Systemic lupus erythematosus pathophysiology: Difference between revisions

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{{Systemic lupus erythematosus}}
{{Systemic lupus erythematosus}}


{{CMG}}; {{AE}} {{CZ}} {{RT}}
{{CMG}}; {{AE}} {{MIR}}, {{CZ}}, {{RT}}


==Overview==
==Overview==
:Template Sentence 6: [Disease/malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
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 [[Gene|genes]] involved in the [[pathogenesis]] of SLE include [[HLA-DR2]], [[HLA-DR3]], [[HLA]] class 3, C1q, and [[IRF5|interferon (IFN) regulatory factor 5]]. The most prominent events involving [[immune]] abnormalities are related to persistent activation of [[B cells]] and [[Plasma cell|plasma cells]] that make [[Autoantibody|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]] [[Keratinocyte|keratinocytes]], [[vacuolization]] of the [[basement membrane]], and [[dermal]] [[mucin]] deposition are characteristic findings of SLE [[dermatitis]], and active or inactive [[Endocapillary proliferative glomerulonephritis|endocapillary]] or extracapillary segmental [[glomerulonephritis]] are characteristic findings of [[lupus nephritis]].
:Template Sentence 8: Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
:Template Sentence 9: The progression to [disease name] usually involves the [molecular pathway].
:Template Sentence 10: The pathophysiology of [disease name] depends on the histological subtype.
 
==Pathogenesis==
==Pathogenesis==
The progression of systemic lupus erythematosus usually 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, it will deposit in different tissuses and vessles, which 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.
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.
[[File:Lupus2.jpg|left|size:800×591 pixels]]
<br clear="left" />
=== Environmental factors ===
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.
* Infections
** 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
** Include:
*** [[Parvovirus B19]]
*** [[Epstein Barr virus|Epstein-Barr virus (EBV)]]
*** [[Trypanosomiasis]]
*** [[Mycobacterial]] infections
*** SLE flares may follow [[bacterial infections]]
* [[Ultraviolet|Ultraviolet (UV)]] light:
** Can stimulate [[B-cells]] to produce more [[antibodies]]
** May activate [[macrophages]], interfere with [[antigen processing]], and therefore increase the degree of [[autoimmunity]]


=== Immune abnormalities ===
=== 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 autoantibodies are more persistently activated and thus make more auto antibodies. These auto antibodies are targeted predominantly to intracellular nucleoprotein particles 
The development of systemic lupus erythematosus (SLE) is due to the activation of different mechanisms that may result in [[auto-immune|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 [[Antigens|self-antigens]], leading to development of an [[Autoimmunity|autoimmune]] disease and producing [[autoantibodies]] as a response. During disease progression, [[B cell|B cells]] and [[Plasma cell|plasma cells]] that make [[Autoantibody|autoantibodies]] are more persistently activated due to signaling abnormalities, causing them to make more [[Autoantibody|autoantibodies]]. These [[autoantibodies]] are targeted predominantly to [[intracellular]] [[nucleoprotein]] particles.<ref name="pmid8519610">{{cite journal |vauthors=Elkon K |title=Autoantibodies in systemic lupus erythematosus |journal=Curr Opin Rheumatol |volume=7 |issue=5 |pages=384–8 |year=1995 |pmid=8519610 |doi= |url=}}</ref><ref name="pmid25449682">{{cite journal |vauthors=Yaniv G, Twig G, Shor DB, Furer A, Sherer Y, Mozes O, Komisar O, Slonimsky E, Klang E, Lotan E, Welt M, Marai I, Shina A, Amital H, Shoenfeld Y |title=A volcanic explosion of autoantibodies in systemic lupus erythematosus: a diversity of 180 different antibodies found in SLE patients |journal=Autoimmun Rev |volume=14 |issue=1 |pages=75–9 |year=2015 |pmid=25449682 |doi=10.1016/j.autrev.2014.10.003 |url=}}</ref> This increase in [[autoantibody]] production and persistence is supposed to be [[Downregulate|downregulated]] by anti-idiotypic [[antibodies]] or regulatory [[immune cells]], but the massive [[Immunology|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: 
 
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
==== Microparticles ====
** It is associated with increased disease activity and renal disease and thus can be used even as a disease activity marker.
Increased level of microparticles (MPs):<ref name="pmid23672591">{{cite journal |vauthors=Dye JR, Ullal AJ, Pisetsky DS |title=The role of microparticles in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus |journal=Scand. J. Immunol. |volume=78 |issue=2 |pages=140–8 |year=2013 |pmid=23672591 |doi=10.1111/sji.12068 |url=}}</ref>
** It can damage and kill endothelial cells and promote inflammation in atherosclerotic plaques, which may contribute to accelerated atherosclerosis in systemic lupus erythematosus
*Microparticles are small, membrane-bound vesicles enclosing [[DNA]], [[RNA]], [[nuclear]] proteins, [[cell adhesion molecule]]<nowiki/>s, [[Growth factor|growth factors]], and [[Cytokine|cytokines]]
*They are shed from cells during [[apoptosis]] or activation
*Microparticles can drive [[inflammation]] and [[autoimmunity]] by their derivatives
==== Pro-inflammatory cytokines ====
Increased expression of specific [[Genetic|genetic factors]] may be associated with promoting [[autoimmunity]]. The most important cytokine changes include:<ref name="pmid15593221">{{cite journal |vauthors=Kirou KA, Lee C, George S, Louca K, Papagiannis IG, Peterson MG, Ly N, Woodward RN, Fry KE, Lau AY, Prentice JG, Wohlgemuth JG, Crow MK |title=Coordinate overexpression of interferon-alpha-induced genes in systemic lupus erythematosus |journal=Arthritis Rheum. |volume=50 |issue=12 |pages=3958–67 |year=2004 |pmid=15593221 |doi=10.1002/art.20798 |url=}}</ref><ref name="pmid23672591" />
*Increased expression of [[interferon alpha]] (IFN-α) inducible [[RNA]] transcripts by [[Mononuclear cells|mononuclear]] cells 
*Increased [[Interferon type I|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 [[Kidney|renal tissue]] in [[lupus nephritis]]) correlate with active disease


* These changes promote the production of antinuclear antibodies
==== Signaling abnormalities ====
[[Protein kinase|Protein kinases]] are responsible for [[intracellular]] [[cytokine]] signals. [[Intracellular signaling]] leads to various types of cell response, such as:
* [[Cell migration]]
* [[Cell proliferation]]
* [[Inflammatory response]]
[[Cell signaling]] abnormalities leads to:
* T and B [[Lymphocyte|lymphocytes]] cellular hyperactivity
* T and B [[Lymphocyte|lymphocytes]] hyper responsiveness
* Persistence of auto-reactive [[T cell|T cells]] that would otherwise have been deleted
Signaling abnormalities of T and B [[Lymphocyte|lymphocytes]], may be due to:
* Abnormal [[Potassium channels|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
==== B-Cell role ====
* Increase in circulating [[plasma cells]] and [[Memory B cell|memory B cells]] that are associated with SLE activity
* [[Polyclonal antibody|Polyclonal]] activation of [[B cell|B cells]] and abnormal [[B-cell receptor]] signaling
* Increase in [[B cell|B cells']] life span
==== T-Cell role ====
* Decrease in [[cytotoxic T cells]], decrease in [[suppressor T cells|suppressor T cell]] function, and impaired generation of [[T-cell|polyclonal T-cell]] [[cytolytic]] activity
* Increased number and activity of [[T helper cell|helper T cells]]
===== Neutrophil role =====
*Increased number of circulating [[neutrophils]] undergoing NETosis (NET=[[neutrophil extracellular traps]]), a form of [[apoptosis]] specific for [[Neutrophil|neutrophils]], releases [[DNA]] bound to [[protein]] in protein nets, which stimulates anti-DNA and [[Interferon-alpha|IFN-alpha]] production
*Increased [[neutrophil]] extracellular trap leads to: <ref name="pmid26658004">{{cite journal |vauthors=Barnado A, Crofford LJ, Oates JC |title=At the Bedside: Neutrophil extracellular traps (NETs) as targets for biomarkers and therapies in autoimmune diseases |journal=J. Leukoc. Biol. |volume=99 |issue=2 |pages=265–78 |year=2016 |pmid=26658004 |doi=10.1189/jlb.5BT0615-234R |url=}}</ref>
** [[Thrombus]] formation
** Increased disease activity and [[Lupus nephritis|renal disease]] and thus can be used even as a disease activity marker
** [[endothelial cells|Endothelial cell]] damage and [[inflammation]] in [[Atherosclerosis|atherosclerotic]] [[plaques]], which may contribute to accelerated [[atherosclerosis]] in systemic lupus erythematosus


