Micro I-12, 13, 14 Adaptive Immunity I, Ii, Iii

Front 1

What is adaptive immunity?
Magnitude of response increases with?
Responses are generated by?

Back 1

- specific lymphocyte response to foreign antigen, which includes
the development of immunological memory.
- Magnitude of response increases with successive exposure to antigen
- These responses are generated by clonal selection of lymphocytes

Front 2

What is clonal selection?

Back 2

Clonal selection is the process by which lymphocytes are
activated and expanded by encounter with antigen that
is specifically recognized by the antigen receptor (TCR/BCR)

Front 3

What is the diff in specificity btwn innate vs adaptive immunity?

Back 3

- Structures shared by groups of related microbes vs. antigens of microbial and non-microbial origin

Front 4

What is the diff in diversity btwn innate vs adaptive immunity?

Back 4

- Limited; germline encoded vs. Essentially unlimited; Receptors produced by V-D-J recombination

Front 5

What is the diff in immunological memory btwn innate vs adaptive immunity?

Back 5

- No memory vs. memory for most antigens

Front 6

What is the diff in Soluble mediators btwn innate vs adaptive immunity?

Back 6

- Complement vs. Antibodies

Front 7

What is the diff in general cell types btwn innate vs adaptive immunity?

Back 7

- Phagocytes, NK cells vs. Lymphocytes

Front 8

What are other names for CD4+ T cell?
Function?

Back 8

- Helper T lymphocyte = Th cell
- direct and facilitate adaptive
and innate immune responses

Front 9

What are other names for CD8+ T cell?
Function?

Back 9

- Cytotoxic (“Killer”) T lymphocyte = Tc cell = CTL
- killing of cells infected with viruses and other intracellular pathogens

Front 10

What is the function of B cell?

Back 10

- production of antibodies

Front 11

Under what condition will cytoplasmic signal be initiated by the TCR?

Back 11

- If a TCR specifically recognizes the complex of peptide + MHC

Front 12

What does TCR recognition of specific antigen and MHC lead to?
What does ITAM stand for?
What are ITAMs?

Back 12

- tyrosine phosphorylation of CD3 and z-chain ITAMs
- immunotyrosine activation motif
- These are tyrosines in the cytoplasmic regions of specific lymphocyte receptors that become phosphorylated in response to cellular signaling

Front 13

MOA of T cell activation?
What family of tyrosine kinases are ZAP-70?
What are the three transcription factors?

Back 13

- Phosphorylation of TCR-z ITAMs -> ZAP-70 tyrosine kinase is activated -> cascade of downstream events,
-> activation of three transcription factors that are
critical for production of IL-2 -> proliferation, and acquisition of T cell effector functions
- “syk” family
- NFAT, NF-kB, AP-1

Front 14

What directly causes activation of NFAT of a TCR-regulated cytoplasmic signaling event?

Back 14

- Increased cytosolic calcium

Front 15

What happens if there is a blockade of TCR signaling?

Back 15

- prevents production of IL-2 and generation of T cell responses

Front 16

What would be the response of CD4+ T cells to IL-2?
What would be the response of CD8+ T cells?

Back 16

- Production of cytokines
- killing of targets infected
with intracellular pathogens

Front 17

What are the two drugs that inhibit the activity of calcineurin?
MOA?

Back 17

- Cyclosporine A (cyclosporine; CsA), FK-506 (tacrolimus)
- blocks activation of NFAT -> blocks synthesis of IL-2

Front 18

What is the effect of rapamycin?

Back 18

- inhibits signaling from
the IL-2 receptor -> block T cell proliferation and acquisition of effector functions = immunosuppresion

Front 19

What form of disease is ZAP-70 deficiency?
Moa?
Tx?

Back 19

- Form of severe combined immunodeficiency (SCID)
- Inhib nuclear transcription factors production -> Complete lack of CD8+ T cells & CD4+ T cells are non-functional -> frequent opportunistic infections -> failure to thrive
- bone marrow transplant

Front 20

What are T cell mitogens?
What are three main examples?

Back 20

- polyclonal stimulators that stimulate proliferation
- Bacterial superantigens, Mitogenic lectins, Pharmacological activators

Front 21

How does bacterial superantigen cause polyclonal activation?
Result?

