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Immunology > Autoimmunity > Flashcards

Autoimmunity Flashcards

1
Q

What do TC receptors recognise and what occurs in response?

A

Linear peptide epitope presented by MHC

TC proliferation
Cytokine production
BC interaction
Cytotoxicity

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2
Q

What do BC recognise and what occurs in response?

A

Conformational epitopes bind Fab regions of BCR

Antibody production
Antigen presentation

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3
Q

What process enables variation in TC and BC receptors?

A

VDJ rearrangement

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4
Q

What is central T cell tolerance?

Where does it occur and what selection processes are involved?

A

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
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5
Q

What is the function of regulatory TC?

A

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

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6
Q

How are peripherally generated T regs formed?

A

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

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7
Q

What occurs as part of B cell tolerance?

A

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

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8
Q

What is an autoimmune disease?

A

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

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9
Q

What are possible contributary factors towards autoimmunity?

A

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

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10
Q

What alleles are associated with MHC? Why can these alleles be associated with disease?

A

HLA
MHC1:
-HLA A/B/C

MHC2:
-HLA DP/DQ/DR

HLA alleles can present autoreactive peptides to TC

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11
Q

What is the autoimmune mechanism for type 1 diabetes?

A

CD8 TC kill pancreatic beta cells

BC produce autoantibodies for islet cells

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12
Q

What is the autoimmune mechanism for myasthenia gravis?

A

(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

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13
Q

What is the autoimmune mechanism for RA?

A

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

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14
Q

What methods of immune suppression can be used to manage autoimmune disease?

A

(Starting from generic)
Steroids + anti-metabolites

CNIs and Rituximab

JAKi (specific pathway)

Anti-cytokine monoclonals (molecule specific)

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15
Q

What is the action of corticosteroids in treating AI disease?

A

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

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16
Q

What are some of the SE of taking steroids?

A 
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
17
Q

How do anti-metabolites work to treat autoimmune disease?

Give examples

A

(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

18
Q

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?

A

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

19
Q

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?

A

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

20
Q

What is the MOA of rituximab?
What conditions can it be used to treat?
What infections are at increased risk of occuring whilst taking

A

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

21
Q

What is the MOA of Tocilizumb?
What conditions can it be used to treat?
What infections are at increased risk of occuring whilst taking?

A

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

22
Q

What are 2 examples of tumour supressor drugs?
How do these drugs work?
What is the possible adverese affect on the immune system?

A

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

23
Q

Why can Ipilumumab cause pancytopituitarism?

A

Due to pituitary stalk being covered in CTLA4 because they are acting to create an immune privileged site
Leads to destruction of this protection

24
Q

What drugs can cause drug induced lupus?

Why is this?

A

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

Immunology (13 decks)

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