=== Hormonal abnormalities ===
=== Hormonal abnormalities ===
The following evidence is suggestive of the hormonal predisposition of SLE:
The following evidence is suggestive of the [[Hormone|hormonal]] predisposition to SLE:
* Sexual predilection of females: Shows the relationship of female hormones and the onset of SLE
* Predilection of the disease for females shows the relationship between female hormones and the onset of SLE
* Significantly increased risk for SLE in:17393454
* Significantly increased risk for SLE in:<ref name="pmid17393454">{{cite journal |vauthors=Costenbader KH, Feskanich D, Stampfer MJ, Karlson EW |title=Reproductive and menopausal factors and risk of systemic lupus erythematosus in women |journal=Arthritis Rheum. |volume=56 |issue=4 |pages=1251–62 |year=2007 |pmid=17393454 |doi=10.1002/art.22510 |url=}}</ref>
** Early age of menarche
** Early age of [[menarche]]
** Early age at menopause or surgical menopause
** Early age at [[menopause]] or surgical [[menopause]]
** Women that are treated with estrogen-containing regimens such as oral contraceptives or postmenopausal hormone replacement therapies
** Women that are treated with [[estrogen]]-containing regimens such as [[oral contraceptives]] or [[postmenopausal]] [[Hormone replacement therapy|hormone replacement therapies]]
Hormones that are related to SLE disease progression:10503654
Hormones that are related to disease progression include:<ref name="pmid10503654">{{cite journal |vauthors=Lahita RG |title=The role of sex hormones in systemic lupus erythematosus |journal=Curr Opin Rheumatol |volume=11 |issue=5 |pages=352–6 |year=1999 |pmid=10503654 |doi= |url=}}</ref>
* Gonadotrophins like prolactin
==== Prolactin: ====
** Stimulants of immune functions and is elevated in SLE
*Stimulates the [[immune system]] 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 ===
==== Exogenous estrogen ====
* Infections can stimulates some antigen specific cells and lead to SLE disease:
* Including [[oral contraceptive]] use and [[postmenopausal]] [[hormone replacement therapy]]: <ref name="pmid10503654">{{cite journal |vauthors=Lahita RG |title=The role of sex hormones in systemic lupus erythematosus |journal=Curr Opin Rheumatol |volume=11 |issue=5 |pages=352–6 |year=1999 |pmid=10503654 |doi= |url=}}</ref><ref name="pmid25155581">{{cite journal |vauthors=Hughes GC, Choubey D |title=Modulation of autoimmune rheumatic diseases by oestrogen and progesterone |journal=Nat Rev Rheumatol |volume=10 |issue=12 |pages=740–51 |year=2014 |pmid=25155581 |doi=10.1038/nrrheum.2014.144 |url=}}</ref>
** 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
** Stimulates the type 1 [[IFN]] pathway
** Trypanosomiasis or mycobacterial infections may have the same effect as EBV
** Stimulates [[thymocytes]], [[CD8]]+ and [[CD4]]+ [[T cell|T cells]], [[B cell|B cells]], [[Macrophage|macrophages]], and causes the release of certain [[cytokines]] (eg, [[IL-1]])
** SLE active disease flares may follow bacterial infections as well
** Prompt maturation of [[B cell|B cells]], especially those that have a high affinity to anti-DNA [[antibodies]] by decreasing the [[apoptosis]] of self-reactive [[B-cells]]<ref name="pmid16724801">{{cite journal |vauthors=Cohen-Solal JF, Jeganathan V, Grimaldi CM, Peeva E, Diamond B |title=Sex hormones and SLE: influencing the fate of autoreactive B cells |journal=Curr. Top. Microbiol. Immunol. |volume=305 |issue= |pages=67–88 |year=2006 |pmid=16724801 |doi= |url=}}</ref>
* 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
** Stimulate expression of [[HLA]] and [[endothelial cell]] [[Adhesion molecule|adhesion molecules]] ([[VCAM-1|VCAM]], [[ICAM-1|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
** Down-regulates [[T cell|T-cell]] proliferation and increases the number of [[CD8 cytotoxic lymphocyte|CD8 cells]]
** Act mainly as a protective agent
* Both [[progesterone]] and high levels of [[estrogen]] promote a [[Th2]] response, which favors [[autoantibody|auto-antibody]] production


==Genetics==
==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.
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 [[Immune systems|immunologic system]].
 
The following evidence is also suggestive of the [[genetic predisposition]] of SLE:<ref name="pmid10768211">{{cite journal |vauthors=Sullivan KE |title=Genetics of systemic lupus erythematosus. Clinical implications |journal=Rheum. Dis. Clin. North Am. |volume=26 |issue=2 |pages=229–56, v–vi |year=2000 |pmid=10768211 |doi= |url=}}</ref>
The following evidence is also suggestive of the genetic predisposition of SLE:
* Increase occurrence of disease in [[identical twins]]
* Increase of disease occurrence in identical twins
* Increased disease frequency among first degree relatives
* The increase in frequency of SLE among first degree relatives
* The increased occurrence of the disease in siblings of SLE patients
* The increased risk of developing the disease in siblings of SLE patients
{| class="wikitable"  
{| class="wikitable"  
|Gene class
! style="background: #4479BA; color: #FFFFFF; " align="center" |Class
| colspan="1" rowspan="1" |Gene subtype
! style="background: #4479BA; color: #FFFFFF; " align="center" |Gene subtype
! colspan="1" rowspan="1" style="background: #4479BA; color: #FFFFFF; " align="center" |Function
! style="background: #4479BA; color: #FFFFFF; " align="center" |Pathological effect and Molecular mechanisms
|-
! style="background:#DCDCDC;" |Autoantigen presentation
| style="background:#DCDCDC;" align="center" |[[HLA]] class 2<ref name="pmid12867584">{{cite journal |vauthors=Lee HS, Chung YH, Kim TG, Kim TH, Jun JB, Jung S, Bae SC, Yoo DH |title=Independent association of HLA-DR and FCgamma receptor polymorphisms in Korean patients with systemic lupus erythematosus |journal=Rheumatology (Oxford) |volume=42 |issue=12 |pages=1501–7 |year=2003 |pmid=12867584 |doi=10.1093/rheumatology/keg404 |url=}}</ref>
| colspan="1" rowspan="1" |
* Contains [[genes]] encoding [[glycoproteins]] that process and present [[peptides]] for recognition by [[T cells]] ([[Antigen-presenting cell|antigen presenting cells]])
* The most important related [[Gene|genes]]:
** [[HLA-DR2]]
** [[HLA-DR3]]
|
* Associated with an overall 2- to 3-fold increase in the risk of SLE
* More common in European and Asian people
* [[HLA-DQ]] and [[HLA-DR]] alleles:
** Strong association with SLE [[autoantibodies]]
|-
! rowspan="2" style="background:#DCDCDC;" |Immune complex dependent response
| style="background:#DCDCDC;" align="center" |[[HLA]] class 3<ref name="pmid11079100">{{cite journal |vauthors=Pickering MC, Botto M, Taylor PR, Lachmann PJ, Walport MJ |title=Systemic lupus erythematosus, complement deficiency, and apoptosis |journal=Adv. Immunol. |volume=76 |issue= |pages=227–324 |year=2000 |pmid=11079100 |doi= |url=}}</ref>
|
* Contains important [[Gene|immune genes]] including:
** C2 [[gene]]
** C4 [[gene]]
** Encode [[Complement|complement proteins]]
* The [[complement system]] acts through [[opsonization]]:
** Facilitates the clearance of [[Apoptosis|apoptotic debris]] and cellular fragments
** The fragments may contain nuclear antigens, which are targets for SLE-associated [[autoantibodies]]
* [[Complement]] C4-A has a higher affinity for [[immune complexes]]
* Circulating [[complement]] C4 proteins clear [[Immune complex|immune complexes]]
|
* Complete C2 and C4 deficiencies:
** Rare
** Associated with a mild form of SLE that affects mostly the [[joints]] and [[skin]]
* Stronger [[Genetics|genetic]] evidence for an association with SLE in C4A than C4-B
* Circulating complement C4 proteins deficiency will promote [[autoimmunity]]
|-
|-
|HLA genes  
| style="background:#DCDCDC;" align="center" |C1q genes<ref name="pmid11079100">{{cite journal |vauthors=Pickering MC, Botto M, Taylor PR, Lachmann PJ, Walport MJ |title=Systemic lupus erythematosus, complement deficiency, and apoptosis |journal=Adv. Immunol. |volume=76 |issue= |pages=227–324 |year=2000 |pmid=11079100 |doi= |url=}}</ref>
| colspan="1" rowspan="1" |DR2, DR3, DR4, DR7, DR8, DRw12, DQw2, DQA1,
| colspan="1" rowspan="1" |
DQB1, DQ6, DQw6, DQ7, DQw7, DQw8, DQw9, B61, B8
* The [[complement system]] acts through [[opsonization]]:
** Facilitates the clearance of [[Apoptosis|apoptotic debris]] and cellular fragments
** The fragments may contain nuclear antigens, which are targets for SLE-associated [[autoantibodies]]
|
* [[Homozygous]] deficiency of ''C1q:''
** Rare
** Develop a severe and early onset form of SLE
** Associated with severe [[glomerulonephritis]] and [[skin]] manifestations
|-  
|-  
|Complement genes
! rowspan="4" style="background:#DCDCDC;" |Innate response 
| colspan="1" rowspan="1" |C2, C4, C1q
| style="background:#DCDCDC;" align="center" |[[IRF5|Interferon (IFN) regulatory factor 5]]<ref name="pmid20080916">{{cite journal |vauthors=Löfgren SE, Yin H, Delgado-Vega AM, Sanchez E, Lewén S, Pons-Estel BA, Witte T, D'Alfonso S, Ortego-Centeno N, Martin J, Alarcón-Riquelme ME, Kozyrev SV |title=Promoter insertion/deletion in the IRF5 gene is highly associated with susceptibility to systemic lupus erythematosus in distinct populations, but exerts a modest effect on gene expression in peripheral blood mononuclear cells |journal=J. Rheumatol. |volume=37 |issue=3 |pages=574–8 |year=2010 |pmid=20080916 |doi=10.3899/jrheum.090440 |url=}}</ref>
|-  
| colspan="1" rowspan="1" |
|Non-HLA genes  
* Codes a [[transcription factor]] in the type 1 [[interferon]] pathway
| colspan="1" rowspan="1" |Mannose binding lectin polymorphisms
* Regulates:
Tumour necrosis factor α
** Expression of [[IFN]]-dependent [[genes]]
 
