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MICB 202: Immunology


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Other name for WBCs
The two categories of WBC
Mononuclear and Polymorphonuclear (PMN)
All blood cells arise from undifferentiated cells in bone marrow called ___
Hematopoietic (pluripotent) stem cells
Lymphoid stem cell gives rise to these three cells
T, B, and NK Lymphocytes
The most important cell for T Cell activation
Dendritic cell
The primary lymphoid organs
bone marrow, thymus
The secondary lymphoid organs
spleen, lymph nodes, bone marrow
Location of thymus
situated above heart
Location of spleen
left side of abdominal cavity
Lymph fluid drains back into circulatory system thru the _____
thoracic duct
List the three general barriers in order of activation
physiological, innate immunity, adaptive immunity
List the physiological barriers
skin, mucous membranes, cilia, body temperatures (fevers especially), stomach acids, lysozyme in tears and saliva, defensins
What are defensins and what are thier function?
cationic peptides that bind to bacteria and kill them by disrupting the cell wall
The 5 main functions of innate immunity
opsonization, activation of complement, chemotaxis, phagocytosis, activation of proflammatory cytokines
Define opsonization
the binding of a molecule to a pathogen to enhance the process of phagocytosis
Three qualities of prokaryote PAMPs
1) infrequent mutation
2) not produced by host
3) shared by large groups of pathogens
3 examples of PAMPs
peptidoglycan of Gram+ bacteria
LPS of Gram- bacteria
PRR stands for
Pattern Recognition Receptor
PAMP stands for
Pathogen-Associated Molecular Pattern
What are the two categories of PRR?
1) soluble proteins
2) cell-associated membrane receptors
There are two groups of cell-surface PRRs. What are they?
1) phagocytosis receptors
2) cytokine release signallers (eg TLR-4)
TLR stands for
Toll-like Receptor
TLR-4 recognizes
TLR-5 recognizes
TLR-9 recognizes
bacterial DNA
Define extravasation
the movement of white blood cells from the capillaries to the tissues surrounding it
Define Complement
A set of plasma proteins that work together to attack extracellular pathogens
Is it effective against intracellular pathogens?
Name the two Compliment pathways
Classical (C) and Alternative (C')
The C Complement pathway involves what type of immune response?
The C' (alternative) pathway involves what type of immune response?
The key event in the complement pathway is
The generation of C3 convertase (whichever form)
What does C3 convertase do in the context of Complement?
It cleaves C3 into C3a and C3b
The Complement system is initiated by
antibodies binding to pathogens
Which antibodies binding to pathogens can initiate Complement?
IgM and IgG
After what step is everything the same in the two Complement pathways?
cleavage of C3
C3b functions as an _____
___ and ___ act to increase the permeability of blood vessels during Complement cascade, and to activate phagocytes and mast cells to release histamine and TNF-alpha
C5a and C3a
3 cleavage products of complement called 'anaphylatoxins'
C3a, C4a, C5a
___ is a powerful chemoattractant for neutrophils and monocytes (Complement system)
Five key features of Adaptive Immunity
diversity, inducibility, specifity, memory, self-tolerance (DISMS)
What does "inducibility" refer to?
The ability to respond to antigens
What is the goal of vaccines?
To induce a primary response to trigger memory, without making the person sick
MHC Class I proteins are expressed on ___
All nucleated cells
MHC Class II proteins are expressed on ___
Activated B Cells, Macrophages, Dendritic Cells
MHC I is used for presenting (intra/extra)cellular antigenic peptides
MHC II is used for presenting (intra/extra)cellular antigenic peptides
The ___ prevents MHC II from binding an antigenic fragment prematurely
Invariant chain
MHC I has two chains, ___ of which is/are transmembrane
MHC II has two chains, ___ of which is/are transmembrane
what is the function of B2-microglobulin?
It is required for the expression of MHC Class I proteins on the cell surface
Are the MHC alpha and beta chains identical?
No. Not for class I or II.
Where is the peptide-binding groove located for MHC Class I proteins?
within the alpha chain
Where is the peptide-binding groove located for MHC Class II proteins?
between the alpha and beta chain
How many types of MHC Class I proteins do humans have? Name them. Are they expressed on all nucleated cells?
