone marrow stromal cells
Also secreted by macrophages, monocytes, endothelial cells, fibroblasts
10
Q
What drives “emergency myelopoiesis”?
A
Cytokine stimulation and the binding of PAMPs/DAMPs to PRRs on hematopoietic stem cells
11
Q
What is a main factor for steady-state neutrophil production
A
The constant presence of PRR signaling in hematopoietic stem cells and progenitors stimulated by commensal microflora
12
Q
Cytokines and growth factors that stimulate neutrophil release from the bone marrow
A
G-CSF
Granulocyte macrophage (GM)-CSF
TNF-alpha
TNF-beta
Complement 5a
13
Q
Cytokines vs. Chemokines
A
Used for communication between cells vs. chemokine guide immune cells on where to go
14
Q
Th1 cytokines
A
Type I immune response- drive by Type I T-helper cells- cellular immunity against intracellular pathogens- activation of CD8 T cells/NK cells/macrophages
15
Q
Some of the cytokines involved in Th1/type I immune response
A
IL-2 (T cell survival, proliferation and differentiation)
IL-12 (activates NK cells)
TNF-alpha (can cause cell death)
LT-alpha (lymphotoxin-alpha)
LT-beta
IFN-gamma (antiviral, activates macrophages)
16
Q
Th2
A
Type II immune response
Activates humoral responses (antibodies produced by B cells)
Strong presence of eosinophils, mast cells
17
Q
Th2 cytokines
A
IL-4 (mast cell growth, stimulated eos)
IL-5
IL-13 (signals to make IgE)
IL-25
IL-10 (Ab production)
18
Q
Three main lines of defense of the immune system
A
Physical barriers
Nonspecific (innate immunity)
Specific (adaptive immunity)
19
Q
Where is the marginated pool of neutrophils
A
They roll slowly along the endothelium of smaller vessels and capillaries and tend to stagnate in post capillary venules; in dogs is about half of the total and in cats is 3/4 the total
20
Q
Does the CBC measure the marginated or circulating pool
A
Circulating pool
21
Q
Neutrophils have the (shortest/longest) half life in circulation
A
Shortest
22
Q
Two bone marrow-centric mechanisms for neutropenia
A
Depletion of neutrophil progenitor cells (bone marrow hypoplasia)
Ineffective granulopoiesis (plenty of progenitors, they just aren’t working; maturational arrest, or retention/destruction of mature neutrophils in the bone marrow)
23
Q
Infectious causes of depletion of granulocytic progenitor cells
A
Parvovirus
Ehrlichia canis (more often the cause compared to other rickettsial)
FeLV
FIV
24
Q
FIV can also cause neutropenia because infected bone marrow cells secrete _____
A
Myelosuppression factors that depress granulopoiesis
25
Medications which can cause idiosyncratic neutropenia
Anticonvulsants
Methimazole
Colchicine
26
Main mechanism for neutropenia associated with myelophthisis
Decimation of bone marrow by infiltration of abnormal tissue --> loss of granulocytic progenitor cells
Loss of nurturing marrow microenvironment following destruction of bone marrow stromal cells
27
Cyclic hematopoiesis
"gray Collie syndrome"
Autosomal recessive
Severe neutropenia every 10-14 days
Mutation in the ELANE gene which encodes neutrophil elastase
28
Dysgranulopoiesis
Dysplastic granulocytes in the bone marrow in normal to excessive amounts, however peripheral neutropenia
Myelodysplastic syndrome (MDS)
Secondary dysmyelopoiesis
Congenital dymyelopoiesis
29
Myelodysplastic syndrome (MDS)
Mutated granulocytes do not follow normal maturation pathway and undergo apoptosis prior to release in circulation
Increased number of blasts in marrow
Can occur with FeLV
30
Secondary dysmyelopoiesis
Similar to MDS, but no increase in number of blasts in bone marrow
Can occur secondary to IMHA, ITP, lymphoma
Can also be seen following administration of certain drugs- chemo, phenobarbital, estrogen, cephalosporins, chloramphenicol, lithium in cats, colchicine
31
Trapped neutrophil syndrome in Border Collies
Hyperplastic granulopoiesis with no evidence of dysplasia/maturation arrest, but severe circulating neutropenia
32
Immune-mediated neutropenia
Antibodies are produced against neutrophil surface proteins and either activate complement-mediated death or opsonization and phagocytosis
33
Neutrophil count above which prophylactic antibiotics may not be necessary (unless febrile/sick)
0.75
34
How does G-CSF work
Increases differentiation of progenitor cells into neutrophils
Increases release of neutrophils into circulation
Acts on mature neutrophils to increase chemotaxis, enhance the respiratory burst, and improve IgA mediated phagocytosis
35
Initial PLT count is not correlated/predictive of survival; instead, presence of ____ at presentation is associated with poorer prognosis and higher requirement for transfusions