** [[Cytokine|Inflammatory cytokines]]
T cell receptor
** [[Genes]] involved in [[apoptosis]]
 
|
Interleukin 6
* The most strongly and consistently SLE-associated loci outside the [[MHC|MHC region]]
 
* Upon activation, [[IRF5]] activates transcription of [[Interferon type I|type I IFN]] and [[proinflammatory]] cytokines such as [[TNFα]], [[IL-12]] and [[IL-6]]
CR1
* Specific combinations of several [[polymorphisms]] in the [[IRF5]] region interact to increase disease risk
 
|-
Immunoglobulin Gm and Km
| style="background:#DCDCDC;" align="center" |[[STAT4]]<ref name="pmid18579578">{{cite journal |vauthors=Sigurdsson S, Nordmark G, Garnier S, Grundberg E, Kwan T, Nilsson O, Eloranta ML, Gunnarsson I, Svenungsson E, Sturfelt G, Bengtsson AA, Jönsen A, Truedsson L, Rantapää-Dahlqvist S, Eriksson C, Alm G, Göring HH, Pastinen T, Syvänen AC, Rönnblom L |title=A risk haplotype of STAT4 for systemic lupus erythematosus is over-expressed, correlates with anti-dsDNA and shows additive effects with two risk alleles of IRF5 |journal=Hum. Mol. Genet. |volume=17 |issue=18 |pages=2868–76 |year=2008 |pmid=18579578 |pmc=2525501 |doi=10.1093/hmg/ddn184 |url=}}</ref><ref name="pmid19109131">{{cite journal |vauthors=Kariuki SN, Kirou KA, MacDermott EJ, Barillas-Arias L, Crow MK, Niewold TB |title=Cutting edge: autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-alpha in lupus patients in vivo |journal=J. Immunol. |volume=182 |issue=1 |pages=34–8 |year=2009 |pmid=19109131 |pmc=2716754 |doi= |url=}}</ref><ref name="pmid18516230">{{cite journal |vauthors=Taylor KE, Remmers EF, Lee AT, Ortmann WA, Plenge RM, Tian C, Chung SA, Nititham J, Hom G, Kao AH, Demirci FY, Kamboh MI, Petri M, Manzi S, Kastner DL, Seldin MF, Gregersen PK, Behrens TW, Criswell LA |title=Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus |journal=PLoS Genet. |volume=4 |issue=5 |pages=e1000084 |year=2008 |pmid=18516230 |pmc=2377340 |doi=10.1371/journal.pgen.1000084 |url=}}</ref><ref name="pmid18803832">{{cite journal |vauthors=Kawasaki A, Ito I, Hikami K, Ohashi J, Hayashi T, Goto D, Matsumoto I, Ito S, Tsutsumi A, Koga M, Arinami T, Graham RR, Hom G, Takasaki Y, Hashimoto H, Behrens TW, Sumida T, Tsuchiya N |title=Role of STAT4 polymorphisms in systemic lupus erythematosus in a Japanese population: a case-control association study of the STAT1-STAT4 region |journal=Arthritis Res. Ther. |volume=10 |issue=5 |pages=R113 |year=2008 |pmid=18803832 |pmc=2592800 |doi=10.1186/ar2516 |url=}}</ref>
 
|
FcγRIIA (IgG Fc receptor)
* Encodes the signal transducer and activator of transcription 4 protein
 
|
FcγRIIIA (IgG Fc receptor)
* Associated with a more severe SLE [[phenotype]]:
 
** Disease-onset at a young age (<30 years)
PARP (poly-ADP ribose polymerase)
** High frequency of [[nephritis]]
 
* Associated with the presence of [[antibodies]] towards [[Double-stranded DNA helix|double-stranded DNA]]
Heat shock protein 70
* [[Mutation]] lead to an increased [[sensitivity]] to [[Interferon-alpha|IFN-α]] signaling in peripheral blood [[mononuclear cells]]
 