Three. HLA-A, HLA-B, HLA-C. Yes.
How many types of MHC Class II proteins do humans have? Name them. Where are they expressed?
Three. HLA-DP, HLA-DQ, HLA-DR. All are expressed on macrophages, B cells, and dendritic cells.
Are MHC genes co-dominantly expressed? What is the consequence of this?
Yes. Your cells will express two different versions of HLA-A, HLA-B etc... So, for any given pathogen, at least some of the population will be able to present peptides and mount an immune response towards it; a lack of MHC polymorphism would predispose a species to infectious disease.
Define self antigen
A substance from within the body
Define foreign antigen
A substance from outside the body
Antibody receptors recognize
small regions called epitopes (or antigenic determinants) on antigens
T cell receptors only recognize ___
processed and presented peptide antigens
These two cells can activate T cells
Dendritic cells and macrophages
Can B cells recognize unprocessed, intact antigen?
the epitope (antigen) fits into the ___ (self)
intracellular proteins are degraded into peptides by ___
proteasome, a protease complex
Complement C: During the first step, the ___ ___ binds to the pathogen-bound antibody
C1 complex
Complement C: ___ and ___ bind to the pathogen surface to form the C3 convertase
C4b and C2b
Complement C and C': ___, ___, and ___ join to form the C5 convertase
C2b, C3b, C4b
Complement C and C': What is the function of C5 convertase?
To cleave C5 into C5a and C5b
Complement C and C': ___ deposited on the surface of the ___ initiates the assembly of C6, C7, C8, and C9
C5b, pathogen
Complement C and C': C6, C7, C8, and C9 form the ___
Membrane-Attack Complex (MAC)
Can complement proteins bind directly to bacteria?
Yes, for some types
Complement C': 1) Small amounts of C3 in serum spontaneously form ___ via ___
C3(H2O), Hydrolysis
Complement C': 2) ___ binds to factor B, which is cleaved by ___ into ___ and ___
C3(H2O), factor D, Ba, Bb
Complement C': 3) ___ binds to the pathogen surface
Complement C': 4) Factor ___ binds to ___ on the cell surface, and is cleaved by factor D forming a C3 convertase complex
B, C3b
Complement C': 5) Factor ___ stabilizes the C3 convertase complex
Does activation of complement produce a local inflammatory response?
What produces the local inflammatory response in Complement? (3 things)
C3a, C4a, C5a
Complement C and C': The binding of ___ to the pathogen surface is an important step in the formation of C5 convertase
Complement C and C': In the final step, ___ is deposited on the pathogen surface and initiates the assembly of the terminal compliment components to form the MAC
How many compliment pathways are there? Name them.
Three. Classical, Alternative, Lectin
In the skin, dendritic cells are known as ___
Langerhans Cells (LC)
Can Langerhans Cells process antigen? Can they present antigen to T cells?
Yes. No.
Dendritic cells that have migrated to the lymph node are known as ___
Interdigitating cells
Can Interdigitating Cells present antigen to T cells?
What is the role of dendritic cells?
To phagocytose, process, and transport the remains of pathogens to the local lymph node
Do DC's express the same PRR's as macrophages?
When activated, a DC will up-regulate expression of surface molecules, which do what?
promote DC interactions with T cells
When activated, a DC will produce two cytokines, __ and __, which serve to promote the selective development of ___
IL-12 and IL-18, Th1 cells
What is the function of IL-12 and IL-18?
To promote development of T cells into Th1 cells
The immune system has two main weapons, ___ to combat intracellular infections, and ___ to combat extracellular infections
antibodies produced by B cells, T cells
When self-tolerance fails, the individual is said to have a/an ___ ___
autoimmune disease
MHC Class II proteins leave the ER in ___, and fuse with the organelles in which antigen processing occurs, namely ___ or ___
vesicles, endosomes or phagolysosomes
Degraded intracellular peptides are transported by proteins called ___
TAP proteins
___ proteins transport peptides from the cytoplasm into the lumen of the ER, where they will bind to MHC Class ___ proteins
TAP is involved in (intra/extra)cellular protein presentation.