Melena
36
Proposed mechanism of ITP in dogs and cats
Increased phagocytosis by splenic macrophages due to autoantibodies bout to platelet integrin alpha-IIb-beta-3 (fibrinogen receptor) and glycoprotein Ib-IX (vWF receptor)
37
T/F: Thrombocytopenia severity in sepsis is associated with mortality
True
38
Two bacteria that can interact directly with platelets and cause platelet activation and aggregation
E. coli
Streptococcus
39
Canine platelet interactions with pathogens
Interact directly with pathogens by expressing functional TLR-4 which augments platelet activation in the presence of LPS and ADP
Once activated, platelets interact with circulating neutrophils to form NETs
40
Uremia-associated platelet dysfunction
Multifactorial
Due to defects in PLT adhesion, secretion, and aggregation
Diminished vWF binding activity (may look like type II vWF deficiency)
41
Platelet dysfunction/thrombocytopenia and liver disease
Decreased platelet aggregation in response to collagen and arachidonic acid - mechanism unknown
42
Broad drug categories that can affect platelet function
Anti-PLT drugs
NSAIDs
Drugs that increase cyclic nucleotides in PLT (pimo, sildenafil, theophylline/aminophylline)
Nitric oxide donors (nitroprusside, nitroglycerin)
Antithrombotics (heparin, factor Xa inhibitors)
Fibrinolytic drugs
Antimicrobials (beta lactams, cephalosporin)
SSRIs
Synthetic colloids
Vitamin E
43
Half-life of aspirin in dogs and cats
37.5 hours (cats)
8.5 hours (dogs)
44
Platelet inhibition with clopidogrel can last as many as _____ days
14 days
45
Rate-limiting enzyme in conversion of arachidonic acid to eicosanoids
Cyclooxygenase (COX)
46
PLT express mainly COX-1 or COX-2
COX-1
47
Expression of COX-2 by platelets is higher than normal during ______
Thrombopoiesis
48
Type I vWD
Deficiency of all vWF multimers
Dobermans
49
Type II vWD
Qualitative abnormalities in vWF
Four subtypes: 2A, 2B, 2M, 2N
Type 2A vWD (GSP's) more severe bleeding diatheses
50
Type III vWD
Most severe form
Cats, some dog breeds (Chessies, Shelties, Scotties, Koikers)
Complete absence of vWF - spontaneous mucosal bleeding and life threatening bleeding after procedures/trauma
51
Glanzmann thrombasthenia
Mutation of ITGA2B gene which encodes the alpha-II-b subunit of the integrin alpha-II-b-beta-3
Without the receptor, fibrinogen binding and outside-in signaling do not happen --> severe hemorrhage following minor procedures
Otterhounds, Great Pyrenees
52
Bernard-Soulier syndrome
Glycoprotein Ib-IX-V complex abnormality
Macrothrombocytopenia and decreased PLT survival
Self-limiting mucocutaneous hemorrhage
Cocker Spaniels
53
Defective PLT agonist receptor
P2RY12 gene
Greater Swiss Mountain Dog
54
Chediak-Higashi
Autosomal recessive
Persian cats
Intrinsic platelet storage pool defect in the platelet dense granules, causing impaired PLT aggregation in response to collagen
Bleeding diatheses despite normal PLT concentration
Cats with oculocutaneous albinism
55
Alterations in PLT signal transduction pathways
Variants in CalDAG-GEF1 gene
Basset Hounds
Spits
Landseer
56
Canine Scott syndrome
German Shepherds
TMEM16F gene
Inability of phosphatidylserine to be externalized for creation of procoagulant membrane surface and facilitate thrombin generation
57
Definitive diagnosis of type I and II vWD
vWF antigen levels
58
Discontinuation of anti-platelet drugs prior to surgery - recommendations
D/c one (ideally clopidogrel) if on two, 5-7 days prior to procedure, in patients considered high risk for elective procedure
D/c anti platelet drugs 5-7 days prior if low risk bleeding
59
Tx for vWF deficiency
FFP: type I, II, or III
DDAVP: type I or II
Cryo: type I, II, or III
60
RBC changes associated with oxidative injury
Heinz bodies
Eccentrocytes
Pyknocytes
61
Pennies minted after ____ contain copper-plated ______
1982
Copper plated zinc
62
Osmotic fragility
Abysinninan and Somali cats
ESS
63
Phosphofructokinase deficiency
ESS
Cocker spaniels
64
Pyruvate kinase deficiency
Basenji
Dachshund
Mini poodle
Chihuahua
Pug
Westies
Labs
Somali cats
Abyssinian cats
65
Hemotropic mycoplasma in cats
Presumably transmitted via fleas
Cyclical, variable hemolysis
Can be Coombs positive
66
Babesia
Tick borne or blood borne
B. gibsoni ("small" babesia)
Pittbulls
Atovaquone azithromycin
B. canis (AKA vogeli) "large" babesia
Greyhounds
Imidocarb
67
Cytauxzooan
Tick
Hemolytic anemia
Fever
Organ failure from occlusion with schizont-laden monocytes
Atovaquone and azithromycin
68
Most common form of IMHA
Immunoglobulin mediated type II hypersensitivity reaction leading to extravascular hemolysis
69
Saline agglutination test
