Adaptive Immunity Flashcards
what role does the liver have in acute inflammation?
synthesis of acute phase proteins
what role does bone marrow have in acute inflammation?
production and mobilisation of neutrophils (neutrophilia is hallmark of acute inflammation)
what is the acute phase response?
systematic response involving changes in plasma concentrations of specific proteins in response to inflammation
=it’s driven by pro-inflammatory mediators released by activated macrophages
= mediated by liver hepatocytes which produce a variety of acute phase proteins
what are some acute phase proteins?
-C3 and MBL (complement system proteins)
-C reactive protein (CRP)
what is CRP function?
C reactive protein = a major acute phase protein in humans
-primes certain bacteria for destruction by complement system & phagocytes (functions as an opsonin so enhances phagocytosis)
-has a prognostic role (can monitor how sick a patient it by severity & duration of inflammation) = used as marker for inflammation
what is the complement system?
made up of a large number of distinct plasma proteins that react with one another to opsonize pathogens and induce a series of inflammatory responses that help to fight infection.
in healthy systems - what levels of complement proteins are found?
LOW levels of INACTIVE complement proteins found in extracellular fluids
what happens when complement system activated?
creates a cascade of chemical reactions that promote:
-opsonization of pathogens
- direct pathogen killing
- acute inflammation
- leukocyte recruitment
what are the 3 pathways of complement system?
- classical pathway
- alternative pathway
- mannose binding lectin pathway
*don’t yet need to know (much later)
how does C3 get cleaved to C3a and C3b in mannose lecting binding pathway?
-instead of antibody/antigen trigger, presence of mannose lectin binding protein
-mannose lectin binding protein undergoes conformational change and eventually makes c3 convertase which cleaves c3 to c3a and c3b
what is problem with C3 convertase?
cleaves thousands of C3 to C3a and C3b per second and if loads of C3b keeps being produced then eventually could kill human cell as human cells only have finite number of inhibitors to tell C3b to not kill them
(C3b just binds and kills the surface of cell it’s bound to so if human cell - it needs to say “don’t killl me”)
how is C3b stabilised?
by binding to surface of cell & then killing if bacterial cells
how is C3b involved in amplification loop/step?
C3b is always floating and just binding to bacterial cell surface it comes across so other factors can help stabilise it and make C3 convertase to keep loop going
how is MAC formed?
Membrane Attack Complex
-C3b binds back next to C3 convertase to form C5 convertase which cleaves C5-> C5a and C5b
-C5b, C6, C7, C8 join together and start to penetrate through pathogen membrane
-C9 joins forming MAC which creates channel into membrane (which allows fluid & killer cells to go in) and can destroy pathogens (especially gram- bacteria)
what can C3a and C5a also do?
they can amplify acute inflammatory responses
(they’re chemotaxis)
what is C3b?
an opsonin molecules = makes phagocytosis more efficient as opsonin makes more attractive and easier to pick up (think as it like pathogen slippy before opsonin)
what is involved in innate immune system response?
- acute inflammation
-macrophages
-mast cells
-natural killer cells
-neutrophils
-complement system
what is involved in acquired immune system response?
- B cells
-T cells - antibodies
what are B cells?
- Responsible for humoral immune responses
- Produce antiBodies that attack pathogens circulating in the blood and lymph
- Key role in defense against extracellular pathogens
(they release antibodies)
what are T cells?
- Responsible for cellular immune responses
- Key role in defense against intracellular pathogens
(have 2 types)
what are 2 types of lymphocytes?
B & T cells
what are the 2 types of T cells?
CD4+ T cells = Key regulators of the entire immune system (helper cells as help other immune cells)
CD8+ T cells = Kill virally infected body cells (cytotoxic cells as kill)
what are lymphocytes activated by?
antigens - as they develop they’re tested and if they’re too reactive to self-antigens they’re (usually!) destroyed as they’re supposed to distinguish between self and non-self antigens
what is non specific recognition?
-limited number of PAMPs. which are common to many different pathogens
- only a small number of different PRRs are required to stimulate the innate immune system
(PRRs detect PAMPs)
what is specific recognition?
- millions of different antigens - unique to individual pathogenic species
- individual T & B cells only express 1 specific antigen receptor which binds to only 1 specific antigenic epitope
what is BCR?
B-cell receptor = an antibody
- different antibodies have different variable regions that each bind to 1 specific antigenic epitope as well as conserved constant regions
what is the structure of the BCR?
complex of 4 polypeptide chains (2x light chains and 2x heavy chains)
how many copies (roughly) of 1 specific antibody does each B cell produce?
50 000 copies
what are 2 forms B cell antibodies can be expressed?
