Immunology Flashcards
1
Q
Over immune system
A
- Costly
- Well balanced
- Infectious agents spectrum
- Self from non-self
2
Q
Components of immune system
A
- Myleoid stem cells
- Lymphoid stem cells
- Dendritic cells bridge innate + adaptive systems
3
Q
Innate vs adaptive immune systems
A
- Innate = 1st line of defence, rapid
- Adaptive = 2nd, slower but specific
4
Q
Major histocompatibility complex
A
- Genetic locus, 3000kb
- Encodes MHC class I + II
- Similar = receptor for foreign peptide
- Polymorphic
5
Q
MHC class I
A
- a chain 450kDa, B2 micro globulin
- Membrane-distal (a1 + a2)
- Peptide binding groove (defines groove but degenerate)
- Foreign protein denatured 7-9aa fragment
- All somatic cells have
6
Q
MHC class I endogenous pathway
A
- Proteosome = 700kD, 15-20 enzymes
2. Transporter associated w/ antigen processing (TAP) = translocates small peptides across membrane
7
Q
MHC class II
A
- Restricted to APCs
- a chain (33kD) and B chain (28kD), each folds to 2 domains
- Have peptide binding groove
8
Q
MHC class 2 endocytic pathway
A
- Ag matures → late endoscope
- Environment ↑ acidic, degrades protein
- MHCII assembled in ER
- MHCII intersects endocytic pathway at late endosome
9
Q
Recognition of foreign Ag (T cells)
A
- Important in adaptive immune response
- T cell = leukocyte
- Activated T cells by recognition of specific ligand through TCR
10
Q
TCR
A
- Composed of 2 chains, a and B, 40-50kD
- Peptide binding to MHC recognised by TCR
11
Q
TCR diversity
A
- Problem with diversity (diverse ligands, MHC polymorphic, peptide to MHC binding is degenerate)
- Solution (TCRs differ in membrane distal portion, 10^9 versions of TCR)
- Generating diversity (a+b composed of various regions encoded by separate genes, a = v,j,c b = v,j,c,d, randomly combine v,j,c,d, excise intervening DNA, a pairs w/ b → 10^9-10^16 different TCRs
12
Q
T cell types
A
- CTL = made in thymus, express TCR + CD8, recognise MHCI, needed for defence against IC pathogens
- Th1 = responds to IC pathogens, has CD4+, secretes IL-2 that activates macropgage
- Th2 CD4+, humeral immunity, EC organisms, produces activation signals like IL-10 to proceed Ab
13
Q
CTL response
A
- Secretion of cytokines (TNFa + IFNy)
- Production + release of cytotoxic granules
- Perforin + granzymes - Destruction of infected cells w/ Fas/FasL (activated CD8+ express FasL, binds Fas → Fas trimerises → caspase cascade, CD8+ express Fas + FasL so can kill each other in contraction phase)
14
Q
Immunoglobulin
A
- Bridges adaptive + immune system
- V(D)J recombination, need to recognise ↑ Ag
- Heavy chain of Ig = v,d,j,c light chain = v,j,c
- Somatic hypermutation, clonal expansion, changes affinity
15
Q
Immunoglobulin repsonse
A
- Neutralisation
- Opsonisation (coat pathogen w/ complement factors, assists phagocyte binding, or fab portion of igG Ab binds to Ag, Fc of Ab binds FCR which traps organism at surface + stimulates phagocytosis)
- Complement fixation (innate defence, classical = triggered by activation of C1 by C1q binding to Ch3 of IgM or Ch2 of IgG, C1q binds at least 2 Ig Fc)
16
Q
Lymphoid organs
A
- Naive T/B confined
- Io/2o organs
- Functions of 2o lymphoid organs (overcomes unfavourable odds of T/B encountering specific Ag)
- Rapidly screen repertoire + see appropriate clones
- Disadv = time needed to identify + expand relevant clones leaves host vulnerable
17
Q
Acute inflammatory response
A
- Innate immune system transports Ag from infection to lymphoid to present to T/B cells via inflammatory immune response
- Limits spread of infection
- Infectious microorganism = detected by PRR + NCR
- These receptors = invariant
- Diff TCRs bind diff PAMP
- Inflammation = triggered by damaged cells or basophils → local changes at site of infection (vasodilation, ↑ vascular permeability)
18
Q
Complement system role
A
- w/o Ig, use alternative pathway
- C5a = chemoattractant, causes secretion of elastase
- Lysis of bacteria
- Opsonisation
19
Q
Microbial killing
A
- Mø undergoes respiratory burst
- Kills internalised cell by O2-dependent mechanism
20
Q
Dendritic cell
A
- Immature DCs = acquire Ag by phagocytosis + endocytosis
- In response to inflammation, x phagocytose
- Migrate to lymph nodes, mature (Cd40/86)
- Span adaptive and innate
21
Q
TLR
A
- Receptors for MAPM
- MAPM include dsRNA, LPS, flagellin