49 drops saline to 1 drop blood
70
Coombs test
Helpful when spherocytosis minimal and auto agglutination absent
Used to detect the presence of antibodies against circulating red blood cells (RBCs) in the body
71
Cat breeds in the US that are more likely to be type B blood
British Shorthair
Devon Rex
Abyssinian
Russian Blue
Somali
72
Classification of anaphylactic reactions
Immune-mediated (bites/stings, food, transfusion reactions)
Non-immune-mediated (heat/exercise)
73
Type I hypersensitivity
IgE
Mast cells
Soluble antigen
"anaphylactic"
Anaphylaxis, urticaria, hives, atopy, food allergy (peanuts in people)
74
Type II hypersensitivity
IgG
Cell or matrix-associated antigen
Phagocytes, NK cells
"cytotoxic"
IMHA, transfusion reactions
75
Type III hypersensitivity
IgG
"immune complex"
Soluble antigen
Phagocytes, complement
Serum sickness
Glomerulonephritis
Blue eye
76
Type IV hypersensitivity
T-cell mediated
Soluble, cell-associated antigen
Macrophages, eosinophils, cytotoxic T-cells
Contact dermatitis, flea and food allergy
77
Cell receptor on mast cells and basophils that the IgE antibodies bind to in type I hypersensitivity
Fc-episilon-R1
78
Non-immune-mediated anaphylaxis mechanisms
Does not require sensitization
Direct mechanical stimulation leading to mast cell degranulation
79
Mast cell degranulation products
Histamine
Tryptase
Heparin
Cytokines
80
Prostaglandins and anaphylaxis
Bronchoconstriction
Constriction of coronary and bronchial smooth muscle
81
Leukotrienes and anaphylaxis
Slower acting
Delayed response
82
Coagulation system and anaphylaxis
Release of platelet activating factor --> bronchoconstriction, increased vascular permeability, vasodilation, and platelet aggregation
Heparin from mast cells
83
Tryptase
Activates complement
84
Histamine receptors
H1: activates smooth muscle contraction and endothelial changes resulting in vasodilation and increased vascular permeability
H2: modulate gastric acid secretion and regulation of cardiac myocytes
H3: peripheral neurotransmitter release
H4: central neurotransmitter release
85
Cat lungs and anaphylaxis
Cat lungs have higher proportion of mast cells
86
Dog liver and anaphylaxis
Histamine alters blood flow
Concurrent arterial vasodilation and venous dilation
--> significant portal hypertension, transudation of fluid, and decreased venous return to the heart
87
Mechanism of shock in dogs with anaphylaxis
Mostly vasodilatory
Can also hypovolemic and cardiogenic
88
Epinephrine
a-1 receptor activity --> vasoconstriction (improved BP and coronary flow, improved upper airway obstruction and mucosal edema)
B-1 receptor activity --> inotropy, chronotropy, improved cardiac output
B-2 receptor activity --> bronchodilation and stabilization of mast cells (decreasing further degranulation)
89
Monocytes not only indicate inflammation, they also indicate ___ or ____
Tissue necrosis or an increased demand for phagocytes
90
A persistent eosinophilia and lymphocytosis occurs in __-__% of Addisonian patients
10-15%
91
Blood smear findings with liver disease
Non-regenerative anemia with acanthocytes
Target cells
92
Cellularity of normal CSF
<3 WBC/micro liter
NO neutrophils, plasma cells, macrophages
93
Mild to moderate predominantly mononuclear pleocytosis
Inflammatory diseases- often viral or rickettsial
Can also be seen with inflammatory brain disease, and IVDD
94
Moderate to marked predominantly neutrophilic pleocytosis
Infectious/inflammatory diseases such as bacterial ME, SRMA, FIP
95
Moderate to marked predominantly mononuclear pleocytosis
GME, breed-related necrotizing encephalitis (Pugs, Yorkers, Maltese, Chihuahuas)
Lymphoma
96
Marked pleocytosis with a predominance of eosinophils
Idiopathic eosinophilic meningitis
Parasitic migrations, protozoans, fungal disease
97
Mild to marked mixed pleocytosis
Fungal or protozoal ME
Infectious/inflammatory disease that is "aging" or being treated with medications that can alter cellular populations.
Necrosis due to infarction
98
Albuminocytological dissociation
When the total cell count is normal, but the protein level is high
Non specific
Degenerative or demyelinating diseases
Chronic IVDD/stenosis/neoplasia causing compression
Neoplasia
99
Normal stress leukogram findings
Neutrophilia
Monocytosis
Lymphopenia
Eosinopenia
100
Mechanism for neutrophila in stress leukogram
Shift from the marginating pool to circulating pool. A small amount may also be due to increased neutrophil release from BM and delayed apoptosis.
Since cats have a higher marginating pool, their neutrophilia can be more than 1:1 higher than the upper reference limit.
