Immunology Flashcards
1
Q
What are the 2 main components of the immune system?
A
- Innate Immunity
2. Adaptive Immunity
2
Q
What is the innate immune system and name several effector cells?
A
Available for immediate defense with no prior exposure required!
Components: Physical and chemical barriers, Circulating cells, complement, cytokines, interferons, defensins
Cells: Neutrophils, eosinophils, mast cells, macrophages, dendritic cells
3
Q
What components of complement lead to more inflammation?
A
Anaphylatoxins = C3a and C5a
4
Q
What is the final outcome of complement activation?
A
Stimulates activation of terminal complement components (C5b-C9-membrane attack complex)
5
Q
What is a TLR?
A
Toll-like receptor - recognizes intracellular and extraceullar bacteria/virus
On neutrophils - Result in cytokine production = Inflammatory response
TLR2 - Bacterial lipopeptide
TLR4 - LPS
6
Q
What is a NLR?
A
NOD-like receptor - recognizes intracellular bacteria/virus
On neutrophils - Result in cytokine production = Inflammatory response
NLRs = Bacterial lipopeptides
7
Q
What are cytokines and chemokines?
A
Cytokine: Proteins that are made by affector cells to affect behavior of other cells
Chemokines: Cytokines that are important for chemotaxis
8
Q
Name the 3 cytokines important for inflammation/fever.
A
IL-1
IL-6
TNFa
9
Q
What are 2 major chemokines?
A
IL-8
CXCL1
10
Q
What are the 3 major cell types of adaptive immunity?
A
Lymphocytes (B and T cell)
Antigen presenting cells
11
Q
What is humoral immunity?
A
B cells recognize antigen through surface bound Ig> Once activated to become a plasma cell or long-lived memory cell = Secrete Ig, which bind pathgens in extracellular space - leading to their destruction through phagocytosis and complement binding
12
Q
What is cell mediated immunity?
A
T cells (via T cell receptors) recognize INTRACELLULAR antignes on cell surface of antigen presenting cells (DO NOT bind free antigen, unlikely B cells)! Based on specialized cellular gylocproteins (gene cluster) = Major Histocompatibility Complex (MHC). Once activated, T cell differentiate into cytotoxic cells (CD8+) or helper cells (CD4+)
13
Q
Cytotoxic T cells are CD___+.
A
CD8+
14
Q
Helper T cells are CD___+.
A
CD4+
15
Q
Name 3 antigen presenting cells.
A
Macrophages, dendritic cells, B cells
16
Q
What is the role of an antigen presenting cell?
A
Along with MHC internalize, process, and present antigen+MHC on their cell surface to be recognized by T cells
17
Q
Where do B cells and T cells “live” in the body?
A
B cells = BM
T cells = Thymus
18
Q
What is colonal selection?
A
Single lymphocyte progenitor produces millions of cells with DIFFERENT and SPECIFIC antigen receptor on each cells - occurs through rearrangement of gene segments in variable region of antigen receptors EACH LYMPHOCTE EXPRESSES ONLY 1 SPECIFIC RECEPTOR
19
Q
What happens once a lymphocyte is activated?
A
Interaction of the receptor with a foreign antigen with sufficient binding = activates lymphocyte → Produces CLONES with the SAME SPECIFIC receptor. Clones are known as effector cells, capable of eliminating antigens
20
Q
How do T cells differ from B cells in term of differentiation?
A
T cells are MHC restricted!! T cells can recognize foreign antigen only in form of peptide bound to a self MHC molecule on APC.
21
Q
What is positive selection?
A
T cells must be able to recognize the body’s own MHC molecules (since they are MHC restricted and can only recognize a foreign antigen when it is bound to a self MHC molecule on an APC)
22
Q
What is negative selection?
A
T cells must be able to recognize self peptides bound to self MHC molecules and become self tolerant. Cells binding with high affinity are deleted = negative selection
23
Q
What happens when a T cell fails positive and negative selection?
