Co-stimulation T cells & APC
- CD28 (Tcell on switch) binds to CD80/86 (B7.1 B7.2) on APC - keys on
- Once Tcell on, APC puts CD40 to surface, which connect to CD40 L on Tcell - accelerates T cell (stimulates IL2 which fuels itself via CD25)
- But T cell also puts CTLA4 & PD1 on surface
- B7.1,B7.2 bind better to CTLA4 than CD28 so “stops” activation of T cell
- Tcell & APC lose connection & Tcell transendocytoses B7.½
CTLA4 is an “off” switch for T cell
CTLA4/PD1/PDL1 inhibitors - MoA
- Infused a mAb that binds to CTLA4 & PD1 on T cell
- Renders them ineffective so continual T cell actiation
- (S/E are the unopposed AI effects - shows drug working)
- CTLA4: ipilimumab
- PD1: Nivolivumab, Pembrolizumab
- PDL1: Atezolizumab, Durvalumab (NSCLC, urothelial)
Use of CTLA4-Ig fusion molecules in AI conditions
- Infuse brake pedals to STOP T cell activation in first place
- Because B7 connects stronger to CTLA4 than CD28, can infused CTLA4 which blocks it from connecting to T cell CD28 to initiate activation
- Belatacept - transplant
- Abatacept - RA
Signal 1 (T cell activation)
STOP signal - when TCR binds to matching MHC complex on APC
Adhesion molecules bind tightly
Takes place secondary lymphoid tissue
Signal 2 (co-stimulation)
- CD80 (B7.1) & CD86 (B7.2) bind to CD28 which turns T cell on
- CD40 (APC) & CD40L (Tcell) ramp up . accelerates
- T cell produces IL2 (coffee) which bind to CD25 & further proliferates (signal 3)
- To regulate response - CTLA4 (CD152) onto surface
- Binds tighter to CD80/86 than CD28 so slows process
- Reduces adhesion molecules grip, start to lose each other
- Transendocytosis - T cell just eats up B7.½ and disengage
Vasculitis - ANCA Types (& Abs)
GPA - c-ANCA PR3
MPA - 70% ANCA+ + 70% p-ANCA MPO
EPG - only 50% ANCA + , and 50/50 each (MPO>PR3)
Drug induced ANCA after >18months - PTU
- SLE causing drugs eg hydralazine - Allopurinol - Minocycline, Cephalosporins, Cipro (Rx: stop & monitor v short course steroids)
Immune cells involved in CAR-T A/E
CRS: IL6 (cytokine storm)
ICANS - IL-1B means BBB impaired
Conditions w/ IL6 over activation
- Castlemans Dis
- Adult onset Stills dis
- Juvenile idiopathic arthritis
- GCA
- AA amyloidosis
Th1 response
- Naive T cell stimulated by_______to make Th1
- Th1 releases ________to cause ___________
Stimulated by IL-12
Releases: IL2 (coffee), IFNy, TNFa
Effect: INFLAM RESPONSE + Macrophage activation
Intracell org - viruses
IgG + CMI
Th2 response
- Naive T cell stimulated by_______to make Th2
- Th2 releases ________to cause ___________
Stimulated by IL-4
Releases: IL-4, IL-5 (E), IL-13
Effect: ALLERGIC RESPONSE - IgE, Mast cells, (Eisinophils)
Parasites, Allergies, Mucosal (asthma)
Mast cells have high affinity IgE receptor (FcεR1) & bind then degrade contents
Th-17 response
- Naive T cell stimulated by_______to make Th-17
- Th-17 releases ________to cause ___________
Stimulated by IL-6, TGF-B, IL-1
Releases: IL-17, IL-22
Effect: NEUTROPHILS - (monocytes)
Extracellular, bacteria, fungi, (viruses out of cell)
AI, “humoral”, T3 immunity - ILC3
Th-reg response
- Naive T cell stimulated by_______to make T-reg
- Th-reg releases ________to cause ___________
Stimulated by TGF-B, IL-2
Releases: TGF-B, IL-10
TGF - good, TNF not good (TH1)
Effect: IMMUNE BRAKE
Th-Fh response
- Naive T cell stimulated by_______to make Th-Fh
- Th-fh releases ________to cause ___________
Stimulated by IL-21 (bcl-6)
Releases: IL-21 (CXCR5 expression)
Effect: Presents to B cells in germinal centres, aids survival
Initiator of Lectin pathway
MBL + MASP-1, MASP-2
MBL assoc sensing protein
Joins C4b + C2b (+C3b)
Classic C’ pathway (initiator)
Initiated by: Ag-Ab, CRP, B-amyloid, DNA/cell death
Ab usu IgM or IgG
C1r + C1s (C1q)
C4b + C2b then C3b
Alternative pathway
Initiated by C’ (C3) & unknown pathogen molecules
Factor B, D
C3Bb3b
Then common pathway
C’ pathways - C3b role
Opsonisation
C’ pathways - C5b role
MAC complex
C’ pathway - C3a, C5a, C4a role
Inflammation, (anaphylatoxin)
B1 cells
- T cell independent (naive B cell response - never activated)
- Ab restricted to IgM subtype
- No memory cell (as requires T cell & class switching in LN)
- CD5 on surface
- Found in body cavity & marginal zone of spleen
- Quick & direct mechanism to scan splenic blood flow for bacteria
- Recognises cell surface lipids/CHO
- Binds to (roughly - IgM) and releases Abs
B2 cells
- T cell dependent - need help from T cells to function
- Respond to T dependent antigens
- Undergo class switching so all isotypes of Ab can be produced
- Find in follicles of LN
- Do not express CD5
- Already class switched (had T cell interaction) - all non-IgM are B2
Antigen - B cell BINDING
- Antigen within tissue, floats round ECF to LN, encounters follicle w/ B cell
- Antigen binds to BCR on B2 cell - internalises antigen & stacks on MHC II
- Presents to T cell:
1. STOP signal - TCR binds to APC (MHC II complex w/ antigen peptides)
2. CO-STIMULATION - CD80/86 to CD28 (CD40-CD40L accelerate)
T Cell proliferates, IL2 produced
CTLA4 surface- binds CD80/86 to downregulate
3. IL2 → T cells differentiate into each Th army & feedback to B cell - Th1 cytokines (IFNy, IL2, TNF) - IgG (macrophage intracellular)
- Th2 cytokines (IL4, IL5, IL13) - IgE/IgA (parastitic, asthmatic)
- Th FH (IL21) - plasma cells to make highest affinity Abs they can