101
Mechanism for Lymphopenia in stress leukogram
Decreased efflux from lymph nodes, decreased proliferation/active cytokines (such as IL-2) for lymphocyte and lymphotoxic effects (induction of apoptosis, usually this is chronic or with higher steroid doses)
102
Eosinopenia, monocytosis mechanisms for stress leukogram
Monocytosis- unknown; maybe shift from marginating to circulating?
Eosinopenia- suspected to be decreased release from bone marrow
103
Changes seen with physiologic leukocytosis (i.e. stress RESPONSE)
Most commonly seen in cats, and younger animals
Neutrophilia
Lymphocytosis
Eosinophilia, basophilia in cats
104
Mechanisms for neutrophilia in physiologic leukocytosis
Shift from marginating to circulating
105
Mechanism of lymphocytosis with physiologic leukocytosis
Release from the spleen
106
Classic changes seen with inflammatory leukogram
Neutrophilia
Left shift
Toxic change
Monocytosis
Concurrent Lymphopenia (+/- eosinopenia)
107
Thrombocytosis can be seen with inflammatory leukogram due to
Inflammatory cytokines such as IL-1 and IL-6
108
Explain protein abnormalities that be seen in inflammatory states
Changes in albumin and globulins: This is usually comprised of low albumin or high globulin concentrations or a combination of both.
The low albumin concentration is due to a negative acute phase response (downregulation of production in hepatocytes) and the high globulin concentrations will be due to a positive acute phase response (increased production of α2 globulins by hepatocytes) or antigenic stimulation (polyclonal increase in immunoglobulins) or a combination of both.
109
Hematocrit is calculated- what is the formula
HCT (%) = (MCV x RBC) /10
110
Why is measurement of aggregate reticulocytes more reflective of regeneration in cats?
Aggregate retics last 12-24 hours vs. punctate last 7-21 days.
Punctate reticulocytes do not reflect the most recent bone marrow response (e.g. an anemic cat with only punctate reticulocytes is not actively regenerating at this time, but has shown some bone marrow regeneration in the past 7-21 days).
111
Mechanism of anemia secondary to inflammatory disease
Cytokine suppression of erythropoiesis (decreased EPO release and response)
Hepcidin-mediated sequestration of iron
Decreased RBC lifespan (some component of hemolysis)
112
NRIMA/PIMA bone marrow findings compared to PRCA bone marrow findings
PCRA- no or few erythroid precursors
PIMA- erythroid hyperplasia
113
Fragmentation morphologies
Keratocytes, schistocytes, acanthocytes
114
Proposed mechanisms for iron deficiency anemia (microcytic, hypo chromic; can be regenerative or non-regenerative)
1) Because immature RBC in the bone marrow stop dividing once a critical concentration of hemoglobin is reached within a RBC, deficient hemoglobin production will result in increased cell division. With each division, RBC become smaller, thus an iron deficiency anemia is characterized by microcytic and hypochromic RBC indices.
2) Iron deficiency affects enzyme activity which will alter receptor expression on erythrocytes which govern release. If iron deficient, the erythrocytes are no longer released and when they are retained in the marrow, they continue to divide. Later-stage RBC precursors do express Lutheran adhesion molecules, but there is no evidence to date that iron deficiency decreases their expression.
3) Possibly iron deficiency affects macrophages in marrow causing delayed extrusion of the nucleus of erythroid progenitors so they cannot be released from marrow (a protein in erythroblasts called erythroblast macrophage protein is required for extrusion and their interaction with macrophages).
115
Cytokines that play a role in anemia of inflammation (anemia of chronic disease)- normocytic, normchromic
TNFα, IFNγ, IL-1β, and IL-6
116
Anemia seen with chronic kidney disease mechanisms
Decreased EPO production
Increased hepcidin (--> iron sequestration)
Suppression of erythropoiesis (cytokines, uremia)
Decreased RBC lifespan (uremia)
Hemorrhage (uremia)
Malnutrition
117
Pernicious anemia
Pernicious anemia is a relatively rare autoimmune disorder that causes diminishment in dietary vitamin B12 absorption, resulting in B12 deficiency and subsequent megaloblastic anemia. The anemia is megaloblastic and is caused by vitamin B12 deficiency secondary to intrinsic factor (IF) deficiency.
