Organ-specific immunity: JOINT & BONE Flashcards
What is the synovial membrane made up of?
Type A (mAcrophage) and type B (fibroBlast) synoviocytes
What are the layers of the joint lining?
The sublining, lining (fibroblast and barrier-forming macrophages) and the synovial fluid)
How are type A synoviocytes connected?
Tight junctions
What happens to the Type A lining during arthritis?
The lining is disrupted, enabling infiltration of myeloid cells
What is the sublining composed of?
Different types of macrophages and fibroblasts (than those of the lining).
What happens (disease-wise) in early RA?
Immune infiltration and proliferation of the synovial lining, blood vessel formation.
What happens (disease-wise) in established RA?
Synovial lining is overlaying the cartilage, produced enzymes lead to cartilage and bone destruction
What are chondrocytes?
Cartilage cells
What do macrophages do in arthritis?
They release a lot of inflammatory cytokines as well as IL-10 and TGFß (to try to dampen the whole thing) and interact with T and B cells through soluble factors and direct contact
What causes RA?
Environmental factors (smoking, stress, microbes) and genetic predisposition are involved
What happens before clinical symptoms?
Pre-arthritis, which is a bit auto-immune like but not yet arthritis.
Can pre-arthritis be detected?
Yes, there are some antibodies that can be detected in some patients, such as IgG-RF and/or anti-CCP
What are ACPAs directed against and what does binding do?
Citrullinated protein on osteoclast precursors. This causes further activation and maturation of osteoclasts and IL-8 production
What do osteoclasts usually do?
Bone resorption which is necessary for maintenance, repair and remodeling
How do ACPAs induce pain?
IL-8 produced by mature osteoclasts can interact with (sensory) nociceptor.
Recruitment of neutrophils can lead to inflammation and progression, which is also painful
What does knocking out IL-12 in RA patients do, and why does knocking out IFNy not have the same effect?
Dampens symptoms, while knocking out IFNy makes symptoms worse.
So what is driving RA autoimmune processes?
IL-17/IL-23 (so Th17), not Th1
What does Th17 have an effect on?
Monocytes, B cells and fibroblasts
What is the proportion of IL-17 in early RA patients, and why?
Higher compared to healthy controls, due to a CCR6 polymorphism
What is the pro-inflammatory loop in RA?
Th17 ->TNFα and L-17 ->fibroblast ->IL6 and IL8 which act on Th17 and so on.
Is Th17 plastic?
Yes
What are possible treatments?
Rituximab, CD80/86 inhibitors, JAK inhibitors, TNF inhibitors, IL6R inhibitors
What are the two kinds of RA?
Activating complement and binding to Fc receptors on macrophages
What is RF?
Rhematoid factors are autoantibodies directed against IgG Fc that can form enormous immune complexes
What is ACPA?
Antibodies (general) against Citrullinated Protein antigens
What is anti-CCP?
Anti-cyclic citrullinated Peptide, which is an artificial peptide used to measure ACPA using ELISA (so anti-ACPA)
What is citrullination?
Totally normal. Post-translational amino acid modification (arginine -> citrulline), can occur in every protein
Why is smoking a risk factor for RA?
Inflammation (lungs) results an increase citrullination and breakdown of tolerance in genetically predisposed individuals
What is fine specificity in ACPA?
ACPA is very specific for specific citrullinated proteins