Back 21

- simultaneous binding to TCR Vb and non-polymorphic region of MHC protein
- Superantigens activate up to 1/5 of T cells in the body -> massive release of cytokines -> moderate to severe illness, depending on the exposure

Front 22

What is Toxic shock syndrome caused by?
Major symptoms?

Back 22

- Caused by Staphylococcus aureus superantigen, TSST-1
- hypotension, organ failure, fever, etc.

Front 23

What is S. aureus food poisoning caused by?

Back 23

- Caused by S. aureus enterotoxins (superantigens): SEA, SEB, SEC, SED, SEE

Front 24

How do antigen-specific T cells find APCs presenting
the appropriate stimulatory peptide+MHC?

Back 24

- inflammatory stimuli -> Dendritic cells take up antigen in tissues -> migrate to peripheral lymphoid organs -> present foreign antigens to naïve T cells

Front 25

What are mitogenic lectins?

Back 25

- Plant derived carbohydrates that crosslink T cell surface receptors, mimicking antigen stimulation

Front 26

What is concanavalin A (ConA)?
What is effect?

Back 26

- Mitogenic lectin
- Activate T cells only

Front 27

What is phytohemagglutinin (PHA)?
What is effect?

Back 27

- Mitogenic lectin
- Activate T cells only

Front 28

What is pokeweed mitogen (PWM)?
What is effect?

Back 28

- Mitogenic lectin
- Activate both T & B cells

Front 29

What effect does phorbol ester (phorbol myristate acetate = PMA) in conjunction with ionomycin have?
MOA of PMA?
MOA of ionomycin?

Back 29

- T cell activation as a pharmacological stimulator
- Inc NF-kB and AP-1 -> inc IL-2 -> T cell act.
- NFAT -> inc IL-2 -> T cell act.

Front 30

MOA of naïve T cells encountering dendritic cells?
MOA of naïve T cell that doesn’t encounter specific antigen?

Back 30

- Naïve T cells recirculate thru secondary lymphoid organs -> leave blood at HEV -> enter lymph node cortex -> mingle with professional APC (dendritic cells and macrophages) -> activateTcells to proliferate -> T cells differentiate into effector cells -> leave lymph node in efferent lymph -> enter circulation
- Leave lymph node in efferent lymph and eventually rejoin bloodstream

Front 31

How do naïve T cells gain entry to lymph nodes from blood?

Back 31

- Circulating lymphocyte enters HEV in lymph node -> binding of L-selectin of lymphocyte to GlyCAM-1 and CD34 to allow rolling adhesion -> LFA-1 (integrin) of lymphocytes activated by chemokines bound to extracellular matrix -> activated LFA-1 binds tightly to ICAM-1 -> diapedesis

Front 32

When do dendritic cells stimulate CD4+ T cells during the interaction?
MOA?

Back 32

In presence of exogenous antigen
- Dendritic cells uptake of extracellular ptns -> processed by lysosomes -> biosynth and transport of class II MHC in vesicles -> expression of peptide-MHC complexes on cell surface -> complex with TCR

Front 33

Following specific antigen activation, naïve T cells differentiate into what?

Back 33

- either effector T cells or memory T cells

Front 34

What allows effector (and memory) T cells to leave the blood and enter infected cells?
MOA?

Back 34

- Changes in their pattern of expression of cell interaction molecules to “find” sites of peripheral inflammation
- naïve T cell (high L-selectin/No VLA-4) interact w/ CD34 -> recirculation btwn blood and lymph nodes -> effector cell (low L-selectin/high VLA-4) interact w/VCAM-1 -> recirculation btwn blood and inflamed peripheral tissues

Front 35

Why do effector (and memory) T cells arrive AFTER cells of the innate
immune system?
What conclusion can be made about the T cells?

Back 35

- due to delayed expression of VCAM-1 by activated
endothelial cells
- Effector and memory (but not naïve) T cells efficiently bind to
activated endothelium and transmigrate into inflamed tissues

Front 36

Where do naïve T cells preferentially migrate?
Where do effector and memory T cells preferentially migrate?

Back 36

- from the blood to lymph nodes
- From the blood to inflamed peripheral tissues

Front 37

What are the 3 reasons why memory T cells (CD4+ and CD8+) are more rapidly activated than naïve T cells?

