Lecture 25 - Rheumatoid Arthritis - Introduction Flashcards
How many different types of arthritis are there?
Over 100
What is the burden of arthritis?
- approx. 3.3 million
* $55 billion spent
What is the definition of RA?
Chronic inflammatory autoimmune disease of unknown aetiology
Describe the primary manifestation of RA
Synovitis (synovial inflammation) Erosion of: • Bone • Cartilage • Peri-articular structures
What is the incidence of RA?
0.5% - 1%
Is RA more common in males of females?
Females (2-3x more common)
What is the age of onset of RA?
40-70 years
What is the central paradigm of autoimmune disease?
Genetic susceptibility + Environmental trigger
→ Breakdown of immune tolerance
→ Autoimmune disease
Outline the categories of risk factors for RA
- Genetic
- Epigenetic
- Hormonal
- Environmental
Describe the genetic risk factors for RA
1. HLA class II • DRB1 gene, which encodes HLA-DR • Allelic variants
- non-HLA II
What do twinning studies show about genetic risk of RA?
Genetics accounts for 50-60% of disease susceptibility
The remainder is due to other factors
On which chromosome are the genes for HLA class II?
Chromosome 6, p arm
Which alleles of HLA-DR predispose to RA?
HLA-DRB1* 0401
HLA-DRB1* 0404
What is the ‘shared epitope’?
What is its role in RA?
Five aa sequence: QKRAA
Present in the HLA-DR β chain
Surrounds the peptide binding groove; thus determining antigen presentation in the context of HLA II)
Role in RA:
• Efficient binding of arthritogenic peptides
• Thymic selection of autoimmune T cells
What are the proposed roles of the SE?
SE: Shared epitope
- Target for T-cells (molecular mimicry)
- Marker of immunoreactivity
- Polarises T cell differentiation to Th17 (autoimmunity)
List some non-HLA genetic risk factors for RA
There are many other genes that have been identified
e.g.
PTPN22:
• has a role in B and T cell signalling
• Carries a 2 fold risk of RA in caucasians
What is microchimerism?
Give an example of it in RA
What is NIMA?
Microchimerism:
• the presence of a small number of cells that originate from another individual (usually the mother)
• Genetically distinct from the cells of the host individual
• The cells often come from the mother during gestation
• Maybe responsible for autoimmune disease, however the mechanisms are still unclear
In RA:
NIMA: Non-inherited maternal antigens
Persistence of maternal antigens in a child throughout life (from gestation)
These antigens are not ‘inherited’
Cells expressing SE from mother persist
What is epigenetics?
Modification of chromosome that leads to altered gene expression without changes to the DNA sequence
What are some epigenetic mechanisms seen in RA?
- Increased histone deacetylase
•In fibroblasts
→ increased cell proliferation - DNA methylation
(suppression of gene expression)
• In RA, there is an abnormal pattern of DNA methylation
of genes associated with RA - microRNAs
• Pre-translational modification of genes thought to be associated with RA
List some hormonal risk factors for RA
- Oestrogen exposure
→ Thus women more prone to RA - Pregnancy
• High levels of Oestrogen and Progesterone (as well as IL-10)
• Immune suppressive effect during pregnancy
• Relapse postpartum
Describe how oestrogen exposure predisposes to RA
- B cells
• Eostrogen exposure makes them become more resistant to apoptosis
• These are the cells that are producing the auto-antibodies - Fibroblasts
• Eostrogen exposure leads to increased metalloproteinase secretion
→ damage of joints - TNF
• Eostrogen exposure to macrophages increases their release of TNF
Describe how pregnancy exposure predisposes to RA
In pregnancy there are high levels of Oestrogen and Progesterone
1st & 2nd trimester: > 75% of the women have improvement of RA
3rd trimester: remission
• Lots of oestrogen circulating
**(is oestrogen beneficial or harmful?)
What is Citrullination?
Post-translational conversion of arginine to citrulline by PADI enzymes
What is the function of PADI enzymes?
Where are they active (on a cellular level)?
Conversion of arginine to citrulline
Occurs post-translation
Active intra- or extracellularly
What is the role of citrulline in RA?
- Citrulline binds the Shared Epitope (SE) more avidly
- Break down in tolerance
- Presence of anti-citrullinated protein Ab
What is ACPA?
What are some of its targets?
Anti–citrullinated protein antibody
Some targets: • α-enolase • Keratin • Fibrinogen • Fibronectin • Type II collagen
When is PADI expressed?
Not specific to joint or RA
Happens in many instances:
• Tissue stress
• Inflammation
How many isoforms of PADI are there in humans?
Which are abundant in inflamed synovium?
There are four isoforms
Abundant in inflamed synovium:
• PADI -2
• PADI -4
What does PADI stand for?
Peptidyl-arginine deiminase
Describe the citrullination reaction
Arginine → Citrulline
List some environmental risk factors for RA
- Smoking
• increased PADI 2 expression - Microbiome
- Infections
• Epstein-barr virus (molecular mimicry)
• Porphyromonas gingivitis (increased PADI4 expression) - Bronchial stress
• Exposure to silica - TLR activation
Describe the features of synovitis
1. Inflammatory cell infiltration • Fibroblasts • Macrophages • Lymphocytes • Mast cells
- Vascular neogenesis
- Ectopic lymphoid neogenesis
- Synoviocyte neogenesis