Lecture 8: Activation Of Adaptive Immunity Flashcards
The innate immune response initiates the adaptive immune response by providing what 2 signals?
- Processing and presentation of Ag to T cell
2. Generation of surface molecules that function as co-stimulatory signals with Ag to activate T and B cells
The concept of histocompatibility was first identified in mice using __________ tissue.
Transplanted
[if accepted as “self” = histocompatibility, if foreign = histoincompatibility]
MHC is the mouse gene, the human equivalent is HLA. What does HLA stand for?
Human leukocyte antigens
HLA genes are tightly linked in clusters and have unprecedented levels of _______________. More than 150 separate alleles have been identified within the HLA.
MHC/HLA location and organization is on chromosome ___, and is divided into 3 distinct classes (I, II, and III - I and II are for antigen presentation)
Polymorphism
6
The total set of MHC alleles are present on each chromosome. The set of alleles on each chromosome is called an MHC/HLA __________, which encodes protein Ags central for immune system to discriminate between ______ and _________
Haplotype
Self; non-self
Most humans are _________ and have ____ MHC haplotypes
Heterozygous; two
Both haplotypes of MHC are expressed simultaneously, which is also referred to as _____________ expression. This allows for more diversity.
Co-dominant
What is the significance of the co-dominant expression of HLAs, meaning that both parental alleles of each MHC gene are expressed?
Increases the number of different MHC molecules that can present peptides to T cells
What is the signficance of polymorphisms in MHC/HLA haplotypes, meaning that there are many different genes present in the population?
Ensures that different individuals are able to respond to different microbial peptides
In what clinical scenario would you want to get the best match possible between recipient and donor for both class I and class II genes?
Transplantation
Someone’s MHC/HLA __________ refers to the expressed protein.
Allotype/isoform
What 3 gene regions are encoded by class I MHCs?
HLA-A
HLA-B
HLA-C
Class I genes code for membrane-bound ________.
They are expressed on _________ cells
They present antigen to _______ cells
They bind inhibitory receptors on _____ cells
Glycoproteins
All (nucleated)
CTLs
NK
Class I MHCs are formed of ______ extracellular globular domains that are evolutionarily ________.
They consist of a heterodimer of 2 proteins: the _____ chain is encoded by the HLA class locus and forms 3 of the 4 globular domains.
The ___________ makes up the 4th globular domain and is NOT HLA encoded. It associates non-covalently with the ____ domain of the other chain.
Four; conserved
Alpha
B2-microglobulin; alpha3
Which structural site of class I MHCs has the greatest polymorphism?
The peptide binding groove (area between alpha1 and alpha2 domains)
Class I MHCs bind peptides about ____-____ amino acids in length. The ______ ends of the groove limit the size of amino acids that can bind.
___________ of the groove also dictates what peptides can bind. Each allele of Class I MHC has a different range of peptides that can bind the groove.
8-10; closed
Conformation
During synthesis of class I MHCs, the alpha chain is translated in the ______ as a glycoprotein.
While there, it interacts with the _____________, and associates with peptides derived from ___________ proteins.
From there, the entire complex is transported to the cell surface via the normal passage of glycoproteins through ______ and ______
ER
B2-microglobulin; cytosolic
ER; golgi
Key features of Class I MHCs include:
All alleles of class I can be expressed at the same time on each cell, and there are ___ different MHC/HLAs
These have slightly different shapes and present different sets of peptides
6
Class II genes are encoded by the HLA-___ region which contains 3 sets of genes (alpha and beta chains)
What are the 3 sets of genes?
D
HLA-DP
HLA-DQ
HLA-DR
Class II MHCs are membrane bound glycoproteins
Primarily found on _______ cells
Present Ag to _____ cells
APCs
CD4+ T
Each class II MHC is composed of 2 proteins, an _______ chain and a ______ chain, both of which are encoded by HLA-D gene region.
It has a _______ globular domain structure with a conformation similar to that of class I.
The two chains are strongly associated and _____ covalently linked
Alpha; beta
Four
NOT
What forms the peptide binding groove in Class II MHCs?
Alpha1 and Beta1 globular domains
Class II MHCs bind peptides between ____-____ amino acids. The _______ ends allow larger peptides to bind.
_________ of the groove also dictates what peptides can bind.
13-18; open
Conformation
Each allele of class II MHC has a different range of peptides that can bind in the groove. Which domains have the greatest polymorphism?
Alpha1 and Beta1 (because this is the binding groove)
During class II MHC synthesis, the alpha and beta chains are synthesized in the ER and interact with a third protein called the ___________ chain.
This chain binds to the alpha and beta chains, blocking the peptide binding groove, then directs the transport of class II molecule to an ___________ compartment.
Invariant
Endocytic
During class II MHC synthesis, once in the endocytic compartment, the invariant chain is ____________, which frees the peptide binding groove.
Class II molecules bind peptides that have entered the cell via _______ (thus they came from outside the cell).
The class II HLA is then transported to the cell surface
Degraded
Endocytosis (phagocytosis)
Key features of MHC class II include:
All alleles of the alpha and beta chains are expressed (______ alpha chains and ______ beta chains)
Any alpha chain allele can associate with any beta chain allele which adds to the ________ of the peptide binding groove
6; 6 [because 3 from mom, 3 from dad]
Diversity
Antigenic peptides and MHC molecules bind in a ________ and ____ affinity interaction.
