9-14 immuno Flashcards
give 2 examples of extracellular pathogens
streptococcus pneumonia
clostridium tetani
what is a serotype?
a form of a bacterium that can be recognised specifically by characterised antibodies
how do s. pneumoniae and Haemophilus influenzae interact in the body?
- they compete with each other
- HI responds to competition by signalling the immune system to attack SP
how does clostridium tetani evade the immune system?
a typical dose of tetanospasmin is too small to produce an immune response
how does the parasite which causes african sleeping sickness evade the immune system?
the protozoan acquires a dense layer of glycoproteins that continually change, allowing the parasite to dodge an attack from the host’s immune system
is antigenic drift very rapid or very slow in HIV?
very rapid - it outpaces development of the immune system
how does flu rapidly evolve?
through recombination of its RNA segments
what is antigenic variation?
when a pathogen alters its surface proteins to avoid the host immune responses
how long does the primary adaptive immune response take to develop?
7-10 days
how long does the secondary adaptive immune response take to develop?
4-6 days
what is the blood brain barrier?
it is tight junctions around brain capillaries to separate circulating blood from the brain extracellular fluid
what are the main barriers used in the first line of the innate immune system?
- skin
- tight junctions between epithelial cells
- acidic stomach pH
- mucus layers
what cell intrinsic responses are used by the innate immune system?
- pathogen induced phagocytosis
- degradation of dsRNA
what specialised cells are used by the innate immune system?
- professional phagocytes (neutrophils, macrophages)
- natural killer cells
- the complement system
is the innate immune response specific to particular pathogens?
no
what is the mucus layer made up of?
secreted mucins and other glycoproteins
what are defensins?
small, positively charged antimicrobial peptides which have hydrophobic or amphipathic helical domains
do defensins have antimicrobial activity?
yes
what organisms possess defensins?
all animals and plants
are defensins more or less active on membranes containing cholesterol?
less
what does the innate immune system recognise to produce an immune response?
they recognise pathogen-associated or microbe-associated immunostimulants
- these are present on pathogen cells but not on host cells
what classes of PAMPs are recognised by human cells?
- peptidoglycan
- bacterial flagella
- lipopolysaccharide
- mannans, glucans, and chitin from fungi
- CpG motifs in bacterial or viral DNA
- N-formylmethionine (fMet) used for bacterial translation initiation
what receptors in the body recognise PAMPs?
- soluble receptors in the blood
- cellular receptors
what is complement?
around 20 soluble proteins that are activated sequentially upon infection
what is the lectin pathway for complement?
- it uses mannose and fucose binding proteins
- proenzymes activate the next complement component by cleavage, resulting in an amplified proteolytic cascade to activate C3
what occurs in the alternative pathway for complement?
- when a pathogen’s surface is encountered, other proenzymes activate C3
what happens when C3 is activated?
- C3 is cleaved into C3a and C3b
1 - C3a is produced - this attracts phagocytes and lymphocytes, stimulating inflammation
2 - C3b is produced - this binds covalently to the pathogens plasma membrane
3 - pathogen bound C3b simulates a local cascade of reactions (C5-C8) at the marked membrane
4 - C9 is inserted into the membrane
5 - a C9 pore (membrane attack complex) breaches the membrane
6 - the pathogen lyses
what is toll?
a Drosophila transmembrane protein with a large extracellular domain with repeating motifs
what molecule do toll-like receptors bind? what is the effect of this?
PAMPs
- it signals to the nucleus, which results in gene transcription for inflammation
where are toll like receptors usually found in the body?
- on the cell membrane of epithelial cells and macrophages, dendritic cells, and neutrophils
how does Neisseria Gonorrhoeae evade the innate immune system?
- the capsule has no LPS
- it takes sugars from the host immune system (including sialic acid) and presents these
- it is resilient to bactericidal effects
what are the 3 major classes of phagocytes?
- neutrophil
- eosinophil
- macrophages
which of the 3 classes of phagocytes are classified as granulocytes?
neutrophils and eosinophils
describe the main features of neutrophils
- they are the most common type of granulocyte
- short lived cells
- abundant in blood
- not present in normal healthy tissues
what recruits neutrophils to infection sites?
- activated macrophages
- peptide fragments of cleaved complement proteins
- some PAMPs
what are the main features and uses of macrophages?
- they are much larger and longer lived than neutrophils
- they recognise and remove senescent, dead, and damaged cells
- they are able to ingest large microorganisms such as protozoa
what are the uses of eosinophils?
they help to:
- destroy parasites
- modulate allergic inflammatory response
- they collectively recognise and kill cells with complement
what recognises cell surface receptors displayed on phagocytes?