- membrane bound
- soluble
what is the only type of antigen T cells can recognise?
peptide antigens (rather than carbohydrate or lipid)
antigen receptor can only bind to really short protein
- also only recognises them when presented on MHC molecules (like platter)
what is the hypervariable region?
region formed by tips of alpha/beta TCR chains that form antigen binding variable region and unique to each T cell
what does MHC stand for? what else can it be referred to as?
Major Histocompatibility Complex
- can also be referred to as HLA (Human Leucocyte Antigens) in humans
what is MHC function?
to display peptide antigens to T cells (can present many different peptides to T cells)
what is class 1 MHC?
present peptides to CD8+ T cells (killer cells) - important for activating CD8+ T cells
= present on all nucleated cells
what is class 2 MHC?
present peptides to CD4+ T cells (helper cells)
=expressed only on professional antigen presenting cells (APC) like dendritic cells & macrophages etc
where do B & T cells encounter antigens?
secondary lymphoid tissue like lymph node
where are T & B cells produced?
in primary lymphoid tissue like bone marrow & spleen
what is route of B&T cells?
Mature, quiescent (inactive), antigen-specific T cells and B cells constantly re-circulate between the different blood, secondary lymphoid tissues and lymphatic vessels
what do stromal cells do?
capture opsonized cells and hold them there for a very long time
-> which means even if a B cell that comes past doesn’t have specific antigen receptor then it doesn’t matter because opsonized cell will be held in place until right one comes along
how do the T & B cells develop the correct features?
they segregate into different areas within secondary lymphoid tissues
what is process of how dendritic cells get prepared for T cell activation?
- if infected, inflamed tissues. Dendritic cells recognise & internalise pathogen derived particles & antigens
- Pro-inflammatory TNF alpha stimulates immature tissue-resident dendritic cells to increase expression of co-stimulatory molecules
- Dendritic cells digest ingested proteins and display small peptides derived from these on their cell surface in complex with MHC I and MHC II molecules
what happens when B cells encounter antigens?
- There are a limited numbers of each antigen-specific cell within the human body – these few antigen-cells are not sufficient to kill and eliminate an antigen-carrying pathogen.
- So once activated, B cells clonally proliferate and differentiate into two different types of effector cells:
→Plasma cells - produce and secrete soluble, antigen-specific antibodies
→Memory B cells - long lived cells that continue to circulate around the body
how many signals do B cells need to become fully active and what are they?
2 signals:
- Antigen
- Helping signal (co-stimulation)
(depends on nature of antigen they’re responding to for what helper signal is needed)
… this means B cell ready for differentiation to plasma cells
what type of antibody are initially secreted by B cells after differentiating to plasma cells?
low affinity specific IgM antibodies are first secreted by short lived plasma (these are not as good antibodies and NOT heavy chain so quicker produced so you always start with them)
-> it takes time to find specific antigen though (so takes time before replication and production of more antibodies)
when does production switch from low to high affinity antibody production?
when B cells mutate they can secrete “better” antibodies
= switches antibody isotype to IgG antibodies allowing delivery of pathogen to phagocytes
when are memory B cells made?
after IgM antibody B cells mutate and switch antibody isotype to IgG. the B cells differentiate iinto long-lived plasma cells that screte antigen-specific antibodies and also differentiate into antigen-specific memory B cells
what are the 2 signals for non-protein antigens that activate B cells?
signal 1 = B cell receptor + antigen
signal 2 = PRR + PAMP
what are signals for B cells with antigens with repetitive antigenic epitopes?
signal 1 + 2 = multiple B cell receptors & antigens engaged (lots of same receptors & antigens)
what are the 2 signals for B cells with protein antigens?
signal 1 = B cell receptor binding to antigen
signal 2 = help from Th cells
- this displays peptide (MHC 2)by antigen activated B cell so we have T cells response to produce lots of Tfh
why do you want protein in your vaccine if you can?
because it means you make MHC 2 and stimulate T cells to produce Tfh which make long lived plasma cells that secrete high affinity antibodies
- memory B cells also made
how do antibodies help kill & eliminate antigens/pathogens?
- antibodies have Ig heavy chain and Ig light chain
the tops of both chains = recognition function
- binding to antigen mediated by variable region
the bottom stem that connects up = effector function
- clearance mechanisms mediated interaction of heavy chain constant region (Fc region) with effector molecules (complement & Fc receptors)
what are the types of antibodies?