118
Vitamin B12 functions
Within all eukaryotic cells, cobalamin acts as an essential cofactor for the intracellular enzymes methionine synthase and methylmalonyl-CoA mutase
119
Pro-inflammatory cytokines
Released from Th-1 cells, CD4+ cells, macrophages, and dendritic cells
IL-1
IL-6
TNF-α
IL-2
IL-8
IL-12
IL-17
IL-18
IFN-γ
120
Erythropoietin
Source: endothelium
Receptor: EpoR
Target cells: stem cells
Major function: RBC production
121
G-CSF
Source: endothelium, fibroblasts
Receptor: CD114
Target cells: stem cells in bone marrow
Major function: granulocyte production
Classification: pro-inflammatory
122
GM-CSF
Source: T cells, macrophages, fibroblasts
Receptor: CD116
Target cells: stem cells
Major function: growth/differentiation of monocytes, and eosinophil/granulocyte production
Classification: adaptive immunity
123
IL-1
Source: macrophages, B cells
Receptor: CD121a
Target cells: B cells, NK cells, T-cells
Major function: pyrogenic, pro inflammatory, bone marrow cell proliferation
Classification: pro-inflammatory
124
IL-2
Source: Th1 cells
Receptor: CD25
Target cells: Activated T and B cells, NK cells
Major function: proliferation of B cells, activated T cells; NK cell function
Classification: adaptive immunity
125
IL-3
Source: T cells
Receptor: CD123, CDw131
Target cells: stem cells
Major function: Hematopoietic precursor proliferation and differentiation
Classification: adaptive immunity
126
IL-4
Source: Th cells
Receptor: CD124
Target cells: B- and T-cells, macrophages
Major function: enhances MHC II expression, stimulates IgG and IgE production
Classification: adaptive immunity
127
IL-5
Source: Th2 cells and mast cells
Receptor: CDW125, 131
Target cells: Eosinophils, B cells
Major function: B cell proliferation and maturation, stimulates IgA and IgM production
Classification: adaptive immunity
128
IL-6
Source: Th cells, macrophages, fibroblasts
Receptor: CD126, 130
Target cells: B cells, plasma cells
Major function: B-cell differentiation
Classification: pro-inflammatory
129
IL-7
Source: BM stromal cells, epithelial cells
Receptor: CD127
Target cells: stem cells
Major function: B and T cell growth factor
Classification: adaptive immunity
130
IL-8
Source: macrophages
Receptor: IL-8R
Target cells: Neutrophils
Major function: chemotaxis for neutrophils and T cells
Classification: pro-inflammatory
131
IL-9
Source: T cells
Receptor: IL-9R, CD132
Target cells: T cell
Major function: growth and proliferation
Classification: adaptive immunity
132
IL-10
Source: T cells, B cells, macrophages
Receptor: CDw210
Target cells: B cells, macrophages
Major function: Inhibits cytokine production and mononuclear cell function
Classification: ANTI-inflammatory
133
IL-11
Source: BM stromal cells
Receptor: IL-11Ra, CD130
Target cells: B cells
Major function: Induces acute phase proteins
Classification: pro-inflammatory
134
IL-12
Source: T cells, macrophages, monocytes
Receptor: CD212
Target cells: NK cells, macrophages, tumor cells
Major function: Activates NK cells, phagocyte activation, endotoxic shock, cachexia, tumor toxicity
Classification: anti-inflammatory
135
IFN-alpha
Source: macrophages, neutrophils
Receptor: CD118
Target cells: various
Major function: anti-viral
Classification: pro-inflammatory
136
IFN-beta
Source: fibroblasts
Receptor: CD118
Target cells: various
Major function: anti-viral, anti proliferative
Classification: pro inflammatory
137
IFN-gamma
Source: T cells and NK cells
Receptor: CDw119
Target cells: various
Major function: MHC-I and -II expression on cells, antiviral, macrophage and neutrophil function
Classification: pro-inflammatory
138
TNF-alpha
Source: macrophages
Receptor: CD120a,b
Target cells: macrophages
Major function: phagocyte activation, toxic shock
Classification: pro inflammatory
139
TNF-beta
Source: T cells
Receptor: CD120a,b
Target cells: Phagocytes, tumor cells
Major function: chemotactic, phagocytosis, oncostatic, induces other cytokines
Classification: pro-inflammatory
140
TGF-β
Source: T and B cells
Receptor: TGF-βR1, 2, 3
Target cells: activated T and B cells
Major function: inhibits hematopoiesis, promotes wound healing, inhibits T and B cell proliferation
Classification: anti-inflammatory
141
Anti-inflammatory cytokines
TGF-β
IL-10
IL-12
IL-22
IL-38 (IL-1F10)
IL-37 (1L-1F7)
142
Bacterial lipopolysaccharides
LPS
PAMP found on cell membrane of gram-negative bacteria
Recognized by TLR 4
143
Peptidoglycan
Another PAMP found on gram negative bacteria
Recognized by TLR2 (heterodimer of TLR1 or TLR6)
144
Lipoteichoic acid (LTA)
Gram positive bacteria
Recognized by TLR2, and TLR1 or TLR6
145
Bacterial lipoproteins (sBLP) from gram positive bacteria
Recognized by TLR2, and TLR1 or TLR6
146
Phenol soluble factor from Staph. epidermidis
Recognized by TLR2, and TLR1 or TLR6
147
Zymosan, a component within yeast walls
Recognized by TLR2, and TLR1 or TLR6
148
DAMP- HMGB1
Cell nucleus
Receptor is TLR2, TLR4, RAGE
149
DAMP- HMGN1
Cell nucleus
Receptor is TLR4
150
DAMP- Defensins
Come from granules
Receptor is TLR4
151
DAMP- Syndecans
Come from plasma membrane
Receptor is TLR4
152
DAMP- Cathelicedin
Comes from granules
Receptor is P2X7, FPR2
153
DAMP- heat shock proteins
Comes from cytosol
Receptors are TLR4, TLR2, CD91
154
Alpha vs. beta defensins
a-defensins - produced constitutively
majority of b-defensins are inducible
a-defensins operate mainly from within phagosomes, whereas b-defensins are produced primarily by epithelial cells.
