Inflammation - Immunology - Antigens & Adaptive Responses; Major Histocompatibility Complexes Flashcards
Define: toxoid.
An inactivated toxin
(look-alike toxin)
Are the two ‘arms’ of an antibody the same or different?
They are identical
Do either B cell or T cell surface receptors change over time?
B cells
Why might a B cell antigen receptor change over time?
Repeated exposures –>
somatic hypermutation + class switching
Via what two methods does a B cell antigen receptor change over time?
Somatic hypermutation;
class switching
What is a CDR?
How does it change when faced with subsequent antigen exposures?
Complementary-determining region (the variable region);
increased affinity
The antibody hypervariable region is also known as the what?
How many are there and which is most important?
Complementary-determining region (CDR);
3, the third
True/False.
Repeated antigen exposures (e.g. booster shots or repeated infections) increase the affinity of T cell receptors for the antigen via somatic hypermutation and class switching.
False.
Repeated antigen exposures (e.g. booster shots or repeated infections) increase the affinity of B cell receptors for the antigen via somatic hypermutation and class switching.
Via what basic mechanism does somatic hypermutation (upon repeated antigen exposure) lead to B cells with a higher affinity for the antigen?
Competition between B cells
(B cells with higher affinities are more affective and more activated)
What stimulus increases B cell antigen receptor somatic hypermutation?
Repeated antigen exposure
__________ maturation refers to the process of B cell receptor class switching (I.e., IgM –> IgG or IgA).
Affinity
Which antibody class has the lowest affinity for antigens?
IgM
All antibody receptors begin as IgM. To what can they class switch? Can they class switch more than once? Can they go back to IgM after switching?
IgM –> IgA or IgE or IgG;
no;
no
(I.e., after a B cell has switched from IgM to Ig__, it will remain that class forever)
True/False.
A high-antigen booster shot will create a higher affinity immune response than a low-antigen booster shot.
False.
A low-antigen booster shot will create a higher affinity immune response than a high-antigen booster shot.
(Due to increased competition between B cells)
In which portion of the germinal center does proliferation and somatic hypermutation occur?
The dark zone
In which portion of the germinal center does B cell positive selection / competition occur?
The basal light zone
In which portion of the germinal center does cell generation (memory and plasma) and class switching occur?
Apical light zone
Name the basic B cell occurance(s) of each of the following portions of the germinal center:
Dark zone
Basal light zone
Apical light zone
Dark zone - Proliferation + somatic hypermutation
Basal light zone - Positive selection + competiton
Apical light zone - class switching + memory/plasma cell generation
What is found in the γ-globulin serum fraction?
Immunoglobulins
There are __ basic classes of antibody.
All antibodies have one of two light chain types, __ or __.
All antibodies have two heavy chains and two light chains in what arrangement?
5;
κ, λ (κ > λ);
L - H - H - L
What two immunoglobulins exist as polymers?
What is required for their polymerization?
IgM (pentamer), IgA (dimer);
the J chain
Which immunoglobulin class is most abundant in serum?
What are the second two most abundant?
IgG (~80%);
IgA (~10%; only serum fraction), IgM (~10%)
What immunoglobulins are only found in tiny percentages in the serum?
IgD (0.2%);
IgE (0.002%)
What two immunoglobulin classes are mostly found outside the bloodstream?
IgE (mast cells);
IgA (in secretions)
The __ chain is necessary to IgM polymerization (into pentamers) and IgA polymerization (into dimers).
J
Papain cuts antibodies into how many pieces?
Pepsin cuts antibodies into how many pieces?
3 (2 variable regions + Fc region);
2 (connected variable region + Fc region)
What generic type of bond/force holds antigens and antibodies together?
Non-covalent forces
(H+, Van der Waals, hydrophobic, etc.)
The antibody ____tope binds the antigen ____tope.
Para;
epi
How many CDR sites does a single heavy or light chain have?
3
(so, 12 per antibody)
How many CDR sites does a single IgG have?
12
(3 per chain)
How many binding sites does a single IgG have?
And an IgM?
2;
10
(6 CDRs per binding site)
Antibody avidity is cooperative, functional affinity for an antigen created by what?
