Rheumatoid Arthritis - Pathogenesis Flashcards
Function of synovium
Maintain intact tissue surface Lubricate cartilage Control synovial fluid volume Control synovial fluid composition - hyaluronan, lubicin Nutrition of chondrocytes
RA is a chronic, symmetric and polyarticular inflammatory joint disease. What are 3 features of rheumatoid synovitis?
Inflammatory cell infiltration
Synoviocyte proliferation
Neoangiogenesis
What cells are found in the synovial fluid of a rheumatoid joint?
Neutrophils
What is pannus?
An abnormal layer of fibrovascular or granulation tissue that forms over the articular surface
Causes bone and cartilage destruction leading to joint deformity
Which antibodies are associated with rheumatoid arthritis?
Rheumatoid Factor
Anticitrullinated protein
Autoantibodies to type II collagen and systemic antigens eg glucose phosphate isomerase
What process is activated by autoimmune responses in RA?
Complement
Leads to inflammation
Seropositive RA patients have which antibodies?
Rheumatoid Factor
Anticitrullinated Protein Antibodies ACPA
How is seropositive RA diagnosed?
Anti-CCP assays recognise self citrullinated proteins
Which proteins will be recognised to be self citrullinated in anti CCP diagnostic assays?
Keratin, fibrinogen, alpha enolose, fibronectin, collagen, vimentin
How does prognosis for patients compare between seropositive and seronegative cases of RA?
Seropositive have a less favourable prognosis
Which genetic polymorphism is associated with RA?
HLA DRB1 - promotes autoimmunity
Others -PTPN22, CTLA4, c-rel
What environmental factors may contribute to RA?
Smoking
Bronchial stress
Infection
Which infectious agents are associated with Rheumatoid arthritis?
Viruses E.coli Mycoplasma Periodontal disease - Porphyromonas gingivalis Gut microbes of the microbiome
3 events in pathogenesis of RA leading to ACPA response
Repeated insults in genetically susceptible individual
Formation of immune complexes and rheumatoid factor
Alteration in citrullination of proteins and breakdown of tolerance
What is citrullination?
Conversion of arginine to citrulline
What cells take up the citrullinated atingen in the ACPA response?
Antigen presenting cells
Which cells are activated by the APCs in the ACPA response?
T cells and B cells resulting in antibody production
Immune complexes are formed from the antibodies produced by activated B cells. What is the effect of the immune complexes in the ACPA response?
Inflammation of the joint
Cycle of complexes forming perpetuates inflammation
What is synovitis?
Inflammation of the synovium
Describe 6 cellular features of synovitis
Villous hyperplasia Infiltration of B cells, T cells Macrophage and plasma cell activation Intimal cell proliferation Production of cytokines and proteases Increased vascularity
Self ampifying process
What cell involvement is there in rheumatoid arthritis?
T cells and their cytokines
B cells and cytokines
Stromal cell cytokines
Inflammatory cytokines
What is the effect of T-cell targeted treatment in RA?
Little effect
Low level of cytokines in Synovium
Activation of B cells and macrophages
Name a T-cell targeted medication
Abatacept
What is the effect of a B-cell targeted treatment in RA?
Very effective against pathogenic CD20 + Bcells
What do B cells produce and what is the function of this product?
Autoantibodies
Autoantigen presentation
Cytokines - IL-6, TNF alpha
Which stromal cell cytokines are abundant in the RA synovium?
Macrophage and fibroblast cytokines
Which cells are activated by TLR and NLRs?
Macrophage (M1)
What is the function of chemokines produced in RA synovium?
Recruit inflammatory cells
Anti-inflammatory IL-10 is also present in the synovium. Why does inflammation still occur?
Not produced at high enough levels to offset the proinflammatory cytokines
Functions of inflammatory cytokines (6)
Promote expression of endothelial cell adhesion molecules
Activate synovial fibroblasts, chondrocytes and osteoclasts
Promote angiogenesis
Suppress T-regs
Activate leukocytes
Promote autoantibody production
Which 4 systemic effects are mediated by IL-6?
Anaemia
Acute phase response
Cognitive dysfunction
Lipid metabolism dysregulation
Why is neoangiogenesis crucial in driving RA?
Nutrients provided to hyperplastic synovium
How is blood vessel proliferation enhanced on Rheumatoid synovium?
Hypoxic conditions
IL8 and VEGF - Angiogenic factors
Which 3 cells are responsible for destruction of bonee and cartilage in RA?
Osteoclasts
Synovial lining cells (particularly FLS)- can invade cartilage
FLS - produce proteases
What is produced in the RA synovium to activate osteoclasts?
RANKL
Systemic consequences of RA
Vasculitis, nodules, scleritis, amyloidosis
Cardiovascular disease
Fatigue, reduced cognitive function
Liver - elevated acute phase response, anaemia
Lung - Interstitial lung disease, fibrosis
Muscles - sarcopenia
Bone - osteoporosis
Secondary Sjrogen’s Syndrome
How can RA induce cardiovascular disease?
Altered lipid metabolism
Elevated acute phase reactants
Increased endothelial activation
How can RA induce anaemia?
IL6 increases hepatocyte production of hepcidin which regulates iron levels
