Systemic lupus erythematosus pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2] Raviteja Guddeti, M.B.B.S. [3]
Overview
The progression of systemic lupus erythematosus involves the immune system. There are other factors like genetic factors, hormonal abnormalities, and environmental factors that play some roles as well. The most prominent events involving immune abnormalities are related to persistent activation of B cells and plasma cells that make auto-antibodies more auto antibodies during disease progression. The most prominent events involving hormonal abnormalities are due to prolactin and estrogen. The most important environmental factors related to disease progression are ultraviolet (UV) light and some infections. 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.
Pathogenesis
The progression of systemic lupus erythematosus involves the immune system. Near all of the pathologic manifestation of SLE are due to antibody formation and the creation of immune complexes in different organs of the body. When the immune complexes designed, they will deposit in different body tissues and vessels, which will lead to more complement activation and more organ damage. There are other factors like genetic factors, hormonal abnormalities, and environmental factors that play some roles as well.
Immune abnormalities
Development of systemic lupus erythematosus (SLE) is the result of different mechanisms that at the end lead to auto-immune response of the body. As a result, body tissues lose their self-tolerance. Affected patients are no longer entirely tolerant to all of their self-antigens and consequently progress an autoimmune disease and develop auto antibodies as a response. During disease progression, B cells and plasma cells that make auto-antibodies are more persistently activated and thus make more auto antibodies. These auto antibodies are targeted predominantly to intracellular nucleoprotein particles
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This increase in auto antibody production and persistence suppose to be down regulated by anti-idiotypic antibodies or regulatory immune cells, but due to immunologic response it is not appropriately been responded.
The most important immune abnormalities that are related to SLE develop and progression:
- Increase in circulating plasma cells and memory B cells that is associated with SLE activity
- Decrease in cytotoxic T cells and in functions of suppressor T cells and impaired generation of polyclonal T-cell cytolytic activity
- Increase in helper T cells and also their function
- Polyclonal activation of B cells and abnormal B-cell receptor signaling
- Prolonged lives of B cells
- Signaling abnormalities of T and B lymphocytes
- Cellular hyperactivity
- Hyperresponsiveness
- May be due to genetically defects
- Increased expression of IFN-alpha-inducible RNA transcripts by mononuclear cells that lead to elevated levels of IFN-alpha. 15593221
- Increase in specific genetic factors expression that may be associated with autoimmunity promotion
- Dysfunctional signaling in T and B cells that may be due to:
- Increased calcium responses to antigen stimulation
- Hyperphosphorylation of cytosolic protein substrates
- Decreased nuclear factor kB
- Abnormal voltage-gated potassium channels: These channels facilitate excessive calcium entry into T cells
- Increased levels of microparticles (MPs):
- Microparticles are small, membrane-bound vesicles enclose 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 23672591
- Elevated levels of circulating TNF-alpha correlate with active disease, and TNF is expressed in renal tissue in lupus nephritis
- abnormally high levels of E-C4d and low levels of E-CR1 are characteristic of SLE, and combined measurement of the 2 molecules has high diagnostic sensitivity and specificity for lupus.
- Increased numbers of circulating neutrophils undergoing NETosis, 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 formation: 26658004
- It may promote thrombus formation
- It is associated with increased disease activity and renal disease and thus can be used even as a disease activity marker.
- It can damage and kill endothelial cells and promote inflammation in atherosclerotic plaques, which may contribute to accelerated atherosclerosis in systemic lupus erythematosus
- These changes promote the production of antinuclear antibodies
Hormonal abnormalities
The following evidence is suggestive of the hormonal predisposition of SLE:
- Sexual predilection of females: Shows the relationship of female hormones and the onset of SLE
- Significantly increased risk for SLE in:17393454
- Early age of menarche
- Early age at menopause or surgical menopause
- Women that are treated with estrogen-containing regimens such as oral contraceptives or postmenopausal hormone replacement therapies
Hormones that are related to SLE disease progression:10503654
- Gonadotrophins like prolactin
- Stimulants of immune functions and is elevated in SLE
- Exogenous estrogen - include oral contraceptive use and post-menopausal hormone replacement therapy: 10503654- 25155581
- Stimulates the type 1 IFN pathway
- Stimulates thymocytes, CD8+ and CD4+ T cells, B cells, macrophages, the release of certain cytokines (eg, IL-1)
- Prompt maturation of B cells especially those that have a high affinity to ant-DNA antibodies by decreasing the apoptosis of this self-reactive B-cells 16724801
- Stimulate expression of HLA and endothelial cell adhesion molecules (VCAM, ICAM)
- Increases macrophage proto-oncogene expression
- Enhanced adhesion of peripheral mononuclear cells to endothelium
- Progesterone:
- May inhibit the type 1 interferon pathway, suggesting that a balance between estrogen and progesterone may be critical for the body to remain healthy
- Downregulates T-cell proliferation and increases the number of CD8 cells
- Both progesterone and high levels of estrogen promote a Th2 response, which favors autoantibody production
Environmental factors
- Infections can stimulates some antigen specific cells and lead to SLE disease:
- Epstein-Barr virus (EBV): may induce anti-DNA antibodies or even lupus-like symptoms. It is associated with higher risk of SLE and also triggering the active course of disease in children
- Trypanosomiasis or mycobacterial infections may have the same effect as EBV
- SLE active disease flares may follow bacterial infections as well
- Ultraviolet (UV) light: Can stimulates B-cells to produce more antibodies. It can also interfere with antigen processing by activation of macrophages and hence increase the degree of autoimmunity
Genetics
Systemic lupus erythematosus is transmitted in poly-genic inheritance pattern. Genes involved in the pathogenesis of systemic lupus erythematosus include HLA class polymorphism, complement genes, and other genes related to immunologic system as well.