A
It undergoes apoptosis
Estimated that 98% of immature T cells die this way
24
Q
Which lymphocyte is produced throughout life?
A
B cells
25
What are the major steps in lymphocyte migration to sites of inflammation?
1. Teter and rolling: Based on P and E selectins on endothelial cells or L-selectin (LN). Rolling mediated by binding of integrins (WBCs) to VCAMS or ICAMS (on endothelial cells)
2. Activation: Baed on chemokines (IL-8)
3. Arrest: Based on b integrins to ICAMs asn MadCAMs
26
What portion of an antibody binds to the antigen?
Variable region (Fab) - varies extensively to match antigen variety
27
What portion of an antibody binds to the APC?
Constant region (Fc) - leads to recruitment of additional immune cells and destruction of pathogen
28
What determines the antibody isotype and name the 5 types of antibodies?
Constant (Fc) region determines the isotype
| IgM (pentamer), IgG, IgD, IgE, IgA (Dimer)
29
How is a B cell activated?
Antigen binding to transmembrane B Cell antigen receptor stimulates clonal expansion (lots of phosphorylations) and differentiation to an antibody secreting plasma cell (short lived) or memory cells (long-lived) occurs
30
What is a common leukocyte antigen?
CD45 (present on all WBCs) - Transmembrane surface glycoprotein
31
What is the main function of the MHC?
To process and present pathogenic peptides to 2 distinct classes of T cells
32
What is the difference btwn MCH I and MCH II molecules?
MHC I: a chain and b2 microglobulin - Does NOT cross the membrane = Expressed on majority of nucleated cells
MCH II: a and b chains - crosses the membrane = Mainly expressed in APCs and in thymus (self recognition)
Great polymorphorism is present in MCH molecules
33
What is DLA?
Dog Leukocyte Antigen
34
What is the role of MCH Class I in antigen processing and presentation?
Presents peptides to CD8+ (cytotoxic, killer cells)
Pathogens that are found in cytosol (viruses, tumor antigen, some bacteria) = Cell death
Cytosolic pathgenic proteins are degraded by proteosomes and delivered to ER where MHC I molecule is ready , peptide binding occurs = MHC I: Peptide complex transported to surface where it is exposed to CD8+ T cells
35
What is the role of MCH Class II in antigen processing and presentation?
Present peptides to CD4+ (T helper 1 or 2). Th1 - Acitvate inflammatory cells to kill intravesicular pathogens, Th2 - activate B cells to secrete Ig to eliminate extracellular bacteria/toxin
Antigen exists or is transported to intracellular vesicle and degraded into peptides, which fuse with MCH II and move to cell surface and exposed to CD4+ cells
36
What is the difference btwn Th1 and Th2?
```
Th1 = Activate inflammatory cells to kill pathogen (intravesicular)
Th2 = Activate B cells to produce Ig (extracellular)
```
37
What are the components of the T cell receptor complex?
Resembles the Fab portion of Ig (contains constant and variable region in a and b chains
Assoicated with CD3 complex (intracellular signaling) and CD45 (on all WBCs)
Co-receptor: CD4 or CD8 (some carry both)
38
What is the superantigen?
Binds ACROSS the MCH:T cell receptor (without processing) = Activation leads to massive production of cytokines by CD4 cells that leads to SIRS!!!
Bacteria (Stap enterotoxins, and some viral proteins)
39
Discuss the activation of naïve T Cells to effector T cells.
1. Naïve T cells migrate to peripheral lymph organs were they are exposed to APCs (MP, dendritic cells, B cells) - Encounter of T cells with an antigen (on APC surface) = Primary immune response
2. Recognition of MCH: Antigen complex
3. CO-STIMULATORY SIGNAL delivered by same APC - binding of cell surface molecule B7 found on APC to CD 28 on T cell
4. Activated T cells makes IL-2 = Drives T cell growth and clonal proliferation = Armed effector cell that is capable of carrying out cytotoxic or helper functions WITHOUT co-stimulation
40
What 2 steps are required for T cell activation?
