Summary - Immunopathology of lecture 6

LES 6 TOLERANCE AND COSTIMULATION DENDRITIC CELLS

- Dendritic cells
o Apc
 Micropinocytosis and phagocytosis by tissue dc viral infection
 Mhc expression is low on tissue dc
High on dc in lymphoid tissues
 Co stimulator delivery
niet-fagocyterende lymfoïde dendritische cellen continu co-stimulatoire
signalen leveren, zonder dat een externe trigger nodig is, om immuuncellen,
zoals T-cellen, te activeren en een immuunrespons te ondersteunen.Antigen
presented
Peptide, viral antigen, allergens
 Location
Ubiquitous throughout the body
o Dc – dynamically interacting with environment
Moving trough lymph node stretching out dendrites to make contact with other cells
o Ralph Steinman  demonstrate cross talk between DC and naïve t cell occur with 3
signals (TCR with MHC class, costimulation, cytokines
o Linking innate and adaptive
 DC communicate with t cell and activates t cel with three signals
 On DC  pathogen or pamp on PRR or Toll
 TCR to fe MHC class 2
 Costimualtion CD80/86 from dc with CD28 from T cel
o Cd80/86: cd28  facilitates t cell activation, proliferation,
survival and cytokine production
 Cytokine
 Il 12  th1
 Il 4  th2
 Il 23 and TGF beta and il 6  Th17






, 

- Application
o Costimulation blockade
 Rheumatoid artritis (more female)
 Polyartritis, symmetric, hand and feet and large joint, destructive,
extra articular
 DCs activate T cells, which then produce inflammatory cytokines and
signals that cause inflammation and tissue destruction.
o Activated macrophages
o Ifn gamma
o Il2
o Tnf alfa  chondrocyt
o RANK-L activates osteoclasts, leading to bone erosion.
o B cells produce autoantibodies and cytokines like IL-6 and
rheumatoid factor, contributing to inflammation.
Blocking interactions between DCs and T cells can dampen this
inflammatory cascade, potentially reducing damage to tissues and
bone.

 CTLA 4  downregulation CD28 mediated t cell activation
Bigger affinity for cd80/86  co inhibitory signals
 Abatacept  CTLA-4ig  recombinant fusion protein  treatment for RA
 Fc domain from igG and bovenste= CTLA-4
  ctla-4ig bind to CD80/86 -> no t cel activation
  downstream effect  no activation of pro inflammatory cytokine
and chondrocyte and osteoclast
 This treatment does not deplete t cells or leukocytes, allowing the
immune system to still function against infections = specific target
therapy
 Treat with abatacept  ACR response 20, 50, 70  20% decrease or
50% or 70%
You get dubble blind  patient do not know which drug
Open label extension  all patient get drug
80% ACR20 response