They have a _____ “on-rate”, and a ______ “off-rate”
Saturatable; low
Slow; VERY slow [this allows peptide-HLA complexes to persist long enough to interact with T cells]
How many peptides can bind to a molecule of MHC at a time?
Just one. Each MHC can bind multiple peptides, just not at the same time
Peptide-MHC binding involves pockets in the floors of the peptide-binding clefts. The side chains of the amino acids fit into these pockets and anchor the peptides in the cleft.
The rest of the peptide contains some residues that bow upwards and are recognized by ____ receptors on T lymphocytes
Ag
Which minor class of HLA is associated with acute rejection of male grafts in female recipients?
H-Y
______ binds to the _____ domain of MHC class I
CD8; alpha3
_____ binds the _____ domain of MHC class II
CD4; Beta2
What are the 3 main APCs that express class II MHCs?
Macrophages
Dendritic cells
Macrophages
Other cells that express class II MHC/HLA can act as APCs in some cases, like _____ _______ cells
Thymic epithelial
Class II MHC expression is _______ in dendritic cells, and increases with maturation and _____ stimulation
Constitutive; IFN-y
Expression of co-stimulators is ________ in dendritic cells, and increases with matruation: increased by ______ ligands, ______ stimulation, and T cells via ______-______ interactions
Constitutive
TLR
IFN-y
CD40-CD40L
What is the principle function of dendritic cells presenting via MHC II?
Presentation to NAIVE T cells in the initiation of T cell responses to protein antigens (priming)
Expression of Class II MHC in macrophages is ______, and is up-regulated by ______ stimulation
Low/negative
IFN-y
Expression of co-stimulators in macrophages is ________, and is upregulated by ______ ligands, _______ stimulation, and T cells via _____-_____ interactions
Low
TLR
IFN-y
CD40-CD40L
What is the primary function of macrophage presentation via MHC II?
Ag presentation to CD4+ effector T cells in effector phase of cell-mediated immune response
Expression of class II in B cells is _________, and is increased by cytokines like _____
Constitutive
IL-4
Expression of costimulators in B cells is ________ by T cells via _____-_____ interactions
Induced; CD40-CD40L
[also antigen receptor crosslinking]
What is the principle function of Ag presentation from B cells via MHC II?
Ag presentation to CD4+ T cells in humoral immune responses
During the capture of Ags, microbes enter the body and are phagocytosed by APCs.
They then lose adhesive markers and up-regulate ______, as well as increase expression of ______, _______
CCR7; MHC; CD80
Which MHC processes intracellular pathogens?
Class I
Which MHC processes extracellular pathogens?
Class II
In the class II MHC pathway, ___________ proteins are ingested and degraded.
Alpha and beta and ________ chains are synthesized in the ER and transported through the golgi.
The peptide is not loaded until late __________. The invariant chain acts as a place holder and is degraded to _______. ______ acts as a peptide exchanger, facilitating the removal of CLIP and addition of peptides to class II MHC.
Unbound MHC molecules will not be displayed
Exogenous
Invariant
Endosome; CLIP; HLA-DM
In the class I MHC pathway, _________ antigens are degraded by the ________ after tagging by ubiquitin.
______ transports the peptide fragments from the cytosol to the ER where the peptide is trimmed and loaded into class I.
The entire complex is then exocytosed to the cell surface.
Endogenous (cytosolic); proteosome
TAP
True or false: protein degradation and peptide transport for antigen presentation only occur in times of infection
False, these occur even in the absence of infection!
MHCs carry peptides derived from normal self proteins, but normally these do not provoke immune responses
What is the basis of cross presentation?
Dendritic cells ingest virally infected cells and display antigens to CTLs via MHC I, but can also display to Ths via MHC II
What is the major limiting factor to transplantation?
Immune response of recipient to donor; MHCs play a huge role!
A large number of _______ diseases and susceptibility to infectious agents are associated with particular HLA genes.
Most HLA associated diseases have unknown etiologies that contribute to immunologic abnormalities
Autoimmune
__________ __________ is a condition involving inflammation of the spine
Ankylosing spondylitis
Over 88% of those with ankylosing spondylitis express the ______ allele.
Each allele has a limited number of peptides it can present. It is possible that it cannot bind a critical peptide, or that it presents a critical antigenic peptide against the agent, causing disease
HLA-B27
Patients who have the _____ allele are more prone to rheumatic fever, which is a sequelae of strep pyogenes infection.
Involves the generation of antibodies against streptococci that can cross react with _________ tissue
HLA-DR4
Cardiac
Other HLA associations include:
Sjogren’s syndrome = defect in salivation and lacrimation, associated with HLA ______
Insulin-dependent DM = associated with HLA-______
Psoriasis = associated with HLA -___
DR3
DQw8
B3
There are multiple defects of the antigen-processing machinery components in human neuroblastoma
Class ____ antigen-processing defects in renal cell carcinoma due to downregulation of _____ transporter
I; TAP
What causes Bare Lymphocyte Syndrome?
TAP protein is nonfunctional, so no peptides can enter the ER
Since class I molecules cannot leave the ER unless peptide is bound, cells cannot present Ags on their surface (so they’re bare)
Symptoms = chronic respiratory infections, poor response to viruses
In bare lymphocyte syndrome, HLA II genes are turned on by a transcriptional activator called _______, which itself is induced by _______.
Another form of BLS can be caused by an inherited defect in CIITA, leading to a deficiency in HLA class II expression on cells and non-functioning T cells.
CIITA (HLA class II transactivator); IFN-y
