Systemic Inflammatory Disease Symposium Flashcards
1
Q
What is Rheumatoid arthritis?
A
- 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
2
Q
What are the key cytokines involved in RA pathophysiology? (3)
- what are their main effects?
A
- TNF, IL-1, IL-6
- cytokines make atherosclerotic plaques unstable
- MI and strokes
- muscle and adipose tissue becomes insulin resistant
- diabetes
3
Q
Review the comorbidities in RA?
- what is the cause of these?
A
- 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
4
Q
What is the joint damage pattern in RA?
- how does it present
- what are the process that cause this?
A
- 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
5
Q
What are the clinical markers of RA?
A
- Elevated ESR (Erythrocyte sedimentation rate)
- Elevated CRP (C-reactive protein)
- Presence of autoantibodies:
- Rheumatoid factor (RF)
- Cyclic citrullinated peptide (anti-CCP) antibodies
6
Q
What is Rheumatoid factor (RF)?
A
- 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
7
Q
What is Anti-cyclic citrullinated peptide (CCP) antibody?
A
- 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
8
Q
What is Citrullination
- how does it present in the body?
A
- 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
9
Q
How might anti-CCP have a pathogenic role in RA?
A
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
10
Q
Explain the genetic factor within RA
A
- 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
11
Q
What are some specific genes associated with RA (4)
A
- 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)
12
Q
Explain the hormonal factor within RA
A
- 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
13
Q
What is the association between smoking and RA?
A
- 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+
14
Q
How are infections associated with RA?
A
- 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
15
Q
Give an overview of Molecular mechanisms of joint destruction in RA
A
- 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
16
Q
What is the difference between a normal joint and a rheumatoid joint?
A
17
Q
What is the composition of synovial tissues in the Pannus structure in RA
A
- mainly macrophages (40%)
- fibroblast (10-15%)
- T lymphocytes (40%)
- B lymphocytes (5%)
22
Q
What is the role of Neutrophils in RA?
A
- When activated neutrophils can undergo a special form of cell death termed ‘NETosis’ releasing nuclear chromatin
- Neutrophils infiltrate synovial fluid
- Enhanced NETosis correlates with the presence of anti-CCP antibodies
- NETs release citrullinated proteins
- these can activate and become immune complexes with autoantibodies already present
24
Q
Review the cellular interactions in RA
A
25
Q
Review the risk factors for RA and its presentation as it progresses
A
