L21, L25, L27- Antigen Presentation, Recognition Flashcards
B-cells recognize (1) type molecules in (2) form
1- proteins (mainly), polysaccharides, lipids, nucleic acids
2- soluble form, or cell surface-associated antigen
T cells recognize (1) type molecules in (2) forms
1- peptide fragments
2- presented on specialized molecules (MHCs via APCs)
antigens are usually presented to T-cells via (1) on (2) cells after its migration/maturation in (3) via (4) molecules and (5) signaling
1- MHC-II receptors 2- dendritic cells 3- lymph nodes, paracortical area 4- chemokines 5- TLR-signaling
the most important APC is (1) and usually presents its antigen in the (2) area of (3)
1- dendritic cells
2- paracortical area
3- lymph nodes
list the 3 signals that stimulate T-cells via antigen signaling
1) antigen presentation: MHC/peptide (dendritic cell) recognized by T-cell receptor
2) co-stimulatory signal: CD28 (T-cell) recognized by CD8o/CD86 (dendritic cell)
3) CK secretion: CKs (dendritic cells) recognized by T-cells
MHC genes are found on the (1) cluster of genes on Chromosome (2)
1- HLA (human leukocyte antigen)
2- chr. 6
list the MHC-I gene classes
HLA-A, HLA-B, HLA-C
list the MHC-II gene classes
DP(αβ), DQ(αβ), DR(αβ)
MHC-I receptors are found on (1) cells
MHC-II receptors are found on (2) cells
1- all nucleated cell
2- APCs
MHCs genes are expressed in a _______ fashion
co-dominant expression (both parental alleles are expressed)
describe the components of MHC-I
α-chain (α1, α2, α3): transmembrane, encoded by A/B/C regions of MHC complex
β2-microglobulin: encoded by highly conserved gene (different chromosome)
Of the MHC-I complex:
- (1) is the highly polymorphic polypeptide binding region
- (2) binds to CD8 of T(c) cells
- peptides that are (3) peptides long are recognized (antigen)
- antigens presented are processed (endo/exo)-genously
1- α1/α2 subunits (target cell) binds to T cell receptor
2- α3
3- 8-10 AAs
4- endogenously
describe the components of MHC-II
Heterodimeric protein (Ig superfamily)
- α1, α2: transmembrane
- β1, β2: transmembrane
Of the MHC-II complex:
- (1) is the highly polymorphic polypeptide binding region
- (2) binds to CD4 of T(h) cells
- peptides that are (3) peptides long are recognized (antigen)
- antigens presented are processed (endo/exo)-genously
1- α1/β1 (α2 is highly conserved region)
2- β2
3- 13-25 AAs
4- exogenously (via Ig)
list the APCs
dendritic cells, macrophages, B-cells
MHC-I receptors are recognized by (1) on (2) cells and will result in the release of (3) and (4) with the following functions, (5) and (6) respectively
1- CD8
2- T(c) cells
3/5- perforins: forms pores in cell membrane
4/6- granzymes: protein breakdown + cell lysing
MHC-II receptors are recognized by (1) on (2) cells and will result in the release of CKs resulting in (3) which will produce different CKs activating (4)
1- CD4
2- T(h) cells
3- T-cell clones
4- B-cells, T(c) cells
list the two antigen presenting pathways, their alternate names, and their MHC/T-cell association
Cytosolic, endogenous, non-lysosomal pathway (produced in cell): MHC-I, CD8 T(c) cells
Endocytic, exogenous, lysosomal pathway (taken via endocytosis): MHC-II, CD4 T(h) cells
In the cytosolic antigen presenting pathway, infected proteins are marked with (1) to be degraded by (2). The resulting peptides will bind to (3).
1- ubiquitin
2- proteosome
3- MHC-I
proteosome components in cytosolic antigen presenting pathway are activated via….
INF-γ (inc number of proteosome components)
Peptides from the proteosome in the Cytosolic pathway enter the ER via (1) and bind to (2). Once loaded on, (2) will signal for (3) or (4) via the Golgi apparatus.