155
Nuclear factor kappa beta
NF-kB signaling is one of the main down-stream path- ways responsible for HDP production.
NF-kB is a transcription factor involved in the integration of numerous parallel signaling pathways and a variety of cellular responses central to an immediate and functional immune response, including the production of cytokines and cell adhesion molecules
156
LPS
Lipopolysaccharide fromthe Gram-negative bacterial cell wall has been demonstrated to induce inflammation by promoting pro-inflammatory cytokines and release of HMGB1 in innate immune cells
TLR4 is receptor
157
LPS induced endotoxiemia in dogs
In dogs with experimentally induced endotoxemia, lipopolysaccharide (LPS)-treated dogs
had greater IL-6, IL-10, and tumor-necrosis factor-𝛼 (TNF-𝛼) concentrations during the first 24 hours after LPS administration compared
with dogs that received placebo
158
Cell-free DNA
Cell-free DNA is a DAMP that
stimulates the immune system via TLR9
159
Cytokines in dogs with sepsis (JVECC)
IL-6
CXCL8
KC-like
CCL2
All substantially increased compared to healthy controls
160
GDV and HGMB1 levels
In dogs with GDV, high HMGB-1 concentrations were
associated with gastric necrosis and with nonsurvival
161
CCL2
Chemokine (C-C motif) ligand 2 (CCL2) (also called monocyte chemoattractant protein-1) is a member of the C-C chemotactic cytokine family, and a potent chemotactic factor for macrophages
162
Cytokines in sick cats (Frontiers 2020)
Revealed that sick cats (sepsis or septic
shock) had significantly higher plasma concentrations of IL-6, IL-8, KC-like, and RANTES
compared to healthy controls. The combination of MCP-1, Flt-3L, and IL-12 was
predictive of septic shock. None of the cytokines analyzed was predictive of outcome
in this study population.
163
CRP, SIRS in dogs (JVECC 2018)
Conclusions – Serum CRP concentration is increased in dogs with SIRS, and decreases during treatment and hospitalization. Serum CRP, plasma IL-6, and plasma TNF-a =concentrations cannot predict outcome in dogs with SIRS.
164
Use of pRBCs in dogs with IMHA (vs. whole blood)
Dogs with IMHA typically are euvolemic, making pRBC preferable to whole blood because the plasma provides no added benefit, increases the risk of volume overload, and may increase the risk of transfusion reaction.
165
Downsides of bovine hemoglobin solutions
BHS scavenge nitric oxide, potentially activating platelets and causing vasoconstriction, which increases risk
of hypertension.3
BHS exert a greater colloid osmotic (oncotic)
pressure than do RBCs, increasing the risk of intravascular volume expansion and hypertension.
166
Two statistically proven outcome factors on chemistry for dogs with IMHA
Bilirubin
BUN
167
Rationale for anticoagulant drug administration in patients with IMHA
Thrombosis in IMHA predominantly affects the venous system, where thrombi form under low-shear conditions. Such thrombi typically are rich in fibrin, and their formation is less dependent upon platelet number or function, providing a rationale for administration of anticoagulant drugs.
168
Poor prognostic factors in dogs with ITP
The presence of melena or high BUN concentration in the study suggested a poor prognosis for affected dogs.
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Platelet specific antibody
The PSAIgG assay is sensitive and specific for detecting platelet-bound antibodies; however, it does not discriminate between primary and secondary IMT, and positive results are possible in dogs with glomerulonephritis, neoplasia, hepatitis, or pancreatitis
170
Immune dysfunction in critically ill dogs (JVIM 2028)
TLDR: These findings suggest dogs with CI develop immune system alterations that result in reduced respiratory burst function and cytokine production despite upregulation of TLR-4.
Immunologic evaluation: LPS-induced leukocyte production of TNF-a, IL-6, and IL-10 was significantly less in the CI group compared to the healthy dogs
Unstimulated (PBS) leukocyte production of TNF-a was reduced in the CI group compared to the healthy dogs
Compared to phagocytic cells from healthy dogs, phagocytic cells from the CI group had a significant decrease in oxidative burst function stimulated both biologically with E. coli and chemically with PMA
There was a significant increase in the percentage of monocytic cells expressing TLR-4 alone as well as co-expressing HLA-DR and TLR-4 in the CI group
One possible explanation for this observation includes the development of endo- toxin tolerance.