- IgM
-IgG
-IgD
-IgA
-IgE
describe IgM antibody
- very good cell surface b receptor
- 2 flavours
In membrane-bound monomeric form = IgM serves as the B cell antigen receptor
In its secreted, pentameric form = IgM is the first Ig type produced during a humoral immune response (human)
- Present in plasma and secretory fluids
→Agglutination
→Complement system activation(activation by antibodies)
(forms like lattice structure - trapping pathogen)
what is agglutination?
the action of an antibody when it cross-links multiple antigens producing clumps of antigens
(mediated by specific antigen binding to IgM and IgG)
why is agglutination good?
- Agglutination increases the efficacy of pathogen elimination byphagocytic cells
→Agglutination also prevents viruses from binding to and infecting host cells
in complement system - which antibody is effective at what?
IgM is efficient at engaging at least 2 different heads (to start cascade of downstream steps to cleave C1 to make from inactive to active)
what are the functions of antibody IgG?
→Agglutination
→Complement system activation
→Foetal immune protection
→Neutralisation
→Opsonisation
→Natural Killer cell activation
(very versatile)
what is IgG antibody?
- The most abundant antibody in normal human serum - monomeric
- The dominant Ig type produced during a secondary (memory) immune response
what is IgG role in foetal immune protection?
- IgG antibodies are transported across the placenta, directly into foetal blood circulation
- important as newborns own immune system not fully developed and can’t sufficeintly produce antibodies until 6 months
- window at about 3 months where all newborns have very low circulating antibody (why they always get ill - bad immune response
what is neutralisation (in relation to antibodies)?
- basically binding to antigens on surface of viruses (physically blocking) (to prevent damage by virus)
Mediated by specific antigen binding to high affinity IgG and secretory IgA (sIgA) antibodies
what is opsonization?
- IgG antibodies are excellent opsonins
- phagocytes express an Fc receptor that binds specifically to constant region of the Igɣ heavy chain
what is natural killer cell activation in innate response?
intracellular pathogens infect host cells and PAMPs binding means secretion of Interferons alpha/beta which stimulates natural killer cells to kill infected host cells & produce pro-inflammatory mediators
what is natural killer cell activation in adaptive/acquired immune response?
antigen bound IgG activates
describe IgD antibody
- In membrane-bound monomeric form,IgD serves as a B cell antigen receptor
- Mediates B cell activation
- Function of the secreted form of IgD is not well understood
- Found at extremely low concentrations in blood
describe IgA antibody
- Second most abundant Ig type
- Present in serum in a monomeric form (IgA)
→Functions: Neutralisation
- Present in secretory fluids in a dimeric form(secretory IgA , sIgA)
= Neonatal defence (important for it)
= Neutralisation (at mucosal sites)
why do clinicians say try breast feed of you can?
secretory IgA (sIgA) antibodies are transported into colostrum & breast milk to protect GI tract of neonates
describe IgE antibody
- IgE antibodies can trigger allergic responses
- allergy, asthma, anaphylaxis
what is the physical change for lymphocytes by activation?
when inactive = metabolically inert and don’t look interesting under microscope, big nucleus & little bit of cytosol
when activated = they get bigger & cytosol increases
what is an activated CD4+ T cell?
Th0 cell - T helper naught cell
( requires both signals, antigen & co-stimulation for proliferation to Th0 cells)
what do Th0 cells differentiate into?
-Th1, Th2, Tfh, Th17 and regulatory T cells
= different effector T helper cells
=differentiate depending on environment, cytokine signals etc
why do all cells express MHC class 1 molecules?
because MHC class 1 molecules present antigen to CD8+ T cells which are cytotoxic T cells (killer cells) so you’re cells in body want to be able to tell killer cells that they’ve been infected and need to be killed
what are the 2 signals that activate T cells?
- when T cells bind to antigen = antigen presented by MHC molecule (mHC class 1 = presents CD8+ and MHC class 2 = CD4+)
- co-stimulation = when ligand on surface of T cell binds to ligand on surface of antigen-presenting cell
what is effect of co-stimulation?
the interaction of ligands on cell surfaces at immune synapse sends signal which increases production of cytokines like IL-2 & TNF alpha
- fully activates CD4+ T cell which then secretes lots of IL-2 and IL-2 binds back on T cell (like making & eating it’s own food)
what does IL-2 do?
it’s a cytokine that is secreted by CD4+ T cells (which also have IL-2 recptors) so IL-2 binds back to CD4+ cells and helps cause cell division
- it also stimulates differentiation into different effector cells
what is the helper response of CD4+ for CD8+?
CD4+ produce IL-2 cytokines for CD8+ T cells too as CD8+ aren’t as good at making them on their own
what happens to Th1 after they’re produced?
they’re activated so go to site of inflammation (still with their same specific antigen response)
-they do have to get reactivated by MHC class 2 molecule on specialised presenting cell, macrophage
what happens to help macrophages that have particularly tricky pathogens that can infect & survive within macrophage?