The following evidence is also suggestive of the genetic predisposition of SLE:
- Increase of disease occurrence in identical twins
- The increase in frequency of SLE among first degree relatives
- The increased risk of developing the disease in siblings of SLE patients
| Gene class | Gene subtype |
| HLA genes | DR2, DR3, DR4, DR7, DR8, DRw12, DQw2, DQA1,
DQB1, DQ6, DQw6, DQ7, DQw7, DQw8, DQw9, B61, B8 |
| Complement genes | C2, C4, C1q |
| Non-HLA genes | Mannose binding lectin polymorphisms
Tumour necrosis factor α T cell receptor Interleukin 6 CR1 Immunoglobulin Gm and Km FcγRIIA (IgG Fc receptor) FcγRIIIA (IgG Fc receptor) PARP (poly-ADP ribose polymerase) Heat shock protein 70 Humhr 3005 |
- 10768211
Homozygous deficiencies of the components of complement especially C1q are associated with developing immunologic diseases especially SLE or a lupus-like disease : 11564823 The FcγRIIA polymorphism has been associated with nephritis in African Americans and Koreans as well as Hispanic patients. Both FcgammaRIIa and FcgammaRIIIa have low binding alleles that confer risk for SLE and may act additively in the pathogenesis of disease24997134
Associated Conditions
IC deposition and subsequent complement activation in the kidney is responsible for much of the tissue damage of lupus nephritis
Gross Pathology
On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name]. Gross, enlarged very pale kidneys with flea bite or ectasia.
A good example of kidneys from a patient with nephrotic syndrome (subacute glomerulonephritis) File:Systemic lupus erythematosus 001.jpg File:Systemic lupus erythematosus 046.jpg Lupus Erythematosus Libman Sacks Embolism: Gross fixed tissue large hemorrhagic infarcts due to embolism 19yo female with known lupus and history of TIAs File:Systemic lupus erythematosus 027.jpg Lupus Erythematosus Libman Sacks Endocarditis: Gross natural color mitral valve small lesions but cause much trouble in form of TIAs and terminally multiple hemorrhagic brain infarcts File:Systemic lupus erythematosus 021.jpg Brain: Lupus Erythematosus, Systemic; Microinfarct in Cerebral Cortex File:Systemic lupus erythematosus 047.jpg Lupus Erythematosus Hepatitis: Gross natural color. A 19yo female with lupus erythematosus and hepatitis characterized by periportal cell necrosis and sinus thrombosis cause uncertain photo shows focal grid-like hyperemia File:Systemic lupus erythematosus 004.jpg
Microscopic Pathology
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.
