immunology exam 3

immuno exam 3

What is the lymphatic system?

a network of vessels that collect excess fluids and directs them to the largest lymph vessel and empties to the left subclavian vein

What is the largest lymph vessel?

thoracic duct

Where do lymph nodes congregate?

where extremities come off of the trunk and near major joints

What are lymph nodes?

small filter-like nodules

How to DC cells create an immune response?

1. DCs exit the bone marrow in an immature state and enter circulation
2. DCs leave circulation and take up station in peripheral tissue
3. infection
4. contact with pathogen, recipient of activation signals through pathogen recognition receptors
5. transition to activation and processing of protein antigens
6. maturation and migration
7. antigen presentation to T cell and initiation of T-dependent immune response

What are protein antigens?

unit of recognition in the adaptive immune system

What are co-stimulatory molecules?

CD80 and CD86

What is CCR7?

chemokine receptor expressed on activated dendritic cells and naiive T cells

Explain maturation and migration of DCs

DCs cross a basement membrane and enter draining lymphatics making their way to regional lymph nodes

What are the cradles of T-dependent immune response?

lymph nodes

How do T cells enter lymph nodes?

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1. naïve T cells highly express L selectin that interacts with carbohydrate groups of endothelium bound CD34 and GlyCAM-1
2. slows T cells and initiates rolling
3. LFA-1 on T cell binds to ICAM-1 and 2 on endothelium
4. CCR7 on T cells interacts with membrane bound CCL19 and 21
5. T cells move up CCL concentration gradient and initiate diapedesis across endothelium into lymph node cortex

What is TCR made up of?

alpha and beta subunits

TCR \_____ signal by itself. It requires \____

cannot; CD3 complex

What is the CD3 complex composed of?

two epsilon, two zeta, one delta, and one gamma chain

What doe CD3 subunits possess?

ITAM (immunoreceptor tyrosine-based activation motif)

How is signal 1 transduced?

1. opposing faces of DC and T cell bring into contact their respective transmembrane protein (MHC/peptide complex and CD3 on DC / CD4 on T cell)


2. when TCR complex binds to MHC/peptide complex and CD4 interacts with MHC --> conformational change and physical proximity leads to activation of the scr homology tyrosine kinases (Fyn and Lck)
3. these phosphorylate the double-tyrosine motifs found in the ITAMs
4. tyrosine kinase ZAP-70 binds to phosphorylated ITAM on zeta chain --> ZAP-70 becomes activated
5. ZAP-70 phosphorylated SLP-76
6. SLP-76 interacts with GADS to form an activated complex
7. PLC binds to LAT and SLP-76 but needs to also bind to Itk--> one interacted with Itk, PLC quires full enzymatic activity

What is the resting phase of signal 1?

in the resting state, ITAM motifs on CD3 are not tyrosine phosphorylated. Fyn and Lck kinases are not activated

What does activated PLC catalyze?

breaks down PIP2 to DAG and IP3

What happens when IP3 binds to IP3 receptors?

opens calcium channels in the ER to release stored calcium

What does the increase in calcium concentration trigger?

calcium release activated calcium channels (CRAC)

What is the result of the calcium channels opening?

greatly increased calcium levels in the cytoplasm

What is calmodulin?

calcium binding protein

What is calcinerin?

\-phosphatase

\-remove phosphate groups

How do calcineurin and calmodulin work together?

regulate the activity of target proteins as a consequence of changes in intercellular calcium concentrations

What is NFAT?

\-nuclear factor activate t cells

-target of calcineurin

-when a conformational change takes place, unmasking of a nuclear translocation signal

What can DAG initiate?

additional signaling pathways by binding to and activating protein kinase C-0 (PKC-0) and RasGPR

What is the main purpose of T cell signaling?

to transcriptionally activate the gene encoding the T cell autocrine growth factor IL-2

What do T cells need to proliferate and expand?

IL-2 (IL-2 is critical for the initiation of any T cell dependent immune response

CD80 and CD86 intact with CD38 on the T cell to

supply signal 2

What does signal 2 accomplish?