- TLRs
- receptors for antibodies produced by the adaptive immune system
- receptors for complement C3b proteins
what occurs when a receptor binds to a phagocytes cell surface receptors?
- it activates phagocytes, enhances killing power, and causes cytokine release to attract more white blood cells
- it induces actin polymerisation on the site - the phagocyte’s plasma membrane surrounds the pathogen to enguld if in a membrane-enclosed phagosome
what are granules?
dense membrane-bound lysosomal derivatives
what are the functions of granules in granulocytes?
- they fuse with the phagosome membrane and release their contents to digest pathogen cell walls
- granules also contain defensins to destabilise pathogen membranes
what is a respiratory burst?
- an increase in oxygen consumption
- NADPH oxidase complexes form on the phago-lysosomal membrane, and a respiratory burst by phagocytes allows NADPH oxidase complexes to produce highly toxic oxygen derived compounds
do neutrophils survive after phagocytosis?
no, they eject their own DNA to trap bacteria
how do some bacteria resist respiratory bursts?
- they survive and replicate inside the neutrophil by expressing virulence factors to protect against these bursts
- e.g. Neisseria gonorrhoeae
how do some bacteria resist actin polymerisation in phagocytosis?
- they neutralise actin polymerisation by injecting a toxin that disrupts assembly of the actin cytoskeleton
- e.g. Yersinia pestis
how do sites of inflammation form?
- blood vessels dilate leading to local swelling and the accumulation of complement cascade components
- macrophages secrete cytokines which attract neutrophils
how does the innate immune system recognise viruses?
it recognises:
- CpG motifs in viral DNA by TLR9
- viral dsRNA
how are interferons produced?
- IFN-alpha and IFN-beta are produced by all cells in response to viral dsRNA
- IFN-gamma is produced by T cells when activated by their cognate antigen
what are the main functions of interferons?
- it warna neighbouring cells of infection and induces expression of other cytokines
- it activates dssRNA nuclease which degrades host ssRNA non-specifically
- it inhibits the process of translation in neighbouring cells
- it limits viral spread by promoting apoptosis of the infected cells
- it upregulates viral peptide display on infected cells to provide increased recognition by activated T cells
- it stimulates expression of the immunoproteasome to process and destroy viral proteins
- attracts natural killer cells and activates macrophages
- fights cancers
what are the functions of natural killer cells?
- NK cells recognise cells with low expression of immune system recognition
- they are also attracted to virally infected cells by IFNs and induce apoptosis
define what is meant by an antigen
any substance capable of generating an adaptive immune response
how does a vaccine cause immunisation?
1 - an antigen is injected in the form of a suspension containing adjuvant
2 - adjuvant activates innate immunity responses
3 - the activated innate responses also responds to the antigen in the vaccine
4 - the innate immune response then trains the adaptive immune response
where do lymphocytes develop from?
in central lymphoid organs:
- bone marrow
- thymus
where do lymphocytes migrate to after development?
to peripheral lymphoid organs:
- adenoids
- tonsils
- lymph nodes
- spleen
- Peyer’s patch (in the small intestine)
- appendix
- skin
- respiratory tract
what are the main functions of dendritic cells?
- they display a wide variety of TLRs
- they phagocytose and degrade invading microorganisms
- they display the peptides from the degraded organisms on their cell surface
- they then migrate to a nearby lymphoid organ and activate the adaptive immune response
how do T cells develop?
hematopoietic stem cells -> common lymphoid progenitor cells -> thymocytes -> t-cells
- occurs in the thymus, stem cells come from bone marrow
how do dendritic cells activate T cells?
1 - DCs present peptides to T cells in the lymphoid organs
2 - T cell TCR recognises non self antigen and activated mitosis and clonal expansion of these specific T cells
why do APCs only present to T cells?
1 - co-stimulatory molecules on APCs ‘dock’ with T cell specific co-stimulatory molecules
2 - the peptide is held in the groove of an APC and is scanned by the TCR
what are the different classes of T cells?
- T helper
- T cytotoxic
- T regulator/suppressor
what are the functions of T helper cells?
- they activate macrophages, dendritic cells, and B cells
- they maintain cytotoxic t cell activity by secreting a variety of cytokines
what is the function of T regulatory cells?
- they inhibit the function of helper T cells, cytotoxic T cells, and dendritic cells
what is the function of cytotoxic t cells?
- they kill infected cells by persuading them to undergo apoptosis
how do cytotoxic t cells induce apoptosis?
- they secrete perforins which assemble and form a channel in the target cell wall
- they secrete specific proteases which enter the target cell wall and activate caspases (the effector proteins of apoptosis)
what do B cells differentiate into?
- they differentiate into effector B cells (plasma cells)
- they can secrete antibodies into the surrounding environment
what is the basic structure of an antibody?