|-
Humhr 3005
| style="background:#DCDCDC;" align="center" |The ''[[IRAK1]]-[[MECP2]]'' region
|
* Encodes a [[protein kinase]]:
** Regulates multiple pathways in both [[Innate immune system|innate]] and [[Adaptive immune response|adaptive immune responses]] by linking several immune-receptor-complexes to [[TNF]] receptor-associated factor 6
** Critical role in the [[Transcriptional regulation|transcriptional suppression]] of [[methylation]]-sensitive genes
|
* The exact [[Pathogenicity|pathogenetics]] is not completely known
|-
| style="background:#DCDCDC;" align="center" |[[Fc region|FcγR genes]]<ref name="pmid10413210">{{cite journal |vauthors=Yap SN, Phipps ME, Manivasagar M, Tan SY, Bosco JJ |title=Human Fc gamma receptor IIA (FcgammaRIIA) genotyping and association with systemic lupus erythematosus (SLE) in Chinese and Malays in Malaysia |journal=Lupus |volume=8 |issue=4 |pages=305–10 |year=1999 |pmid=10413210 |doi=10.1191/096120399678847876 |url=}}</ref>
|
* Encode [[proteins]] that:
** Recognize [[immune complexes]]
** Are involved in [[Antibody-dependent cellular cytotoxicity|antibody-dependent]] responses
|
* [[Mutation]] associated with:
** Low affinity for [[Immunoglobulin G|IgG2-opsonized]] particles
** Reduced clearance of [[immune complexes]]
|-
! rowspan="2" style="background:#DCDCDC;" |Cell apoptosis regulators
| style="background:#DCDCDC;" align="center" |[[TREX1]]
|
* Encodes a major [[exonuclease]]:
** Proofreads [[DNA polymerase]]
** Functions also as a [[DNA]]-degrading enzyme in [[granzyme]]-A-mediated [[apoptosis]]
** Act as a [[cytosolic]] [[DNA]] sensor
|
* Mutation lead to impairs [[DNA damage]] repair, that lead to:
*# Accumulation of [[endogenous]] retroelement-derived [[DNA]]
*# Defective clearance of this [[DNA]] induces [[IFN-α|IFN]] production
*# An [[Immune-mediated disease|immune-mediated inflammatory response]]
*# Systemic [[autoimmunity]]
|-
| style="background:#DCDCDC;" align="center" |[[Interleukin 10|IL-10]]
|
* Encodes [[IL-10]]
* An important [[Cytokine|regulatory cytokine]] with both [[immunosuppressive]] and [[Immunostimulator|immunostimulatory]] properties
|
* Increased [[IL-10]] production by [[B cells]] and [[monocytes]] from patients with SLE is known to correlate with disease activity
|-
! rowspan="2" style="background:#DCDCDC;" |IFNα regulators
| style="background:#DCDCDC;" align="center" |[[TNFAIP3]] and [[TNIP1]]
|
* Encode key regulators of the [[NFκB]] signaling pathway
* Modulate cell activation, [[cytokine]] signaling and [[apoptosis]]
|
* The exact [[Pathogenicity|pathogenetics]] is not completely known
|-
| style="background:#DCDCDC;" align="center" |PHRF1
|
* Encodes an [[elongation factor]]
|
* Related to SLE-associated [[Autoantibody|autoantibodies]] and elevated [[IFN-α]] activity
|-
! rowspan="7" style="background:#DCDCDC;" |Regulators of Lymphocytes
| style="background:#DCDCDC;" align="center" |TNFSF4
|
* The [[genes]] in this loci produce interaction induces the production of co-stimulatory signals to activate [[T cells]]
|
* Inhibits the generation and function of [[IL-10]] producing CD4+ [[T cells]]
* Induces [[B-cell]] activation and differentiation
* Induces [[IL17A|IL-17]] production
* [[Mutation]] lead to predisposition to SLE:
** Augmenting the interaction between [[T cells]] and [[antigen-presenting cells]]
** Influencing the functional consequences of [[T cell|T-cell activation]]
|-
| style="background:#DCDCDC;" align="center" |[[BLK (gene)|BLK]]<ref name="pmid19180478">{{cite journal |vauthors=Ito I, Kawasaki A, Ito S, Hayashi T, Goto D, Matsumoto I, Tsutsumi A, Hom G, Graham RR, Takasaki Y, Hashimoto H, Ohashi J, Behrens TW, Sumida T, Tsuchiya N |title=Replication of the association between the C8orf13-BLK region and systemic lupus erythematosus in a Japanese population |journal=Arthritis Rheum. |volume=60 |issue=2 |pages=553–8 |year=2009 |pmid=19180478 |doi=10.1002/art.24246 |url=}}</ref>
|
* Encodes a [[protein kinase]]:
** Mediates [[intracellular signaling]]
** Influences [[B cells]] proliferation and differentiation
** Influences tolerance of [[B cells]]
|
* More common in Chinese and Japanese populations
|-
| style="background:#DCDCDC;" align="center" |[[PTPN22]]<ref name="pmid19302045">{{cite journal |vauthors=Gregersen PK, Olsson LM |title=Recent advances in the genetics of autoimmune disease |journal=Annu. Rev. Immunol. |volume=27 |issue= |pages=363–91 |year=2009 |pmid=19302045 |pmc=2992886 |doi=10.1146/annurev.immunol.021908.132653 |url=}}</ref>
|
* Encodes a [[lymphoid]]-specific [[Phosphatases|phosphatase]] that inhibits [[T cell|T-cell]] activation
|
* Associated with a higher risk of developing [[Autoimmune disease|multiple autoimmune diseases]]
* More seen in European populations
* [[Mutation]] increases the intrinsic [[lymphoid]]-specific [[Phosphatases|phosphatase]] activity that lead to:
** Reduction of [[T cell receptor|T-cell receptor (TCR)]] signaling threshold
** Promotion of [[autoimmunity]]
|-
| style="background:#DCDCDC;" align="center" |BANK1<ref name="pmid11782428">{{cite journal |vauthors=Yokoyama K, Su Ih IH, Tezuka T, Yasuda T, Mikoshiba K, Tarakhovsky A, Yamamoto T |title=BANK regulates BCR-induced calcium mobilization by promoting tyrosine phosphorylation of IP(3) receptor |journal=EMBO J. |volume=21 |issue=1-2 |pages=83–92 |year=2002 |pmid=11782428 |pmc=125810 |doi=10.1093/emboj/21.1.83 |url=}}</ref><ref name="pmid18204447">{{cite journal |vauthors=Kozyrev SV, Abelson AK, Wojcik J, Zaghlool A, Linga Reddy MV, Sanchez E, Gunnarsson I, Svenungsson E, Sturfelt G, Jönsen A, Truedsson L, Pons-Estel BA, Witte T, D'Alfonso S, Barizzone N, Barrizzone N, Danieli MG, Gutierrez C, Suarez A, Junker P, Laustrup H, González-Escribano MF, Martin J, Abderrahim H, Alarcón-Riquelme ME |title=Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus |journal=Nat. Genet. |volume=40 |issue=2 |pages=211–6 |year=2008 |pmid=18204447 |doi=10.1038/ng.79 |url=}}</ref>
|
* Encodes a [[B cell|B-cell]] adaptor protein
* Facilitates the release of [[intracellular]] [[calcium]]
* Alters the [[B-cell]] activation threshold
| rowspan="2" |
* Mutations lead to hyperctivation of [[B-cell receptor|B-cell receptors]] and the subsequent [[B-cell]] hyperactivity that is commonly observed in SLE
|-
| style="background:#DCDCDC;" align="center" |LYN<ref name="pmid18204446">{{cite journal |vauthors=Harley JB, Alarcón-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL, Tsao BP, Vyse TJ, Langefeld CD, Nath SK, Guthridge JM, Cobb BL, Mirel DB, Marion MC, Williams AH, Divers J, Wang W, Frank SG, Namjou B, Gabriel SB, Lee AT, Gregersen PK, Behrens TW, Taylor KE, Fernando M, Zidovetzki R, Gaffney PM, Edberg JC, Rioux JD, Ojwang JO, James JA, Merrill JT, Gilkeson GS, Seldin MF, Yin H, Baechler EC, Li QZ, Wakeland EK, Bruner GR, Kaufman KM, Kelly JA |title=Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci |journal=Nat. Genet. |volume=40 |issue=2 |pages=204–10 |year=2008 |pmid=18204446 |pmc=3712260 |doi=10.1038/ng.81 |url=}}</ref>
|
* Mediates [[B-cell]] activation
* Mediates [[B-cell]] inhibition
|-
| style="background:#DCDCDC;" align="center" |ETS1<ref name="pmid17967903">{{cite journal |vauthors=Moisan J, Grenningloh R, Bettelli E, Oukka M, Ho IC |title=Ets-1 is a negative regulator of Th17 differentiation |journal=J. Exp. Med. |volume=204 |issue=12 |pages=2825–35 |year=2007 |pmid=17967903 |pmc=2118518 |doi=10.1084/jem.20070994 |url=}}</ref><ref name="pmid19838195">{{cite journal |vauthors=Gateva V, Sandling JK, Hom G, Taylor KE, Chung SA, Sun X, Ortmann W, Kosoy R, Ferreira RC, Nordmark G, Gunnarsson I, Svenungsson E, Padyukov L, Sturfelt G, Jönsen A, Bengtsson AA, Rantapää-Dahlqvist S, Baechler EC, Brown EE, Alarcón GS, Edberg JC, Ramsey-Goldman R, McGwin G, Reveille JD, Vilá LM, Kimberly RP, Manzi S, Petri MA, Lee A, Gregersen PK, Seldin MF, Rönnblom L, Criswell LA, Syvänen AC, Behrens TW, Graham RR |title=A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus |journal=Nat. Genet. |volume=41 |issue=11 |pages=1228–33 |year=2009 |pmid=19838195 |pmc=2925843 |doi=10.1038/ng.468 |url=}}</ref>
|
* Negatively regulates the differentiation of [[B cells]] and type 17 [[T-helper cells]]
* Regulates [[Lymphocyte|lymphocytes]] by inhibiting the function of an important [[transcription factor]] in [[Plasma cell|plasma cells]]
|
* The exact [[Pathogenicity|pathogenetics]] is not completely known
|-
| style="background:#DCDCDC;" align="center" |[[IKZF1]]<ref name="pmid17357110">{{cite journal |vauthors=Wojcik H, Griffiths E, Staggs S, Hagman J, Winandy S |title=Expression of a non-DNA-binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis |journal=Eur. J. Immunol. |volume=37 |issue=4 |pages=1022–32 |year=2007 |pmid=17357110 |doi=10.1002/eji.200637026 |url=}}</ref>
|
* Encodes a [[lymphoid]]-restricted [[transcription factor]]
* Regulates:
** [[Lymphocyte]] differentiation and proliferation
** Self-tolerance through regulation of B-cell-receptor signaling
|
* A novel SLE susceptibility locus in a Chinese population
* A strong candidate locus in European-derived populations
|-
! style="background:#DCDCDC;" |Genes involved in immune complex clearance
| style="background:#DCDCDC;" align="center" |ITGAM<ref name="pmid19838195">{{cite journal |vauthors=Gateva V, Sandling JK, Hom G, Taylor KE, Chung SA, Sun X, Ortmann W, Kosoy R, Ferreira RC, Nordmark G, Gunnarsson I, Svenungsson E, Padyukov L, Sturfelt G, Jönsen A, Bengtsson AA, Rantapää-Dahlqvist S, Baechler EC, Brown EE, Alarcón GS, Edberg JC, Ramsey-Goldman R, McGwin G, Reveille JD, Vilá LM, Kimberly RP, Manzi S, Petri MA, Lee A, Gregersen PK, Seldin MF, Rönnblom L, Criswell LA, Syvänen AC, Behrens TW, Graham RR |title=A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus |journal=Nat. Genet. |volume=41 |issue=11 |pages=1228–33 |year=2009 |pmid=19838195 |pmc=2925843 |doi=10.1038/ng.468 |url=}}</ref>
|
* Encodes a [[protein]] that binds the [[complement]] cleavage fragment of [[C3b]]
|
* Contributes to SLE susceptibility
|}
|}
: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==
==Associated Conditions==
IC deposition and subsequent complement activation in the kidney is responsible for much of the tissue damage of lupus nephritis
* [[Homozygous]] deficiencies of the components of [[complement]], especially C1q, are associated with developing immunologic diseases, particularly SLE or a lupus-like disease.<ref name="pmid11564823">{{cite journal |vauthors=Petry F, Botto M, Holtappels R, Walport MJ, Loos M |title=Reconstitution of the complement function in C1q-deficient (C1qa-/-) mice with wild-type bone marrow cells |journal=J. Immunol. |volume=167 |issue=7 |pages=4033–7 |year=2001 |pmid=11564823 |doi= |url=}}</ref>
 
