Systemic lupus erythematosus pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]

Pathophysiology

Lupus is an example of pathophysiology, a disturbance of the normal functioning of the body. One manifestation of lupus is abnormalities in apoptosis, a type of programmed cell death in which aging or damaged cells are neatly disposed of as a part of normal growth or functioning.

Genetics

The first mechanism may arise genetically. Research indicates that SLE may have a genetic link. Lupus does run in families, but no single "lupus gene" has yet been identified. Instead, multiple genes appear to influence a person's chance of lupus developing when triggered by environmental factors. The most important genes are located on chromosome 6, where mutations may occur randomly (de novo) or be inherited. Additionally, people with SLE have an altered RUNX-1 binding site, which may be either cause or contributor (or both) to the condition. Altered binding sites for RUNX-1 have also been found in people with psoriasis and rheumatoid arthritis.

Environmental triggers

The second mechanism may be due to environmental factors. These factors may not only exacerbate existing lupus conditions, but also trigger the initial onset. They include certain medications (such as some antidepressants and antibiotics), extreme stress, exposure to sunlight, hormones, and infections. Some researchers have sought to find a connection between certain infectious agents (viruses and bacteria), but no pathogen can be consistently linked to the disease. UV radiation has been shown to trigger the photosensitive lupus rash, but some evidence also suggests that UV light is capable of altering the structure of the DNA, leading to the creation of autoantibodies. Some researchers have found that women with silicone gel-filled breast implants have produced antibodies to their own collagen, but it is not known how often these antibodies occur in the general population and there is no data that show these antibodies cause connective tissue diseases such as lupus.

Drug reactions

Drug-induced lupus erythematosus is a reversible condition that usually occurs in patients being treated for a long-term illness. Drug-induced lupus mimics systemic lupus. However, symptoms of drug-induced lupus generally disappear once a patient is taken off the medication which triggered the episode. There are about 400 medications currently in use that can cause this condition, though the most common drugs are procainamide, hydralazine and quinidine.

Non-SLE forms of lupus

Discoid (cutaneous) lupus is limited to skin symptoms and is diagnosed via biopsy of skin rash on the face, neck or scalp. Often an anti-nuclear antibody (ANA) test for discoid patients is negative or a low-titre positive. About 10% of discoid lupus patients eventually develop SLE.

Transmission

In SLE, the body's immune system produces antibodies against itself, particularly against proteins in the cell nucleus. SLE is triggered by environmental factors that are unknown.

"All the key components of the immune system are involved in the underlying mechanisms" of SLE, according to Rahman, and SLE is the prototypical autoimmune disease. The immune system must have a balance (homeostasis) between being sensitive enough to protect against infection, and being too sensitive and attacking the body's own proteins (autoimmunity). From an evolutionary perspective, according to Crow, the population must have enough genetic diversity to protect itself against a wide range of possible infection; some genetic combination's result in autoimmunity. The likely environmental triggers include ultraviolet light, drugs, and viruses. These stimuli cause the destruction of cells and expose their DNA, histones, and other proteins, particularly parts of the cell nucleus. Because of genetic variations in different components of the immune system, in some people the immune system attacks these nuclear-related proteins and produces antibodies against them. In the end, these antibody complexes damage blood vessels in critical areas of the body, such as the glomeruli of the kidney; these antibody attacks are the cause of SLE. Researchers are now identifying the individual genes, the proteins they produce, and their role in the immune system. Each protein is a link on the autoimmune chain, and researchers are trying to find drugs to break each of those links.

SLE is a chronic inflammatory disease believed to be a type III hypersensitivity response with potential type II involvement.

Abnormalities in apoptosis

• Apoptosis is increased in monocytes and keratinocytes
• Expression of Fas by B cells and T cells is increased
• There are correlations between the apoptotic rates of lymphocytes and disease activity

Tangible body macrophages (TBMs) are large phagocytic cells in the germinal centers of secondary lymph nodes. They express CD68 protein. These cells normally engulf B cells which have undergone apoptosis after somatic hypermutation. In some patients with SLE, significantly fewer TBMs can be found, and these cells rarely contain material from apoptotic B cells. Also, uningested apoptotic nuclei can be found outside of TBMs. This material may present a threat to the tolerization of B cells and T cells. Dendritic cells in the germinal center may endocytose such antigenic material and present it to T cells, activating them. Also, apoptotic chromatin and nuclei may attach to the surfaces of follicular dendritic cells and make this material available for activating other B cells which may have randomly acquired self-specificity through somatic hypermutation.

