Autoimmunity Flashcards
What do TC receptors recognise and what occurs in response?
Linear peptide epitope presented by MHC
TC proliferation
Cytokine production
BC interaction
Cytotoxicity
What do BC recognise and what occurs in response?
Conformational epitopes bind Fab regions of BCR
Antibody production
Antigen presentation
What process enables variation in TC and BC receptors?
VDJ rearrangement
What is central T cell tolerance?
Where does it occur and what selection processes are involved?
Occurs after pro-thymocytes leave bone marrow and travel to thymus to become thymocytes
Need to check that matured CD4 and CD8 TCR can recognise foreign antigens and self-MHC
Positive selection:
- Cortical epithelial cells in thymus present MHC cells
- if TCR can recognise MHC, passes to next step
- if not, then destroyed
Negative selection:
- dendritic cells in thymus present self-antigens
- if recognise, then will be destroyed
- if do not recognise self antigens then release to periphery
- if there is a moderate interaction between thymic MHC and TCR, TC might become regulatory TC
What is the function of regulatory TC?
Produce immunosuppressive cytokines i.e. IL-10 and TGF-beta
CTLA-4 strips costimulatory molecules (CD80 + CD86) from surface of APC to decrease ability to activate TC
Metabolic disruption by high expression of CD25 which deprives other TC of IL-2 (which is necessary for expansion)
Direct killing of other immune cells via GRANZYMES/PERFORIN
Therefore, if recognises self MHC on surface of cell, will prevent immune response
How are peripherally generated T regs formed?
Self antigen expressed by DC w/o PAMPS or DAMPS
DC doesn’t provide any further stimulation ofr differentation leading to anergic or induced TREG
What occurs as part of B cell tolerance?
The process occurs in the bone marrow
1st check if pre-B cell is able to produce Ig on surface
I.e. heavy chain then light chain
Immature B cell tests fully rearranged Ig against self-antigen in BM
-no reactivity= released into periphery to complete maturation
-if autoreactive to self-antigen there are 2 options:
1. Attempt to rearrange receptor chains so no longer self-reactive + tested again
2. Apoptosis
Therefore, aims to ensure that no BC enters periphery which has the ability to form self-reactive Ig
What is an autoimmune disease?
Inappropriate, self-directed inflammatio caused by autoreactive T and B cell responses arising from failure of immune tolerance to self antigens
Arises when MULTIPLE regulatory mechanims fail
What are possible contributary factors towards autoimmunity?
MHC polymorphisms
Autoreactive TCR
Persistant inflammatory cytokines
Failure of TREGs
Failure of regulatory molcules i.e. CTLA4
Inappropriate recognition of danger signals
Autoreactive BCR
Autoantibodies
What alleles are associated with MHC? Why can these alleles be associated with disease?
HLA
MHC1:
-HLA A/B/C
MHC2:
-HLA DP/DQ/DR
HLA alleles can present autoreactive peptides to TC
What is the autoimmune mechanism for type 1 diabetes?
CD8 TC kill pancreatic beta cells
BC produce autoantibodies for islet cells
What is the autoimmune mechanism for myasthenia gravis?
(Antibody mediated)
Antibodies cause crosslinking of AchR leading to internalisation of the receptor and delated synaptic transmission
Antibody activatesr complement fixation which results in C5-9 MAC inserting into synaptic membrane
-allows free movement of ions across membrane causing electrophyiological dysruption
What is the autoimmune mechanism for RA?
Usually occurs on background of HLA-DR4 and smoking (genetic and environmental risk factors)
Smoking induces inflammation in lungs and breaks immunological tolerance of citrulinated peptides causing autoreactive TC to be generated
CD4 TC releases IFN-gamma and IL-17 causing invasive fibroblast-like synoviocytes to occur in joints
Leads to proinflammatory cytokines and growth factros being release and MMP causing tissue destruction and complex deposition
What methods of immune suppression can be used to manage autoimmune disease?
