1. “Systemic Lupus Erythematosus” (SLE)
Iraj Salehi-Abari
“Systemic Lupus Erythematosus” (SLE)
Iraj Salehi-Abari MD.,
Internist
Rheumatologist
SLE

2. Definition: Chronic disease Systemic/Multi-organ disease
Iraj Salehi-Abari
Definition:
Chronic disease
Systemic/Multi-organ disease
Inflammatory/Autoimmune disease
Autoantibody/Immune Complex
Skin, Joints, Kidneys, Lungs, Nervous system, Serous membranes,… y
SLE

3. Etiology: Unknown Multifactorial: Genetic Hormonal Immunologic and
Iraj Salehi-Abari
Etiology:
Unknown
Multifactorial:
Genetic
Hormonal
Immunologic and
Environmental factors
SLE

4. Iraj Salehi-Abari
Genetic factors:
High concordance rate (14-57%) of SLE in monozygotic twins
(+) Family history of SLE in 5-12% of cases
(+) ANA in 27% of children of mothers with SLE
GWAS studies: 50 Gene loci with polymorphisms predispose to SLE
SLE

5. Iraj Salehi-Abari
Genetic factors:
The most common genetic predisposition is found at the MHC: Class I HLA (-A, -B, -C) and Class II HLA (-DR, -DQ, -DP)
Presence of “susceptibility genes” or absence of “protective genes” or combination of both are required for sufficient genetic susceptibility to permit SLE development.
SLE

6. Hormonal factors: “Immunoregulatory Hypothesis”
Iraj Salehi-Abari
Hormonal factors:
“Immunoregulatory Hypothesis”
Estradiol, Testosterone, Progesterone,
Dehydroepiandrosterone (DHEA)
Pituitary hormones including prolactin
Modulate the incidence and severity of SLE
SLE

7. Hormonal factors: Estrogen as a risk factor of SLE :
Iraj Salehi-Abari
Hormonal factors:
Estrogen as a risk factor of SLE :
SLE is more common in ladies with childbearing ages
Estrogen-OCP  50% increase in the risk of SLE
Early onset of menarche (< 10 years)  doubles the risk of SLE
Estrogen therapy in postmenopausals  doubles the risk of SLE
SLE

8. Hormonal factors: Testosterone is protective:
Iraj Salehi-Abari
Hormonal factors:
Testosterone is protective:
SLE is less common in men
SLE is more common in women with low testosterone (DHEA)
SLE is more common in men with Klinefelter’s syndrome (XXY) due to lack of testosterone
SLE

9. Hormonal effects on Immune system :
Iraj Salehi-Abari
Hormonal effects on Immune system :
Estrogen stimulates:
Thymocytes, CD8+ and CD4+ T cells, B cells and macrophages
The release of interleukin (IL)-1,…
Expression of VCAM and ICAM
Reduce apoptosis in self-reactive B cells
Promote aTh2 response  Autoantibody
SLE

10. Hormonal effects on Immune system :
Iraj Salehi-Abari
Hormonal effects on Immune system :
Progesterone:
Downregulates T cell proliferation
Increases the number of CD8+ T cells
Promote a Th2 response  Autoantibody
Hyperprolactinemia  SLE flares
SLE

11. Immune abnormalities :
Iraj Salehi-Abari
Immune abnormalities :
“Loss of self Tolerance”:
Self-Antigens are not tolerated
Exaggerated response to exogenous Antigens
So Antigen excess  Antibody excess
“Autoantibodies”
“Immune complexes”
SLE

12. Immune abnormalities :
Iraj Salehi-Abari
Immune abnormalities :
“The location of Antigens”:
Intracellular antigens: not to be recognized
Cell surface antigens: can be recognized
Clear away (released from cell) antigens: can be formed to immune complexes
SLE

13. Immune abnormalities :
Iraj Salehi-Abari
Immune abnormalities :
Phagocytosis and Clearing of Immune complexes, Apoptotic cells and Necrotic cell-derived material are defective in SLE due to depressed levels of C1q and C4 (complement deficiency)
SLE

14. Immune abnormalities :
Iraj Salehi-Abari
Immune abnormalities :
Auto-reactive B cells are more persistently activated and driven to maturation due to:
Defectve ”Apoptosis”
By B cell activating factor (BAFF), also known as B lymphocyte stimulator (BLyS)
SLE

15. Immune abnormalities :
Iraj Salehi-Abari
Immune abnormalities :
Auto-reactive B cells are more persistently activated and driven to maturation:
By defectve ”Apoptosis”
By B cell activating factor (BAFF), also known as B lymphocyte stimulator (BLyS) that are elevated in the patients of SLE
By persistently activated T helper cells
SLE

