L3.3 Rheumatoid Arthritis & psoriasis Flashcards
What is central and peripheral tolerance?
Self-reacting usually prevented by central & peripheral tolerance
- Central = regulating the type of T cell produced via CD8+ immune surveillance
- Peripheral = involves a series of suppressions on T and B cells
What is autoimmunity and how does it occur?
immune system unable to discriminate b/w non-self & self
- Occurs via:
- Breakdown of tolerance
- Post-translational modifications (env + epigenetics + susceptible genes)
Hard to remove AI disease if memory T & B cells are involved
Into what cytokines do CD4 cells differentiate into?
- Th17 produces th17 cytokines
- Brings neutrophils to injury sites
What can th17 cells be induced into?
Could be induced into:
- Th17 - from TGF-B & IL6
- Produces IL17
- Th1 - from T-bet
- Produces IF-γ
Features of R.A
- Unknown etiology (origins)
- Females > males (3:1)
- Diagnosis:
- Morning stiffness > one hour
- Arthritis in 3 or more joints
- Disease symmetrical
- Radiological changes
- Smoking is the main risk factor
Mechanism of RA
- Synovial membrane (synovitis)
- Inflammation not resolved
- Tissue hyperplasia, inflammatory cells invade & pannus formation
- Pannus = benign tumour
- Pannus self-irritates → grows → recruits more inflammatory cells
- Neoangiogenesis → to sustain inflammatory cells to site
- Generalise vasculitis → ↑risks of heart attack
- Pro-inflammatory cytokines permeate bones → cartilage/bone degeneration
- GM-CSF irritate macrophage → promotes further breakdown of joint tissues
- May also affect brain functions (depression)
Drugs targeting RA
- CCR1 Antagonists
- p38 inhibitors
- ICE inhibitors
- NSAIDs
CCR1 antagonists
- Block chemokine receptors that assist leukocyte infiltration into tissue
- But fairly non-specific - problems with infection
p38 inhibitors
- P38 is one of the main signalling molecules in inflammation cascades
- Ass with lots of problems e.g. lung infections
ICE inhibitors
- ICE is a converting enzyme that converts many molecules
NSAIDs
- Classically target PGE2
Limitations of GC
- Systemic SE with long term admin
- Represses cartilage and bone formation
- Accelerates joint degeneration
Limitations of DMARDs
- “Disease modifying anti-rheumatic agents
- Immunosuppressant of T-cells
- ↑side effects & ↓effectiveness
- Delayed onset on action
Changes in treatment
- Earlier use of aggressive treatment
- Biological + combination therapy → allows earlier/permanent remission
2 examples of Anti-TNF biologicals
- Etanercept & Infliximab
Why are TNFs targeted?
- TNF abundant in joint fluid (pro-inflam)
- Further activates macrophages
- Anti-TNF antibodies → mops up excessive secreted TNF
- Binds via CDR regions → blocks TNF from bidning to receptor
- Macrophage not activated → TNF removed via immune system
Features of Psoriasis
- Auto-immune skin disease
- Irritation to skin repair system
- Attacks connective tissues under skin → chronic inflam → hyperprolif
- Skin becomes thick & scaly → keration stacks
- Bacteria lodged in fissures/lesions → infections
Pathogenesis of psoriasis
MHC link → shows immune reaction to skin self antigen
What are langerhan cells
- (type of dendritic cell)
- where APC is localised to skin
Treatments for psoriasis: topical
- Steroids → effective but large S.E
- Dermal atrophy
- Betamethosone, anthraline
- Coal tar derivatives
- Local suppression for macrophages and T cells
- Promotes skin cacer
- Vit D analogues
- Calcipotriene
- Teratogenic (causes birth defects)
Treatments of psoriasis: Phototherapy
- UV light to suppress growth of hyper replicating dermis
- Cancer risk
Treatment of psoriasis: Systemic
- Vit A analogues
- Forces cells to mature, go into quiet state
- Also teratogenic
-
Cyclosporin
- Immune suppressant
- Methotrexate - anti-prolif
- Biologicals
- Anti-TNF & Anti-IL17 (IL17 found in plague form of disease)
- Effective in around 40% of people
- Ustekinumab (blocks IL12)
- Brodalumab & ixekizumab (blocks IL17)
- Anti-TNF & Anti-IL17 (IL17 found in plague form of disease)
