Systemic lupus erythematosus pathophysiology
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The pathophysiology of systemic lupus erythematosus involves the immune system. Other factors such as genetic factors, hormonal abnormalities, and environmental factors also play a role. The most important environmental factors involved in the pathogenesis of SLE include ultraviolet (UV) light and some infections. The most important genes involved in the pathogenesis of SLE include HLA-DR2, HLA-DR3, HLA class 3, C1q, and interferon (IFN) regulatory factor 5. The most prominent events involving immune abnormalities are related to persistent activation of B cells and plasma cells that make auto-antibodies during disease progression. The disease developmental process begins with the release of microparticles and proinflammatory cytokines from the cells that are undergoing apoptosis. Due to excess amount of apoptosis, the body is unable to clear these microparticles entirely, and these microparticles are presented to dendritic cells as antigens. Dendritic cells process these microparticles and mature, and present these as antigens to T-cells. T-cells, microparticles, and proinflammatory cytokines themselves trigger B-cell activation and autoantibody production. As a result, body tissues lose their self-tolerance. The most prominent events involving hormonal abnormalities are due to prolactin and estrogen. On microscopic histopathological analysis, apoptotic keratinocytes, vacuolization of the basement membrane, and dermal mucin deposition are characteristic findings of SLE dermatitis, and active or inactive endocapillary or extracapillary segmental glomerulonephritis are characteristic findings of lupus nephritis.
The progression of systemic lupus erythematosus (SLE) involves the immune system. Nearly all of the pathological manifestations of SLE occur due to antibody formation and the creation and deposition of immune complexes in different organs of the body. When the immune complexes are formed, they deposit on different body tissues and vessels, which may lead to complement activation and more organ damage. There are other factors such as genetic factors, hormonal abnormalities, and environmental factors that also play a role in the pathogenesis of SLE.
The environmental factors and genetic factors are the most important risk factors for developing SLE because they may jump-start the disinhibited cellular apoptosis chain. This apoptosis step is the first step in the pathogenesis of lupus.
- May stimulate some antigen specific cells and increase apoptosis
- May induce anti-DNA antibodies
- May mimic lupus-like symptoms
- Associated with higher risk of SLE
- Associated with triggering the active courses and flare ups of disease in children
- Ultraviolet (UV) light:
The development of systemic lupus erythematosus (SLE) is due to the activation of different mechanisms that may result in auto-immunity. The disease developmental process begins with the release of microparticles and proinflammatory cytokines from the cells that are undergoing apoptosis. Due to excess amount of apoptosis, the body is unable to clear these microparticles entirely, and these microparticles are presented to dendritic cells as antigens. Dendritic cells process these microparticles and mature, and present these as antigens to T-cells. T-cells, microparticles, and proinflammatory cytokines themselves trigger B-cell activation and autoantibody production. As a result, body tissues lose their self-tolerance. Affected patients are no longer entirely tolerant to all of their self-antigens, leading to development of an autoimmune disease and producing autoantibodies as a response. During disease progression, B cells and plasma cells that make autoantibodies are more persistently activated due to signaling abnormalities, causing them to make more autoantibodies. These autoantibodies are targeted predominantly to intracellular nucleoprotein particles. This increase in autoantibody production and persistence is supposed to be downregulated by anti-idiotypic antibodies or regulatory immune cells, but the massive immunologic response in SLE prevents this downregulation from taking place. After formation of immune complexes, the classical complement pathway is activated, which leads to the deposition of immune complexes in different organs and is responsible for flare ups and long term complications. The most important immune abnormalities that are related to SLE development and progression are:
Increased level of microparticles (MPs):
- Microparticles are small, membrane-bound vesicles enclosing DNA, RNA, nuclear proteins, cell adhesion molecules, growth factors, and cytokines
- They are shed from cells during apoptosis or activation
- Microparticles can drive inflammation and autoimmunity by their derivatives
- Increased expression of interferon alpha (IFN-α) inducible RNA transcripts by mononuclear cells
- Increased IFN-I production due to increased availability of stimulatory nucleic acids
- May be responsible for SLE chronic characteristics
- Elevated levels of circulating TNF-alpha (expressed by renal tissue in lupus nephritis) correlate with active disease
Cell signaling abnormalities leads to:
- T and B lymphocytes cellular hyperactivity
- T and B lymphocytes hyper responsiveness
- Persistence of auto-reactive T cells that would otherwise have been deleted
Signaling abnormalities of T and B lymphocytes, may be due to:
- Abnormal voltage-gated potassium channels, these channels facilitate excessive calcium entry into T cells and lead to increased calcium responses to antigen stimulation
- Hyperphosphorylation of cytosolic protein substrates
- Decreased nuclear factor kB
- Increase in circulating plasma cells and memory B cells that are associated with SLE activity
- Polyclonal activation of B cells and abnormal B-cell receptor signaling