1. Recognition of MCH: Antigen complex
2. CO-STIMULATORY signal delivered by SAME APC (Binding of cell surface molecule B7 found on APC to CD 28 found on T cell)
41
Which cytokines result in Th1 vs Th2 T cell development?
IL-12 drives inflammatory or Th1 response (Cell mediated immunity)
IL-4 drives a helper or Th2 response (humoral immunity)
42
What cytokines are seen with Th1 cells?
IFN gamma, TNF alpha and beta, IL-2
43
What is IFN gamma and TNF alpha?
Cytokines that are macrophage activators
44
What is IFN gamma?
Cytokine that blocks viral replication
45
What is TNF beta?
Cytokine that is cytotoxic
46
What is IL-2?
Cytokine that is needed for growth of Th1 cells
47
What are Th2 cytokines?
IL-4, 5, 6, 10, TGF beta
48
What is IL-4?
```
Cytokine that is a growth factor for Th2 cells and B cells
Induced class switch from IgG to IgE
```
49
What is IL-5?
Cytokines that induced IgA switch and activates eosinophils
50
What is IL-6?
Proinflammatory cytokine - induced acute phase response
51
What is IL-3?
Cytokine that is hematopoetic growth factor that activates mast cells
52
Name 4 primary mechanisms of the humoral immune response.
1. Neutralization: Binding to extracellular pathogens to inhibits toxic effects
2. Opsonization - facilitation of uptake and destruction of pathogens by Ig binding to pathogen at Fab region and binding to the Fc receptor of phagocytic cell
3. Complement Activation - Leads to enhanced opsonization and cell lysis
4. Functions as APC with MCH II
53
Which cell type plays a role in isotype switching of B cells?
Th2 cells
54
What is a plasma cell?
A B cells that has differentiated. Lacks surface Ig for bindings and contains low to zero MHC II = Plasma cells are no longer able to interact with antigen OR T cells
Ig secretion INDEPENDENT of these factors
Life span = 4 wks
55
What is immunologic memory?
Ability of immune system to respond more rapidly and effectively to a pathogen that is has encountered before. Due to pre-existence of clonally expanded population of antigen specific lymphocytes (controversial how memory is maintained)
Gives ability to vaccinate or immunize
56
What is the primary antibody response?
IgM and then it changes to IgG +/- other subtypes
57
Name 5 Fc receptor bearing cells.
Macrophages, PMN, nautral killer cells, eosinophils, mast cells = All secrete toxic mediators when Fc receptor engaged
58
What are the most effective opsonins?
Antibodies and complement
59
How do dogs and cats differ in clearing bacteria from bloodstream?
Dog - Use Kupfer cells (macrophages) in the liver
| Cat - Use pulmonary intravascular macrophages
60
What are the 3 pathways of complement?
1. Alternative Pathway (innate)
2. Lectin Pathway (innate)
3. Classical Pathway (adaptive)
61
How are the innate complement pathways activated?
Recognizing PAMPs
62
How is the adaptive/classical pathway of complement activated?
Antibodies that are bound to foreign antigen
63
Which part of complement results in opsonization of microbes?
C3b
64
Which part of complement results in inflammation?
C5a (chemoattractant)
65
What are the 3 main steps of complement activation?
1. Complement must be activated (PAMP or antibody:antigen)
2. C3b must be generated
3. Terminal complement complex assembled through amplification pathway
66
What is an example of a complement deficiency that is seen in dogs?
Canine C3 deficiency = Increased susceptibility to infections
Seen in colony of Brittany Spaniels (autosomal recessive)
67
What is the shock organ of the dog? Symptoms? And Major mediators?
Hepatic veins
Collapse, Dyspena, Diarrhea, Vomiting
Histamine, Leukotrienes, Prostaglandins
68
What is the shock organ of the cat? Symptoms? And Major mediators?
