Immunology II Flashcards
Describe some features of adaptive immune systems
- immense Diversity
- alterations in repertoire
- memory
- TCR and BCR (jawed vertebrates)
- VLR (jawless fish)
Describe the immense diversity of adaptive immune systems
– alteration of genomic sequence
- “Anticipatory Repertoires”
Describe repertoire alterations in adaptive immunity
cell proliferation and clonal distribution of receptors according to circumstance
Describe adaptive immune receptors
- antibodies
- T cell receptors
Describe antibodies
- duplicated heterodimer (heavy and light chains
- two forms
- secreted by B cells
- membrane bound (B cell receptor)
- recognise diverse products (e.g. protein or carbohydrate)
- epitopes can be linear or conformational
Describe T cell receptors (TCR)
- always membrane-bound heterodimer
- TCRab and TCRgd
- TCRab recognise linear peptide in context of a
presentation complex called MHC
MHC
major histocompatibility complex
Adaptive immunity stimuli
- antigen or immunogen
- epitope
- antigenic or immunogenic molecules
Describe antigens and immunogens
a molecule seen by the adaptive immune syste
Describe epitopes
the specific part of the antigen involved in recognition
Describe antigenic or immunogenic molecules
molecule capable of stimulating a specific adaptive response
Describe anticipatory repertoire generation
- rearrangement with junctional modification
- four chains, two heterodimeric pairs
- TCRab and TCRgd
- conserved organisation of TCR loci (multiple V regions, [D], J and C regions)
- up to 10^15 different TCRVb rearrangements in humans
- we only express ~108 different TCR at any time
Describe T cell receptor rearrangement
- TCRalpha or TCRgamma with TCRbeta and TCRdelta D
region inserts between the V-J junction - nucleotide modification
D region
Diversity region
CDR3 region
complementary determining region 3
The RAG complex
- initiates rearrangement
- Recombination Activation Gene
RSS=
Recombination signal sequence
Describe the action of the RAG Complex
- RAG1/2 binds RSS
- synapsis of RAG complices
- cleavage of RSSs
- Ku70:Ku80 binds 5’-phorphorylated DNA ends at signal and coding joints
- DNA-PK:Artemis opens hairpin
- TdT processes DNA ends and adds N-nucleotides
- stands are paired
- exonuclease removes unpaired nucleotides
- gaps filled by DNA synthesis
- DNA ligase IV:XRCC4 ligates DNA ends
- forms coding joint
- creates junctional diversity
TdT
terminal deoxynucleotidyl transferase
What is the importance of extreme diversity in the adaptive immune response?
avoidance of self-reactivity
Describe the avoidance of self-reactivity
- clonal distribution of the receptor
- selective removal of self-reactive cells
The rarity of successful cells means that success depends upon:
– self-renewal andrapid replication in the face of challenge
- evolution of the lymphocyte (T cell and B cell)
- specialised selective sites (e.g. Thymus for T cells)
Describe thymic T cell development
- an ordered process
- TCRbeta, gamma and delta at DN3 Allelic exclusion at DN4
- RAG on in late DN2
- RAG off in DN4
- RAG on in early DP
- RAG off in SP
DN
double negative
Describe memory in T cells
- thymic selection
- response
- memory
Describe antibodies (imunoglobulins) as functional molecules
multiple antigen binding sites
Describe the Antibody Classes
have different numbers of units in the mature structure
List some antibodies
- IgG/IgE
- IgM
- IgA
Describe soluble antibody morphology
- two effective domains
- antigen binding Fab fragment (two in each unit)
- Fc region recruits other molecules (complement), or is bound by cells expressing the Fc-receptor
Describe the mechanisms of antibody activity
- block function (bind to important molecules on the pathogen)
- agglutinate (stick pathogens together)
- activate Complement
- opsonise (Fc recognised by receptors on cells)
Describe the main T cell types
- TCRalphabeta and TCRgammadelta
- TCRalphabeta divided into two subsets based upon co-receptor expression, type of MHC presenting the peptide and cytokine production
Describe CD4+ cells
- restricted to MHC class II
- TH1, TH2, TH3, TH17 and T-reg cells
TH
T helper
Describe CD8+ cells
- restricted to MHC class I
- TC1 and TC2 cells
TC
T cytotoxic
CD=
- Cluster of Differentiation
- A term for cell surface molecules
Describe the relationship between TH and TC cells
distinct and overlapping functions
Describe CD4 cells
- help B cells make antibody (Th2 via IL4)
- help macrophages become activated (Th1 via IFNg)
What drives Th0 cell proliferation?