- Increase in B cells' life span
- Decrease in cytotoxic T cells, decrease in suppressor T cell function, and impaired generation of polyclonal T-cell cytolytic activity
- Increased number and activity of helper T cells
- Increased number of circulating neutrophils undergoing NETosis (NET=neutrophil extracellular traps), a form of apoptosis specific for neutrophils, releases DNA bound to protein in protein nets, which stimulates anti-DNA and IFN-alpha production
- Increased neutrophil extracellular trap leads to: 
The following evidence is suggestive of the hormonal predisposition to SLE:
- Predilection of the disease for females shows the relationship between female hormones and the onset of SLE
- Significantly increased risk for SLE in:
Hormones that are related to disease progression include:
- Stimulates the immune system and is elevated in SLE
- Including oral contraceptive use and postmenopausal hormone replacement therapy: 
- Stimulates the type 1 IFN pathway
- Stimulates thymocytes, CD8+ and CD4+ T cells, B cells, macrophages, and causes the release of certain cytokines (eg, IL-1)
- Prompt maturation of B cells, especially those that have a high affinity to anti-DNA antibodies by decreasing the apoptosis of self-reactive B-cells
- Stimulate expression of HLA and endothelial cell adhesion molecules (VCAM, ICAM)
- Increases macrophage proto-oncogene expression
- Enhanced adhesion of peripheral mononuclear cells to endothelium
- May inhibit the type 1 interferon pathway, suggesting that a balance between estrogen and progesterone may be critical for the body to remain healthy
- Both progesterone and high levels of estrogen promote a Th2 response, which favors auto-antibody production
Systemic lupus erythematosus is transmitted in a polygenic inheritance pattern. Genes involved in the pathogenesis of systemic lupus erythematosus include HLA class 2 (especially DR2 and DR3), HLA class 3 (especially complement genes including C2 and C4 genes), IFNRF5 gene, and other genes related to the immunologic system. The following evidence is also suggestive of the genetic predisposition of SLE:
- Increase occurrence of disease in identical twins
- Increased disease frequency among first degree relatives
- The increased occurrence of the disease in siblings of SLE patients
|Class||Gene subtype||Function||Pathological effect and Molecular mechanisms|
|Autoantigen presentation||HLA class 2|
|Immune complex dependent response||HLA class 3||
|Innate response||Interferon (IFN) regulatory factor 5|
|The IRAK1-MECP2 region||
|Cell apoptosis regulators||TREX1|
|IFNα regulators||TNFAIP3 and TNIP1||
|Regulators of Lymphocytes||TNFSF4||
|Genes involved in immune complex clearance||ITGAM||
- Homozygous deficiencies of the components of complement, especially C1q, are associated with developing immunologic diseases, particularly SLE or a lupus-like disease.
- The FcγRIIA polymorphism has been associated with nephritis in African Americans, Koreans, and Hispanics. Both FcgammaRIIa and FcgammaRIIIa have low binding alleles that confer risk for SLE and may act in the pathogenesis of disease. 
- Women treated with estrogen-containing regimens such as oral contraceptives or postmenopausal hormone replacement therapies are more predisposed to SLE.
- Annular or psoriasiform skin lesions are associated with anti-Ro (SS-A) and anti-La (SS-B) antibodies.
- Anti-Ro, anti-La, anti sm, and anti RNP antibodies have been associated with mucocutaneous involvement and less severe nephropathy.
On gross pathology the most important characteristic findings are:
- Kidney: Bilateral pallor and hypertrophy
- Brain: Infarct regions and hemorrhages
- Heart: Cardiomegaly and valvular vegetation
- Lung: Peural fibrosis and pleural effusion
On microscopic histopathological analysis, lupus erythematosus (LE) cells can be seen in SLE. LE cells are neutrophils that have engulfed an intact nucleus. LE cells are also known as LE bodies.
On microscopic histopathological analysis, apoptotic keratinocytes, vacuolization of the basement membrane, and dermal mucin deposition are characteristic findings of SLE dermatitis, and active or inactive endocapillary or extracapillary segmental glomerulonephritis are characteristic findings of SLE nephritis. Microscopic findings in systemic lupus erythematosus are based on the involved organ system.
Common shared histopathologic features among all different subtypes of cutaneous lupus include:
- Epidermal atrophy
- Dermal mucin deposition
- Liquefactive degeneration of the basal layer of the epidermis and vacuolization
- Thickening of the basement membrane
- Pigment incontinence
- Mononuclear cell infiltration at dermo-epidermal junction
- Superficial, perivascular, and perifollicular areas (due to mononuclear cell inflammatory infiltrate)
|SLE dermatitis subtype||Specific microscopic findings||Preview|
|Acute cutaneous lupus erythematosus|
|Subacute cutaneous lupus erythematosus|
|Chronic cutaneous lupus erythematosus||
|Class||SLE nephritis subtype||Light microscopy findings||Light microscopy previews||Electron microscopy/Immunofluorescence findings|
|I||Minimal mesangial lupus nephritis||-||
|II||Mesangial proliferative lupus nephritis||
|III||Focal lupus nephritis|
|IV||Diffuse lupus nephritis||
|V||Lupus membranous nephropathy||
|VI||Advanced sclerosing lupus nephritis||
- Nonspecific histopathologic findings
- Superficial fibrin-like material
- Local or diffuse synovial cell lining proliferation
- Vascular changes:
- Atrophy of rete processes
- Superficial and deep inflammatory infiltrates
- Edema in the lamina propria
- Continuous or patchy periodic acid-Schiff (PAS)-positive deposits in the basement membrane zone
- Deposition of intercellular mucin
- Deposition of immunoglobulin and complement at the dermal-epidermal junction
Lupus nephritis histopathology
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