Respiratory Tract (intestines)
Dyspnea, Vomiting, Diarrhea, Pruitus (head/neck)
Histamine, Leukotrienes
69
What is a type I hypersensitivity?
Immediate Hypersensitivity
Results from IgE attached to mast cell (proclud earlier from Th2 response) is cross-linked by antigen = = Degranulation of mast cell = Acute inflammation (anaphylaxis)
70
Which of the DEA are clinically significant?
DEA 1 antigen (expressed by 60% of dogs, no naturally occurring antibodies)
DEA 1.1 (33-45% of dogs, universal recipients; if negative for DEA 1.1 = universal donor
DEA 1.2
71
What is the major blood group system in cats?
```
AB system (glycolipids)
A = 75-95% of cats (only 35% have anti-B IgM or IgG)
B = 5-25% of cats (of these cats 95% have anti-A IgM
AB = < 1% of cats
```
72
Why is cross-matching essential in cats?
If a B cat gets A blood they will go into shock and likely will die!
73
Name another blood types in cats, besides AB system?
Mik blood antigen
74
What is Type II hypersensitvity?
Cytotoxic Hypersensitivity
Antibody mediated = Antibodies and complement destroy normal cells
IMHA, incompatible blood transfusion
75
What is Type III hypersensitivity?
Immune Complex Formation
Soluble antigens and antibodies combine to form immune complexes that can bind with complement and get stuck in ""filter"" areas (capillaries, joints, kidneys) = Activates neurophils = Inflammation/tissue destruction
Glomerulonephritis and Polyarthritis
76
What us Type IV hypersensitivity?
Delayed hypersenstivity
3 types: Th1 cells (activated MPs), Th2 cells (activated eosinophils, IgE), Cytotoxic T cells activation
Tubuculin Rxn, allergic contact dermatitis (Stevens-Johnson syndrome)
77
What is the purpose of the Coomb's test?
To detect antibody and complement on RBCs
78
What does the regent for the Coomb's contain?
Anti-IgG, anti-IgM, and anti-C3 (species specific)
79
What is the prozone effect?
Relative excess of antiglobulin in relation to antigen (Ig or C3 on RBCs) at lower antisera dilutions resulting in decreased cross-linking of RBCs causing failure to agglutinate at low antisera dilutions
80
What helps to increase the sensitivity of the Coomb's test?
Use of monovalent reagents, increased dilutions of antiglobulin to avoid a prozone effect, and testing at 4C
81
What is the MOA of glucocorticoids?
* Bind to cytosolic glucocorticoid receptor (GR), translocate to nucleus and binds to specific DNA sequence (glucocorticoid responsive elements) - enhance and inhibit transcription of genes
* Anti-inflammatory: Stabilization of cell membranes of granulocytes, mast cells, and monocytes-MP, inhibition of phospholipase A2 (prevent release of arachidonic acid metabolites - COX and LOX pathways)
* Prevent release of cytokines IL-1 and IL-6 = proinflammatory
* Effects on complement and RAPID downregulation of Fc receptor expression on MP (reducing phagcytosis of opsonized RBCs and plts), esp with IM dz
82
What is the MOA of azathioprine?
* Cytotoxic synthetic imidzaole derivative of 6-mercaptopurine (6MP) - thiopurines that interfere with purine synthesis = BAD nucleotides = NO DNA or RNA made, mitosis and cell metabolism is disrupted
* ""Lead - in"" time of 11 days prior to clinical effects, can have lag period for up to 3-5 weeks
* Cell Mediated Immunity - Reduction in lymphocytes and T cell dependent antibody production
* Synergistic effects with steroids, allows for rapid taper of steroids (""steroid sparing effect"")
83
What are the 4 major side effects of azathioprine?
* Myelosupression
* Acute pancreatitis
* Hepatopathy
* Gastrointestinal Distress
84
What immunosupressant is there a documented breed variation?