Th1 cells migrate to lymph node & inflamed tissue and since macrophages are specialised presenting cell they present specific peptide on MHC class 2 molecule (as still helper cell with CD4+) to reactivate molecule
- reactivated Th1 can now produce pro-inflammatory cytokines (like IFN gamma) to act on macrophage to turn into very good killer
what are examples of tricky pathogens that can infect macrophage by infecting & escaping into cytosol?
Listeria, Shigella, Mycobacteria, Legionella species
what do Th1 cells do? (simple explanation)
they help macrophages become super killers
how does IFN gamma help macrophage be super killer?
interferon gamma (produced by Th1 cells activated by struggling macrophages) increases expression of NADH components of macrophage so they can do oxidative burst so more efficiently kill bacteria before they escape from phagolysosome
what is function of Tfh cells? (simple terms)
they help B cells proliferate and differentiate to form long-lived plasma cells and memory B cells
how are effector Tfh cells re-activated?
- Protein antigen bound to BCR is internalised by the B cell via receptor-mediated endocytosis.
- This antigen is degraded, and peptides derived from it are presented on the B cell surface in complex with MHC-II molecules
- Effector TFH cells move into B cell zone of the lymph node where they are re-stimulated by B cells in an antigen-specific manner (if they express the correct T cell antigen receptor (TCR) for the peptide antigen being presented by MHC-II
how do re-activated Tfh cells stimulate conversion of B cells to long-lived plasma cells & memory B cells?
they do 2 things:
1. increasing the expression of cell surface co-stimulatory molecules (that bind to partner molecules that are constitutively expressed by B cells)
2. secreting cytokines that further activate the B cell and stimulate the Germinal Centre response.
what do long-lived plasma cells do?
secrete high affinity antibodies like IgG (the helper cells can switch B cell isotype to different antibody production)
what are CTL’s?
cytotoxic T lymphocytes = that express CD8+
CD8+ cells proliferate & differentiate to killer cells
what does cytotoxic T lymphocytes do?
they kill any cell that’s infected with pathogen
- every cell that has MHC class 1 molecule that will pick up viral peptide & display so if CTL floats past and detects specific antigen then it will bind and reactivate and kill cell by triggering apoptosis then move on to repeat again
what are the ways CTL’s kill infected host cells?
- secretion of contents of cytotoxic granules
- expresion of fas ligand
how do CTL’s secret cytotoxic granules into infected cell?
as soon as CTL engages with cell, the granules migrate along and membranes of 2 cells fuse and granules chucked in tiny gap
how do cytotoxic T lymphocytes (CTL’s) kill infected cell with cytotoxic granules?
with proteins in granules
1. perforin = polymerizes to from a pore on target membrane
2. granzymes = serine proteases which activate apoptosis once in cytoplasm of target cell
3. granulysin = induces apoptosis
how do CTL’s kill infected cell with expression of fas ligand?
fas ligand (on CTL) engages with fas (on target cell) and engages apoptosis
what lymphocytes are left at end of immune response?
- T&B cells are short lived so die off naturally
- you’re left with long-lived plasma cells & memory B cells
-often you’re left with more memory cells than cells in general that you started with (a good thing)
what happens to macrophage after infection?
change character so anti-inflammatory and secret growth factors & repair factors and anti-inflammatory cytokines
-help return to steady state & mop up dead & dying cells
when do antibodies decay?
after a few weeks
what is difference to secondary immune response to first immune response?
- in first immune response there is a lag then small production of IgM antibodies then a bit later a slightly higher production of IgG antibodies
- in secondary immune response, there is no lack, small amount of IgM antibodies produced from start AND very large amount of IgG antibodies- ALSO produced from start
-secondary response antibodies also produced for longer
what do you try to do in vaccine?
induce primary response so if you actually come across disease you get secondary response and can tackle quicker
what are acute phase proteins?
proteins that change their serum concentration in response to inflammatory cytokines
why are dendritic cells the link between innate and adaptive immune response?
innate response : they are stimulated by proteins released in debris from phagocytosis, the proteins bind to dendritic cells and the cells then display MHC class molecules
adaptive response: MHC molecules present antigens to T cells and they get specifically activated
what is the mnemonic for remembering functions of interleukins and therefore what are there functions?
Hot T-bone steak
IL-1 (hot) = induces fever
IL-2 (T) = stimulates T cells
IL-3 (bone) = stimulates bone marrow
IL-4 (e) = stimulates IgE production
IL-5 (a) = stimulates IgA production