\-increases stability of IL-2 mRNA and it also activates additional nuclear facts that enhance IL-2 genes transcription resulting in 20-30-fold increase in IL-2 secretion

-formation of high affinity IL-2 receptor on activate T cell

What is the low-affinity form of the IL-2 receptor?

comprised of a beta and a gamma chain

What is the high affinity form of the IL-2 receptor?

comprised of a beta and a gamma and an alpha chain

when is co-stimulation required?

only needed for naïve T cells

Naïve T cells are stimulated with only signal I,

they will fail to activate and enter anergy

What does anergic mean?

T cell will be resistant to later activation

What are the proteins on T cells that act as off switches?

\-PD-1 (interact with PD-1 ligand)

\-CTLA-4 (interact with costimulatory molecules)

What provides a third signal to T cells that affect their development?

soluble factors secreted by DCs and other accessory cells

What is Leishmania sp.?

a protozoan parasite transmitted by bite of the sand fly

Explain Leishmania sp.

\-engulfed by macrophages, can survive in phagosome

\-two disease syndrome result, localized (Bagdhad boil) or disseminated “mucocutaneous”

What is leprosy caused by?

mycobacterium leprae

Explain leprosy

\-two distinct disease syndromes, tuberculoid leprosy and lepromatous leprosy

Explain tuberculoid leprosy

localized infection analogous to the Bagdhad boil

What is the bagdhad boil?

a controlled infection resulting from Th1 dominated immunity

Th1 immunity is responsible for

localized disease

Th2 immunity is responsible for

disseminated disease

What is the primary cytokine produced by Th1?

INF-gamma (activator of macrophages, destructive to phagocytic microbes)

How does Th1 help macrophages kill?

\-Th1 effects have CD40L

\-when macrophage is presenting antigen to T cell, CD40L can signal through CD40 on macrophage

\-this with INF-gamma endows the macrophage with the capacity to fuse lysosome with phagosome and kill pathogen

What is cell mediated immunity?

activated Th1 cells produce a host of factors that each coordinately support immunity against intravesicular pathogens

Activated Th1 cell : INF-gamma and CD40L

activated macrophage to destroy and engulf bacteria

What is the containment strategy?

\-production of granuloma

\-center contains infected macrophage that has undergone membrane fusion to form multinucleate giant cells

\-unfused macrophages called epithelioid cells surround giant cells

\- these are surrounded by T lymphocytes

\-live microbes can persist for years in granuloma, reawake infection when immune system is weak

What do Th2 type T-cells specialize in?

supporting humoral immunity (antibody mediated)

Th2 produces IL-4 which

promotes class switching in B cells

\-tendency to switch to non-complement-fixing and non-opposing Ab that serves neutralization function and promoted IgE AB involved in allergy and control **of** helminths

How is Th2 adapted for eliminating multicellular helminths?

interplay between Th2 cells, mast cells, and eosinophiles

What is IgE produced by B cells a result of?

high Th2 derived IL-4 and IL-5 binds to the FcERI on both mast cell and activated eosinophiles

What does antigen binding to IgE allow for?

release of histamine from mast cells

Explain histamine

\-poisonous to helminths, increases mucous production and gut motility facilitating the flushing of parasites.

What do eosinophils do?

\-mediate a form of antibody dependent cellular toxicity

\-disgorge their granular contents upon the helminths and kill them directly

Signals 1 and 2

naïve CD4 T cell → proliferating T cell

Signals 3

proliferating T cell → immature effector T cell → Th2 and Th1

Th1 cell

INF-gamma, IL-2

macrophage activation

B cell activation

production of opsonizing antibodies like IgG1

Th2 cell

Il-4, IL-5

general activation of B cells to make antibodies

What is Th17 subset?

the newest accepted Th subset

What is Th17 associated with?

successful clearance of a variety of infections including bacterial and fungi

\- many of these establish infection on mucosal surfaces

(also maybe contributing factor to autoimmune disease)

Explain the Treg subset

\-not promote immune response, limit them

\-function to maintain peripheral tolerance and tone down severity of strong ongoing inflammatory response (quiet things down once threat is eliminated)

\-may inhibit anti-cancer response because of how strong

Il-12 to CD4 to Th1

\-INF-gamma, IL-4, IL-5

\-intracellular pathogens, acute inflammation

IL-4 to CD4 to Th2

\-IL-4, IL-5, INF-gamma, IL-10, IL-13

\-helminths, allergy

IL-23, 6, 1beta to CD4 to Th17

\-IL-17, INF-gamma, IL-4

\-extracellular bacteria, fungi, chronic inflammation, autoimmunity?

