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
8519610
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 |
|---|---|---|
| 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
Lupus is a chronic autoimmune disease in which the body's own defense system attacks otherwise healthy tissue. The body's immune system produces antibodies against itself, particularly against proteins in 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.
SLE is a chronic inflammatory disease believed to be a type III hypersensitivity response with potential type II involvement.[1]
Clinically, it can affect multiple organ systems including the heart, skin, joints, kidneys and nervous system. The exact mechanisms for the development of systemic lupus erythematosus (SLE) are still unclear since the pathogenesis is a multifactorial event.
Minimal mesangial lupus nephritis (class I): mesangial immune deposits that are identified by immunofluorescence alone or by both immunofluorescence and electron microscopy, but such patients do not have light microscopic abnormalities
Mesangial proliferative lupus nephritis (class II): mesangial hypercellularity (of any degree) or mesangial matrix expansion
A few isolated subepithelial or subendothelial deposits may be seen on immunofluorescence or electron microscopy
Focal lupus nephritis (class III): Light microscopy: Active or inactive endocapillary or extracapillary segmental glomerulonephritis (Less than 50 percent of glomeruli are affected)
Electron microscopy: immune deposits in the subendothelial space of the glomerular capillary and mesangium
Glomeruli affected by fibrinoid necrosis and crescents
Presence of tubulointerstitial or vascular abnormalities
Diffuse lupus nephritis (class IV): Light microscopy: more than 50 percent of glomeruli are affected that display endocapillary with or without extracapillary glomerulonephritis and Mesangial abnormalities
Electron microscopy: subendothelial deposits, at least during the active phase and diffuse wire loop deposits, but with little or no glomerular proliferation
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. 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. [2][3][4]
- 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.
Other abnormalities include:
- Increased expression of FcεRIγ, which replaces the sometimes deficient TCR ζ chain
- Increased and sustained calcium levels in T cells
- Moderate increase of inositol triphosphate
- Reduction in PKC phosphorylation
- Increased desire of animal protein intake.
- Reduction in Ras-MAP kinase signaling
- Deficiencies in protein kinase A I activity
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
- 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.
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.[5]
Clearance deficiency
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)
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.
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.
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.[6]
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.[7]
Gross Images
Microscopic Images
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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
Videos
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References
- ↑ University of South Carolina School of Medicine lecture notes, Immunology, Hypersensitivity reactions. General discussion of hypersensitivity, not specific to SLE.
- ↑ Anisur Rahman and David A. Isenberg (February 28, 2008). "Review Article: Systemic Lupus Erythematosus". N Engl J Med. 358 (9): 929–939. doi:10.1056/NEJMra071297. PMID 18305268.
- ↑ Mary K. Crow (February 28, 2008). "Collaboration, Genetic Associations, and Lupus Erythematosus". N Engl J Med. 358 (9): 956–961. doi:10.1056/NEJMe0800096. PMID 18204099.
- ↑ Geoffrey Hom, Robert R. Graham, Barmak Modrek; et al. (February 28, 2008). "Association of Systemic Lupus Erythematosus with C8orf13–BLK and ITGAM–ITGAX". N Engl J Med. 358 (9): 900–909. doi:10.1056/NEJMoa0707865. PMID 18204098.
- ↑ Gaipl, U S; Kuhn, A; Sheriff, A; Munoz, L E; Franz, S; Voll, R E; Kalden, J R; Herrmann, M (2006). "Clearance of apoptotic cells in human SLE". Current directions in autoimmunity. 9: 173–87. PMID: 1639466 Abstract (full text requires registration).
- ↑ Poole BD, Schneider RI, Guthridge JM; et al. (2009). "Early targets of nuclear RNP humoral autoimmunity in human systemic lupus erythematosus". Arthritis Rheum. 60 (3): 848–859. doi:10.1002/art.24306. PMID 19248110. Unknown parameter
|month=ignored (help) - ↑ Pan HF, Wu GC, Li WP, Li XP, Ye DQ (2009). "High Mobility Group Box 1: a potential therapeutic target for systemic lupus erythematosus". Mol. Biol. Rep. doi:10.1007/s11033-009-9485-7. PMID 19247800. Unknown parameter
|month=ignored (help)