Multiple binding sites on a single molecule
(e.g. IgM pentamers have a high avidity)
Which immunoglobulin class has the lowest affinity?
Which immunoglobulin class has the highest avidity?
IgM;
IgM
Which immunoglobulin class cannot undergo somatic hypermutation?
How does it make up for this?
IgM (decreased affinity);
increased binding sites (increased avidity)
What is an antigen?
What is an immunogen?
A foreign substance capable of binding a lymphocyte receptor;
an antigen that stimulates an immune response
All ________ (immunogens/antigens) are ________ (immunogens/antigens), but not all ________ (immunogens/antigens) are ________ (immunogens/antigens).
All immunogens are antigens, but not all antigens are immunogens.
(I.e., not all antigens induce an immune response.)
A foreign molecule binds a lymphocyte receptor but fails to induce an immune response.
Is this molecule an immunogen?
Is it an antigen?
No (no immune response);
yes (binds lymphocyte receptors)
What are some of the characteristics of a good immunogen (antigen that induces an immune response)?
Large size;
lots of 2° and 3° structure;
rigid;
accessible epitopes
What some examples of antigens that would likely be good immunogens?
Large size
Lots of 2° and 3° structure
Rigid
Accessible epitopes
Large, globular proteins;
long, repeating polysaccharides
Why do large antigens make better immunogens?
What type of antigen is too small to do this on its own and must conjugate to something bigger to become a successful immunogen?
They can cross-link lymphocyte receptors;
a hapten
A hapten is an antigen that is too _______ to induce a successful immune response on its own, and so it must be conjugated to what?
Small;
a large molecule/structure
What type of antibody production is induced by T-independent B cell activation?
IgM
What type of antibody production is induced by T-dependent B cell activation?
IgG
What type of B cell activation (T-dependent or T-independent) induces formation of IgM?
What type of antigen is it especially geared towards? How?
T-independent;
bacteria –> complement activation
Which type of immunoglobulin is especially good at complement activation?
IgM
What type of antigen causes T-independent B cell activation?
What type of immunoglobulin is produced?
Bacterial polysaccharides;
IgM
What type of antigen causes T-dependent B cell activation?
What type of immunoglobulin is produced?
Protein antigens;
IgG
True/False.
IgM production is dependent on T cells.
False.
What T cell and what receptors are involved in T-dependent B cell activation in response to a protein antigen?
Production of what is induced by this process?
TH cells;
MHC class II, CD40
–>
IgG
Antigenicity is the ability of an antigen to what?
Immunogenicity is the ability of an antigen to what?
Bind a lymphocyte receptor;
induce an immune response
An antigen’s ability to bind a lymphocyte receptor is known as what?
An antigen’s ability to induce an immune response is known as what?
Antigenicity;
immunogenicity
Hyper-IgM syndrome may occur due to a defect of what receptor on what cell?
CD40L;
TH cells
Class switching (e.g. IgM to IgG) is induced by binding of TH cell _____ to a B cell _____ receptor.
CD40L;
CD40
What type of antigen is most likely to cause T-dependent B cell activation?
What type of antigen is most likely to cause T-independent B cell activation?
Protein antigens (IgG production);
large, bacterial polysaccharides (IgM production)
What purposes does the Fc region of an antibody have?
Complement activation;
cell binding
What type of antibody binds to Fc receptors?
Cytophilic antibodies
(i.e. Fc region bound to cell, creating a cell-surface antibody/receptor)
What is an example of a cytophilic antibody?
IgE on mast cells
Cytophilic antibodies are bound to cells via what region of the antibody?
The Fc region
What cell type binds the Fc regions of IgE?
Mast cells
What occurs following mast cell IgE cross-linking?
Degranulation
(release of histamine, eosinophil chemotactic factors, TNF, IL-6, prostaglandins, etc.)
Immunoglobulin-mediated oposonization of foreign substances is facilitated by macrophage cell-surface ___ receptors.
Fc
True/False.
Most macrophages and other phagocytic cells have Fc receptors.
True.
How many subtypes of the IgG class are there?
