Rheumatoid Arthritis Flashcards Preview

Immunology Of Disease > Rheumatoid Arthritis > Flashcards

Flashcards in Rheumatoid Arthritis Deck (10)
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1
Q

Genetics of RA

A

Patients have common epitope of QKRAA at HLA-DR1/HLA-DR4 variants. Upregulation of HLA-DR shows increased cytokines
SNP - PTPN22
Heritability is only 15% concordance between monozygotic twins.

2
Q

RA

A

Chronic inflammatory disease of unknown autoimmune etiology.
- Inflammation of the synovium (synovial fluid is produced between joints to nourish and lubricate cartilage). Capsule becomes stretched, increased flow of blood and joints wobbly.
Thickening of the synovial lining layer due to proliferation of FLS. Influx of T, B, monocytes. Pro-inflammatory cytokines, chemokines, MMPs.
- Mostly in joints but also extra-articular involvement such as lung, heart, nervous, gastrointestinal, skin and eyes.

3
Q

Pathogenesis

A

Initiated in the peripheral lymphoid organs by DCs. DCs present self-antigens to T cells.

  • Macrophages activate MHC II molecules
  • Th cells then activate B cells. Produces autoantibodies in the joint and form immune complexes. Secrete cytokines and growth factors
4
Q

Cytokines present

A

TNF and Il-1 lead to cartilage damage.

5
Q

Cellular involvement

Synovial membrane

A

Synoviocytes:

  • Macrophagic synoviocytes phagocytose waste debris in joint cavity, can be APCs.
  • Fibroblast-like synoviocytes (FLS) produce inflammatory cytokines and proteases that lead to cartilage, ECM destruction
  • produces matrix-metallo proteinases (MMPs) degrading enzymes, IL-6, IL-8
6
Q

Cellular involvement

Peripheral blood

A

B cells:
- produces autoantibodies
- activates T cell
- treatment via Rituximab. B cell depleting antibody. but does not reduce rheumatoid factor.
Monocytes:
- treatment via DMARDS Disease-modifying antirheumatic drugs.
- differentiate into osteoclasts/tissue macrophages

7
Q

Pathogenesis

A

1) DC recognizes and presents antigen to T cells. T cells produce IFNy (th1) and Il-17 and proliferate.
- Th1 cytokines recruit macrophages and FLS within the synovial membrane. Macrophages and FLS then produce cytokines like TNFa, Il-1 and Il-6 which are pro-inflammatory.
- Il-17 stimulates FLS to migrate to other joints, also produces chemokines like Il-8 and CCL2. With FLS, Il-17 induces expression of RANKL, a ligand that binds to RANK on pre-osteoclasts and differentiates them into multinucleated osteoclasts that absorb bone tissue. Bone resorption erodes the joints of RA patients.

2) B cell involvement.
Th2 cells activate B cells. B cells produce autoantibodies to target the autoantigens.
- Produces rheumatoid factor, a primarily IgM antibody (actually, an antibody against the Fc receptor of IgG), that can bind to IgG and activate complement pathway.
- Factors such as smoking can citrullinate peptides to produce in response anti-citrullinated peptide antibodies (ACPA). The production of these peptides alters the self-antigen to be recognized as an immunogenic body and thus cause the B cells to produce these autoantibodies.

8
Q

Anti-citrullinated protein antibody

A

Autoantibodies against citrullinated peptides and proteins in RA. Deimination of arginine residies into citrulline residues makes them targeted antigens. High specificity for RA.
- high association between ACPAand HLA-DR4.

9
Q

Th17 cell involvement

A
  • T cells recruit macrophages
  • Activate B cells to produce autoantibodies
    1) Th17
    - produces Il-17 (recruits myeloid cells like macrophages to secrete proinflammatory TNFa, Il-1, Il-6) (TNFa inhibits Tregs).
    - stimulates FLS to produce IL-8 and CCL2 to attract neutrophils.
    - is an osteoclastogenic subset. Il-17 increases RANKL expression so it binds to RANK on pre-osteoclasts to make tham differentiate and drive bone resorption.
    - produces Il-22 and Il-21 that also increase RANKL on FLS and osteoblasts.
    - drive cartilage degradation. MMP production in FLS. Chondrocytes that induce proteoglycan and collagen (that make up cartilage) release.

2) Treg. Reduced differentiation in RA.
- Th17 and Treg linked. Blocking EP4 of arachidonic acid pathway (pro-inflam) reduces Th17 differentiation. Reduces Il-17 levels, reducing inflammation and increasing Tregs present. But in RA, T cells choose to differentiate to Th17 and that inhibits Foxp3 expression, blocking Treg differentiation.
- dysfunctional, cannot suppress T cell effector functions or reduce cytokine production. Cannot disrupt metabolism, inhibit APC maturation.
- abnormality in CTLA-4, immune checkpoint.

Lineage plasticity, Il-6 promotes T17, redues Treg.

3) Animal models
- knock out of IL-17 and presence of anti-Il-17 antibodies, and inhibition of STAT3 TF for Th17 decreased osteoclastogenesis.
- fetal mouse metatarsals Il-17 stops proliferation of chondrocytes (secretes cartilage)

10
Q

Mouse models

A

CIA - collagen-induced arthritis.

  • rats develop following injection of type II collagen.
  • onset at 2 weeks, some resolve by 6 weeks.
  • symptoms, foot edema and joint/bone destruction