Week 2 systemic lupus erythematosus-pathogenesis and clinical overview Flashcards
Give the general overview of the pathogenesis of SLE.
- A T and B cell dependent disorder of immune regulation caused by loss of tolerance to self antigens
- genetic, gender, and environmental factors involved. Tend to affect women more.
- Consequence of altered homeostasis often triggered by infections–>decreased clearance of apoptotic cells and impaired regulatory T cell function
Review of tolerance induction and maintenance. What are ways in which tolerance develop and what is defective in SLE?
- clonal deletion -not all deleted in thymus
- clonal anergy: lack of reaction to antigen-need 2 signals - defective in SLE
- apoptosis- decreased in SLE and decreased clearance of apoptosed cells
Which toll-like receptors are involved in SLE?
the ones that react to nuclei
TLR3, TLR7/8, TLR9 all react to RNA or DNA
What are genetic susceptibility factors in SLE?
- T cell defects
- hyper responsive to self-antigens
- resistant to tolerance induction
- impaired function of Tregs - B cell abnormalities
- hyper responsiveness
- increased spontaneous activation
- become APCs for nuclear auto antigens
- produce numerous autoantibodies - Gender-female predominance 10:1
What are environmental triggering events for SLE?
- infectious agents - co-stims for auto reactive T cells
- sunlight - cellular injury altering self antigens
- drugs e.g. procainamide, hydrazine
- cause lupus like disease
- activate self react T cells by inhibiting DNA methylation
What fail-safe mechanisms in tolerance and immunity are broken down in SLE?
- failure to clear cells that did apoptosis
- antigen processing of nucleosomal peptides by immunogenic DCs trigger auto reactive t cells
- failure of regulatory cell network to block activation, differentiation, proliferation of auto reactive T and B cells
- failure of FcR receptors to control B cell activation and maturation
- failure to eliminate self reactive T and B cells
Discuss the epidemiology of SLE.
- prevalence in USA is 5-8-100/100,000
- more common among African americans, hispanics, and asians compared to caucasians
How is the diagnosis of SLE made?
- multisystem involvement
- malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis
- renal disorder, heme disorder, neuro disorder, immunological disorder, positive ANA - immunologic abnormality
- autoantibodies to nuclear antigens - exclusion of other medical conditions
What are the important antinuclear antibodies that are characteristic of SLE?
- anti-ds DNA- goes up and down with lupus activity
2. anti-Smith (spliceosome)
What is the significance of ANA in LSE?
- diagnostic criteria for SLE
- ->form immune complexes, deposition in target organs–>inflammation and C’ activation–>tissue damage
- however, not cytotoxic to cells, most can’t penetrate cell membrane
- no evidence that it actually causes disease, may be product/marker of disease
- babies born to SLE mothers. maternal ANA cross the placenta, and most babies are healthy and don’t get SLE. Except in case of
- Neonatal Lupus Syndrome: rare, transient photosensitive skin rash, congenital heart block (ssa and sub antibodies)-fibrosis of AV node, transient cytopenias, liver abnormalities
How do organ-specific autoantibodies cause disease in SLE?
Example: anti-erythrocytes, anti-WBC, anti-platelets
- surface accessible antigens
1. activate complement system and cause lysis of target cell
2. cause premature removal of target cell from circulation via phagocytosis - eg. immune thrombocytopenia
3. Cause inactivation - e.g. anti phospholipid antibodies
What are hematologic abnormalities seen in SLE?
- Anemia
- Leucopenia
- Thrombocytopenia
- Circulating anticoagulants
What is antiphospholipid syndrome?
- Hypercoagulability
- arterial or venous thrombosis
- pregnancy related complications - associated with presence of antiphopholipid antibodies including “lupus anticoagulant”
- DVT, digital gangrene
What are respiratory abnormalities that can occur with SLE?
- pleuritis
- affecting the lung parenchyma: interstitial lung fibrosis, acute lupus penumonitis, alveolar hemorrhage (emergency), functional abnormalities
- will have complaints of chest pain
What are cardiac abnormalities that can occur with SLE?
- pericarditis w/ or w/out effusion
- valvulitis
- myocarditis
- vasculitis
- Libman Sacks endocarditis
