Systemic Inflammatory Disease Symposium Flashcards
What is Rheumatoid arthritis?
- an Autoimmune disease
- women are 3x more affected than men
- an increase in dysregulated and persistent inflammation
- systemic inflammation is seen
- Inflammation of the synovial joint
What are the key cytokines involved in RA pathophysiology? (3)
- what are their main effects?
- TNF, IL-1, IL-6
- cytokines make atherosclerotic plaques unstable
- MI and strokes
- muscle and adipose tissue becomes insulin resistant
- diabetes
Review the comorbidities in RA?
- what is the cause of these?
- MI’s Stroke (artherosclerotic plaque instability)
- Diabetes due to adipose and muscle insulin resistance
- causes by cytokines TNF, IL-1 and IL-6
- TNF - causes negative mood affects
What is the joint damage pattern in RA?
- how does it present
- what are the process that cause this?
- Usually multiple joints in a symmetrical fashion
- Morning stiffness
- Swelling, heat, redness and pain
- Loss of function
Destructive process
- Bone erosion
- Synovial and cartilage damage
joint damage is irreversible and joint damage is mirrored across the body
What are the clinical markers of RA?
- Elevated ESR (Erythrocyte sedimentation rate)
- Elevated CRP (C-reactive protein)
- Presence of autoantibodies:
- Rheumatoid factor (RF)
- Cyclic citrullinated peptide (anti-CCP) antibodies
What is Rheumatoid factor (RF)?
- Rheumatoid factor are antibodies directed against the Fc portion of another antibody, leading to immune complex formation
- Present in 60-70% of patients with RA
- Of some use in diagnosis, but:
- Not specific for RA (only 86%), also present in other autoimmune diseases, infectious diseases and some healthy individuals
- RF also found in other diseases e.g., Sjogren’s syndrome, SLE and hepatitis B
- Some RA patients are ‘seronegative’
- Levels do not correlate with disease activity
- RF+ patients have a more severe disease
What is Anti-cyclic citrullinated peptide (CCP) antibody?
- Also known as ACPA (anti-citrullinated peptide antibodies)
- Antibodies directed against CCP are found in 60-70% of patients with RA (anti-CCP+)
- Very rarely found in healthy people who do not go on to develop RA (high specificity 98%)
- Detectable in the blood many years before disease onset
- Anti-CCP+ RA has a more aggressive clinical course of disease
What is Citrullination
- how does it present in the body?
- Process of replacing protein arginine residues with citrulline residues
- Occurs normally in the body but if occurs on an unusual part of the protein, they may be recognised as foreign, leading to an antibody response
- Citrullinated self-proteins are detected in RA patients by anti-CCP antibodies; examples are α-enolase, keratin, fibrinogen, fibronectin, collagen and vimentin
- might be seen in joint synovial tissue
How might anti-CCP have a pathogenic role in RA?
Unable to induce arthritis alone, but can enhance the development and severity of inflammation in mice when mild synovitis is already present.
- Possible mechanisms:
- Activation of inflammatory cells by anti-CCP immune complexes
- Anti-CCP mediated neutrophil cell death producing NETs
- Direct binding of anti-CCPs to drive osteoclastogenesis
Explain the genetic factor within RA
- Most genes show a relatively low gene penetrance. Variants are not found in many of the RA patients.
- No individual gene is necessary or sufficient
- Susceptibility and severity is determined by a combination of genes
- Must be other factors that in addition to genetics that have a role in the susceptibility and severity of autoimmune diseases.
Many of the genes identified regulate the immune system, possibly in response to environmental agents
What are some specific genes associated with RA (4)
- HLA-DRB1 SE Human leukocyte antigen (HLA), accounts for 30-50% of the overall genetic risk
- PTPN22 Negative regulator of antigen receptor signalling in T and B cells (protein tyrosine phosphatase 22)
- CTLA4 Co-stimulation suppressor that regulates interactions between T cells and antigen presenting cells (downregulated in RA)
- TNFAIP3 (A20) Inhibitor of NF-κB and TNFα mediated apoptosis (downregulated in RA)
Explain the hormonal factor within RA
- Men who get RA usually have low testosterone levels
- RA patients often experience remission during pregnancy
- Early menopause (age <45 years) has been associated with both an increased risk of RA, as well as RF positivity
- Use of oral contraceptives modestly decreases risk of anti-CCP+ RA
- Mixed data on HRT - may reduced the risk of anti-CCP+ RA in postmenopausal women >50 years of age, many other studies show no effect
What is the association between smoking and RA?
- Heavy smoking of both sexes increase the risk of RA among persons with susceptibility HLA-DR4 alleles.
- Twin studies have demonstrated the gene–environment interaction by showing the effect of smoking is greater in genetically susceptible individuals, particularly if HLA DRB1+
- Smoking and HLA-DRB1 alleles increase the risk of being anti-CCP+
How are infections associated with RA?
- Viral/bacterial infections have been suggested for many decades as an initiating cause of autoimmunity
- difficult to prove as infection may no longer be present once the disease is established
-
Porphyromonas gingivalis (P. gingivalis) has some indications of being linked with RA
- has its own version of PAD (P-PAD) and can citrullinate our proteins but possibly in a different way to normal and thus activate the immune system which then triggers autoantibody formation that then also recognises normally citrullinated proteins.
- this infection occurs in Periodontitis
Give an overview of Molecular mechanisms of joint destruction in RA
- Swelling over extensor tendons, wrist and MCP joints
- Synovium hyperplasia (an increase in cell numbers)
- Synovial fibroblasts have reduced apoptosis, enhanced anchorage, upregulated adhesion molecules and increased proliferation