* 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. <ref name="pmid24997134">{{cite journal |vauthors=Li R, Peng H, Chen GM, Feng CC, Zhang YJ, Wen PF, Qiu LJ, Leng RX, Pan HF, Ye DQ |title=Association of FCGR2A-R/H131 polymorphism with susceptibility to systemic lupus erythematosus among Asian population: a meta-analysis of 20 studies |journal=Arch. Dermatol. Res. |volume=306 |issue=9 |pages=781–91 |year=2014 |pmid=24997134 |doi=10.1007/s00403-014-1483-5 |url=}}</ref>
* Women treated with [[estrogen]]-containing regimens such as oral [[contraceptives]] or [[HRT|postmenopausal hormone replacement therapies]] are more predisposed to SLE.
* Annular or [[Psoriasis|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]].
== Gross Pathology ==
== Gross Pathology ==
On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
On gross pathology the most important characteristic findings are:
* [[Kidney]]: Bilateral [[pallor]] and [[Hypertrophy (medical)|hypertrophy]]
* [[Brain]]: [[Infarct]] regions and [[hemorrhages]]
* [[Heart]]: [[Cardiomegaly]] and [[valvular]] vegetation
* [[Pleura|Lung]]: [[Pleural fibrosis|Peural fibrosis]] and [[pleural effusion]]


== Microscopic Pathology ==
== Microscopic Pathology ==
Synovial histopathology tends to be nonspecific, with superficial fibrin-like material and local or diffuse synovial cell lining proliferation . Vascular changes have included perivascular mononuclear cells, lumen obliteration, enlarged endothelial cells, and thrombi .  
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.


Skin hystopathology:
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 proliferative glomerulonephritis|endocapillary]] or extracapillary segmental [[glomerulonephritis]] are characteristic findings of [[Lupus nephritis|SLE nephritis]]. [[Microscopic]] findings in systemic lupus erythematosus are based on the involved organ system.


Common shared histopathologic features include hyperkeratosis; epidermal atrophy; vacuolar interface dermatitis (liquefactive degeneration of the basal layer of the epidermis); a superficial, perivascular, and perifollicular mononuclear cell inflammatory infiltrate; thickening of the basement membrane; and pigment incontinence
=== Skin histopathology ===
Common shared [[histopathologic]] features among all different subtypes of cutaneous lupus include:
* [[Hyperkeratosis]]
* [[Epidermal]] [[atrophy]]
* Dermal mucin [[Deposition (chemistry)|deposition]]
* [[Liquefactive necrosis|Liquefactive]] degeneration of the basal layer of the [[epidermis]] and [[vacuolization]]
* Thickening of the [[basement membrane]]
* [[Pigment]] [[incontinence]]
* [[Mononuclear cells|Mononuclear]] cell infiltration at dermo-epidermal junction
* [[Superficial]], [[Perivascular cell|perivascular]], and perifollicular areas (due to [[Mononuclear cells|mononuclear cell]] inflammatory infiltrate)
{| class="wikitable"
! style="background: #4479BA; color: #FFFFFF; " align="center" |SLE dermatitis subtype
! style="background: #4479BA; color: #FFFFFF; " align="center" |Specific microscopic findings
! style="background: #4479BA; color: #FFFFFF; " align="center" |Preview
|-
! style="background:#DCDCDC;" align="center" |Acute cutaneous lupus erythematosus
|
* Lymphohistiocytic infiltrate in the [[superficial]] dermis <ref name="pmid20482683">{{cite journal |vauthors=Sepehr A, Wenson S, Tahan SR |title=Histopathologic manifestations of systemic diseases: the example of cutaneous lupus erythematosus |journal=J. Cutan. Pathol. |volume=37 Suppl 1 |issue= |pages=112–24 |year=2010 |pmid=20482683 |doi=10.1111/j.1600-0560.2010.01510.x |url=}}</ref>
| rowspan="3" |[[File:Vacuolar interface dermatitis - high mag.jpg|thumb|300px|<SMALL><SMALL>''[https://librepathology.org/wiki/Main_Page/ Adapted from Librepathology]''</SMALL></SMALL>]]
|-
! style="background:#DCDCDC;" align="center" |Subacute cutaneous lupus erythematosus
|
* Less [[Follicular cell|follicular]] plugging and [[hyperkeratosis]] in comparison with dischoid lupus erythematosus
* Superficial appendageal and [[Perivascular cell|perivascular]] lymphocytic infiltration
* Absence or minimal change of [[basement membrane]] thickening
|-
! style="background:#DCDCDC;" align="center" |Chronic cutaneous lupus erythematosus
|
* [[Discoid lupus erythematosus]] :
** [[Follicular Hyperkeratosis|Follicular plugging]]
** [[Mononuclear cell]] infiltration near the dermal-epidermal junction, [[Blood vessels|dermal blood vessel]]<nowiki/>s, and appendages
* Lupus erythematosus tumidus:
** Consists of predominately [[CD3|CD3+]]/[[CD4+]] [[lymphocytes]]
** Focal interface changes
* Lupus profundus (lupus panniculitis):
** [[Perivascular cell|Perivascular]] infiltrates of [[mononuclear cells]] plus [[panniculitis]]
** [[Hyaline]] fat necrosis
** Direct [[immunofluorescence]]: immune deposits in the dermal-epidermal junction
|}


On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
=== Glomerulonephritis histopathology ===
 
{| class="wikitable"
Lupus is a chronic [[Autoimmunity|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.
! style="background: #4479BA; color: #FFFFFF; " align="center" |<small>Class<small>
 