- Bind TLR
22
Q
T-B cell cooperation
A
- B cells = like APC but use specific Ig
- Th2 activated (MHC on DC) and then migrates to B cell
- Recog. of same peptide-MHC → secretion of cytokine → activate B cell → ↑ secretion of Ig
23
Q
Cost of immune system
A
- Specific for self + foreign Ag
24
Q
Self tolerance
A
Innate = Ag receptor = germline encoded, use non-protein Ag, response inflexible Adaptive = receptors rearranged, response is flexible
25
T cell differentiation
- Mature in thymus
- 4 subsets of thymocyte
- Interactions w/ stroll cell cells → thymocyte along a diff pathway
26
T cell diff checkpoints
1. Transition from CD4-8- to CD4+8+
- Express product of gene rearrangement expressed at surface w/ pre-TCR a antigen
- Ligantion of pre-TCR by ligand signals to thymocyte B chain is functional → a chain rearrangement can start
2. Transition from CD4+8+ → mature CD4+8- (Th cell) or CD4-8+ (CTL)
- Involves +ve selection
- TCRs that complement shape of MHC molecule = +ve
- If x fit die by neglect
- -ve selection
- Screen cells w/ functional TCRs for self reactivity
Paradox
- +ve selection ensures MHC-restricted recognition
- -ve selection ensures cells are self-tolerant
- Both involve ligation of TCR by complexes btw self-peptide + MHC determinant
- Same ligand recognised by same TCR but → diff outcome
27
Differential affinity model
- Avidity of Ag recognition = to do w/ affinity for self-peptide-MHC
- x affinity = dies
- Too high = deleted by DC
28
Issues w/ -ve selection
- Self-components may x be present (developmental Ag, immunologically-privileged sites)
- Can release sequestered self compounds
- Cross-reactivity btw self components + infectious agents → molecular mimicry
29
Myasthesia Gravis
- Muscle weakness
- Ab for AchR
- Binding of Ab to AchR means Ab compete w/ Acc for binding → functional blockade → x open → x muscle contraction
30
Antigen presentation (extra)
MHC I
- Peptide translocated to ER by TAP
- Peptides bind MHC I, chaperone are released, MHCI leaves ER
MHC II
- Cathepsin S + L are activated + digest MHC Class Ii → CLIP
- CLIP exchanged for antigenic peptide derived from protein in eadosomal pathway
31
NK vs CD8 cell
1. Recognition
- CD8 = single TCR, NK = several (inhibitory + activator)
- Missing self recognition (MHC I switches off NK cell)
- CD8 needs CD80/86 or CD28
- CD28 needed for cytokine secretion + proliferation in NK cells
- T cells also need pro-inflam. cytokines
2. Destroying cells
- Perforin + granzymes
- Both have FasL
- CTL = stable contact w/ target, NK forms transient
- NK have more perform, CD8 have more granzyme B
- NK have cytotoxic granules already, CD8 x (memory do)
3. Memory
- CD8 undergo contraction, 5% remain → memory T
- Faster 2o response
- NK cells undergo contraction
- NK memory x as stable, NK cells decay at same rate
32
How 'self' Ag arise
- Body needs ↑ diverse immune
- Random re-arrangement
- Random → specificities that recog. own
33
Central tolerance (T cell)
- 1o lymph tissues
- T cells / low affinity for self MHC → diff to CD4 or CD8 single +ve (+ve selection)
- High affinity TCR for self-MHC die
- If x bind die
- Zipper model (zipper btw membrane-proximal domain of CD8B + peptide of a chain of TCR)
34
Central tolerance (Aire)
- Some peptides expressed in other cells
- AIRE in thymic medulla induces expression of ↑
- ↑ efficiency of -ve selection
- APECED
35
Central tolerance (B cell)
- Auto-reactive → auto-Ab → autoimmune
- Strength of BCR to Ag
- If weak leave bone marrow
- Tolerance x as strong, help from T helpers
36
Clonal deletion
- 2/3 of T cell
- Fas-FasL apoptosis
- Nur77 + Bim
37
Peripheral tolerance
- Some Ag are seen w/ inadequate affinity or have too ↓ conc
- Tolerance needs to be incomplete
38
Peripheral tolerance (T cell)
- Intrinsic = T cell anergy, phenotype skewing
| - Extrinsic = reg. by Treg cells
39
Peripheral tolerance (B cell)
- Somatic mutation → B cell w/ new Ag specificities
| - Th for activation
40
Anergy
- Cells x killed but inactive
- Following peptide + MHC engagement for T cell or free epitope engagement for B cell
- Absence of co-stim receptor activates NFAT, w/o APA-1
41
Tregs
- FoxP3
- Natural / induced Tregs
- Regulate effector T by ↑ mechanisms
- Tregs down-reg. APC function by CTLA-4-dependent mechanism
- Secrete immunosuppressor molecules
- Maintain population