Where do lymphoid precursor stem cells mature into T cells?
Precursor T cells form in the bone marrow, then migrate to the thymus where they mature.
Developing T cells are known as ___
The T cell receptor (TCR) is a membrane-bound receptor composed of the ___ and ___ chains, joined by a ___ bond
alpha, beta, disulfide
Are there secreted forms of the TCR?
What two regions do both of the TCR chains have?
The constant and the variable region.
How many antigen binding sites does each TCR have?
A mature T cell has approximately ___ (identical/different) TCR's on its cell surface.
100,000. Identical
Developing thmocytes are subjected to two screening processes, called ___ and ___
positive and negative selection
What happens to developing thmocytes with TCR that cannot recognize self-MGC proteins at all?
They die of neglect
___ cells can deal with autoreactive T cells that escaped negative selection
regulatory T cells
What happens to developing thmocytes with TCR that binds to self-MHC with too high an affinity?
negative selection
What is the function of the AIRE gene?
Promotes the expression of a wide variety of tissue self-antigens, which allows negative selection to function.
Where is AIRE expressed?
In thymic epithelial cells
Less than ___% of developing thmocytes can develop into mature T cells
Treg cells are generated in ___
The thymus
Treg cells differ from the conventional CD4 T cells by expressing high levels of ___
What do Treg cells do?
Prevent T cells from mounting an immune response
The TCR complex consists of an antigen-binding portion comprised of ___ and ___ polypeptides, associated signalling subunit (___ complex), and accessory molecules which may be either ___ or ___
TCR(alpha) and TCR(beta) chain, CD3, CD4 or CD8
What is the function of the signalling subunit of the TCR?
To send signals to the inside of the T cell that activates it and causes it to divide
What is the function of the accessory molecules of the TCR (namely ___ or ___)?
CD4, CD8. Thier function is to increase the affinity of the interaction between T cell / APC
Neglected thymocytes in the thymus are said to undergo death by ___
What kind of cell contains AIRE gene?
___ or ___ cells can negatively select (kill) developing T cells
dendritic cells, macrophages
Define clonal selection.
Only mature T cells whose TCR binds a certain MHC-peptide complex can be activated
T cells that express CD4 recognize antigens presented by MHC Class ___ proteins
T cells that express CD8 recognize antigens presented by MHC Class ___ proteins
CD4 T cells function as T ___ cells
CD8 T cells function as ___ cells
How many signals are required for full activation of a T Cell? What are they?
1) TCR and MHC-peptide complex interaction
2) CD28 on T cell interacts with B7 on APC
If a T cell recieves only signal 1, what happens?
It enters a state of unresponsiveness known as clonal anergy
Define Complete DiGeorge syndrome. How is it treated?
Lack of a thymus. Treated with thymus transplant usually placed in leg muscle.
Define APECED. What does it result in?
No AIRE is present and negative selection does not occur. Results in a range of severe autoimmunity diseases.
Less than ___% of the bone marrow cells are stem cells
The myeloid stem cell gives rise to these seven cells.
mast cells
platelets (from megakaryocyte)
eryothrocytes (RBC's)
What are the key cells of the innate immune system?
Macrophages and Dendritic Cells (from Monocytes), Neutrophils
What does a monocyte differentiate into?
Either a macrophage or a dendritic cell
PRRs come in these three flavors.
soluble proteins thatcirculate,
cell-associated phagocytosis receptors,
What happens when a pathogen binds a cell-associated phagocytosis receptor?
It is engulfed in a phagosome
Give an example of a PRR that circulates in the blood.
LPS binding protein
What does TLR 2/6 recognize, and on what types of pathogen?
Lipopeptides on bacteria, zymosan on fungi, GPI-linked proteins on parasites
What does TLR 7/8 recognize?
Viral single-stranded RNA
What are the 5 steps of the TLR signalling pathway?
