theme 1 (pt. 1 - immunity)

drie lagen van afweer → van buiten naar binnen

• fysiek/chemisch

• innate

• adaptive

cellen die horen bij innate → 7

• neutrofielen, basofielen, eosinofielen

• macrofagen

• DC, NK-cellen

• mastcellen 

wat zijn PAMPs → 2 voorbeelden

• pathogen associated molecular patterns

• recognized by → pathogen recognition receptors (PRRs)

  • Toll like receptor is a PRR

• LPS, dsRNA → stuff that isn’t on host cells

what are DAMPs → 2 voorbeelden

• damage-associated signals → signal tissue injury

• ATP extracellular, DNA buiten cel → it’s on host cells

3 complement routes + how activated

• lectine/MBL → needs MBL/lectin/ficolins

• classic → CRP or antibodies

• alternative → spontaneous

central step for all complement routes

cleavage of C3 → C3a + C3b

function of C3a(/C5a), C3b + MAC (which C?)

• C3a/C5a → anafylatoxines → inflammation + chemotaxis (= recruitement of immune cells)

  • C3a → recruits phagocytes (attracts effector cell)

  • they increase cap permeability → gaps → inflammation

• C3b → opsonization (effector cell binding on bacterium)

• C5b-9 = MAC → lysis 

inflammation caused by C3a/C5a → what enters beside complement and proteins

• leukocytes enter → resident macrophages get activated

happens after increased of blood-vessel permeability 

which Ig’s can activate complement → 3 and which one is most efficient

• IgG1

• IgG3

• IgM → most efficient 

main signals inflammation → 5

• tumor

• rubor

• dolor

• calor

• functio laesa 

which cytokines are produced by macrophages during infection → 5

• IL-1B

• TNF-a

• IL-6

• CXCL8 = IL-8

• IL-12

what does IL-6 do

• activates liver (acute phase proteins) 

• causes fever

• increases metabolism 

function neutrofieles

• quick phagocytosis → kill pathogens in phagolysosoom → die → cleaned up 

3 function of macrophages

• phagocytosis

• cytokineprod

• Ag presentation

how are NK cells activated (2) + what is their function/what do they kill

• type I interferones (IFN-a/B) + IL-12

• kill virus-infected cells through apoptosis

function DC

• schakel innate → adaptive

• present Ag in lymphnodes to T helper cells (CD4)

iC3Bb

• is convertase of soluble C3 → iniates alt pw (kickstart it)

C3bBb

• is convertase of alternative C3

• surface bound amplifier → main effector on microbes 

• protected by factor P

inhibition of C3bBb

• by factor H

• H binds to C3b (esp when on host cell)

  • prevents formation of C3bBb 

  • helps factor I cleave C3b → iC3b (inact)

granulocyte progenitor gives (3)

• neutrophil

• eosinophil

• basophil

what cytokines cause recruitement and activation of immune cells = 3

• CXCL8 

• IL-12

• CCL2

3 things involved in the recruitement of immune cells to sites of infection

• increased blood vessel permeability

• chemokine gradient

• adhesion molecules 

phagocytosis by neutrophils = 5 steps 

1. bac is phagocytosed by neutrophil

2. phagosome fuses with azurophilic and spec granules

3. pH of phagosome rises 

4. antimicrobial responses activated

5. bac is killed 

what happens after bac is killed by neutrophil = 3

1. pH of phagosome decreases 

2. fusion with lysosome allows acid hydrolases to degrade the bac completely

3. neutrophil dies by apoptosis and is phagocytosis by macrophage 

NK cells interferon response = 4

• IFN-a/B are produced by virus infected cells so the interferon response occurs

• induce resistance to viral replication in all cells

• increase expression of ligands for receptors on NK cells

• activate NK cells to kill virus-infected cells

interferon response type I = 3

• drives prolif of NK cells

• also drives differ of NK cells into cytotoxic effector cells 

• effector NK cells kill virus inf cells by inducing apoptosis 

B cell is host defense against

extracellular pathogens = bacteria flowing around

T cell is host defense against

intracellular pathogens = virus

variable region

• T and B cells have it

• is formed by V(D)J recomb

• has Ag binding site → gives specifity

constant region BCR

• determines Ab isotype → IgA, IgG etc

• can exist as membrane bound (BCR) or secreted (Ab)

constant region TCR

• anchors receptor in T cell membrane

• no effector function →

difference of Ag recognition between T and B cells

• BCR/Ab → direct binding to native Ag

  • recognizes native 3D shapes 

• TCR → indirect binding, only to processed peptides in MHC 

  • recognizes linear peptide fragments (on MHC)

clonal slection = 4

• generate large variety of lymphocytes

• during infection lymphocytes with rec that recogize pathogen are activated 

• select and expand the cell with wanted specifity 

• after prolif + diff of pathogen-activated lymphocytes → give effector cells that terminate infection