4
(IgG1, IgG2, IgG3, IgG4)
Which IgG subtypes are cytophilic (can be displayed by specific Fc-binding cells)?
IgG1, IgG3
Which IgG subtypes activate the classical complement pathway?
IgG1, IgG2, IgG3
Which IgG subtypes can cross the placenta?
All 4
(IgG1, IgG2, IgG3, IgG4)
Which complement pathway does IgM activate?
Classical
What immunoglobulin is produced in response to blood-borne infections identified by the spleen?
IgM
The predominant immunoglobulin in serum is ____.
The predominant immunoglobulin in primary responses is ____.
The predominant immunoglobulin found in secretions is ____.
IgG;
IgM;
IgA
For what antibody function is IgA especially useful in secretions?
Neutralization
Which immunoglobulin is involved in immunity to helminths?
Which immunoglobulin is involved in atopic diseases?
IgE;
IgE
Which immunoglobulin is most likely to be transported across an epithelial layer (basolateral side to apical side)?
IgA
Which immunoglobulins are the three strongest activators of complement?
IgM (strongest);
IgG1, IgG3
What type of immunoglobulin does a fetus receive via the placenta?
What type of immunoglobulin does a newborn receive via breastfeeding?
IgG;
IgA
When do maternal IgG start crossing the placenta to reach the fetus?
How long does it take for maternal antibodies to disappear from a neonate’s system?
6 months gestation (~3 months prepartum);
6 - 12 months postpartum
Growth factors, interleukins, chemokines, tumor necrosis factors, colony stimulating factors, and interferons are all examples of what?
Cytokines
What factor mediates cachexia?
TNF-α
(originally called cachexin)
What are chemokines?
Chemotactic factors
How many epitopes can a single T cell recognize?
Just 1
What are the two main steps of T cell activation?
- MHC-antigen complex recognition
- B7 (APC) - C28 (T cell) co-stimulation
What co-stimulatory factor is required for T cell activation by an APC?
APC B7
(to the T cell CD28)
APCs activate T cells by presenting specific MHC-antigen complexes and a ___ co-stimulatory factor binding the T cell CD___.
B7;
28
What cytokine signals are involved in T cell activation?
IL-1;
IL-2
T cell activation involves (in order):
- Activation by _____-_____ complexes.
- Binding of APC ___ to T cell CD___.
- Stimulation by the cytokines IL-__ and IL-__.
MHC, antigen;
B7, 28;
1, 2
A dendritic cell is activating a TH cell.
What factors does the APC present?
What receptors do they bind, respectively, on the TH cell?
MHC class II (with antigen), B7;
TCR / CD4, CD28
A TC cell is being activated by an APC.
What factors are presented by the APC?
What receptors do they bind, respectively, on the TC cell?
MHC class I, B7;
TCR / CD8, CD28
APCs use B7-CD28 binding in the T cell activating process.
What are a few other names for B7?
CD80 (B7-1); CD86 (B7-2)
(Note: know all of these.)
What are the limitations on a T-independent B cell immune response?
No memory;
IgM secretion only
What do T cells do as they travel from lymph node to lymph node?
They swarm over the mature dendritic cells to check for any antigens they recognize
Name the term given to each of the following steps of T cell response:
1. A T cell finds a dendritic cell presenting the T cell’s specific antigen
2. The T cell undergoes clonal selection and destroys the threat
3. The T cells die off after destroying the threat
4. A proportion of the T cells remain viable in case of a repeat infection
- Activation
- Expansion
- Contraction
- Memory
What stimulatory cytokine plays a large role in T cell clonal expansion by stimulating cell division / maturation in resting T cells?
IL-2
True/False.
IL-2 up-regulates IL-2 affinity and receptor number on T cells in an autocrine and paracrine fashion.
True.
What are the main cytokines released by TH1 cells?
What are the main cytokines released by TH2 cells?
TH1: IL-2, IFN-γ
TH2: IL-4, IL-5
What are the main functions of TH1 cells?
Macrophage and B cell activation,
induction of opsonizing antibodies (e.g. IgG1)
(IL-2, IFN-γ)
What are the main functions of TH2 cells?