! style="background: #4479BA; color: #FFFFFF; " align="center" |SLE nephritis subtype
SLE is a chronic [[inflammation|inflammatory]] disease believed to be a [[Hypersensitivity#Type 3 - immune complex|type III hypersensitivity]] response with potential [[Hypersensitivity#Type 2 - antibody-dependent|type II]] involvement.<ref>[http://pathmicro.med.sc.edu/ghaffar/hyper00.htm University of South Carolina School of Medicine lecture notes, Immunology, Hypersensitivity reactions. General discussion of hypersensitivity, not specific to SLE.]</ref>
! style="background: #4479BA; color: #FFFFFF; " align="center" |Light microscopy findings
 
! style="background: #4479BA; color: #FFFFFF; " align="center" |Light microscopy previews
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. 
! style="background: #4479BA; color: #FFFFFF; " align="center" |Electron microscopy/Immunofluorescence findings
 
|-
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
! align="center" |'''I'''
 
| style="background:#DCDCDC;" |Minimal mesangial lupus nephritis
Mesangial proliferative lupus nephritis (class II): mesangial hypercellularity (of any degree) or mesangial matrix expansion
|<nowiki>-</nowiki>
 
|
A few isolated subepithelial or subendothelial deposits may be seen on immunofluorescence or electron microscopy
|
 
* Mesangial [[immune]] deposits
Focal lupus nephritis (class III): Light microscopy: Active or inactive endocapillary or extracapillary segmental glomerulonephritis (Less than 50 percent of glomeruli are affected)
|-
 
! align="center" |'''II'''
Electron microscopy: immune deposits in the subendothelial space of the glomerular capillary and mesangium
| style="background:#DCDCDC;" |Mesangial proliferative lupus nephritis
 
|
Glomeruli affected by fibrinoid necrosis and crescents
* [[Mesangial proliferative glomerulonephritis|Mesangial hyper cellularity]] (of any degree)
 
* [[Mesangial cells|Mesangial]] matrix expansion
Presence of tubulointerstitial or vascular abnormalities
|[[File:Membranous nephropathy - mpas - very high mag.jpg|thumb|300px|<SMALL><SMALL>''[https://librepathology.org/wiki/Main_Page/ Adapted from Librepathology]''</SMALL></SMALL>]]  
 
|
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
* Isolated [[Subepithelial connective tissue graft|subepithelial]] or subendothelial deposits
 
|-
Electron microscopy: subendothelial deposits, at least during the active phase and diffuse wire loop deposits, but with little or no glomerular proliferation 
! align="center" |'''III'''
 
| style="background:#DCDCDC;" |Focal lupus nephritis
===Genetics===
|
 
* Active or inactive [[Endocapillary proliferative glomerulonephritis|endocapillary]] or extracapillary segmental [[glomerulonephritis]]  
The first mechanism may arise genetically. Research indicates that [[SLE]] may have a [[genetics|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. <ref name="rahman">{{cite journal |author=Anisur Rahman and David A. Isenberg|title=Review Article: Systemic Lupus Erythematosus|journal=N Engl J Med|volume=358|issue=9|pages=929–939|year=2008|date=February 28, 2008|pmid=18305268|url=http://content.nejm.org/cgi/content/full/358/9/929|doi=10.1056/NEJMra071297}}</ref><ref>{{cite journal |author=Mary K. Crow|title=Collaboration, Genetic Associations, and Lupus Erythematosus|journal=N Engl J Med|volume=358|issue=9|pages=956–961|year=2008|date=February 28, 2008|pmid=18204099|url=http://content.nejm.org/cgi/content/full/358/9/956|doi=10.1056/NEJMe0800096}}</ref><ref>{{cite journal |author=Geoffrey Hom, Robert R. Graham, Barmak Modrek, et al.|title=Association of Systemic Lupus Erythematosus with C8orf13–BLK and ITGAM–ITGAX|journal=N Engl J Med|volume=358|issue=9|pages=900–909|year=2008|date=February 28, 2008|pmid=18204098|url=http://content.nejm.org/cgi/content/full/358/9/900|doi=10.1056/NEJMoa0707865}}</ref>
* Involvement of glomeruli < 50%
 
|[[File:1599px-Focal segmental glomerulosclerosis - high mag.jpg|thumb|300px|<SMALL><SMALL>''[https://librepathology.org/wiki/Main_Page/ Adapted from Librepathology]''</SMALL></SMALL>]]  
* The most important [[gene]]s are located on [[Chromosome 6 (human)|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]].
* Immune deposits in the subendothelial space of the [[Glomerular capillaries|glomerular capillary]] and [[mesangium]]
 
* [[Fibrinoid necrosis]] and crescents in glomeruli
 
* [[Tubulointerstitial diseases of the kidney|Tubulointerstitial]] or vascular abnormalities
Other abnormalities include:
|-
*Increased expression of [[FcεRI]]γ, which replaces the sometimes deficient TCR ζ chain
! align="center" |'''IV'''
*Increased and sustained calcium levels in [[T cell]]s
| style="background:#DCDCDC;" |Diffuse lupus nephritis
*Moderate increase of [[inositol triphosphate]]
|
*Reduction in [[Protein kinase C|PKC]] phosphorylation
* [[Endocapillary proliferative glomerulonephritis|Endocapillary]] [[glomerulonephritis]]  
*Increased desire of animal protein intake.
* Extracapillary [[glomerulonephritis]]  
*Reduction in Ras-[[Mitogen-activated protein kinase|MAP kinase]] signaling
* [[Mesangial proliferative glomerulonephritis|Mesangial abnormalities]]
*Deficiencies in [[protein kinase]] A I activity
* Involvement of glomeruli > 50%
===Environmental triggers===
| rowspan="2" |[[File:Membranoproliferative glomerulonephritis - very high mag.jpg|thumb|300px|<SMALL><SMALL>''[https://librepathology.org/wiki/Main_Page/ Adapted from Librepathology]''</SMALL></SMALL>]]  
 
|
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:
* Subendothelial deposits specially during the active phase
* Certain medications (such as some [[antidepressant]]s and [[antibiotic]]s)
* Diffuse wire loop deposits with little or no glomerular proliferation
* Extreme [[stress]]
|-
* Exposure to sunlight
! align="center" |'''V'''
* [[Hormones]]
| style="background:#DCDCDC;" |Lupus membranous nephropathy
* [[Infection]]s - some researchers have sought to find a connection between certain infectious agents ([[virus]]es 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]].
* Diffuse thickening of the [[Glomerular capillaries|glomerular capillary wall]]
* Some researchers have found that women with [[silicone]] gel-filled [[breast implant]]s 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 disease]]s such as [[lupus]].
* [[Immunofluorescence]] or [[electron microscopy]]
 
|
===Abnormalities in apoptosis===
* Global or segmental [[Subepithelial connective tissue graft|subepithelial]] immune deposits
 
|-
*[[Apoptosis]] is increased in [[monocyte]]s and [[keratinocyte]]s
! align="center" |'''VI'''
*[[Gene expression|Expression]] of Fas by [[B cell]]s and [[T cell]]s is increased
| style="background:#DCDCDC;" |Advanced sclerosing lupus nephritis
*There are correlations between the apoptotic rates of lymphocytes and disease activity
|
 
* Global [[sclerosis]]
Tangible body macrophages (TBMs) are large phagocytic cells in the [[germinal center]]s of secondary [[lymph node]]s. 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 cell]]s 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]].<ref>{{cite journal | author=Gaipl, U S; Kuhn, A; Sheriff, A; Munoz, L E; Franz, S; Voll, R E; Kalden, J R; Herrmann, M | title=Clearance of apoptotic cells in human SLE.| journal=Current directions in autoimmunity | volume=9 | issue= | year=2006 | pages=173-87 | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16394661&dopt=Abstract | id = PMID: 1639466 [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16394661&dopt=Abstract Abstract] (full text requires registration) }}</ref>
* Involvement of [[glomeruli]] > 90%
 
|[[File:Crescentic glomerulonephritis (2).jpg|thumb|300px|<SMALL><SMALL>''[https://librepathology.org/wiki/Main_Page/ Adapted from Librepathology]''</SMALL></SMALL>]]
===Clearance deficiency===
|
[[image:Picture1_englisch.jpg|left|thumb|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]].
* Global or segmental [[Subepithelial connective tissue graft|subepithelial]] immune deposits
 
|}
[[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 [[monocyte]]s 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)===
[[image:Picture2_englisch.jpg|left|160px|thumb|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.
<br clear="left" />
 