1)secretion of pro-inflammatory cytokines
2)increased cell recruitment
3)maturation of dendritic cells
4)activation of T cells
5)activation of B cells
NFκB stimulates transcription of these three "alarm" cytokines.
tumor necrosis factor alpha
interleukin 1 (IL-1)
interleukin 6 (IL-6)
When LPS binds to TLR4 it activates a transcription factor known as ___.
Innate immune cells bind to adhesion molecules which cause them to stop rolling and squeeze (___)
Name five things a lysosome and/or phagolysosome contains.
nitric oxide
oxygen radicals
hydrogen peroxide
cationic peptides
Plasma cells (cellules plasmatiques) are also called ___
Plasmocytes or plasmatocytes
The plasmocyte is the final stage of ___ cell differentiation. Thier function is to ___.
B cell. They secrete soluble antibodies.
What are two types of B7 molecule?
CD80, CD86
Why is clonal anergy important?
As a component of peripheral tolerance, it acts as a barrier to T cell activation, preventing the clonal expansion of self-reactive T lymphocytes.
A naive T cell can only be activated by ___ cells
Are endothelial cells professional APC's?
Are resting macrophages professional APC's? What about activated macrophages?
No. Yes - when it is activated it increases expression of MHC Class II and B7.
Do resting B cells express MHC Class II? Do they express it in small or great amounts? Do they express B7 proteins?
Yes. In small amounts. No.
___ activates a B cell.
The binding of an antigen to the B cell receptor.
What does a B cell do after being activated?
It increases its expression of MHC Class II and begins to express B7 proteins.
Dendritic cells express (no/little/lots of) MHC Class I and II. Dendritic cells express (no/little/lots of) B7. Are they good T cell activators?
They express large quantities of all three, and are very good T cell activators.
What is the role of CD4? And CD8?
CD4 directs helper T cells to MHCII-peptide complex presenting cells. CD8 directs T cells to MHCI-peptide complex presenting cells.
What is "signal 2" in the context of T cell activation?
The interaction between B7 (CD80 or CD86) and CD28 on the T cell.
What are the two ways to develop antibodies for use in medicine?
By immunizing animals, or by growing hybridomas.
Give 4 examples of medical uses of antibodies.
1) Detection of pathogens in patient samples
2) Detection of Abs in blood indicating exposure (eg HIV test)
3) Measurement of hormone levels (insulin, preg. tests etc.)
4) Analysis of blood cells and immune cells
How is polyclonal antiserum made?
By immunizing animals with antigen (eg virus) then isolating the antibodies from the animal's serum.
How might a snake bite have been treated 20 years ago?
From immunized horse antiserum.
Give three disadvantages of using polyclonal antiserum.
1) non-standardized reagent
2) limited supply
3) somtimes necessary to detect only one epitope
Give three desirable qualities of antibody production.
infinite supply
identical antibodies
detects only one epitope
What is the first step in monoclonal antibody production?
Repeated immunization of a mouse with antigen to get a good secondary response.
Monoclonal antibody production: The mouse's ___ is removed, containing many AB-secreting ___ cells
Spleen. Plasma.
Monoclonal antibody production: To make the plasma cells immortal, they are fused with a ___ cell, which is a type of tumor cell.
Monoclonal antibody production: The fused ___ / ___ cells become a hybrid called a ___.
Plasma / myeloma. Hybridoma.
Monoclonal antibody production: What allows fusion of the plasma and myeloma cell?
Polyethylene glycol.
Monoclonal antibody production: How are hybridoma clones selected?
Culture medium is taken from each well of a 96 well tissue culture plate, and an ELISA assay is used to detect whether the hybridoma is secreting the appropriate antibody.
Monoclonal antibody production: What type of assay is used for antibody-secretion detection?
ELISA assay.
Monoclonal antibody production: Give the 7 steps of MA production.
1) antigen in mouse. secondary response
2) antibody producing B cells isolated from spleen
3) fusion with myeloma
4) growth of cells in vitro
5) cloning individual hybridomas
6) testing clones for antibodies
7) selecting and perpetuating as cell culture
What does ELISA stand for?
enzyme-linked immunoadsorbent assay
What is ELISA used for?
