Pathology of Rheumatoid Arthritis Flashcards
Describe the genetics of RA
- Complex polygenetic disorder - genetic markers explain 30% of the risk of developing RA
- RA patients have increased HLA DR4 serotype (set of alleles at HLA DRB1 gene locus strongly associated with RA)
- RA related to MHC class II
What are HLA genes?
Group of genes that code cell surface markers (MHC molecules), proteins involved in immune function
Describe the interaction in RA of genes and smoking?
- Cigarette smoking (and gingivitis) leads to increased citrullination of proteins
- In RA, an autoimmune response develops against citrullinated peptides via production of anti-CCP (cyclic citrullinated protein) antibodies
- Therefore, smoking + epitope producing anti-CCP means you are 40x more likely to develop RA
- Patients can also often present with new diagnosis of RA after infection/immunisation
Which autoantibodies may be present in patients with RA up to 14 years before they present with symptoms?
- IgM RF
- Anti-CCP
What does the immune system do in the synovium in RA?
1) Adaptive and innate immune pathways integrate
2) Pro-inflammatory cytokine milieu develops - TNFalpha, IL-6, GM-CSF
3) Stimulate macrophages, fibroblasts, mast cells and osteoclasts
4) Attract neutrophils
5) Promote tissue remodelling and damage
How does bone damage occur in RA?
1) Inflammation and release of cytokines (RANKL) cause activation of osteoclasts (which differentiate from inflammatory cells that infiltrate the joint)
2) Angiogenesis also occurs, allowing further influx of inflammatory cells
3) Osteoclasts drive erosion of bone and mineralised cartilage
4) The pannus invades and erodes cartilage and bone
What is the pannus?
The hypertrophied synovium in RA
What does a normal synovial joint look like?
- Thin synovial membrane
- Preserved cartilage
- Small synoviocytes
Describe the joint in early RA
- Angiogenesis (small capillaries)
- Thicker synovial membrane
- Influx of inflammatory cells
Describe the joint in established RA
- Huge influx of inflammatory cells
- Extensive angiogenesis
- Beginning of bone erosion and pannus
Why does the inflamed joint inhibit smooth movement?
- The synovial fluid contains inflammatory cells and is a lot more viscous
- Narrow joint space with worn down cartilage
- There is increased pain and swelling
What happens to the synovial membrane in RA?
It becomes an inflammatory site that releases a range of inflammatory mediators which cause cartilage and joint degradation
What are the inflammatory mediators in RA?
- TNFalpha
- IL-1, IL-6, IL-8, IL-10, IL-17
- PGE2
Describe the actions of the mediators/cytokines in RA?
1) TNFα is produced by inflammatory cells and starts to induce the release of other mediators/cytokines e.g. IL-1
2) These can act on each other to stimulate inflammation and on synovial sites which release IL-6, IL-8, IL-10 (anti-inflammatory) and IL-17
3) The cytokines (TNFα and IL-1) can act to degrade the cartilage and bone
What is the action of PGE2 in RA?
Cytokines release prostaglandins which are involved in mediating some of the pain and swelling observed in arthritis
What are the cytokines driving inflammation in RA?
TNF and IL-6
What is the most abundant cytokine within the RA synovium?
IL-6
What are the effects of IL-6?
1) Drives acute phase response (CRP)
2) Mediates chemokine driven lymphocyte trafficking - helps bring in lymphocytes
3) Induction fo RANK-L (cytokine which activates osteoclasts) through JAK/STAT signalling
What types of hypersensitivity is involved in RA?
Type II, III and IV
Which type of hypersensitivity mediates joint and tissue damage?
Type III
How thick is the synovial membrane usually?
1-2 cells thick (in RA, proliferates and becomes much thicker)
Why is mast cell and their mediators involvement in RA not type 1 hypersensitivity?
Bc it is not triggered by IgE
Describe synovial membrane cellular involvement in RA
- Macrophages = type A synoviocyte
- Fibroblasts = type B synoviocyte (FLS)
- Synovectomy relieves symptoms for several years
What mediators are present in the RA joint?
- MMP-1,3 and 9
- Cytokines = TNF, IL-1, IL-6
- Chemokines = CCL2, CCL5, IL-8