Back 37

- Activation is independent of costimulation
- Generation of effectors is very fast (hours (vs. days for naïve T cells))
- “Secondary” (memory) response results in much more rapid recognition and clearance of pathogens than “primary” (naïve) response

Front 38

What allows memory T cells to be long-lived?
What is the clinical relevance?

Back 38

- By Maintaining in a resting state, scanning peripheral tissues until antigen is encountered
- memory cells are gradually lost with age, as evidenced by re-emergence of VZV (chicken pox virus) in the elderly, as “shingles”

Front 39

What does the CD4+ Th1 subset produce?
Effect?
What can inhibit the activation of macrophages?

Back 39

- interferon-g (IFN-g) and CD40 ligand
- bind to MHC II -> Activate macrophages -> inc MHC and co-stim molec, inc TNF (inflam cytokine), inc IL-8, inc toxic oxygen radicals, inc phagocytic activity -> kill intravesicular bacteria
- IL-10

Front 40

In response to viruses and intracellular bacteria, what do macrophages and dendritic cells produce?
Effect?

Back 40

- produce IL-12.
- IL-12 promotes the production of IFN-g by NK cells -> differentiation of naïve CD4+ T cells to Th1 cells -> Th1 cells produce IFN-g -> amplify Th1 differentiation

Front 41

What does Th2 do upon antigen recognition?
Result?

Back 41

- Induce CD40 ligand and cytokine (IL-4, IL-5, IL-6) expression
- stimulates B cell proliferation and differentiation -> immune response to certain parasites

Front 42

How do Th2 cells inhibit Th1 responses?
How do Th1 cells inhibit Th2 responses?

Back 42

- Produce IL-10 and TGF-beta -> IL-10 prevents macrophages from activating Th1 cells by preventing synthesis of IL-12 by macrophage & TGF-beta acts directly on Th1 cells to inhibit their growth
- Produce IFN-gamma -> blocks growth of Th2 cells

Front 43

How do Tuberculoid leprosy differ from lepromatous form of the disease in terms of Th response?
What does this mean in terms of cytokines?

Back 43

- dominant Th1 response vs. Th2 response, respectively
- Tuberculoid causes IL-2, IFN-gamma, TNF-beta secretion & Lepromatous causes IL-4, IL-5, and IL-10 secretion.

Front 44

How can a naïve CD8 T cell be activated directly by a virus-infected dendritic cell?

Back 44

- High tissue inflammation -> Dendritic cells express high levels of B7 and activate naïve CD8 T cells -> activated CD8 T cell makes IL-2 -> prolif and differentiation.

Front 45

How does cytokines indirectly activate naïve CD8+ T cells?

Back 45

- APC stimulates effector CD4 T cell -> activates APC via CD 40L interaction with CD 40 on dendritic cell -> activated APC expresses B7, which co-stimulates naïve CD8 T cell

Front 46

How do cytokines directly activate naïve CD8+ T cells?

Back 46

- APC activates CD4 T cell to make IL-2 and naïve CD8 T cell to express IL-2 R -> IL-2 secreted by activated CD4 T cell is bound by CD8 T cell -> activate CD8+ T cell

Front 47

What effect do effector Th cells have in expressing CD40L?

Back 47

- increase expression of B7 on APCs, helping APCs successfully activate CD8+ T cells

Front 48

What is effect when CTL secretes cytolytic granules?
MOA?
How does T cell become polarized?

Back 48

- induces target cell apoptosis
- Initial adhesion to targe cell has no effect on location of lytic granules -> engagement of T cell R causes T cell to become polarized -> ptns stored in lytic granules are then directed onto target cell.
- Cortical actin cytoskeleton at site of contact reorganizes, enabling microtubule-organizing center, Golgi apparatus, and lytic granules align towards target cell

Front 49

What is the effect of interaction between Fas-ligand (CTL) and Fas (of virus infected target cell)?

Back 49

- induce apoptosis of virus-infected target cells

Front 50

What is a T-dependent antigen (TD)?
What does it do?

Back 50

- any antigen with a protein component that can be presented by class II MHC
- Binds to B cells via cell surface Ig molecules (BCR) in the lymph nodes or spleen

Front 51

What happens to pathogens once in the lymph node?

Back 51

- Free pathogens undergo endocytosis by macrophages while dendritic cells carrying pathogens stimulate division of pathogenic specific small lymphocytes into effector lymphocytes.