16. Immune abnormalities :
Iraj Salehi-Abari
Immune abnormalities :
Helper (CD4+) T cells activity: increased
Number of Cytotoxic T cell : decreased
Function of Suppressor T cells: decreased
SLE

17. Immune abnormalities :
Iraj Salehi-Abari
Immune abnormalities :
Multiple signaling abnormalities of T and B cells including cellular hyperactivity and hyperresponsiveness
Defects in B cell tolerance, and increased BAFF
SLE

18. Immune abnormalities :
Iraj Salehi-Abari
Immune abnormalities :
Increased numbers of neutrophils undergoing “NETosis”, a form of apoptosis specific for neutrophils, releases DNA bound to protein in nets, which stimulates anti-DNA
SLE

19. Immune abnormalities :
Iraj Salehi-Abari
Immune abnormalities :
Antigen processing cells and Antigen presenting cells (APC) are macrophages and dendritic cell  Ag + MHC I or MHC II
T cell: MHC I  CD8, MHC II  CD4
B cell: production of antibody against antigen
SLE

20. Immune abnormalities :
Iraj Salehi-Abari
Immune abnormalities :
“The location of Antigens”:
Intracellular antigens: not to be recognized
Cell surface antigens: can be recognized
Clear away (released from cell) antigens: can be formed to immune complexes
SLE

21. Immune abnormalities :
Iraj Salehi-Abari
Immune abnormalities :
“Abnormal cellular breakdown” (apoptosis/necrosis) produces nuclear self-antigens upon apoptotic and necrotic cells  Anti-nuclear antibodies (ANA)
SLE

22. Immune abnormalities :
Iraj Salehi-Abari
Immune abnormalities :
Alternatively, microorganisms may be broken down within APCs into “ mimicry peptides” that have sufficient structural similarity with self-antigen  Auto-antibodies
SLE

23. Environmental factors:
Iraj Salehi-Abari
Environmental factors:
Viral/Bacterial infections:
SLE flares may follow V/B infections
Higher titers of antibodies to EBV in SLE patients
Molecular mimicry
SLE

24. Environmental factors:
Iraj Salehi-Abari
Environmental factors:
Ultraviolet (UV) light:
Stimulate keratinocytes to express more snRNPs on their cell surface
Stimulate keratinocytes to secrete more IL-1, IL-3, IL-6, GM-CSF, and TNF-a
Thereby stimulating B cells to make more antibody
SLE

25. Environmental factors:
Iraj Salehi-Abari
Environmental factors:
Ultraviolet (UV) light:
Damages DNA: Anti-DNA, IC
Activates keratinocytes  abnormal apoptosis  exposing of nuclear antigens  Increases binding of anti-RO, anti-La and anti-RNP
SLE

26. Environmental factors:
Iraj Salehi-Abari
Environmental factors:
Ultraviolet (UV) light:
Alters cellular membrane phospholipid metabolism  cell membrane may be rearranged  Ags of cytoplasmic-facing surface are on the extracellular surface
SLE

27. Environmental factors:
Iraj Salehi-Abari
Environmental factors:
Ultraviolet (UV) light:
Increase the degree of systemic autoimmunity by interfering with antigen processing by and activation of macrophages
Decreases T cell DNA methylation, which may lead to overexpression of LFA-1 these T cells become autoreactive  autoantibody
SLE

28. Environmental factors:
Iraj Salehi-Abari
Environmental factors:
Silica dust, found in cleaning powders, soil, pottery materials, cement and cigarette smoke may increase the risk of developing SLE, especially in African American women
Allergies to medications (antibiotics) are more in SLE patients
SLE

29. Environmental factors:
Iraj Salehi-Abari
Environmental factors:
Higher prevalence of SLE in pet dogs of SLE households: common environmental factor for both human and dog SLE
Moderate alcohol consumption had a protective effect
SLE

30. Environmental factors:
Iraj Salehi-Abari
Environmental factors:
SLE

31. Pathogenesis of clinical manifestations:
Iraj Salehi-Abari
Pathogenesis of clinical manifestations:
Immune complex (IC) deposition:
Lupus nephritis:
Lupus skin rash:
Lupus pericarditis
Lupus pleuritis:
Lupus vasculitis
SLE

32. Pathogenesis of clinical manifestations:
Iraj Salehi-Abari
Pathogenesis of clinical manifestations:
Cell-surface auto-antibodies:
Leukopenia
Thrombocytopenia
Hemolytic anemia
Lupus vasculitis (AECA)
Organic brain disease ( anti-neuronal cell antibody)
Thrombosis (aPL antibodies)
SLE