Skin histo-pathology:
Common shared histopathologic features among all different subtypes of cutaneous lupus include:
- Hyperkeratosis
- 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 |
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| Acute cutaneous lupus erythematosus |
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| Subacute cutaneous lupus erythematosus |
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| Chronic cutaneous lupus erythematosus |
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Glomerulonephritis histo-pathology:
| SLE nephritis subtype | Light microscopy findings | Electron microscopy/Immunofluorescence findings |
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| Minimal mesangial lupus nephritis (class I) | - |
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| Mesangial proliferative lupus nephritis (class II) |
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| Focal lupus nephritis (class III) |
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| Diffuse lupus nephritis (class IV) |
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| Lupus membranous nephropathy (class V) |
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| Advanced sclerosing lupus nephritis (class VI) |
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Synovial histopathology
- Nonspecific histopathologic findings
- Superficial fibrin-like material
- Local or diffuse synovial cell lining proliferation
- Vascular changes:
- Perivascular mononuclear cells
- Lumen obliteration
- Enlarged endothelial cells
- Thrombi
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Lupus erythematosus hepatitis: Micro high mag H&E, periportal sinus thrombosis with liver cell necrosis and noninflammatory infiltrate (possibly viral). A 19yo female with lupus erythematosus -
Spleen: Lupus erythematosus Periarterial Fibrosis: Micro high may H&E. An excellent example of periarterial fibrosis -
Spleen: Lupus erythematosus, periarterial fibrosis: Micro high may H&E. An excellent example of periarterial fibrosis -
Spleen: Lupus erythematosus. Basophilic bodies and periarterial fibrosis: Micro high mag, H&E. Two basophilic bodies and periarterial fibrosis. An excellent example of this rarely seen lupus lesion. -
Lupus Erythematosus, Libman Sacks Endocarditis: Micro low mag trichrome stain thickened valve leaflet with small mural fibrin deposit. A 19yo female with cerebral lupus in form of TIAs due to this lesion. -
Lupus Erythematosus, Libman Sacks Endocarditis: Micro low mag, elastic van Gieson stain, mitral valve thickened, leaflet with small mural fibrin deposit that caused TIAs in 19yo female -
Adrenal: Autoimmune Adrenalitis: Micro high mag H&E focal area of lymphocytic infiltration in zona reticularis in a 19yo female with lupus erythematosus -
Kidney: Lupus Erythematosus: Micro high mag H&E. A nice example of a lesion of chronic glomerulonephritis with lobular scarring. A fibrous type crescent. -
Kidney: Lupus Erythematosus: Micro high mag H&E two glomeruli showing mesangial thickening and focal wire loop type lesions 19yo female with renal failure and embolic brain disease from Libman Sacks lesion on mitral valve -
Lupus Erythematosus Myocardial Necrosis Due To Libman Sacks: Micro low mag H&E focal myocardial necrosis due to embolism from Libman Sacks lesion on mitral valve 19yo female with TIAs due to mitral lesion -
Lupus Erythematosus Focal Myocardial Scar Due To Libman Sacks Embolism: Micro low mag H&E focal scar in myocardium due to embolism -
Lupus Erythematosus Myocardial Scar Due To Libman Sacks Embolism: Micro low mag H&E scar with portion of embolus in small artery -
Lupus Erythematosus Myocardial Necrosis Due To Libman Sacks: Micro low mag H&E well shown focal myocardial necrosis due to embolism from mitral Libman Sacks lesion -
Lupus Erythematosus Embolus From Libman Sacks Lesion: Micro med mag H&E well shown embolus in small artery -
Lupus Erythematosus Hepatitis: Micro low mag trichrome stain periportal liver cell necrosis and sinus thrombosis with no inflammatory reaction cause unknown 19yo female with lupus erythematosus -
Lung: Diffuse Alveolar Damage: Gross natural color section of both lungs with frank meaty appearance case of lupus erythematosus in 19yo female -
Lung: Necrotizing Bronchiolitis: Micro low mag H&E well shown lesion in lung that grossly looked like diffuse alveolar damage which indeed has lesions of this type additionally 19yo female with lupus erythematosus -
Lupus Erythematosus Libman Sacks Endocarditis: Micro low mag H&E mitral valve lesion with easily seen mural thrombi and focal necrobiosis of collagen in thickened valve leaflet 19yo female -
Lung: Necrotizing Bronchiolitis: Micro low mag H&E well shown necrotizing bronchiolitis and surrounding lesions of diffuse alveolar damage 19yo female with lupus erythematosus -
Myocarditis: Micro high mag H&E focal myofiber necrosis typical for this diagnosis but this is case of lupus erythematosus with Libman Sacks lesion and brain emboli and heart emboli did she also have viral myocarditis? This lesion is typical for the diagnosis -
Kidney: Lupus Erythematosus: Micro high mag PAS stain thickened mesangium and capillary basement membranes 19yo female with renal failure and proved lupus -
Artery: Arteritis in Lupus Erythematosus: Micro med mag H&E. A good example of vasculitis -
Kidney: Lupus Erythematosus: Micro high mag PASH typical glomerulonephritis lesion with crescent -
Kidney: Lupus Erythematosus: Micro med mag PASH glomerulonephritis -
Kidney: Lupus Erythematosus: Micro med mag H&E typical glomerulonephritis lesion -
Kidney: Lupus Erythematosus: Micro med mag H&E two glomeruli showing lobular glomerulonephritis lesion -
Kidney: Lupus Erythematosus: Micro med mag PASH typical chronic glomerulonephritis lesion with crescent -
Vessel: lupus, systemic erythematosus; Thrombus in capillary -
Vessel: lupus, systemic erythematosus; Thrombus in capillary -
Vessel: lupus, systemic erythematosus; Thrombus in arteriole and vein -
Vessel: lupus, systemic erythematosus; Thrombus in pial vessel -
Lupus Erythematosus Libman Sacks Endocarditis: Micro high mag H&E atrial surface of mitral valve with small fibrin thrombus representing Libman Sacks lesion 10yo female
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