General B cell activation and antibody production;
eosinophil and basophil activation
(IL-4, IL-5)
What helper T cells is mainly responsible for B cell activation?
What helper T cells is mainly responsible for macrophage activation?
TH2 (IL-4, IL-5);
TH1 (IFN-γ)
Which helper T cell subtype is implicated in allergic and helminthic responses?
TH2
What is the main function of a TH17 cell?
Neutrophil activation
(via IL-17)
What cell type inhibits TH1 activity?
What cell type inhibits TH2 activity?
TH2 cells (via IL-10);
TH1 cells (via IFN-γ)
How do TH2 cells increase B cell proliferation and differentiation into plasma cells?
(Via what T cell surface protein(s) and/or cytokine(s)?)
MHC class II, CD4, CD40L;
IL-4, IL-5, IL-6
For what is IL-2 mainly responsible?
T cell growth
For what is IL-3 mainly responsible?
Hematopoeisis
For what is IL-4 mainly responsible?
B cell activation
For what is IFN-γ mainly responsible?
Macrophage activation
For what is TNF-α mainly responsible?
Inflammation
What happens to T cells that bind APC MHC complexes but do NOT bind a co-stimulatory protein (e.g. B7)?
Anergy or apoptosis
(inactivation)
Why do T cells need a first signal (MHC complex) and a second signal (co-stimulatory protein)?
To reduce autoimmunity
(B7 is only expressed in mature dendritic cells that have sensed a foreign substance under inflammatory circumstances)
When do dendritic cells start expressing B7?
Under what kind of tissue circumstance?
After recognizing a foreign antigen and maturing;
inflammation
What interleukin is the main anti-inflammatory interleukin?
IL-10
A _____-affinity T cell receptor (TCR) causes T cell differentiation into a TH1 cell.
A _____-affinity T cell receptor (TCR) causes T cell differentiation into a TH2 cell.
High;
low
T cells are mainly activated by what cell type?
B cells are mainly activated by what cell type?
Dendritic cells;
TH2 cells
There are multiple types of TH cells (TH1, TH2, TH17, TFH, Treg).
How many types of Tc cells are there?
Just one
T cells are mainly activated by dendritic cells via what substances?
B cells are mainly activated by TH cells via what substances?
MHC/antigen + B7;
MHC/antigen + CD40L + IL-4 +IL-5
The process of T cell and dendritic cell mingling/screening in lymph tissues is known as ____________.
The process of T cells finding, attaching to, and being activated by their respective dendritic cells is known as ____________.
The process of subsequent T cell proliferation is known as ____________.
Dating;
mating;
procreating
How does flow cytometry work?
1. Cells surface proteins are marked with ______________.
2. The cells are passed through a flow cytometer which measures fluorescence.
3. The cells are analyzed according to which surface proteins they express.
4. The results are displayed on an _____.
Fluorescent antibodies;
X-Y plot
(bottom box = negative; top box = positive —> These cells are CD44+)
How does flow cytometry work?
1. Cells surface proteins are marked with fluorescent antibodies.
2. The cells are passed through a flow cytometer which measures ___________.
3. The cells are analyzed according to which __________ they express.
4. The results are displayed on an X-Y plot.
Fluorescence;
surface markers
(bottom box = negative; top box = positive —> These cells are CD44+)
Which T cell type has better maintenance of immunological memory, CD4+ or CD8+?
CD8+
(Note: the X-axis is measured in days)
The two main functions of cell-mediated immunity:
__________ activation.
Direct cellular __________.
The two main functions of cell-mediated immunity:
Macrophage activation (IFN-γ).
Direct cellular cytotoxicity (CD8+; MHC class I).
What activating effect does IFN-γ have on macrophages?
Increased ROS production
Name a few subtypes of helper T cells.
TH1, TH2, TH17, Treg, TFH
T cells only respond to ________ antigens.
Peptide
B cells recognize _________ antigens.
T cells recognize _________ antigens.
Native (unprocessed);
processed
What do MHC class I display on the surfaces of nucleated cells?
What do MHC class II display on APC surfaces?
Fragments of intracellular peptides;
fragments of extracellular peptides
MHC in humans are also known as?