===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.<ref name="pmid19248110">{{cite journal |author=Poole BD, Schneider RI, Guthridge JM, ''et al'' |title=Early targets of nuclear RNP humoral autoimmunity in human systemic lupus erythematosus |journal=Arthritis Rheum. |volume=60 |issue=3 |pages=848–859 |year=2009 |month=February |pmid=19248110 |doi=10.1002/art.24306 |url=http://dx.doi.org/10.1002/art.24306 |issn=}}</ref>
 
===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 [[transcription|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.<ref name="pmid19247800">{{cite journal |author=Pan HF, Wu GC, Li WP, Li XP, Ye DQ |title=High Mobility Group Box 1: a potential therapeutic target for systemic lupus erythematosus |journal=Mol. Biol. Rep. |volume= |issue= |pages= |year=2009 |month=February |pmid=19247800 |doi=10.1007/s11033-009-9485-7 |url= |issn=}}</ref>
 
===Gross Images===
 
[http://www.peir.net Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology]


<gallery perrow="3">
=== Synovial histopathology ===
Image:Systemic lupus erythematosus 001.jpg|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)
* Nonspecific histopathologic findings
Image:Systemic lupus erythematosus 002.jpg|Kidney: Lupus erythematosus: Gross cut surface pale kidneys typical of nephrotic syndrome (subacute glomerulonephritis)
* Superficial [[fibrin]]-like material
Image:Systemic lupus erythematosus 004.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
* Local or diffuse synovial cell lining proliferation
Image:Systemic lupus erythematosus 027.jpg|Brain: Lupus Erythematosus Libman Sacks Embolism: Gross fixed tissue one large and two small hemorrhages 19yo female with history of TIAs
* [[Vascular]] changes:
Image:Systemic lupus erythematosus 028.jpg|Brain: Lupus Erythematosus Libman Sacks Embolism: Gross fixed tissue large hemorrhagic infarcts due to embolism 19yo female with known lupus and history of TIAs
** [[Perivascular cell|Perivascular]] [[mononuclear cells]]
Image:Systemic lupus erythematosus 029.jpg|Brain: Lupus Erythematosus Libman Sacks Embolism: Gross large hemorrhagic infarcts 19 yo female with history of TIAs proved case lupus with renal failure
** [[Lumen]] obliteration
Image:Systemic lupus erythematosus 030.jpg|Brain: Lupus Erythematosus Libman Sacks Embolism: Gross fixed tissue cerebellar hemorrhagic infarcts 19yo female with history of TIAs known lupus case with renal failure
** Enlarged [[endothelial cells]]
Image:Systemic lupus erythematosus 031.jpg|Brain: Purulent Meningitis: Gross fixed tissue excellent example Pneumococcus case of young girl with lupus
** [[Thrombi]]
Image:Systemic lupus erythematosus 032.jpg|Skeletal muscle: Hematoma: Gross natural color flank muscle hematoma old showing typical chocolate appearance of blood coagulum young female with lupus and thrombocytopenia
Image:Systemic lupus erythematosus 047.jpg|Brain: Lupus Erythematosus, Systemic; Microinfarct in Cerebral Cortex
Image:Systemic lupus erythematosus 040.jpg|Kidney: Lupus Nephritis: Gross natural color external view of flea bitten kidneys quite good advanced proliferative type glomerulonephritis of lupus in a 16yo female
Image:Systemic lupus erythematosus 041.jpg|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
Image:Systemic lupus erythematosus 042.jpg|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
Image:Systemic lupus erythematosus 043.jpg|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
Image:Systemic lupus erythematosus 044.jpg|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
Image:Systemic lupus erythematosus 045.jpg|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
Image:Systemic lupus erythematosus 046.jpg|Kidney: Lupus Erythematosus: Gross natural color nice external and cut surface view of uniformly scarred and moderately shrunken kidneys
Image:Systemic lupus erythematosus 021.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
Image:Systemic lupus erythematosus 019.jpg|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
</gallery>


===Microscopic Images===
=== Mucosal histopathology ===
* [[Hyperkeratosis]]
* [[Atrophy]] of rete processes
* [[Superficial]] and deep inflammatory infiltrates
* [[Edema]] in the [[lamina propria]]
* Continuous or patchy [[Periodic acid-Schiff stain|periodic acid-Schiff]] ([[PASK|PAS]])-positive deposits in the [[basement membrane]] zone
* Deposition of intercellular [[mucin]]
* Deposition of [[immunoglobulin]] and [[complement]] at the dermal-epidermal junction


[http://www.peir.net Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology]


<gallery perrow="3">
Image:Systemic lupus erythematosus 003.jpg|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
Image:Systemic lupus erythematosus 005.jpg|Spleen: Lupus erythematosus Periarterial Fibrosis: Micro high may H&E. An excellent example of periarterial fibrosis 
Image:Systemic lupus erythematosus 006.jpg|Spleen: Lupus erythematosus, periarterial fibrosis: Micro high may H&E. An excellent example of periarterial fibrosis 
Image:Systemic lupus erythematosus 007.jpg|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.
Image:Systemic lupus erythematosus 008.jpg|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.
Image:Systemic lupus erythematosus 009.jpg|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
Image:Systemic lupus erythematosus 010.jpg|Adrenal: Autoimmune Adrenalitis: Micro high mag H&E focal area of lymphocytic infiltration in zona reticularis in a 19yo female with lupus erythematosus
Image:Systemic lupus erythematosus 039.jpg|Kidney: Lupus Erythematosus: Micro high mag H&E. A nice example of a lesion of chronic glomerulonephritis with lobular scarring. A fibrous type crescent.
Image:Systemic lupus erythematosus 011.jpg|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
Image:Systemic lupus erythematosus 012.jpg|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
Image:Systemic lupus erythematosus 013.jpg|Lupus Erythematosus Focal Myocardial Scar Due To Libman Sacks Embolism: Micro low mag H&E focal scar in myocardium due to embolism
Image:Systemic lupus erythematosus 014.jpg|Lupus Erythematosus Myocardial Scar Due To Libman Sacks Embolism: Micro low mag H&E scar with portion of embolus in small artery
Image:Systemic lupus erythematosus 015.jpg|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
Image:Systemic lupus erythematosus 016.jpg|Lupus Erythematosus Embolus From Libman Sacks Lesion: Micro med mag H&E well shown embolus in small artery 
Image:Systemic lupus erythematosus 017.jpg|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
Image:Systemic lupus erythematosus 018.jpg|Lung: Diffuse Alveolar Damage: Gross natural color section of both lungs with frank meaty appearance case of lupus erythematosus in 19yo female
Image:Systemic lupus erythematosus 020.jpg|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
Image:Systemic lupus erythematosus 023.jpg|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
Image:Systemic lupus erythematosus 024.jpg|Lung: Necrotizing Bronchiolitis: Micro low mag H&E well shown necrotizing bronchiolitis and surrounding lesions of diffuse alveolar damage 19yo female with lupus erythematosus
Image:Systemic lupus erythematosus 025.jpg|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
Image:Systemic lupus erythematosus 026.jpg|Kidney: Lupus Erythematosus: Micro high mag PAS stain thickened mesangium and capillary basement membranes 19yo female with renal failure and proved lupus
Image:Systemic lupus erythematosus 033.jpg|Artery: Arteritis in Lupus Erythematosus: Micro med mag H&E. A good example of vasculitis
Image:Systemic lupus erythematosus 034.jpg|Kidney: Lupus Erythematosus: Micro high mag PASH typical glomerulonephritis lesion with crescent
Image:Systemic lupus erythematosus 035.jpg|Kidney: Lupus Erythematosus: Micro med mag PASH glomerulonephritis
Image:Systemic lupus erythematosus 036.jpg|Kidney: Lupus Erythematosus: Micro med mag H&E typical glomerulonephritis lesion
Image:Systemic lupus erythematosus 037.jpg|Kidney: Lupus Erythematosus: Micro med mag H&E two glomeruli showing lobular glomerulonephritis lesion
Image:Systemic lupus erythematosus 038.jpg|Kidney: Lupus Erythematosus: Micro med mag PASH typical chronic glomerulonephritis lesion with crescent
Image:Systemic lupus erythematosus 048.jpg|Vessel: lupus, systemic erythematosus; Thrombus in capillary
Image:Systemic lupus erythematosus 049.jpg|Vessel: lupus, systemic erythematosus; Thrombus in capillary
Image:Systemic lupus erythematosus 050.jpg|Vessel: lupus, systemic erythematosus; Thrombus in arteriole and vein
Image:Systemic lupus erythematosus 051.jpg|Vessel: lupus, systemic erythematosus; Thrombus in pial vessel
Image:Systemic lupus erythematosus 022.jpg|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
</gallery>


====Videos====
=====Lupus nephritis histopathology=====
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{{#ev:youtube|Tw07BFaDEo0}}


Latest revision as of 18:29, 23 August 2017

Title
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Systemic lupus erythematosus Microchapters

Home

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Overview

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mahshid Mir, M.D. [2], Cafer Zorkun, M.D., Ph.D. [3], Raviteja Guddeti, M.B.B.S. [4]

Overview

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.