Detecting presence of antibodies or antigens in fluid and determining concentration.
True or False: B cells and macrophages need not be activated by antigen before they provide the co-stimulatory signal to T cells.
False. They must be activated first.
CD4 T helper cells that have been activated are divided into ___ and ___ cells.
Th1 and Th2
Naive CD4 T cells are also known as ___.
Th0 cells
___ and ___ (cytokines) are produced by macrophages and dendritic cells in the early part of the immune response to viruses and intracellular bacterial infections.
IL-12, IL-18
IL-12 and IL-18 are produced in response to what two types of infection?
Viruses and intracellular bacterial infections
When proliferating CD4 T cells are exposed to ___ they differentiate into Th2 cells.
IL-4 is produced by ___ cells.
CD4 T cells recieving IL-12 and IL-18 will differentiate into ___ T cells.
Give two responsibilities of Th1 T cells. What cytokines drive thier development?
Activation of macrophages infected with bacteria, and activation of CTLs. IL-12 and IL-18.
What is the purpose of Th2 helper cells? What cytokines drive thier development?
Providing help to B cells to produce antibodies. IL-4.
The ___ T helper cells are involved in delayed-type hypersensitivity reactions.
Activated CD8 T cells develop into ___.
cytotoxic T cells (CTLs)
Are CTL-P cells capable of killing target cells?
Sufficient concentration of ___ is required to drive the differentiation of CTL-P cells.
Complement consists of a series of plasma proteins, namely ___, ___, ___ and ___ to ___.
C1q, C1r, C1s, C2 to C9
Name the three complement pathways.
Classical, Alternative, Lectin
What initiates the Lectin pathway?
oligosaccharides on infected cells
Only ___ and ___ antibodies can initiate the classical complement pathway.
IgM and IgG
Name the 6 components involved in innate immunity.
Neutrophils, Macrophages, Monocytes, NK Cells, Complement, Anti-microbial Peptides
Name the 2 components involved in adaptive immunity.
T cells and B cells.
Adaptive immunity is only in what type of animal?
Give three ways that antibodies protect against extracellular pathogens.
Promotes killing of bacteria by complement, promotes phagocytosis by phagocytes, and prevents infection of cells.
T cells are effective against (intra/extra)cellular pathogens.
Dendritic cells differentiate from ___.
What is the key difference between dendritic cells and macrophages?
After DC's are done eating, they traffic from the tissue to the lymph nodes where they interact and stimulate T cells.
What degrades intracellular proteins? How long are the resulting peptides?
The proteosome. 8-11 amino acids.
What transports peptides from the cytoplasm into the lumen of the ER, to bind to MHC Class I?
TAP transporter proteins.
True/False: All types of T cell express a TCR.
The entire process of T cell selection in the ___ is called ___ or ___.
Thymus. Clonal Selection or Clonal Deletion.
T-cell precursor rearranges its genes in the ___.
What is Complete DiGeorge Syndrome? How can you identify it? What are the symptoms? How is it treated? Would stem cell transplant be effective?
To be born without a thymus. No T cells found in blood. Overwhelming infection. Treated with a thymus transplant. No - no thymus for cell development.
Describe APECED. What are the symptoms?
A genetic mutation in AIRE gene.
What is the function of AIRE?
To express as many self genes as possible in the thymus.
___ are the only APCs which can activate naive T cells.
Dendritic Cells.
(True/False): Memory/effector T cells can be activated by professional and non-professional APCs.
Depending on the type of ___ that the APC is producing, different types of CD4+ T cells can differentiate from naive cells.
How can you identify Th1 vs. Th2 cells?
They make different cytokines.
The ___ cytokine stimulates the growth of T lymphocytes.
___ and ___ cytokines stimulate differentiation of Th0 into Th1.
IL-12, IL-18
___ cytokine stimulates differentiation of Th0 into Th2.
Th1 cells produce these three cytokines.
IL-2, IFN-gamma, IFN-alpha
Th2 cells produce these four cytokines.
IL-4, IL-5, IL-10, IL-13
IL-12 and IFN-gamma predominate in response to what type of infection?
intracellular bacteria and viruses
IL-4 predominates in response to what type of infection?
parasites and extracellular pathogens
What is the function of Th1 cells?