(Starting from generic)
Steroids + anti-metabolites
CNIs and Rituximab
JAKi (specific pathway)
Anti-cytokine monoclonals (molecule specific)
What is the action of corticosteroids in treating AI disease?
Binds to glucocorticoid receptor on immune cells and is translocate to nucleus to modulate gene expression I.e. can inhibit the transcription of pro-inflammatory cytokines
What are some of the SE of taking steroids?
Steroid-induced DM Hypertension (off-target mineralocorticoid action) Dyslipidaemia Weight gain Peptic ulcers Increased risk of infections Psychosis Poor sleep Osteoporosis Chronic renal suppression Thin skin + easy bruising Glaucoma Acne Cushings syndrome i.e. moon face and buffalo hump
How do anti-metabolites work to treat autoimmune disease?
Give examples
(Known as steroid-sparing agents)
Block pathways involved in nucleotide synthesis and target lymphocytes due to their turnover being higher in AI disease= leads to cellular arrest or apoptosis
Eg
Methotrexate= inhibits difolate reductase to disruption thymidine sythesis
Azathioprine- disrupts purine synthesis
MMF= disrupts de novo production of purine which lymphocytes are purely reliant on i.e. targets directly
What is the MOA for calcineurin inhibitors?
What is their use and what are examples?
What needs to be monitored and why once starting on these drugs?
Targets calcineurin in the kinase cascade which would normal act to alter the expression of transcription factor NFAT (transcribes genes for IL-2)
Inhibition means decreased transcription of IL2 which means decreased TC proliferation
Can be use for dermatitis and RA
Eg Tacrolimus + Ciclosporin
Monitor renal function + BP due the drugs possbily inducing chronic renal toxicity
What is the MOA of anti-TNF?
What conditions can it be used to treat?
What infections are at increased risk of occuring whilst taking?
Targets TNF-alpha to prevent it from binding TNF-alpha receptors via either acting as a monoclonal Ig or being a soluble form of the receptor
RA
Due to TNF-alpha being associated with:
-increased inflammation via endothelial activation
-bone erosion via osteoclasts
-cartilage destruction via MMPs
-sarcopenia/malaise etc from systemic effects
At risk of TB re-activation due to TNF-alpha having an important role in maintain granuloma
What is the MOA of rituximab?
What conditions can it be used to treat?
What infections are at increased risk of occuring whilst taking
Targets CD20 on TC which leads to targetting of plasma cells via complement and ADCC activation
RA
Lymphomas/leukaemia
ITP
AIHA
Can induce hypogammaglobunaemia so at risk of same infections as child with Ig deficiency
PML association with JC virus i.e. neurological infection
What is the MOA of Tocilizumb?
What conditions can it be used to treat?
What infections are at increased risk of occuring whilst taking?
Targets IL-6 receptors which is an important receptor in the acute inflammatory response. Therefore by blocking the receptor IL-6 won’t bind and acute phase response won’t be activated
RA
Cytokine release syndrome following CAR-T
Staphlococcal skin infections
Infections w/o fever or rise in CRP
What are 2 examples of tumour supressor drugs?
How do these drugs work?
What is the possible adverese affect on the immune system?
Ipilumumab
- anti CLTA-4 IgG1 to enhance antitumour affect
- Targets TREG cells expressing high levels of CTLA-4 which are protecting the tumour to enable normal immune system response to kill tumour
Pembrolizumab/Nivolimuab
- block PD-1 stopping CD8 CTL receiving negative signals from intra-tumour PD-1L
- can remove break on potentially autoreactive TC
Can induce autoimmunity
Why can Ipilumumab cause pancytopituitarism?
Due to pituitary stalk being covered in CTLA4 because they are acting to create an immune privileged site
Leads to destruction of this protection
What drugs can cause drug induced lupus?
Why is this?
Procainamide
Hydralazine
Quinidine
Occurs in people who are slow acetylators because it results in the drug being oxidised by ROS and bound to proteins and neoantigens-> induced lupus
