KCP: Rheumatoid Arthritis (Pathogenesis) Flashcards
Overview of three stages of RA?
What happens in stage 1 RA?
Antibodies develop against citrullinated and carbamylated proteins
Why is there a strong association between RA and Human Leucocyte Antigen (HLA) class II genotypes
Antigens are presented to T-cells bound to HLA Class II proteins
What is Citrullination and what promotes it?
Protein citrullination is promoted by smoking, infection, microbiome at mucosal sites
What happens in normal antigen prensenting?
Signal 1 is the presentation of the antibody to the T cell. Signal 2 is the presentation of CD 80/86 - known as co-stimulation, this is signalling not only the antigen but also danger and is required to activate the T-cell
What happens in autoimmune antigen presenting?
What happens in stage 2 of rheumatoid arthritis?
Tissue Invasion
- Initial clinical presentation of disease is with synovitis when inflammatory cells enter the synovial membrane
- Loss of resident macrophages which maintain immune privilege
- Pro-inflammatory CD4 positive short lived effector T cells (SLEC) are key
1. Show evidence of immuno-senescence
2. Proliferate
3. Poor ATP production
4. Undergo pyroptosis-cell death that triggers inflammation
What happens in stage 3 of rheumatoid arthritis?
Chronic inflammation and progressive damage
- Activation of synovial fibroblasts & infiltration by macrophages
* Pro-inflammatory cytokines produced such as IL-1, TNF, IL-6
* T cells also produce RANKL which stimulates osteoclasts - Angiogenesis
* Increased blood flow and synovial swelling - Chronic synovitis, cartilage damage and bone erosions
Overview of RA
Reminder: Diagnoses of RA
Prescence of anti-cyclic citrullinated peptide antibodies
Gull-wing appearance in joints
Reminder: RA Treatment
- Start immunosuppressive treatment early
- Short term course of prednisolone (corticosteroid)
- Methotrexate
4 examples of common disease modifying anti-rheumatic drugs (DMARDs)
a. Methotrexate
b. Hydroxychloroquine
c. Sulfasalazine
d. Leflunomide
What is immune tolerance and what is the significance to RA?
Immune tolerance is the prevention of an immune response against a particular antigen.
Normally the body will develop peripheral tolerance to the autoimmune antibodies however in RA stage 1 this breaks down
What is biological therapy?
A type of treatment that uses substances made from living organisms to treat disease.
TNF inhibitor are a type of biological therey for RA. What are TNF inhibitors?
They block tumor necrosis factor alpha. A protein in the body’s immune system that causes inflamation. It is a pro-inflammatory cytokine
Why do the antibodies produced in response to citrullinated proteins in the mucosa then cause a response in the synovium of the joints?
These antibodies become systemically circulated. A citrullinated protein then can get stuck in the synovium of joints (like hair in a sink). Now lets say a rouge neutrophil passes by and detects it or if it is called there because of damage and then detects it it will attack it. But it can’t engulf it because it is stuck. This causes more and more aggrivation and the neutrophil might release more citrullinated proteins in response cause more of a response.
At this point you have swarming and inflamation and more damage and more immune response and it cascades into dog shit.
Why is RA symmetrical?
Rheumatoid is symmetrical because it is a systemic response
Why do you give the short course of prednisolone as well as DMARDs?
DMARDs take 8-12 weeks to start working, this is a lot of time of pain and time for things to get worse. So giving corticosteroids before the DMARDs kick in gets them into remission really quickly.
Most common RA related antibody and second most common?
- Anti CCP
- RF rheumatoid factor
Joints that are first affected
Radiocarpal
Metacarpophalangeal joints
