Mucosal Origin of Autoimmunity Flashcards
what is the structure of the surface of the colon?
Single cell layer thick barrier between 10^13 bacteria and body - fragile
- Thin barrier is maintained – bilayer of mucous prevents entry of bacteria
- Enormous gut surface full of bacteria – prevents bacteria entering, but enables uptake of metabolites from bacteria to supply immune system
how does the gut microbiome engage with the immune system?
- Epithelial layer of gut
- Large surface – 400 square meters which can engage/interact with bacteria
- M cells – specialised in small particle uptake (not bacteria) to interact with immune system – interaction occurs in nodule follicles sitting beneath surface which function like mini lymph nodes – first place where immune system interacts with bacteria of gut
- Mesenchymal draining lymph nodes with T and B cell zones – control immune tolerance to bacteria
why are interactions with the microbiome crucial?
- Don’t want an immune response to these bacteria as it is a symbiotic relationship with microbiota
- Interaction with healthy microbiome is crucial – metabolites produced by microbiome directly regulate lymphocyte gene transcription
- complex crosstalk
how can autoimmunity be triggered in the gut?
Unbalanced interaction with microbiota can lead to inflammation in the gut and triggering of autoimmunity
- e.g. colitis and Crohn’s
- Fine balance of microbiome and immune system
where can interactions with the gut microbiome go wrong?
- Balance between Tregs and Th17 T cells can go wrong – induces gut inflammation – T cell regulation/homeostasis is crucial
- Disequilibrium in response to bacteria - lack of regulation
- Defects in the thin mucosal barrier
All of these can induce autoreactive T and B cell responses – autoantibody production
what are the roles of the mucosa in initiation of autoimmunity (AI)?
- it is the site of initial contact and as portal of entry - some bacteria that enter may be more pro-inflammatory
- it regulates susceptibility to AI - can form regional ectopic tertiary lymphoid structures
- there may be cross-reactivity between foreign and self antigens - molecular mimicry
- alteration of self proteins e.g. citrullination in RA - Modified proteins from neutrophils – AI response to these proteins
what is a common theme in arthritis?
- damage or dysfunction may occur at the entry surfaces for bacteria, which can lead to increased risk of arthritis
how is inflammatory bowel disease (IBD) linked to arthritis?
40% IBD patients tend to develop enteropathic arthritis - chronic inflammation of joints, similar to RA, but different autoantibodies
- loss of barrier function
- Gut permeability and inflammation can trigger destructive arthritis
how are periodontitis and arthritis linked?
Close association between gum health and RA – patients with RA have high risk of periodontitis and vice versa
- gum inflammation and tooth loss and RA are highly associated
how is psoriasis linked with arthritis?
Psoriatic arthritis – psoriasis = inflammatory response in skin – 30% of these patients can also develop psoriatic arthritis long term – different autoantibodies, so not same as RA
- chronic, destructive joint disease
what tends to be a patient’s journey towards RA?
1st hit: environmental or genetic risk factor
- e.g. HLA-DRB1, or smoking
2nd hit: development of anti-CCPs due to increased citrullination - can still be healthy, so aren’t yet diagnosed
- could treat these people but difficult - need to consider scale of risk and side effects
3rd hit: may develop swelling at finger joints over the next few years
4th hit: meet full diagnostic criteria for RA: swollen joints and anti-CCP
- disease progression can take time
what are ACPA?
anti-citrullinated protein antibodies
- Anti-CCP recognise neoantigen of arginine residue being modified by PAD which can remove amino group to produce modified residue citrulline
- PAD requires calcium
- Citrulline is not made de novo, it is generated by this secondary modification by PAD
how is ACPA implicated in RA?
- highly specific, found in 50-70% of RA patients
- detected years before onset of symptoms
- correlated with disease severity
are all patients seropositive for ACPA?
no, there are seronegative patients which lack anti-CCP
More anti-CCP = more likely to develop worse RA
what has been implicated to produce citrullinated autoantigens?
Samples from RA joints – found NET structures (neutrophils spill out chromatin to capture bacteria and prevent them spreading)
- Lots of neutrophils and NETs in joints of RA patients
- In the patient NETs, there are high CCP levels
- neutrophils generate the CCP autoantigens