Upon binding of LPS, TLR-4 is activated to recruit the myeloid differentiation primary response protein 88 (MYD88) which subsequently induces the production of a variety of cytokines, including TNF-a, IL-6, and IL- 10, through various DNA transcription factors
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Skin physical barriers
Langerhans cells- macrophage system
Dry
Turn over rapidly
low pH
Calprotectin (metal chelator)
Pattern recognition receptors in keratinocytes = C type lectins, mannose receptors, TLRs
Microbiota
172
Respiratory physical barriers
Mucus
SURFACTANT
Upper- IgE
Lower- IgG
Everywhere- IgA
173
GI tract physical barriers
IgA
Mucus
Enterocytes, goblet cells (mucus), paneth cells
Peyer's patches
174
What in gram positive bacterial wall do PRRs recognize?
Peptidoglycans
175
What in acid-fast bacterial wall do PRRs recognize?
Glycolipids
176
What in yeast organism walls do PRRs recognize?
Mannan or beta-glucan rich cell wall
177
What in viruses do PRRs recognize?
Nucleic acids
dsRNA= TLR-3
ssRNA= TLR-7, TLR-8
dsDNA= TLR-9
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On what cells are TLRs found
Sentinel cells of innate immune system (macrophages, neutrophils, mast cells, dendritic cells)
T and B cells of adaptive immune system
Non-immune cells (epithelial cells that line the respiratory and GI tract)
When they're turned on --> INFLAMMATION
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Location of TLR receptor and its purpose/what it recognizes
Outer surface - bacteria
Inside cell in endoscopes - viruses, bacterial nucleic acids
180
Gram positive bacteria PAMPs
Peptidoglycans
Lipotechoic acid
Lipoprotein
181
Acid fast bacteria PAMPs
Glycolipids
Mycolic acid
Galactic
182
Yeasts PAMPs
Mannan or beta gluten rich cell wall
183
Viruses PAMPS
Nucleic acids
dsRNA - TLR3
ssRNA - TLR7, TLR8
dsDNA - TLR9
184
How does a TLR get activated
PAMP binds TLR
TLR activates MyD88
NF-kappa beta activates genes --> IL1, IL6, TNF alpha --> inflammation
IRF3 activates genes --> type I interferons --> virus inhibition
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TLRs located on outer surface of cells (recognize bacteria)
TLR1/2 (recognize triacetylated lipoproteins)
TLR2/6 (recognize diacetylated lipoproteins)
TLR4 (recognizes LPS)
TLR5 (recognizes flagellin)
Dectin-1 (recognizes B-glucans)
RAGE (recognizes HMGB1)
186
TLRs located in endosomes within cells (recognize viruses, bacterial DNA)
TLR3 (recognizes dsRNA)
TLR7 and TLR8 (recognize ssRNA)
TLR9 (recognizes CpG DNA)
187
TLR1
Located on cell surface
Recognizes triacetylated lipoprotein on BACTERIA
188
TLR2
On cell surface
Recognizes lipoproteins on bacteria, viruses, parasites
189
TLR3
Located inside the cell in endosomes
Recognizes dsRNA of viruses
190
TLR4
Located on cell surface
Recognizes LPS (bacteria, viruses)
191
TLR5
Located on cell surface
Recognizes FLAGELLIN on bacteria
192
TLR6
Located on cell surface
Recognizes diacetylated lipoproteins on bacteria, viruses
193
TLR7
Located inside the cell
Recognizes ssRNA and guanosine on viruses (and some bacteria)
194
TLR8
Located inside the cell
Recognizes ssRNA of viruses and some bacteria
195
TLR9
Located inside cell
Recognizes dsDNA, CpG DNA (viruses, bacteria, protozoa)
196
TLR10
Located inside the cell; regulates TLR2 responses
SUPPRESSES INFLAMMATION
197
TLR11
Located on surface of cell
Recognizes profilin, flagellin on protozoa and bacteria
198
TLR12
Located on cell surface
Recognizes profilin of protozoa
199
What are nod-like receptors (NLRs)
PRRs
Nucleotide binding oligomerization doman receptors
Detect INTRACELLULAR PAMPs
200
What does NOD1 recognize
Bacterial peptidoglycans
201
What does NOD2 recognize
Bacterial muramyl dipeptide
General sensor of intracellular bacteria
202
Downstream action of NLR activation
NF-kB --> pro inflammatory cytokines
NOD2 --> defensins (antimicrobial proteins)
203
What are dectins
PRRs
Cell surface glucans
Bind to fungi
204
Bacterial peptidoglycans are recognized by
TLRs, NODs, CD14
205
Types of sentinel cells
Macrophages, dendritic cells, mast cells
Specifically: Kuppfer cells in the liver, splenic macrophages, microglial cells of CNS, alveolar macrophages (dust cells), langerhans cells of skin
206
TNF-a produced by sentinel cells in response to TLR stimulation results in
Inflammation (induces IL1, 6 and 8 production)
Causes signs of inflammation
Later, facilitates transition from innate to adaptive immunity
207
Production of interleukin-1 is secondary to stimulation of ___ and ___
CD14 and TLR4
208
Production of IL6 from macrophages is in response to ___, ___ and ___
IL1
Endotoxins
TNF-a
209
Actions of IL6
Promotes inflammation
Increases hepcidin formation (anemia of chronic inflammation)
210
Histamine
Major source: mast cells, basophils, platelets
Function: increases vascular permeability, pain
211
Serotonin
Produced in platelets, mast cells, basophils
Function: increased vascular permeability
212
Kinins
Major source: plasma kininogens and tissues
Function: vasodilation, increased vascular permeability, pain
213
Prostaglandins
Major source: arachidonic acid
Function: vasodilation, increased vascular permeability
214
Thromboxanes
Major source: arachidonic acid
Function: platelet aggregations
215
Leukotriene B4
Major source: arachidonic acid
Function: neutrophil chemotaxis, increased vascular permeability
216
Leukotriene C, D, E
Major source: arachidonic acid
Function: smooth muscle contraction, increased vascular permeability
217
Platelet activating factor (PAF)
Major source: phagocytic cells
Function: platelet secretion, neutrophil secretion, increased vascular permeability
218
FDPs
Major source: clotted blood
Function: smooth muscle contraction, neutrophil chemotaxis, increased vascular permeability
219
C3a and C5a
Major source: serum complement
Function: meat cell degranulation, smooth muscle contraction, neutrophil chemotaxis (C5a)
220
What are 3 ways that antibodies participate in host defense?
