RA Flashcards
What is affected by inflammation in RA and what happens?
Inner skin of the joints (synovialis),
Inflammation, pannus formation, soft tissue, cartilage and bone destruction
Whats the women/men ration and age of onset in RA?
3:1 women/men
age 35-50 years
Name the three stages/steps of pathogenesis of RA
1) unknown, multifactorial trigger
2) activation of innate immune system
3) formation ob ab against citrullinated proteins
What happens during 1) unknown trigger in RA?
Stress (tobacco smoke, infections, dust, air pollution) on mucosal interfaces
–> barrier dysfunction in mouth lung and intestine
local micromillieu at interfaces: humoral factors (complement, antimicrobial peptides) and cellular factors (APC, neutrophils, TLR-signalling, sec. lymphoid tissues)
–> disturbance of balance = immune reaction and inflammation
How ist the innate immune system 2) induced in RA?
e.g. smoke induces activation of macrophages and DC, chemotaxis of neutrophils, modulation of TLR activity, necrosis –> DAMP release, change of microbiome
Describe the formation of ab against citrullinated proteins 3) in RA
Local inflammation reaction -> increase of PAD expression -> increased citrullination of proteins (generation of neoepitopes)
Presentation of citrullinated neoantigens by activated DC -> activation of citrulline-specific T cells in SLT
Name other sites of autoimmune reactions in RA
Oral mucosa (periodontits, citrullinated proteins and PAD increase, detection of ACPA)
Name features of periarticular and clinical phase
Periarticular: increased ACPA, RF+, no joint involvement
Clinical: systemic loss of tolerance, joint involvement
ACPA are probably ___ because they stimulate…
Pathogenic
complement,macrophages, osteoclasts, neutrophils
Explain the putative mechanism that lead from mucosal immunity to joint inflammation
Increase of citrullinated proteins in healthy joints --> PAD expression by osteoclasts various target structures in the joint (synovial membrane, citrullinated collagen type 2 in cartilage) Epitope spreading (detection of multiple epitopes in one molecule) Cross reactivity of ACPA (collagen type 2 and vimentin)
Adaptive immune system: T cell indepent activation of B cells by TLR crosslinking and stress (inflammation, neutrophils)
T cell dependent B cell activation: exact mechanism unknown (Acpa, RF incerased, citrulline-reactive T cells in HC with RA background)
What does the PAD, what subtypes exist und which ones are associated to RA?
posttranslational conversion of arginine to citrulline (peptidyl-arginine deiminase) PAD1+3: epidermis PAD2: spleen, muscle, macrophages --> RA PAD4: macrophages, neutrophils --> RA PAD&: germ cells
usually intracellular and inactive, activation by incerased Ca2+ levels –> loss of membrane integrity –> extracellular PAD release
What happens during the citrullination of the synovium in RA?
Inflitration of leuko- and monocytes –>differentiation into macrophages –> PAD2 increase
massive cells death/defective clearance
enhanced intraellular CA2+ influx, activation of PAD –> citrullination of vimentin
extracellular PAD release -> activation -> citrullination of extracellular proteins
What kind of cytokines play a role in RA?
Th1 secrete IL2, IFNg and stimulate macrophages, B cells, fibroblasts and osteoclasts
- Macrophages secrete TNFa, IL1, IL6
- AUto-ab form immune complexes –> complement and Fc receptors –> TNFa
- Fibroblasts secrete further cytokines + MMP –> destruction of cartilage and bone
Genetics of RA: Whats the stronges association, what aa is important, how is the theory called?
HLA-DRB1 (conserved region at position 70-74 = shared epitope)
conseved aa at 71 (Lys71) determines aa that fits into binding pocket P4 of HLA antogen binding groove
P4 (HLA-DRB1*04:01, Lsy71 (+), binds citrulline instead of arginine
–> favoured presentation of citrullinated selfantigens
Which HLA is resistamt for RA?
HLA-DRB1*04:02 (asp70, glu71) P4 is neg. charged. Binds both citrulline and arginine