1- TAP1/TAP2
2- MHC-I
3- exportation to cell surface
4- sent to lysosome for degradation (usually if no antigen binds)
list the targets of immunoevasins that interfere with antigen presentation via MHC-I
(virus blocks MHC-I presentation to T(c) cells)
- inhibit peptide transport
- inhibit peptide loading
- cause MHC-I degradation
(1) virus blocks it viral peptide from transport into ER via (2) and leads to (3)
1- HSV
2- TAP1/TAP2
3- MHC-I degradation via lysosome
(1) virus retains MHC-I in the ER, leading to (2)
1- adenoviral protein
2- MHC-I degradation via lysosome
list the mechanisms of exogenous antigen uptake
-phagocytosis, pinocytosis
-Fc receptor, Complement receptor, or membrane Ig receptor mediated phagocytosis
(note- all create an endosome)
after uptake of an antigen into an endosome, the pH (inc/dec) to activate (2) in order to produce (3); note some drugs will (inc/dec) the pH to inhibit endosomal antigen processing
1- dec (more acid)
2- Cathepsin B, D, L proteases
3- ~24 AA peptides from antigens
4- inc pH in endoome
describe the state of MHC-II when unbound to antigen
CLIP is bounded non-covalently to invariant chain to stabilize immature MHC-II complex
(1), which is bounded to immature MHC-II receptors, is removed by (2) and replaces (1) with (3); note (4) may also play a role
1- CLIP
2- HLA-DM
3- antigen
4- HLA-DO
________ is when exogenous antigens normally processed by phagolysosomes (MHC-II) are presented via MHC-I
cross-presentation
describe presentation of antigen for Rickettsia rickettsia
- organism is endocytosed
- rapidly lyses endosomal membrane –> escaping phagolysosome formation
- degraded via proteosome
- presented via MHC-I (although was in endosome)
______ is the presentation of antigen to and activation of T(c) cells
cross-priming
list the mechanism bacteria use to evade MHC-II antigen presentation
- escape endosome
- neutralize endosomal acidification
- block fusion with lysosome
- sequesters MHC-II molecules from fusion / going to the cell surface
(1) lymphocyte recognize antigens to initiate responses
(2) lymphocytes and (3) recognize antigens to perform their function
1- Naive
2- effector T cells
3- Abs
B cells recognize antigens via (1); T cells via (2)
1- Abs
2- T-cell receptors (TCR)
antigen receptors of lymphocytes have (1) components to capture antigen and it is made of (2) and (3); then there are (4) components to carry out function
1- recognition
2- variable/constant regions
3- light/heavy chains
4- signal transduction
BCRs are also (1) and will recognize the following chemical structures: (2). (1) can be expressed as (3) or (4).
(B-cell receptors)
1- Abs
2- proteins, lipids, carbs, nucleic acids (microbes, toxins in native form)
3- membrane-bound Ag receptors on B-cells
4- secreted proteins
the (variable/constant) regions are responsible for recognition of antigens
variable domains, in secreted or membrane-bound form (constant regions on secreted Abs can play minimal role)
describe composition of BCR
4 polypeptide chains: 2 identical heavy chains and 2 identical light chains
the (1) region of the (light/heavy) chain on a BCR recognizes Ag and the (3) region on (light/heavy) chain binds and activates complement
1- Fab region
2- light chain (constant and variable)
3- Fc region
4- heavy (constant)
describe domains of light chain on Ab
- N-terminal is variable and site of antigen binding
- C-terminal is constant, defined as λ or κ
describe domains of heavy chain on Ab
- heavy chain variable region determines class: Ig- G, A, M, E, D
- constant region is nearly invariant, defined as α, γ, δ, µ, ε
Ig(1) and Ig(2) have an extra heavy chain domain in the constant region
IgM, IgE
describe the 3 types of variability found in Igs between people
Isotype: 5 major classes of Abs (H/L chains)
Allotype- alleic variants of constant domain (only one parent’s is expressed)
Idiotype- individual variability of H/L chains in Variable regions
define function for all 5 Igs
- IgM- 1st responder to new Ag
- IgG plasma, memory cells produce as secondary responder (most abundant)