composition of Ig

• 2 heavy and 2 light 

• light → kappa en lambda → contains V and J

• heavy → contains V, D, J segments 

• somatic recombination 

rearrangement of TCRgenes

• scissors → RAG1/2

• part DNA is cut out → genereates recomb circle = TREC 

  • absence of TREC = absence of T cells 

two classes of MHC

• class I → CD8 cytotoxic T cells = intracellular Ag

• class II → CD4 Th cells = extracellular Ag

selection of T cells = 4

• choosing T cells that will not attack your own body

  • may only recognize part of self-MHC

• TC precursor from BM → develop in thymus 

• mature T cells leave thymus → secondary lymphoid tissues 

• in medullary epithelial cell → selection

somatic hypermutation = SHM

• during germinal center reaction

• further diversification of rearranged V ragions by SHM in prolif B cells

affinity mutation

• B cells bearing mutant Ig mol on their surfaces → selected 

• those with  bes binding survive = affinity maturation 

AIRE

• AI regulator protein

• drives transcription of tissue specific antigens in mTECs

• AIRE def = defect in clonal deletion

MHC II

• CD4 binds to beta domain of MHC-II

• bac is outside of cell and binds on surface

• CD4 activates B cells → antibodies 

MHC-I

• virus is already in the cell

• CD8 binds to alpha3 domain of MHC-I

• CD8 cells recognize patho peptide → kill it 

which 2/3 signals are required for T cell activation

• antigen specific signals

• co-stimulation

• cytokines

T cell activation - signal 1

• naive TC binds transiently to APC (DC) → then they recieve signals

• delivery of Ag spec signal through TRC = sig 1 

  • TC-APC interaction = stabilised 

  • TCR w/ CD3 complex → binds peptide-MHC complex on APC 

  • at same time CD4 (II) or CD8 (I) binds to MHC

  • CD3 = always part of TCR complex

T cell activation - signal 2

• required to trigger naive T cell activation (cause they always need a 2nd signal)

• co-stimulation → CD28 (TC) binds to B7-1/2 (CD80/86) on APC

when is only signal one sufficient for TC activation

when it’s activating T memory cells

activation via PRR on APCs

• microbial products = PAMP → bind to TLR (Toll) on APC

  • this increases expression of costim molecules

  • is link between innate and adapative

B7 = CD80/86 can bind to

• CD28 on T cell

CD40L consequences

• binds to CD40 on APC → reverse signal back into APC

• APC becomes more activated

  • upregulates B7 = stronger costim

  • more cytokine secretion = signal 3

  • increase ability to stim TC and help BC

IL 2 driven T cell proliferation

• local inflammation → naive TC expresses low-affinity IL-2 receptor 

  • no prod of IL-2 in TC yet

• Ag presentation + costimulation → act TC

• now TC makes IL-2 → place high aff IL-2 rec on surface

• this signal stimulates clonal expansion

TH 1 cells function + cytokine

• help macrophages to suppress intrac infections

• IGN-y

TH2 function and cytokines

• help basophils, mast clelsm eosinophils and B cells to response to parasite infection

• IL4, IL5

TH17 function and cytokine

• enhance neutrophil response to fungal + extrac bacterial infections

• IL17

T FH function and cytokine

• help BC become activated, switch isotype and increase Ab affinity

• IL21

T reg cells function and cytokines

• suppress the activities of other effector TC populations 

• TGF-B, IL10 

what does T reg suppress 

• CD4 → which will indirectly suppress CD8 (bc no CD4 = no optimal CD8 act) 

• keeps things in check

dark zone

fast proliferation (somatic hypermutation)

light zone

• B cells stop dividing → selection → then differentiation

• product → plasmacells or memory B cells 

effector memory TC = TEM

• mainly in non-lymphoid tissues = skin, lung, intestines

• react immediately when repeated contact with pathogen 

• fast, frontline protection

central memory TC = TCM

• mainly in secondary lymphoid organs → spleen, lymphglands

• can strongly proliferate when herstimulated

• leads to a huge golf of new effector TC when it is needed

TEM + TCM → T eff

• new infection → both TEM and TCM can again become activated

• TCM can then grow into new T effs 

  • TEM does not do this so only TCM leads to increase in TC population 

B cell activation signal 1

• Ag binds to multiple BCR‘s = crosslinkingen → Ag spec signal 

B cell activation signal 2

• BC co-receptor complex 

  • CD19 → signalling chain/amplifies signal 

  • CD21 → CR2 complement

  • surface Ig → specificity  

TC independent Ag

• do not require help of TC for act of B cell 

• but

  • no induction of BC memory

  • no class switching → only IgM

TC dependent Ag = most of them

• they require CD4 cells

• you get

  • induction of BC memory

  • affinity maturation

  • class switching → bc TC dep BC act leads to SHM

T follicular cells = Tfh function

• recognize peptide on MHC-II of BC

  • naive BC binds Ag through its BCR → takes that Ag efficiently → Ag degraded → those peptides are presented on MHC-II

  • BC becomes APC for that specific Ag

• BC receives CD40 and cytokines from Tfh

isotype switching

• DNA recomb of constant part of Ig mol

• while maintaning same Fab fragment = same spec

tolerance

• selection during maturation in BM/thymus = central tol 

  • immature BC in BM binds to self Ag → deletion or inact of immat BC

  • TC spec for and binding too strongly to self Ag → removed in thymus by neg selection

• regulation of B/T cell responses → anergy, Treg → peripheral tol 

Fab 

• each arm on BCR is a Fab 

• so you have 2 in total 

• a Fab consists of 1 heavy and 1 light chain 

• for Ag neutralization binding 

Fc

• lower part of constant region 

• not part of arms 

• complement can bind on it 

• you have one 

IgM function = 1

act of complement sys

IgG1/3 hast the most function = 2

• neutralization

• opsonization

what is J chain

• small polypeptide

• glues monomers (IgA, IgM) together

• allows binding to poly-Ig-receptor transport actress epithelia

Ab mediated activation of complement → what does act C1 do, what happens then?

• activated C1s cleaves

  • C4 → C4a + C4b

  • C2 → C2a + C2b

• C2a binds to surface C4b → C3 convertase = C4b2a

  • C4b2a cleaves C3 → C3a + C3b

antibody dependent cellular cytoxicity

• Ab binds Ags on surface of target cell

• Fc rec on NK cells recognize bount Ab

• crosslinking of Fc rec signals → NK cell to kill target cell → apoptosis

which Ig does a baby have - 2

• IgG

• monomeric IgA → during breastfeeding