- they are tetrameric with 4 polypeptide chains (2 identical heavy chains and 2 identical light chains)
- the chains are held together by covalent disulphide bonds at the hinge and between the heavy and light chains
how are classes of immunoglobulins distinguished?
by their heavy chains
what 5 classes of Igs do mammals have?
IgM - mew heavy chain
IgD - delta heavy chain
IgG - gamma heavy chain
IgA - alpha heavy chain
IgE - epsilon heavy chain
describe the basic structure of IgM
- it is a pentamer of the basic tetrameric unit, held together by a joining chain to aid polymerisation
- valency of 10
- it is the first antibody a B cell makes
what is meant by valency?
the amount of antigens a molecule can bind at one time
which Ig class activates complement?
IgM
what is an opsonin?
a molecule that targets antigens for phagocytosis
describe IgG’s general structure and function?
- has the standard tetrameric structure
- IgM secreting plasma cells can switch to IgG secretion
function: - toxin neutralisation
- binding to microorganisms and opsonization by coating a pathogen and by activating complement
- provision of passive immunity to fetuses and newborns
how does IgG confer passive immunity?
- placental cells take up maternal IgG by pinocytosis
- placental endosomes have receptors that recognise and bind the tail region of IgG antibodies
- the IgG molecules are transported across the placental cells in vesicles
- IgG is released into the foetal circulation
how is IgA secreted
- IgM-secreting plasma cells can switch to IgA secretion
- IgA is a dimer of 2 tetrameric units held together by a J chain, and also an S chain which allows secretion into saliva, tears, milk, and mucus
- IgA protects our mucosal surfaces and provides some passive immunity to newborns via milk
what is the basic function of IgE?
IgE binds Fc receptors on:
- mast cells
- basophils
- eosinophils
- the bound IgE acts as a receptor for the particular antigen to which the original clonal expansion took place
how and why does mast cell/ basophil degranulation occur?
- triggered by IgE
- results in a release of histamine at the site where mast cells and basophils meet the pathogen
- histamines tigger blood vessel dilation and inflammation
describe antibody structure at a domain level
- light and heavy chains are composed of repeating Ig domains
- the N-terminal domains of both chains are called variable domains
- the remaining are constant domains
- the antigen binding site is made from Vl and Vh domain interactions
what is the structure of IgM?
- there are multiple disulphide bonds and the H chain is heavily N-glycosylated
what are the functions of the different domains in IgG?
CY1 and CY2 - bind complement components
CY2, CY3 - bind Fc receptors on neutrophils
CY3 - binds Fc receptor on macrophages and NKs
describe the structure of IgE
- the multiple N-glycans make this a stiff rigid molecule
- good for targeting large pathogens
describe the structure of IgA
- very flexible, good cross-linker
- valency of 4
how do B cells become capable of class switching?
- pre B cells in the bone marrow express IgM membrane bound
- during maturation they express IgM and IgD, membrane bound in lymphoid tissue
- the IgM+ IgD+ b cells are then selected by an antigen and undergo clonal selection
- mature B cells can switch classes from igM to other Ig classes whilst maintaining the same specificity for antigen
how does class switching occur?
- via somatic recombination of DNA
1 - the genomic DNA is looped so a recombination event can occur between sequences called switch regions
2 - cutting and rejoining of DNA results in excision of the loop and class switching
3 - the rearranged gene is transcribed to generate a primary transcript
4 - the segments encoding Vh and Ca are fused in frame at the RNA level to generate mRNA
define clonal selection
individual clones are selected by antigen based on how well the antigen and receptor fit together
define clonal expansion
the selected clones undergo mitosis, proliferate, and differentiate into effector cells
define clonal deletion
lymphocytes that react inappropriately with self antigens are destroyed
how is primary antibody diversity generated?
- the two classes of light chains increase diversity (lamda and kappa)
- there are multiple gene segments encoding V domains that can be combined with C domains by somatic recombination
- the somatic recombination used to select a V gene segment involves selection of small pieces of ‘diversity’ and ‘joining’ DNA to link the V domain with the constant domains
- over time, the antibodies made by B cells improve in affinity and become more specific (affinity maturation)
what is affinity maturation caused by?
an accumulation of point mutations in the V domains
how does affinity maturation occur?
1 - antigen stimulation causes activation and clonal expansion of B cells with pre-existing fits to the antigen
2 - some B cells of the expanded clonal population proliferate in germinal centres and undergo somatic hypermutation, generating antibodies with altered V domain specificity
3 - most of these hypermutations are worse than the original so will not be stimulated by the antigen
4 - the rare b cell with mutation BCR versions that have higher affinity for the original antigen will proliferate resulting in rapid evolution of a high affinity antibody