- IgA- present in blood, serous, mucus secretions
- IgE- allergic responses, parasitic worm infections
- IgD- receptor on B cells
Ig(_)- monomer, produced by plasma cells (primary) and memory cells (secondary), most abundant
IgG
Ig(_)- monomer/dimer, circulates in blood, present in serous/mucous secretions
IgA
Ig(_)- pentamer (5 monomers), 1st class synthesized in Ag encounter (not opsonizer, best complement activator)
IgM
Ig(_)- monomer, receptor of antigen on B cells
IgD
Ig(_)- involved in allergic responses and parasitice worm infections
IgE
_____ is the only Ig that crosses the placenta
IgG
define affinity in a BCR
strength of ONE interaction (note- there’s affinity maturation)
define avidity in a BCR
strength on MULTIPLE interactions (non-covalent)
define cross-reactivity in a BCR
one Ab binding different epitopes
what mediates signalling functions on a BCR
Igα and Igβ (+ other co-stimulators)
explain monoclonal Abs
one clone of B cells makes one Ab specific for one Ag
describe composition of TCRs
2α chains- one constant, one variable 2β chains- one constant, one variable Note- no secreted form, no class switching
_____ region of BCRs and TCRs is the most variable region
CDR3
CD(1) and CD(2) are associated with TCR complex
1- CD3
2- CD4 or CD8
describe CD3 structure and its role in the TCR complex
- 3 dimers: γε, εδ, ζζ/ζη
- cytoplasmic tail: ITAMs (immunoreceptor tyrosine-based activation motif) responsible for signal transduction for TCR complex
list the 3 phases of B-cell development
- Ag-ind.: generate immunocompetent cells
- Ag-dep.: activate mature cells
- differentiation into plasma/memory cells
list the steps of Ag-Indep. phase of B-cell maturation
- HSC (hematopoietic stem cells)
- lymphoid progenitor / stem cell
- Pro-B cell (B cell progenitor)
- Pre-B cell
- Immature B cell
Pro B-cells have high expression of (1) and (2), and (3) is critical for its maturation into Pre-B cells
1- CD45R
2- CD19
3- IL-7
in Pro B cells ______ is present on cell surface
Ig-α, Ig-β
describe the two outcomes of Pro-B cell maturation (what is the determiner)
Rearrangement of Ig H chains:
-successful rearrangement => pre-B cells
-unsuccessful => apoptosis
(mediated by terminal deoxyribonucleotidyl transferase (TdT)
Pre-B cells have presence of (1) in cytoplasm and (2) on cell surface. Recombination of (3) on L chain occurs, and with failure recombination of (4) occurs.
1- Igµ
2- Igα, Igβ with surrogate L chain
3- Igκ
4- Igλ L chain
_______ are expressed in Pro-B cell to Immature B cell phases of development/recombination
RAG1, RAG2
BTK, aka (1), is involved in (2) and its deficiency leads to (3) with the following characteristic, (4)
1- Bruton’s tyrosine kinase
2- B-cell development
3- X-linked agammaglobulinemia
4- no Ab production, normal pre-B cell population (failure to mature, enter circulation)
list the three important characteristics of Immature B cells
- IgM expressed on surface
- functional BCRs appear
- Negative selection (clonal deletion) occurs
Mature B cell, aka (1), expresses (2) and (3) and undergoes further maturation via (4) process
1- follicular B cells
2- IgM
3- IgD
4- RNA processing of H chain
describe characteristics of Naive B cell
- migration out of bone marrow
- quiescent (in Go phase)
- has not encountered antigen
CD_ is the key B cell marker
CD19
CD_ is expressed in all but the first and last stages of B cell development and is a key target of monoclonal Abs in B cell lymphomas/leukemias
CD20
_____ signaling is a key driver of B cell malignancies
dysregulated BCR (note- x targets downstream kinases)
list the order of Thymocyte development (include location)
- HSC (hematopoietic stem cells) in bone marrow
- common lymphoid progenitor, migrates to thymus: IL-7
- T cell precursor (pro-T cell): no TCR, CD3
list 4 outcomes of T cell maturation in the thymus
- weak recognition of MHC-II/peptide => CD4+ T cell (positive selection)
- weak recognition of MHC-I/peptide => CD8+ T cell (pos. sel.)
- no recognition of MHC/peptide => apoptosis (failure of pos. sel.)
- strong recognition of MHC-I/II/peptide => apoptosis (neg. sel.)
