L3.3 Rheumatoid Arthritis & psoriasis

Question 1

What is central and peripheral tolerance?

Answer 1

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

Question 2

What is autoimmunity and how does it occur?

Answer 2

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

Question 3

Into what cytokines do CD4 cells differentiate into?

Answer 3

• Th17 produces th17 cytokines
  
  • Brings neutrophils to injury sites

Question 4

What can th17 cells be induced into?

Answer 4

Could be induced into:

• Th17 - from TGF-B & IL6
  
  • Produces IL17
• Th1 - from T-bet
  
  • Produces IF-γ

Question 5

Features of R.A

Answer 5

• 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

Question 6

Mechanism of RA

Answer 6

1. Synovial membrane (synovitis)
2. Inflammation not resolved
3. Tissue hyperplasia, inflammatory cells invade & pannus formation
   
   • Pannus = benign tumour
4. Pannus self-irritates → grows → recruits more inflammatory cells
5. Neoangiogenesis → to sustain inflammatory cells to site
   
   • Generalise vasculitis → ↑risks of heart attack
6. Pro-inflammatory cytokines permeate bones → cartilage/bone degeneration
   
   • GM-CSF irritate macrophage → promotes further breakdown of joint tissues
   • May also affect brain functions (depression)

Question 7

Drugs targeting RA

Answer 7

• CCR1 Antagonists
• p38 inhibitors
• ICE inhibitors
• NSAIDs

Question 8

CCR1 antagonists

Answer 8

• Block chemokine receptors that assist leukocyte infiltration into tissue
• But fairly non-specific - problems with infection

Question 9

p38 inhibitors

Answer 9

• P38 is one of the main signalling molecules in inflammation cascades
• Ass with lots of problems e.g. lung infections

Question 10

ICE inhibitors

Answer 10

• ICE is a converting enzyme that converts many molecules

Question 11

NSAIDs

Answer 11

• Classically target PGE2

Question 12

Limitations of GC

Answer 12

• Systemic SE with long term admin
• Represses cartilage and bone formation
  
  • Accelerates joint degeneration

Question 13

Limitations of DMARDs

Answer 13

• “Disease modifying anti-rheumatic agents
• Immunosuppressant of T-cells
• ↑side effects & ↓effectiveness
• Delayed onset on action

Question 14

Changes in treatment

Answer 14

• Earlier use of aggressive treatment
• Biological + combination therapy → allows earlier/permanent remission

Question 15

2 examples of Anti-TNF biologicals

Answer 15

• Etanercept & Infliximab

Question 16

Why are TNFs targeted?

Answer 16

• 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

Question 17

Features of Psoriasis

Answer 17

• 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

Question 18

Pathogenesis of psoriasis

Answer 18

MHC link → shows immune reaction to skin self antigen

Question 19

What are langerhan cells

Answer 19

• (type of dendritic cell)
• where APC is localised to skin

Question 20

Treatments for psoriasis: topical

Answer 20

• 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)

Question 21

Treatments of psoriasis: Phototherapy

Answer 21

• UV light to suppress growth of hyper replicating dermis
• Cancer risk

Question 22

Treatment of psoriasis: Systemic

Answer 22

• 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)