- initial stimulus
- IL-2 and IL4
Describe TH1
- active macrophage
- IL-2 and IFNgamma
Describe TH2
- helper B cell
- IL-4, Il-5, IL-6 and IL-10
Describe TH3
- helper B cell (IgA)
- TGFbeta, IL-4, IL-10
Describe TH17
- neutrophil recruitment
- IL17
Describe T-regs
- down-regulate T cell responses
- IL-10
Delineate the two antigen presentation pathways
MHC class I pathway
MHC class II pathway
Describe the MHC class I pathway
- samples the cytoplasm
- endogenous
- CD8+
Describe the MHC class II pathway
- samples the extracellular compartment
- exogenous
- CD4+
Describe the mechanics of the MHC class I pathway
- partly folded MHC class I alpha chains bind to calnexin until Beta2-microglobulin binds
- MHC class I a:beta2m complex is released from calnexin, binds to a complex of chaperone proteins and binds to TAP
- cytosolic proteins and DRiPs are degraded to peptide fragments by the proteasome
- TAP delivers peptides to the ER
- peptide binds the MHC class I molecule and completes its folding
- MHC class I molecule is released from the TAP complex and exported to the cell membrane
What are the chaperone proteins involved in MHC class I antigen presentation
calreticulin, Erp57
How is TAP bound in the MHC class I antigen presentation pathway
tapesin
DRiPs
defective ribosomal products
Describe the mechanics of the MHC class II antigen presentation pathway
- Ii forms a complex with MHC class II molecule, blocking the binding of peptides and misfolded proteins
- Ii is cleaved in an acidified endosome, leaving a short peptide fragment, CLIP, still bound to the MHC class II molecule
- endocytosed antigens are degraded to peptides in endoscopes, but the CLIP peptide blocks the binding of peptides to MHC class II molecules
- HLA-DM binds to the MHC class II molecule, releasing CLIP and allowing other peptides to bind
- the MHC class II molecule then travels to the cell surface
Ii
invariant chain
CD4+ T cells
- restricted to peptides in MHC class II
- only respond to some cell types and use soluble mediators to affect the local area
CD8+ T cells
- restricted to peptides in MHC class I
- “recognise” any cytoplasmically infected cell
- major cytotoxic function
MHC class I is
constitutively expressed by most cells in the body
MHC class II is
constitutively expressed on restricted set of cells (professional APCs)
pAPCs
professional antigen presenting cells
Describe pAPCs
- constitutively express MHC class I and MHC class II
- dendritic cells
- macrophages
- B cells
Describe dendritic cells
- the innate cell that drives the adaptive immune response
- the only cell to stimulate naïve T cells
- after presentation and activation of lymphocytes, they undergo apoptosis
Describe macrophages
active scavengers, activity increased by interaction with CD4+ T cells
Describe B cells
Interactions with CD4+ T cells needed for efficient maturation and antibody production
Describe the immature dendritic cell
- in most tissues
- take up and processes antigens
Describe the mature dendritic cells
- do not take up microbes
- migrate to the lymphoid organs
- present antigens to naive T cells
Describe dendritic cell maturation
- pathogen uptake
- PRR activation
- MHC I + II high
- TCR:MHC (signal 1)
- costimulatory molecules such as CD80/86 (signal 2)
- cytokine production (signal 3) to drive TH0 cell differentiation
NK helps to create
active macrophage on exposure of TH1 to IFNgamma
PMN mast cell helps to create
helper B cell on exposure to IL4 of TH2
Describe immunology memory
- population of specific cells is larger
- easier to activate
- migration patterns differ
Why are memory cells easier to activate?
- transcriptional profile
- signalling status
- surface molecules
- earlier commitment to effector status
Why do memory cell migration patterns differ?
- less focussed on lymph nodes
- migration through tissues
- chemokine receptors
- adhesion molecules
How does a vaccine work?
- antigens from the pathogen stimulate T and B cells and induce memory
Describe the role of the adjuvant in vaccines
- carrier
- immunostimulatory components
- stimulate PRRs
Describe the types of vaccine
- live vaccines
- dead vaccines
- vectored vaccines
Describe live vaccines
- attenuated pathogen
- related pathogen
Give examples of live vaccines
- Sabin polio
- Bacillus Calmette-Guerin vaccine - attenuated form of Mycobacterium bovis, to protect against M. bovis and M. tuberculosis
Describe dead vaccines
- need adjuvant
- whole killed pathogen
- sub-unit
Describe vectored vaccines
Sub-unit delivery using a live carrier or DNA
Give examples of dead vaccines
- Salk polio
- Influenza
- tetanus toxoid