(1) is a transcription factor expressed in the (2) region of the thymus to drive negative selection of self-recognizing T cells; defective (1) can lead to (3)
1- AIRE (autoimmune regulator)
2- medulla
(don’t want cells to recognize self)
3- autoimmune diseases
where in the Abs do people differ based on allotype
constant regions of H and L chains
lymphocytes use (1) number of genes to make over (2) different Abs
1- 500
2- > 1 billion
list the two types of changes genes of lymphocytes undergo
1) somatic recombination (VDJ joining- non-homologous)DNA recombination)
2) Junctional diversity: addition/removal of NTs among VDJ joints
the largest contribution to diversity of antigen receptors is…
junctional diversity
Somatic recombination occurs on (1) of BCRs and (2) of TCRs among the following segments: (3). This occurs during the (4) phase of development / maturation.
1- H and L chains
2- α β δ γ chains
3- Variable, Diversity, Joining
4- Ag-independent phase
RAG1/RAG2 function to (1) during the following phases of B cell development: (2)
1- breakdown and rearrange gene components (H and L chain)
2- Pro-B cell (H chain), Pre-B cell (H chain complete, L chain), Immature B cell (L chain complete)
Ig H chain gene rearrangement occurs during (1) phase of development
Ig L chain occurs during (2) phase
1- Pro-B cell (progenitor) to Pre-B cell
2- Pre-B cell to Immature B-cell
cytoplasmic µ+ is indicative of ____ phase of B cell development
Pre-B cell (µ codes for IgM)
presence of just surface IgM is indicative of ____ phase of B cell development
Immature B cell
presence of surface IgM and IgD is indicative of ____ phase of B cell development
Mature B cell (not in Bone Marrow)
RAG1/RAG2 are critical components of ________ process
somatic recombination
H chain recombination of (1) occurs during pro-B cell phase, (2) during pre-B cell phase
L chain somatic rearrangement occurs during (3) phase
1- DJ
2- VDJ
3- immature cells
define allelic exclusion
B cells will only express genes from a chromosome from ONE parent- never both
junctional diversity includes the following two components…
- junctional flexibility
- P-nucleotide/N-nucleotide addition
define junctional flexibility
exons are spliced, => slight variation in position of segmental joining
describe P-nucleotide addition
addition of random NTs to cleaved hairpin during the joining of segments
describe N-nucleotide addition
-addition of random NTs to 3’ cut end of segments
-TdT (terminal deoxynucleotidyl transferase) adds NTs to heavy chain gene
(Note- V-J, V-DJ, VD-J joints in variable domain inc diversity)
list the two methods of BRC variability after maturation and migration out of the bone marrow
- somatic hypermutation
- class switching
In somatic hypermutation B cells in the (1) area are proliferating following antigen contact, and (2) mutations occur in the (3) region of the Ig via (4) enzyme in order to (5).
1- secondary lymphoid organs 2- point mutations 3- variable region 4- AID (activation induced cytidine deaminase, C --> U) 5- improve affinity
describe class switching of BRCs
- occurs after Ag stimulation
- V-(D)-J units will stay and be associated with different constant regions
- IgM(µ) –> A(α), G(γ), D(δ), E(ε)
- decided by which ever gene is closest (α γ δ µ ε) to variable after rearrangement
- only occurs once
list the regulator(s) of class switching of BRC
-IL-4 predominately
-IFN-γ
-somewhat IL-5 (IgE)
(activation of CD40-CD40L)
AID is important for….
(activation-induced cytidine deaminase)
- somatic mutation
- class switching
(T/F) B-cells and T-cells both undergo somatic mutation
F- only B cells`
TCR rearrangement is analogous to BCR where rearrangement of (1) chains occur in pre-T cell, then (2) chains in immature T cell [included segments]
1- β chain (D-J joining –> DJ-V joining // analogous to H chain)
2- α chain (V-J joining)
list the factors of generating TCR diversity (hint- 6)
- multiple germ-line segments
- combinatorial V-(D)-J joining
- Junctional flexibility: imprecise joining at junctions
- P-region NT addition
- N-region NT addition
- combinatorial association of α and β chains (or γ/δ chains)