Front 52

What is the first step of B cell activation?
What type of receptor is on the mature, naïve B cell?

Back 52

- B cell receptor (BCR) crosslink by repetitive epitopes of antigens on the surface of a bacterial cell.
- IgM B cell receptor and associated Igalpha and Igbeta

Front 53

What does BCR crosslinking by antigen lead to?
MOA?
What other kinase is Syk kinase similar to?

Back 53

- Phosphorylation of Iga and Igb ITAMs , and activation of “syk” kinases
- Clustering of antigen receptors allows receptor-associated kinases to phosphorylate ITAMs -> Syk binds to doubly phosphorylated ITAMs and is activated on binding
- Zap 70

Front 54

What does Syk kinase help produce?
What will this product do?

Back 54

- NFAT, NF-kB, and AP-1 nuclear transcription factors
- allow secretion of IgM

Front 55

What does B cell co-receptor recognize?
What does it do?

Back 55

- the C3d fragment on complement-opsonized antigen
- marks Ag as FOREIGN -> augments signals from BCR

Front 56

What will BCR binding to antigen
lead to?
MOA?

Back 56

- antigen internalization and degradation via the exogenous pathway of antigen processing
- Presented by MHC class II -> specific recognition of this antigen by CD4+ T cells -> B cell differentiation

Front 57

Which MHC binds to extracellular ptns?

Back 57

- class II MHC

Front 58

Naïve B cells are activated in the lymph node by antigen stimulation
of the BCR and interaction with?

Back 58

- antigen-specific Th2 cells

Front 59

Expression of what is induced due to specific antigen recognition/TCR engagement?
T-helper activation of B cells via CD40 + cytokines causes what?

Back 59

- expression of CD40 ligand (CD40L)
- B cell differentiation: Ig class switching and secretion of the non-IgM isotypes (i.e., IgG, IgE, IgA) and somatic hypermutation (affinity maturation) of Ab gene V-regions

Front 60

Antibody isotype switching is dependent upon?

Back 60

- T cell help

Front 61

Besides B cell differentiation events, what does B cell interaction with CD4+ helper T cells lead to?

Back 61

- production of germinal centers in the lymph node and spleen

Front 62

What will somatic hypermutation cause?
What conclusion can be made from this?
MOA of somatic hypermutation and affinity maturation occur in the germinal center?

Back 62

- intro of random mutations in the V-regions
- some mutations are beneficial (improve antibody
affinity for antigen), while many are not (reduce
antibody affinity or introduce a STOP codon)
- Activation of B cells and migration into germinal center -> B cell proliferation -> somatic hypermutation of Ig V genes -> B cell recognition of antigen on follicular dendritic cells; selection of high affinity B cells -> death of B cells that do not bind antigen -> efflux of high affinity antibody-secreting and memory B cells

Front 63

MOA of bCR with high affinity for antigen during affinity maturation?
With low affinity?

Back 63

- Germinal center B cell expresses higher affinity Ig for antigen -> T cell help and B cell R cross link sustain B cell proliferation and diff -> memory B cell and plasma cell
- B cell dies by apoptosis

Front 64

Where do Ab that is secreted by effector B cells, called plasma cells, enter?

Back 64

- enters the lymph and blood plasma

Front 65

The secondary (memory) B cell response to antigen is characterized by what characteristic of production of antibody?

Back 65

- produced at higher levels and have higher affinity than in the primary (naïve) antibody response

Front 66

What is the definition of T-independent antigens?
How do T cells respond to pure carbohydrate antigen?

Back 66

- carbohydrate antigens that provoke an antibody response independent of help from CD4+ T cells
- carbohydrates cannot be presented by MHC, so T cells are incapable of responding to pure carbohydrate antigen

Front 67

How do TI-1 and TI-2 antigen differ in terms of activation of non-specific B cells?
In terms of requiring repeated epitotes?

Back 67

- Does it vs. doesn’t do it, respectively
- Doesn’t do it vs. do it, respectively

Front 68

Is bacterial LPS an example of TI-1 or TI-2 antigen?
What about pneumococcalpolysaccharide?

Back 68

- TI-1 (not BCR-dependent)
- TI-2 9 Antigen-specific binding to BCR)

Front 69

What do carbohydrate antigens with highly repetitive structures
(e.g., carbohydrate coats of “encapsulated” bacteria) bind to?

