“Systemic Lupus Erythematosus” (SLE) Iraj Salehi-Abari “Systemic Lupus Erythematosus” (SLE) Iraj Salehi-Abari MD., Internist Rheumatologist salehiabari@sina.tums.ac.ir SLE

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Environmental factors: Iraj Salehi-Abari Environmental factors: SLE

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

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