Term
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Definition
| A degenerative joint disease whose hallmark is cartilage loss. Leads to joint failure caused by inflammation. At greater risk with age, abormal load, or abnormal cartilage. |
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Term
| What are the three stages of OA? |
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Definition
1) Breakdown of cartilage due to aggrecanases/MMPs
2) Release of proteoglycan and collagen into synovial fluid
3) Chronic inflammation in the synovium, leading to cytokines: IL-1, IL-6, TNF, MMPs. Type 2 and 4 immune rxns.
All 3 stages lead to bone overgrowth |
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Term
| What is the role of cytokines in OA? |
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Definition
Cytokines inhibit anabolism, stimulate catabolism
- TNF and IL-1 - MMPs, iNOS --> IL-6 and bone resorption. iNOS can further activate chondrocyte or breakdown synovium
- IL-6 - bone resorption
- IL-17 - from T cells, induces TNF, IL-1, IL-6 |
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Term
| What is the immune response in OA? |
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Definition
Cartilage debris acts as an antigen, is processed by Tcells/macrophages.
- Type 4 rxn - IFN released, activates macrophages to release more cytokines.
- Type 2 reaction - B cells activated, can act as APCs, release of antibodies. Complement and neutrophils activated. |
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Term
| How are bone spurs formed? |
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Definition
Abnormal bone growth = osteophytes
Chondrocytes release growth factors IGF and TGF, cause pain because bone isn't supposed to be there. |
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Term
| What is rheumatoid arthritis? |
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Definition
| A chronic autoimmune disease where there exists auto-antibodies, and antibodies against proteins that have been citrullinated. Antigen: altered IgG |
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Term
| What types of cytokines are in high concentrations in RA? |
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Definition
| Pro-inflammatory cytokines: TNF, IL-1, IL-17, RANKL, IL-6 |
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Term
| What is the pathology of RA? |
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Definition
| New tissue is granulation tissue (pannus) that grows into the joint, eventually covers and destroys cartilage. Will eventually completely take over joint space and joint can no longer move. |
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Term
| What types of immune responses are present in RA? |
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Definition
- Type 3 humoral immunity - Il-6 starts antibody production in B cells --> RF, anti-CCP, igM/IgG. Immune complexes
- Type 4 cellular immunity - APC activates T cells |
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Term
| What autoantibodies are present in RA? |
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Definition
- Rheumatoid factor - A person with RA produces abnormal IgG, IgM (RF) complexes with IgG. Abnormal Fc portion. Important in diagnostics
- ACPA - citrullinated protein, important diagnostic tool.
Both form complexes leading to a type 3 immune rxn |
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Term
| Review: What are the 3 signals for T-cell activation? |
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Definition
1) Antigen and MHC + Tcell receptor - TCR binds to MHC II, CD4 binds to MHCII
2) Co-stimulators and adhesion - B7 binds to CD28. CTLA4 can block. LFA + ICAM = adhesion
3) Release of IL-2 - proliferation |
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Term
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Definition
| A receptor on B cells activated by the Th17 T cells. Can lead to complement activation. C3 component also diagnostic for RA. |
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Term
| What are the three most important cytokines in RA? |
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Definition
TNF, IL-1, IL-17
TH1 produced TNF, TH-17 produces Il-17. If one is inactive, the other is still working!
Activation --> Synovial fibroblasts, macrophages, chondrocytes, osteoclasts --> inflammation, cartilage damage, bone erosion. |
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Term
| Review: How does a macrophage present antigen to the T cell? |
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Definition
| After Tcell migrates to where macrophage is, TCR + MHC + CD4 --> ICAM/LFA = adhesion, B7 + CD28 --> IL-2 released --> Clonal expansion |
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Term
| What does IL-2 and IL-6 do in RA? |
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Definition
Il- 2 releases IFN --> cytokine release, Inflammation
IL-6 goes to B cell --> antibodies to antigen --> complement |
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Term
| How does TNF affect bone? |
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Definition
| TNF converts Macrophages to osteoclasts, upregulates RANK/RANKL |
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Term
| What three pathways can be drug targets in RA? |
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Definition
1) MAPK pathway
2) NFkB pathways - an inflammatory mediator set off the pathway. IKK phosphorylates IkB --> NFkB --> nucleus and proteins are made
3) JAK-STAT - cytokine enteres, converts monomer to dimer |
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