To increase cell-mediated immunity - eg activating macrophages/phagocytosis. Cellular immunity.
What is the function of Th2 cells? What type of immunity is this?
They help B cells make antibodies. Humoral immunity.
Th1 cells help CD8+ T cells by producing ___, and essential T cell growth factor.
___ cells induce immune responses which rely on the actions of CELLS to destroy pathogens that are INTRAcellular.
___ produce ___ and ___, which help B cells make antibodies
Th2. IL-4, IL-5
True/False: CD4+ cells produce CD8+ growth stimulating cytokines.
True/False: Only naive CD4+ cells need signal 1 + 2 to be activated for the first time.
False. Naive CD8+ cells also need both signals.
CD8+ T cells secrete and express three proteins which kill target cells. Name these, and thier functions.
Perforin (makes holes in membranes)
Granzymes (apoptosis)
FAS ligand (apoptosis)
What is the function of perforin ?
makes holes in cell membranes
What is the function of granzymes?
cause apoptosis
What is the function of FAS ligand?
kills cells by starting apoptosis
CTL-P's are incapable of killing target cells. Activation requires how many signals? Also, what cytokine is usually required to drive growth? What cell secretes this cytokine?
Two signals: MHC1-peptide, CD28-B7. IL-2. CD4+ T cells.
Where do B cells mature?
Entirely in the bone marrow
Explain the role of clonal deletion.
Clonal deletion refers to the destruction of B cells that have bound an antigen while maturing in the bone marrow. It is initiated by the co-stimulatory (Ig alpha and beta) parts of the BCR.
What are the two components of the BCR?
mIg and Ig(alpha)/Ig(beta) co-stimulatory molecules. The mIg component can be IgM or IgD.
Do all of the mIg molecules on a B cell have the same antigen-binding specificity?
What part of the BCR determines the antigen-binding specificity?
The mIg component
What part of the BCR sends the signal to the B cell to become activated?
The Ig(alpha) / Ig(beta) part
How many signals are required for B cell activation? What are they?
1) Binding of antigen to mIg and cross-linking (when one antigen molecule is bound by several mIgs on the B cell)
2) Binding of CD40 on B cell to CD40L on T cell
What happens as a result of cross-linking when a B cell's mIg binds an antigen?
A signal cascade is initiated by Ig(alpha)/Ig(beta) which upregulates MHC class II and B7 expression so the B cell can be an APC for the T cell.
When does a T cell express CD40L? What type of T cell expresses CD40L? What is the purpose of CD40L?
A T cell expresses CD40L after it has been fully activated. Th2 cells express CD40L. CD40L interacts with CD40 on B cells to provide a second signal for B cell activation.
What is the disadvantage of a B cell being activated by an antigen (in this case a mitogen) in the absence of a T cell?
It does not generate memory B cells.
In what sense does B cell activation depend on dendritic cells?
B cell activation requires activated Th2 cells. Th2 cell activation/differentiation from Th0 cells requires dendritic cells.
Antibodies are made by ___.
B lymphocytes
In what three ways do antibodies help protect against pathogens?
1) bind them and prevent them entering cells
2) opsonization (tagging for phagocytosis by neutrophils and macrophages)
3) binding can activate the complement cascade
What is the basic structure of all antibodies?
They consist of 4 polypeptide chains. 2 identical heavy (H) chains and 2 identical light (L) chains.
What are the types of light chain? Heavy chain?
L: kappa, lambda
H: gamma, mu, delta, epsilon, alpha
The type of H chain defines the ___ of the antibody.
isotype (or immunoglobulin class)
What types of heavy chain do the following antibodies have: IgG, IgM, IgD, IgA, IgE
gamma, mu, delta, alpha, epsilon
Within the variable region of the heavy and light chains of antibodies, the ___ region is subject to the most variation.
What part of the antibody contacts the antigen?
The hypervariable region.
Is the constant region of H and L chains identical within a given species of mammmal?
Yes, provided you are comparing the same isotype.

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