Neutralization - IgA - bind pathogens and render them innate; important for viral protection (not aggressive enough for bacteria)
Opsonization - IgG, IgE, C3b, C5b - coat pathogens with Ab to facilitate phagocyte ingestion
Complement activation
221
Complement proteins and their main sources
Hepatic - C3, C6, C8
Macrophages - C2, C4, C5
Mast cells - C1q
Neutrophil granules - C6, C7
222
Three complement pathways
Antigen-antibody reaction - "classical" - Ab+C1q
Mannose binding protein- "lectin" pathway- MBL+MASP-2
Bacterial endotoxin- "alternative" pathway
223
All three pathways lead to activation of ____ which ultimately results in downstream activation/production of membrane attack complex
C3
224
Examples of organisms that activate the "alternate" pathway of complement activation (mannose binding lectin pathway)
Salmonella
Candida
Neisseria
225
Function of C3b and C4b
Opsonization --> activate neuts/macrophages --> phagocytosis
226
Actions of C5B6789 (membrane attack complex)
Ruptures bacterial cell wall, leading to lysis
227
Complement that leads to chemotaxis (3)
C3a --> attracts eosinophils
C5a --> attracts neutrophils and macrophages where antigen is present
C567 --> attracts neutrophils and eosinophils
228
Complement that leads to blood coagulation
C5a --> enhances coagulation, inhibits fibrinolysis; induces expression of tissue factor and plasminogen activator inhibitor I
Thrombin acts on C5a to generate C5a
229
Complement (3) that activate mast cells
C3a, C4a, C5a --> release of inflammatory mediators (histamine, serotonin)
230
Canine C3 deficiency (Brittany Spaniels)
Hereozygotes- normal
Homozygotes- no detectable C3
--> Lower IgG levels
--> Infection (Clostridium, Pseudomonas, E. coli, Klebsiella)
--> Immune complex mediated kidney disease****
--> Amyloidosis
231
Lifespan of a neutrophil
Short
7-10 hours
232
Neutrophil emigration
Endothelial cells express P-selectin
L-selectin on neutrophils binds P-seslctin
Chemokinds and leukotrienes trigger neutrophils to express leukocyte function-associated antigen 1 (LFA-1)
LFA-1 binds intercellular adhesion molecule-1 (ICAM-1) on endothelial cells
Bind PECAM-1 and then diapedese into tissues
233
How long to monocytes circulate in blood before migrating to the tissues where they become macrophages?
~3 days
234
Which chemokine does macrophages make that attracts neutrophils
CXCL8 (IL8)
235
Macrophages are activated by ___, ___, and ___
IFN-y
TNF-a
IL2
236
What triggers fever
IL1, IL6, TNF-a
237
Thermostatic set point alteration
COX-2 in the hypothalamus --> PGE2 production --> new set point
238
IL1 and IL6 trigger production of hepcidin in the liver, which then binds _____ in enterocytes to prevent iron absorption
Hepcidin
239
____ is a protein that tags circulating iron (hemoglobin) for macrophage destruction
Haptoglobin
240
Macrophages in the liver/spleen make _______ which helps steal bacterial siderophores preventing their uptake of iron
Lipocalin-2 (Siderocalin) AKA NGAL
241
All leukocytes have cell marker (CD) _____
CD45
242
Which cluster of differentiation (CD) marker is on B-lymphocytes
CD19
243
All T lymphocytes have CD ___
CD3
244
Cytotoxic T cells have _____
CD8- receptor for MHC I
245
Helper T cells have ____
CD4 - receptor for MHC II
246
Activated T lymphocytes have CD ____
CD25
247
Primary immune response antibody vs. secondary immune response antibody
IgM is high primary (such as with first vaccine)
IgG is high secondary (booster)
248
