Systemic Lupus Erythematosus

1. Systemic Lupus Erythematosus Steve Beesley

2. History • 1948 – Malcolm Hargraves discovers the lupus erythematosus (LE) cell. • 1957 – The first anti-DNA antibody is identified.

3. The LE cell is a neutrophil that has engulfed the antibody-coated nucleus of another neutrophil. LE cells may appear in rosettes where there are several neutrophils vying for an individual complement covered protein. LE Cell

4. Genetic Associations • HLA’s are loci on genes that code for certain β chain on the MHC complex • HLA-DR2 • HLA-DR3 • HLA-DQB1 – Involved in mediating production of antibodies to ds-DNA

5. Symptoms • Non-specific: • Fatigue • Weight loss • Malaise = generally feeling ill • Fever • Anorexia (over time) • Arthritis • 90% of patients experience arthritic symptoms • Symmetrical • Appears in hands, wrists, and knees mainly

6. Skin Manifestations • Malar or Butterfly Rash • Discoid Rash – Stimulated by UV light • Skin manifestations only appear in 30-40% of lupus patients.

7. Renal (Kidney) Manifestations • 50-70% of all lupus patients experience renal developments. • Most Dangerous: • Glomerulonephritis where at least 50% of the glomeruli have cellular proliferation • Glomeruli – capillary beds in the kidney that filter the blood. • Renal Failure because of Glomerulonephritis is the leading cause of death among lupus patients. Normal Glomerulonephritis

8. Other Manifestations • Cardiac • Central Nervous System • Hematological

9. Main Pathology • The plasma cells are producing antibodies that are specific for self proteins, namely ds-DNA • Overactive B-cells • Suppressed regulatory function in T-cells • Lack of T-cells • Activation of the Complement system

10. Overactive B-cells • Estrogen is a stimulator of B-cell activity • Lupus is much more prevalent in females of ages 15-45 • Height of Estrogen production • IL-10, also a B-cell stimulator is in high concentration in lupus patient serum. • High concentration linked to cell damage caused by inflammation

11. T-cell Malfunctions • Fc region switch • ζ εγ • Leads to malfunction in signaling and decreased IL-2 production • Increased levels of Ca2+ • Leads to spontaneous apoptosis

12. T-cell Signal Transduction

13. Activation of Complement System • Complement system is activated by the binding of antibodies to foreign debris. • In this case its over activation • RBCs lack CR1 receptor • Decreasing the affective removal of complexes

14. IgG Pathogen • IgG is the most “pathogenic” because it forms intermediate sized complexes that can get to the small places and block them.

15. DNA is the Main man • DNA is the main antigen for which antibodies are formed. • Extracellular DNA has an affinity for basement membrane where it is bound by autoantibodies. • Classical thickening of the basement membrane

16. Testing • ESR • Urinalysis • Complement Test • Tests levels of C3, C4, CH50 • Low levels indicates possible presence of disease • FANA – Fluorescent antinuclear antibody • Ouchterlony Test – shows interactions

17. FANA • ELISA Test • Generally test for: • ds-DNA antibodies • Antihistone antibodies • Binds to DNA, major constituent of chromatin • Deoxyribonucleoprotein (DNP)

18. Ouchterlony Test • Used to determine immunological specificity • Rules out a false positive • Shows the serum does or does not have antinuclear antibodies

19. Summary • Lupus = Autoimmunity • Systemic and affects connective tissue • Caused by malfunctions of: • T-cells • B-cells • Complement System • Signal Transduction • Can be lethal or not • Unique to each individual