Clearance deficiency

Clearance deficiency

The exact mechanisms for the development of systemic lupus erythematosus (SLE) are still unclear since the pathogenesis is a multifactorial event. Beside discussed causations, impaired clearance of dying cells is a potential pathway for the development of this systemic autoimmune disease. This includes deficient phagocytic activity, scant serum components in addition to increased apoptosis.

Monocytes isolated from whole blood of SLE patients show reduced expression of CD44 surface molecules involved in the uptake of apoptotic cells. Most of the monocytes and tingible body macrophages (TBM), which are found in the germinal centres of lymph nodes, even show a definitely different morphology in patients with SLE. They are smaller or scarce and die earlier. Serum components like complement factors, CRP and some glycoproteins are furthermore decisively important for an efficiently operating phagocytosis. In patients these components are often missing, diminished or inefficient.

The clearance of early apoptotic cells is an important function in multicellular organisms. It leads to a progression of the apoptosis process and finally to secondary necrosis of the cells, if this ability is disturbed. Necrotic cells release nuclear fragments as potential autoantigens as well as internal danger signals, inducing maturation of dendritic cells (DC), since they have lost their membranes integrity. Increased appearance of apoptotic cells also is simulating inefficient clearance. That leads to maturation of DC and also to the presentation of intracellular antigens of late apoptotic or secondary necrotic cells, via MHC molecules.

Autoimmunity possibly results by the extended exposure to nuclear and intracellular autoantigens derived from late apoptotic and secondary necrotic cells. B and T cell tolerance for apoptotic cells is abrogated and the lymphocytes get activated by these autoantigens; inflammation and the production of autoantibodies by plasma cells is initiated. A clearance deficiency in the skin for apoptotic cells has also been observed in patients with cutaneous lupus erythematosus (CLE).

Accumulation in germinal centres (GC)

Germinal centres

In healthy conditions apoptotic lymphocytes are removed in germinal centres by specialised phagocytes, the tingible body macrophages (TBM); that’s why no free apoptotic and potential autoantigenic material can bee seen.

In some patients with SLE accumulation of apoptotic debris can be observed in GC, because of an ineffective clearance of apoptotic cells.

In close proximity to TBM, follicular dendritic cells (FDC) are localized in GC, which attach antigen material to their surface and in contrast to bone marrow-derived DC, neither take it up nor present it via MHC molecules.

Autoreactive B cells can accidentally emerge during somatic hypermutation and migrate into the GC light zone. Autoreactive B cells, maturated coincidently, normally don’t receive survival signals by antigen planted on follicular dendritic cells and perish by apoptosis.

In the case of clearance deficiency apoptotic nuclear debris accumulates in the light zone of GC and gets attached to FDC. This serves as a germinal centre survival signal for autoreactive B-cells.

After migration into the mantle zone autoreactive B cells require further survival signals from autoreactive helper T cells, which promote the maturation of autoantibody producing plasma cells and B memory cells.

In the presence of autoreactive T cells a chronic autoimmune disease may be the consequence.

Anti-nRNP autoimmunity

Autoantibodies to nRNP A and nRNP C initially targeted restricted, proline-rich motifs. Antibody binding subsequently spread to other epitopes. The similarity and cross-reactivity between the initial targets of nRNP and Sm autoantibodies identifies a likely commonality in cause and a focal point for intermolecular epitope spreading.

Others

Elevated expression of HMGB1 was found in the sera of patients and mice with systemic lupus erythematosus, High Mobility Group Box 1 (HMGB1) is a nuclear protein participating in chromatin architecture and transcriptional regulation. Recently, there is increasing evidence that HMGB1 contributes to the pathogenesis of chronic inflammatory and autoimmune diseases due to its pro-inflammatory and immunostimulatory properties.

