Rheumatoid Arthritis Flashcards
What multisystem disorders are associated with rheumatoid arthritis?
- Joint inflammation= multiple small joints hand/feet, multiple large joints
- Cardiovascular disease= hypertension, diabetes
- Respiratory disease= pulmonary fibrosis
Describe Rheumatoid arthritis
Prolonged duration= relapse and remitting course
Presence of specific factors in blood= Rheumatoid Factor (RF)/ Antibodies to citrullinated protein antigens
(conversion of the amino acid arginine in a protein into the amino acid citrulline)
Describe RA epidemiology
Prevalence= 0.5-1% white Europeans, 5-6% Native Americans
Sex= 2-3x more common in women (hormones?)
Genetic factors= 60% risk
Smoking/ dust exposure (silica)/ microbiome/ obesity/ moderate alcohol may be protective
What are the factors initiating autoreactivity?
- Infection (release of sequestered antigen/ upregulation of costimulators on APCs)
- T cell bypass
How is T cell tolerance bypassed by?
- Modification (neoantigen produced by somatic mutation generated by binding of a pathogen to a self component)
- Inflammation (immunostimulatory environment activates self-reactive T cells)
- Molecular mimicry (antibodies or T cells generated in response to infection cross-react with self)
How are neo-antigens created?
Post-translational modification of proteins- intracellular proteins (histones) and matrix proteins (fibronectin- glycoprotein of ECM, collagen, fibrinogen, enolase-enzyme in glycolysis, vimentin- in cytoskeleton)
What genetic factors are associated with RA?
Increased affinity to HLA-DR-SE (Human Leukocyte Antigen- MHC class 2) Generate autoantibodies (antibodies to citrullinated protein antigens= ACPA/ and RF)
When are ACPAs present?
In the sputum of ACPA-positive individuals without arthritis, early ACPA-positive RA
When are lung changes present?
Early untreated ACPA-positive RA, ACPA-positive healthy individuals at increased risk for developing RA
When does elevated IgA occur?
Early in immunity before joint inflammation, remain important in established seropositive (present in blood serum test) RA
Why is the mucosa targeted?
- Smoking increases PAD expression= results in increased citrullinated protein, increased number and activation of APCs
- Gums= Periodontitis caused by bacteria Porphyromona gingivalis, contains its own PAD therefore citrullinated proteins, molecular mimicry
- GI tract= diversity of gut microbiota reduced in RA
What is loss of tolerance/ epitope spreading?
Epitope= part of the antigen that is recognised by the immune system (where antibody binds)
The development of immune responses to epitopes distinct from the first epitope
The development of immune responses against endogenous epitopes, secondary to the release of self-Ag (antigen)
Increased titres of autoantibodies
How are circulating autoantibodies linked to joint disease?
- Monocyte maturation to osteoclast- PAD activation (peptidylarginine deiminase enzymes than citrullinate proteins), increased citrullination
- Osteoclast activation increases IL-8 (CXCL8)= motor function (mechanical and thermal hypersensitivity, decreased locomotor function)
- Osteoclast maturation by immune complexes and antibody binding= bone erosion
How is the synovium affected?
- Produces synovial fluid for joint lubrication (synoviocytes/ fibroblasts/ blood vessel/ scattered immune cells)
- Synoviocytes hypertrophy and activation
- Increased pro-inflammatory cytokine expression= IL1/6, TNF, MMP, prostaglandins and leukotrienes/ signalling pathway activation
- Influx of lymphocytes (plasma cells increase APCA/RF production, CD4+ T cells)
What causes joint destruction?
Trauma/ virus (acute inflammation)
- Synoviocytes release MMP
- Neutrophils (NETosis, Citrullinated proteins on NETs)
- Macrophages (ACPA, Immune complexes)
- Osteoclasts (activation driven by T cells, macrophages, ACPA)