Back 69

- very efficiently crosslink the BCR, stimulating B cell proliferation

Front 70

What are the types of cells involved in TI-independent antigen?
When is it produced?
What cell surface markers are expressed?
MOA?

Back 70

- B-1 B cells
- early in development
CD5
- B-1 cell binds bacterial capsular polysaccharide or cell wall components and is activated by IL-5 -> B-1 cell secretes IgM anti-polysaccharide Ab -> IgM binds polysaccharide capsule -> activation of complement and removal of encapsulated bacteria

Front 71

Why does TI response lack certain features that TD response has?
How do TI and TD responses differ in terms of class switching?
In terms of somatic hypermutation or affinity maturation?
In terms of production of memory B cells?

Back 71

- Because there is no T cell help (no CD40 stimulation) for T-independent (TI) antigens
- TI lacks class switching: antibodies to TI antigens are of IgM isotype only
- TI response has no somatic hypermutation or affinity maturation: antibodies to TI antigens are often low affinity
- TI response has no production of memory B cells: there is thus no TI “secondary” response

Front 72

How do primary and secondary response differ in TI response?

Back 72

- Identical to each other: significant lag time, modest IgM (ab) titer, no memory

Front 73

How are TI responses effective for making vaccines to encapsulated bacteria?
MOA of “conversion” of TI responses to TD responses in vaccine design?

Back 73

- conjugate TI carbohydrate antigens to TD “carrier” proteins, such as tetanus toxoid
- B cell binds bacterial polysaccharide component of vaccine conjugate -> conjugate is internalized and degraded -> peptides from toxoid are presented to T cell -> CD40 stimulation -> activates B cell (->differentiation, isotype switching, somatic hypermutation) -> act B cell differentiates into a plasma cell that produces antipolysaccharide Ab that bind to bacteria -> high affinity, long-lasting IgG

Front 74

What allows IgA to be transported across epithelial surfaces?
MOA?

Back 74

- by the poly-Ig receptor, where it becomes associated with mucosal secretions
- Binding of IgA to receptor on basolateral face f epithelial cell -> receptor-mediated endocytosis of IgA -> transport of Ig A to apical face of epithelial cell -> receptor is cleaved, IgA is bound to mucus through secretory place

Front 75

How is IgG specifically transported across the placenta?

Back 75

- By the FcRB receptor

Front 76

What are the two MOA of antibody-mediated protection from infection with intracellular pathogens?

Back 76

Ab blocks binding of virus to virus receptor -> prevents receptor-mediated endocytosis of virus -> prevents acidification of endosome after endocytosis triggers fusion of virus with cell and entry of viral DNA
- Abs against adhesins block colonization and uptake of bacteria -> bacteria colonize human cell surfaces by using bacterial adhesins -> some species of bacteria become internalized and propagate in internal vesicles

Front 77

What type of receptors are made from IgG?
from IgE?

Back 77

- Fc-gamma: phagocytosis of antigen and ADCC
- Fc-epsilon: mast cell degranulation and eosinophil rxns to parasitic worms

Front 78

What do Fcg receptors do?
MOA?

Back 78

- facilitate endocytosis of opsonized pathogens by macrophages
- Ab binding to bacterium -> Ab-coated bacterium binds to Fc receptors on cell surface -> macrophage membrane surrounds bacterium -> macrophage membranes fuse -> create phagosome (memb-bound vesicle) -> lysosomes fuse with phagosome -> create phagolysosome

Front 79

What do Fcg receptors on NK cells enable?
MOA?

Back 79

- ADCC: Antibody-dependent cell-mediated cytotoxicity
- Ab binds antigens on surface of target cells -> Fc receptors on NK cells recognize bound Ab -> crosslinking of Fc receptors signals NK cell to kill the target cell -> target cell dies by apoptosis

Front 80

How do mast cells get activated?

Back 80

- Resting mast cell has preformed granules containing histamine and other inflam mediators -> multivalent antigen crosslinks IgE Ab bound at mast cell high affinity Fce receptor -> degranulation -> release of inflammatory mediators -> allergy, asthma

Front 81

What contribution does high-affinity Fc-epsilon receptor have on eosinophils?

Back 81

- Contributes to eosinophil responses to parasitic worms