Human Leukocyte Antigens
(HLAs)
What three cell types function as APCs and have MHC class II expressed on their surfaces?
Dendritic cells;
macrophages;
B cells
MHC class I is expressed on all __________ cells.
MHC class II is expressed on all __________ cells.
Nucleated;
antigen-presenting
MHC class I is made of a trimeric α complex bound to a single __-__________.
β2-microglobulin
MHC class I is made of a _________ ___ complex bound to a single β2-microglobulin.
Trimeric α
What HLAs are part of MHC class I?
What HLAs are part of MHC class II?
A, B, C;
DP, DQ, DR
Which MHC class is made of two α subunits and two β subunits?
Which MHC class is made of three α subunits and one β2-microglobulin?
MHC class II;
MHC class I
Which MHC class is open-ended and can hold a larger peptide?
MHC class II
True/False.
The HLA genes are highly polymorphic in humans.
True.
There are many, many variants. Plus, there are six HLA subtypes and two codominant alleles for each. So, an individual can have twelve HLA subtypes in their body, and these twelve can be any of a number of SNPs.
Transplant ‘matching’ refers to what immunogen?
(I.e. what is compared to see if two individuals are able to participate in a transplant?)
HLA compatibility
True/False.
HLAs (MHCs) are co-dominant and multiple are typically expressed simultaneously.
True.
Why do our bodies have multiple HLAs?
Variance in affinities allow for diversity in ability to respond to diverse infectious agents
Where in the body can MHCs be found expressed on cell surfaces with no peptides loaded in their binding grooves?
Nowhere!
All expressed MHCs have loaded peptides.
What type of MHC class expresses viral fragments on infected cells?
What type of MHC class expresses fragments of extracellular infectious agents to T cells?
MHC class I (HLA A, B or C);
MHC class II (HLA DP, DQ, or DR)
Where in the cell are peptide fragments loaded into MHC class I?
The ER
(intracellular peptide fragments)
Where in the cell are peptide fragments loaded into MHC class II?
Acidified endosomes
(endocytosed extracellular peptide fragments)
What channel allows for transport of intracellular peptide fragments to enter the ER to be loaded into MHC class I?
TAP
Why might a virus attempt to block or suppress activity of TAP in infected cells?
To inhibit MHC class I peptide loading / expression
(TAP allows for transport of intracellular peptides into the ER)
A virally infected cell expressing MHC class I (with viral peptides loaded) will be detected and killed by what?
A virally infected cell not expressing MHC class I (potentially due to viral inhibition of TAP) will be detected and killed by what?
TC cells;
NK cells
What are some examples of viruses that attempt to inhibit proper MHC class I peptide loading and expression?
(This is to hide them from passing TC cells)
HHSV1;
adenoviruses;
human CMV
MHC class II is synthesized in the ER but not loaded with a peptide fragment until they reach acidified endosomes.
What peptide acts as a placeholder to maintain the MHC class II structure and prevent incorrect peptides from being loaded?
CLIP
(fragment of the invariant chain, or Ii, protein)
MHC class II is synthesized in the ER and loaded with a peptide fragment in acidified endosomes.
CLIP, a fragment of the _________ chain, acts as a placeholder to maintain the MHC class II _________ and prevent an incorrect _________ from being loaded.
MHC class II is synthesized in the ER and loaded with a peptide fragment in acidified endosomes.
CLIP, a fragment of the invariant (li) chain, acts as a structure and prevent an incorrect peptide from being loaded.
What enzyme of APC acidified endosomes functions by removing low-affinity peptides from MHC class II complexes until a sufficiently high-affinity binding is found?
HLA-DM
Which MHC class is loaded with a peptide in the ER?
Which MHC class is loaded with a peptide in acidified endosomes?
MHC class I;
MHC class II
Describe the basic steps of MHC class II loading in an acidified endosome:
1. MHC class II receptors bound to ______ enter the endosome.
2. HLA-__ removes ______ and all subsequent peptides until a sufficiently ______-affinity peptide is found.
3. The MHC-antigen complex moves to the cell surface.
Describe the basic steps of MHC class II loading in an acidified endosome:
- MHC class II receptors bound to CLIP enter the endosome.