TGF-beta to CD4 to Threg

\-IL-10, TGF-beta

\-regulatory, anti-inflammatory

Explain TGF-beta pathway of CD4 cell

FoxP3 → TGF-beta, IL-10 → Treg cells

Explain IL-12 pathway of CD4 cell

T-bet → IL-2, INF-gamma → Th1 cell

Explain IL-4 pathway of CD4 cell

GATA-1 → IL-4, IL-4 → Th2 cell

Explain IL-23, IL-1beta, IL-6, TGF-beta pathway of CD4 cell

ROR-gamma → IL-17, IL-22 → Th17

The 3rd signal factors are

\-TGF-beta, IL-12, IL-4, and IL-23, IL-1beta, IL-6, TGF-beta

\-drive polarization

The transcription factors are

\-FoxP3, T-bet, GATA-3, ROR-gamma

\-characteristic of subset

\

The factors produced by subset are

TGF-beta, IL-10, IL-2, INF-gamma, IL-4, IL-5, IL-17, IL-22

What do DCs require for IL-12 induction?

dual TLR ligand or INF-gamma plus single TLR ligand stimulation

Activation of CD8 cytotoxic T cells

\-directly kill infected or altered self cells

\-not always make their own IL-2

\-3 general pathways

After naive T cell is activated and gains effector function it

no longer needs co-stimulation with B7 molecules (CD80 and CD86)

Sensitized cytotoxic T cells

are efficient serial killers of target cells bearing the appropriate MHC:peptide complexes

What do cytotoxic T cells produce after initial activation in secondary lymphoid tissue?

cytotoxins that is immediately packaged into lytic granules

How do the lytic granules interact with target cell?

\-through intercellular adhesion molecules

\-the interrogated as to if it expresses the peptide target or ligan of the cells TCR complexed with self class I MHC

\-if target identified, granules migrate to point of interface and disgorge the contents

What to cytotoxic T cells cytotoxins include?

granzymes, granulysin, and perforin

What do granulysin and perforin do?

form pored in the membrane of the target

What do cytotoxins induce?

programmed death of target cell called apoptosis

Mechanism of apoptosis

\-condensation of nucleus and DNA fragmentation → formation of membrane vesicles → breakdown of mitochondria and shriveling of cell

\- second mechanism : Fas ligand that signals through Fas on target cell

What are the mucosal surfaces of the body?

where interior body comes into contact with the outside world

What type of tissue underlies mucosal surfaces?

a layer of epithelial cells line mucosal surfaces

What is mucous?

a thick fluid that contains glycoproteins, proteoglycans, peptides, and enzymes

About 75% of lymphocytes

reside in lymphoid tissues associated with mucosal surfaces

How does mucosal immunity work?

control rather than eliminate microbes with minimal inflammation

What does bacteria in the gut synthesize?

vitamin K (we cannot synthesize it ourself)

What is vitamin K important for?

an important blood clotting factor

Why is normal flora important?

occupies a niche that could potentially be taken over by a disease causing species. if you get rid of commensal, you make room for parasite.

Secondary lymphoid tissues share similarities with

lymph nodes

What are the first encountered secondary lymphoid tissues?

\-in the back of the mouth

\-adenoids, palatine, and lingual tonsils (form Waldeyer’s ring)

What are gut-associated lymphoid tissues (GALT)?

\-largest lymph nodes in the body

\-called the mesenteric lymph nodes

What is lamina propria?

the connective tissues layers underlaying the gut mucosa

What are pyer’s patches and isolated lymphoid follicles?

additional lymphoid tissues extending from the very surface epithelium into the lamina propria

What are villi?

\-characteristic structure in the small intestine to enhance surface area

\-help with absorption

\-finger like projections

What do the dome structures protruding into the intestinal lumen represent?

the outward manifestations of pyer’s patches