Azathioprine: • Converted in liver (and other tissues) to 6MP
• Thiopurine methyltansferase (TPMT) - enzyme in metabolism of 6MP
• Measure it in RBCs
• Variable in TPMT levels correlated with clinical outcomes in humans (high level = reduced efficacy; low level = risk of bone marrow toxicity
• Document breed variations (Low levels in Giant Schnauzers, thus watch for toxicity, and high levels in Alaskan malamutes)
85
What occurs when giant schnauzers are given azathioprine?
Low levels of thiopurine methyltransferase (TPMT) = Watch for toxicity!!
86
What occurs when Alaskan malamutes are given azathioprine?
High levels of thiopurine methyltransferase (TPMT) = Watch for reduced efficacy!!
87
What is the MOA of cyclophosphamide?
* Cytotoxic alkylating agent, cross-links DNA, thus preventing separation
* Suppresses CMI and humoral immunity
88
Name 2 side effects of cyclophosphamide?
Hemorrhagic cystitis
| Myelosupression
89
What is the MOA of cyclopsorine?
* VERY POTENT T CELL INHIBITOR
* ***Blocks transcription of genes required for T cell activation - IL-2 production is blocked
* Binds to cyclophilin (high concentration in cytoplasma of T cells) to form complex that prevents activation of calcineurin (that normally occurs when T cell receptor engages an antigen and triggers influx of Ca into cell)
* Normally calcineurin acts as nuclear factor to induce cytokine gene transcription
* Reduced IL-2 production = reduced clonal proliferation of T cells, and thus B cells
90
Name possible side effects of cyclosporine?
• Gastrointestinal signs (transient)
• SERIOUS opportunistic infections
• Emergence of neoplasia
Gingival hyperplasia
91
What is the MOA of human IV Ig?
* Competitively inhibits the binding of K9 IgG to monocytes by saturation of Fc receptors = prevents phagocytosis of antibody coated RBCs and platelets
* Use in IMHA and IMTP
92
What is the MOA of danazol?
* Synthetic Androgen
* Downregulates MP Fc receptor expression
* Reduced antibody binding to RBCs
* Stabilizes RBCs membranes
93
What is the MOA of vincristine for IMTP?
* Low doses to increase platelet counts by stimulating megakaryocytes and impairs phagocytosis of opsonized platelets by impairing microtubule assembly MP
* Unknown effect on platelet function
94
What is a side effect of danazol in dogs?
Hepatotoxic (dogs)
95
What is the MOA of leflunomide?
* Isoxazole immunomodulating drug
* Primary metabolite - REVERSIBLY inhibits dihydro-orotate dehydrognease (RATE LIMITING ENZYME in de novo pyrimidine synthesis)
* High concentrations = Inhibits cytokine and growth factor receptor associated tyrosine kinase activity
* T and B cell proliferation inhibited
96
What are potential side effects with leflunomide?
* Hepatotoxicity
| * Myelotoxicity
97
What is the MOA of mycophenolate?
* Metabolized in plasma and liver to MYCOPHENOLIC ACID (MPA)
* Reversible inhibitor of inosine monophospahte dehydrogenase (IMPDH) - KEY ENZYME in purine biosynthesis
* Essential for lymphocyte proliferation (T and B cells proliferation, differentiation of Tc Cells and antibody production)
98
Which immunosuppressive drug interferes with pyrimidine synthesis?
Leflunomide
99
Which immunosuppressive drug interferes with purine synthesis?
Azathioprine
| Mycophenolate
100
How quickly can mycophenolate work?
Parenteral form - RAPID inhibition of IMPDH and thus immunosupression - 2-4 hours after dosing (FAST!!)
101
What is the MOA of lipsome-encapsulated clodronate?
* Bisphosphate (management of hypercalcemia associated with Vit B intoxication)
* Preferentially phagocytosed by MP and dendritic cells - APOPTOSIS
* Induced killing in splenic MP and dendritic cells
* Inhibits clearance of opsonized RBCs in normal dogs
* ROLE: Treat antibody mediated cytopenias where MP are key
* Stops RBC and platelet destruction while gaining time for slower acting agents