- HLA-DM removes CLIP and all subsequent peptides until a sufficiently high-affinity peptide is found.
- The MHC-antigen complex moves to the cell surface.
What types of cell have both MHC class I and MHC class II on their surface?
APCs
(dendritic cells, macrophages, B cells)
True/False.
Nucleated cells only present MHC class I in very specific scenarios (e.g. infection, stress).
False.
Nucleated cells are presenting MHC class I with normal intracellular peptides all the time at basal levels.
A virally infected cell will have MHC class I presenting what on the cell surface?
And a healthy, non-infected cell?
Both normal intracellular peptide fragments and viral peptide fragments;
only normal intracellular peptide fragments
True/False.
T cells are constantly scanning all sorts of healthy bodily tissues, searching for infections or damage.
False.
T cells are constantly scanning secondary lymphoid tissues, searching for their complementary antigens on dendritic cells.
Where are dendritic cells found?
Throughout the body
What are the main locations where macrophages are found in the body?
Lymphoid tissue;
connective tissue;
body cavities
Where are B cells found in the body?
Peripheral blood;
lymphoid tissues
In order to be recognized by T cells, sugars must be complexed with what?
Peptides
Besides dendritic cells, macrophages, and B cells, where else are MHC class II found in the body?
Thymic epithelioreticular cells
What main role do CD4 and CD8 play for the TCR receptor?
Stabilizing TCR / MHC binding
CD8 binds the __ subunit of MHC class I.
CD4 binds the __ subunit of MHC class II.
α3;
β2
Are human MHCs constant across all people?
No;
individuals are highly variant in their HLAs
(this is the basis for the important of donor matching in transplant medicine)
Donor matching in transplant medicine involves analysis/comparison of the donor’s and the recipient’s ______.
HLAs (MHCs)
In a non-inflammatory scenario, what happens if a specific viral protein is very similar to one of a patient’s endogenously found proteins?
And if there is severe inflammation?
It is ignored as a self-protein;
it induces autoimmunity (via molecular mimicry)
- (e.g. Guillain-Barre, T1DM, multiple sclerosis, etc.)*
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266166/*
True/False.
Affinity relates to the strength of binding only, and avidity relates to the number of binding sites only, with no overlap between the two.
Thus, IgM pentamers always have higher avidity than IgG monomers.
False.
Avidity is the sum of the affinities.
So, two high-affinity binding sites on an IgG monomer can have a higher avidity than ten weak-affinity binding sites on an IgM pentamer.
Why do FC receptors not usually bind IgM?
IgM FC are bound up in pentamers
Why a vaccine designed to create lasting, robust immunity to a particular polysaccharide will have a peptide conjugated to the polysaccharide:
- A B cell that recognizes the _________ will bind and ingest it (along with the attached _________)
- The activated B cell expresses the peptide on its _____
- A T cell that recognizes that _________ activates the B cell (to produce its antibodies, which happen to be against the _________)
Why a vaccine designed to create lasting, robust immunity to a particular polysaccharide will have a peptide conjugated to the polysaccharide:
- A B cell that recognizes the polysaccharide will bind and ingest it (along with the attached peptide)
- The activated B cell expresses the peptide on its MHC II
- A T cell that recognizes that peptide activates the B cell (to produce its antibodies, which happen to be against the polysaccharide)
So, the peptide-recognizing T cell activates the polysaccharide-recognizing B cell because the B cell has the peptide on its MHC II that is specific to the T cell.
True/False.
A vaccine designed to create lasting, robust immunity to a particular polysaccharide will have a peptide conjugated to the polysaccharide so that the T cell that recognizes the polysaccharide will activate the B cell that recognizes the peptide.
False.
A vaccine designed to create lasting, robust immunity to a particular polysaccharide will have a peptide conjugated to the polysaccharide so that the T cell that recognizes the peptide will activate the B cell that recognizes the polysaccharide.
So, a peptide-recognizing T cell activates a polysaccharide-recognizing B cell because the B cell has the specific peptide expressed on MHC II on its surface.