Gross Images

Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

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  Kidney: Lupus erythematosus: Gross, enlarged very pale kidneys with flea bite or ectasia. A good example of kidneys from a patient with nephrotic syndrome (subacute glomerulonephritis)
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  Kidney: Lupus erythematosus: Gross cut surface pale kidneys typical of nephrotic syndrome (subacute glomerulonephritis)
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  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
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  Brain: Lupus Erythematosus Libman Sacks Embolism: Gross fixed tissue one large and two small hemorrhages 19yo female with history of TIAs
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  Brain: Lupus Erythematosus Libman Sacks Embolism: Gross fixed tissue large hemorrhagic infarcts due to embolism 19yo female with known lupus and history of TIAs
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  Brain: Lupus Erythematosus Libman Sacks Embolism: Gross large hemorrhagic infarcts 19 yo female with history of TIAs proved case lupus with renal failure
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  Brain: Lupus Erythematosus Libman Sacks Embolism: Gross fixed tissue cerebellar hemorrhagic infarcts 19yo female with history of TIAs known lupus case with renal failure
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  Brain: Purulent Meningitis: Gross fixed tissue excellent example Pneumococcus case of young girl with lupus
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  Skeletal muscle: Hematoma: Gross natural color flank muscle hematoma old showing typical chocolate appearance of blood coagulum young female with lupus and thrombocytopenia
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  Brain: Lupus Erythematosus, Systemic; Microinfarct in Cerebral Cortex
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  Kidney: Lupus Nephritis: Gross natural color external view of flea bitten kidneys quite good advanced proliferative type glomerulonephritis of lupus in a 16yo female
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  Brain: Hemorrhage Massive With Lupus Erythematosus: Gross apparently fresh tissue large left frontoparietal hemorrhagic infarct in a 16yo female with advanced lupus nephritis and sepsis
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  Brain: Hemorrhage Massive With Lupus Erythematosus: Gross natural color not the best exposure but OK large left frontoparietal hemorrhage in 16yo female with advanced lupus nephritis and sepsis
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  Brain: Hemorrhage Massive With Lupus Erythematosus: Gross natural color but not best exposure large left frontoparietal hemorrhage in 16yo female with advanced lupus nephritis and sepsis
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  Lung: Tuberculosis Reactivation: Gross fixed tissue close-up of lung hilum with node and parenchyma lesions case of lupus erythematosus treated with prednisone for many years
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  Lung: Tuberculosis Reactivation: Gross fixed tissue close-up of lung showing lesions in nodes and parenchyma case of lupus erythematosus treated for long period with prednisone
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  Kidney: Lupus Erythematosus: Gross natural color nice external and cut surface view of uniformly scarred and moderately shrunken kidneys
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  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
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  Kidney: Lupus Erythematosus: Micro high mag H&E increased mesangial tissue and wire loops 10yo female with renal failure and TIAs due to Libman Sacks endocarditis

Microscopic Images

Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

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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
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  Spleen: Lupus erythematosus Periarterial Fibrosis: Micro high may H&E. An excellent example of periarterial fibrosis
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  Spleen: Lupus erythematosus, periarterial fibrosis: Micro high may H&E. An excellent example of periarterial fibrosis
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  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.
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  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.
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  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
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  Adrenal: Autoimmune Adrenalitis: Micro high mag H&E focal area of lymphocytic infiltration in zona reticularis in a 19yo female with lupus erythematosus
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  Kidney: Lupus Erythematosus: Micro high mag H&E. A nice example of a lesion of chronic glomerulonephritis with lobular scarring. A fibrous type crescent.
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  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
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  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
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  Lupus Erythematosus Focal Myocardial Scar Due To Libman Sacks Embolism: Micro low mag H&E focal scar in myocardium due to embolism
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  Lupus Erythematosus Myocardial Scar Due To Libman Sacks Embolism: Micro low mag H&E scar with portion of embolus in small artery
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  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
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  Lupus Erythematosus Embolus From Libman Sacks Lesion: Micro med mag H&E well shown embolus in small artery
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  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
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  Lung: Diffuse Alveolar Damage: Gross natural color section of both lungs with frank meaty appearance case of lupus erythematosus in 19yo female
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  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
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  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
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  Lung: Necrotizing Bronchiolitis: Micro low mag H&E well shown necrotizing bronchiolitis and surrounding lesions of diffuse alveolar damage 19yo female with lupus erythematosus
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  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
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  Kidney: Lupus Erythematosus: Micro high mag PAS stain thickened mesangium and capillary basement membranes 19yo female with renal failure and proved lupus
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  Artery: Arteritis in Lupus Erythematosus: Micro med mag H&E. A good example of vasculitis
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  Kidney: Lupus Erythematosus: Micro high mag PASH typical glomerulonephritis lesion with crescent
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  Kidney: Lupus Erythematosus: Micro med mag PASH glomerulonephritis
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  Kidney: Lupus Erythematosus: Micro med mag H&E typical glomerulonephritis lesion
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  Kidney: Lupus Erythematosus: Micro med mag H&E two glomeruli showing lobular glomerulonephritis lesion
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  Kidney: Lupus Erythematosus: Micro med mag PASH typical chronic glomerulonephritis lesion with crescent
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  Vessel: lupus, systemic erythematosus; Thrombus in capillary
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  Vessel: lupus, systemic erythematosus; Thrombus in capillary
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  Vessel: lupus, systemic erythematosus; Thrombus in arteriole and vein
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  Vessel: lupus, systemic erythematosus; Thrombus in pial vessel
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  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