Pathogenesis

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.

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Environmental factors

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.

Immune abnormalities

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.[1][2] 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: 

Microparticles

Increased level of microparticles (MPs):[3]

Pro-inflammatory cytokines

Increased expression of specific genetic factors may be associated with promoting autoimmunity. The most important cytokine changes include:[4][3]

Signaling abnormalities

Protein kinases are responsible for intracellular cytokine signals. Intracellular signaling leads to various types of cell response, such as:

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:

B-Cell role

T-Cell role

Neutrophil role

Hormonal abnormalities

The following evidence is suggestive of the hormonal predisposition to SLE:

Hormones that are related to disease progression include:[7]

Prolactin:

Exogenous estrogen

Progesterone:

Genetics

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:[10]

  • 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[11]
  • Associated with an overall 2- to 3-fold increase in the risk of SLE
  • More common in European and Asian people
  • HLA-DQ and HLA-DR alleles:
Immune complex dependent response HLA class 3[12]
  • Complete C2 and C4 deficiencies:
    • Rare
    • Associated with a mild form of SLE that affects mostly the joints and skin
  • Stronger genetic evidence for an association with SLE in C4A than C4-B
  • Circulating complement C4 proteins deficiency will promote autoimmunity
C1q genes[12]
Innate response Interferon (IFN) regulatory factor 5[13]
STAT4[14][15][16][17]
  • Encodes the signal transducer and activator of transcription 4 protein
The IRAK1-MECP2 region
FcγR genes[18]
Cell apoptosis regulators TREX1
IL-10
  • Increased IL-10 production by B cells and monocytes from patients with SLE is known to correlate with disease activity
IFNα regulators TNFAIP3 and TNIP1
  • Encode key regulators of the NFκB signaling pathway
  • Modulate cell activation, cytokine signaling and apoptosis
PHRF1
Regulators of Lymphocytes TNFSF4
  • The genes in this loci produce interaction induces the production of co-stimulatory signals to activate T cells
BLK[19]
  • More common in Chinese and Japanese populations
PTPN22[20]
BANK1[21][22]
  • Mutations lead to hyperctivation of B-cell receptors and the subsequent B-cell hyperactivity that is commonly observed in SLE
LYN[23]
ETS1[24][25]
IKZF1[26]
  • A novel SLE susceptibility locus in a Chinese population
  • A strong candidate locus in European-derived populations
Genes involved in immune complex clearance ITGAM[25]
  • Contributes to SLE susceptibility

Associated Conditions

Gross Pathology

On gross pathology the most important characteristic findings are:

Microscopic Pathology

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.

Skin histopathology

Common shared histopathologic features among all different subtypes of cutaneous lupus include:

SLE dermatitis subtype Specific microscopic findings Preview
Acute cutaneous lupus erythematosus
Adapted from Librepathology
Subacute cutaneous lupus erythematosus
Chronic cutaneous lupus erythematosus

Glomerulonephritis histopathology

Class SLE nephritis subtype Light microscopy findings Light microscopy previews Electron microscopy/Immunofluorescence findings
I Minimal mesangial lupus nephritis -
II Mesangial proliferative lupus nephritis
Adapted from Librepathology
III Focal lupus nephritis
Adapted from Librepathology
IV Diffuse lupus nephritis
Adapted from Librepathology
  • Subendothelial deposits specially during the active phase
  • Diffuse wire loop deposits with little or no glomerular proliferation
V Lupus membranous nephropathy
VI Advanced sclerosing lupus nephritis
Adapted from Librepathology

Synovial histopathology

Mucosal histopathology


Lupus nephritis histopathology

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References

  1. ↑ Elkon K (1995). "Autoantibodies in systemic lupus erythematosus". Curr Opin Rheumatol. 7 (5): 384–8. PMID 8519610.
  2. ↑ Yaniv G, Twig G, Shor DB, Furer A, Sherer Y, Mozes O, Komisar O, Slonimsky E, Klang E, Lotan E, Welt M, Marai I, Shina A, Amital H, Shoenfeld Y (2015). "A volcanic explosion of autoantibodies in systemic lupus erythematosus: a diversity of 180 different antibodies found in SLE patients". Autoimmun Rev. 14 (1): 75–9. doi:10.1016/j.autrev.2014.10.003. PMID 25449682.
  3. ↑ 3.0 3.1 Dye JR, Ullal AJ, Pisetsky DS (2013). "The role of microparticles in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus". Scand. J. Immunol. 78 (2): 140–8. doi:10.1111/sji.12068. PMID 23672591.
  4. ↑ Kirou KA, Lee C, George S, Louca K, Papagiannis IG, Peterson MG, Ly N, Woodward RN, Fry KE, Lau AY, Prentice JG, Wohlgemuth JG, Crow MK (2004). "Coordinate overexpression of interferon-alpha-induced genes in systemic lupus erythematosus". Arthritis Rheum. 50 (12): 3958–67. doi:10.1002/art.20798. PMID 15593221.
  5. ↑ Barnado A, Crofford LJ, Oates JC (2016). "At the Bedside: Neutrophil extracellular traps (NETs) as targets for biomarkers and therapies in autoimmune diseases". J. Leukoc. Biol. 99 (2): 265–78. doi:10.1189/jlb.5BT0615-234R. PMID 26658004.
  6. ↑ Costenbader KH, Feskanich D, Stampfer MJ, Karlson EW (2007). "Reproductive and menopausal factors and risk of systemic lupus erythematosus in women". Arthritis Rheum. 56 (4): 1251–62. doi:10.1002/art.22510. PMID 17393454.
  7. ↑ 7.0 7.1 Lahita RG (1999). "The role of sex hormones in systemic lupus erythematosus". Curr Opin Rheumatol. 11 (5): 352–6. PMID 10503654.
  8. ↑ Hughes GC, Choubey D (2014). "Modulation of autoimmune rheumatic diseases by oestrogen and progesterone". Nat Rev Rheumatol. 10 (12): 740–51. doi:10.1038/nrrheum.2014.144. PMID 25155581.
  9. ↑ Cohen-Solal JF, Jeganathan V, Grimaldi CM, Peeva E, Diamond B (2006). "Sex hormones and SLE: influencing the fate of autoreactive B cells". Curr. Top. Microbiol. Immunol. 305: 67–88. PMID 16724801.
  10. ↑ Sullivan KE (2000). "Genetics of systemic lupus erythematosus. Clinical implications". Rheum. Dis. Clin. North Am. 26 (2): 229–56, v–vi. PMID 10768211.
  11. ↑ Lee HS, Chung YH, Kim TG, Kim TH, Jun JB, Jung S, Bae SC, Yoo DH (2003). "Independent association of HLA-DR and FCgamma receptor polymorphisms in Korean patients with systemic lupus erythematosus". Rheumatology (Oxford). 42 (12): 1501–7. doi:10.1093/rheumatology/keg404. PMID 12867584.
  12. ↑ 12.0 12.1 Pickering MC, Botto M, Taylor PR, Lachmann PJ, Walport MJ (2000). "Systemic lupus erythematosus, complement deficiency, and apoptosis". Adv. Immunol. 76: 227–324. PMID 11079100.
  13. ↑ Löfgren SE, Yin H, Delgado-Vega AM, Sanchez E, Lewén S, Pons-Estel BA, Witte T, D'Alfonso S, Ortego-Centeno N, Martin J, Alarcón-Riquelme ME, Kozyrev SV (2010). "Promoter insertion/deletion in the IRF5 gene is highly associated with susceptibility to systemic lupus erythematosus in distinct populations, but exerts a modest effect on gene expression in peripheral blood mononuclear cells". J. Rheumatol. 37 (3): 574–8. doi:10.3899/jrheum.090440. PMID 20080916.
  14. ↑ Sigurdsson S, Nordmark G, Garnier S, Grundberg E, Kwan T, Nilsson O, Eloranta ML, Gunnarsson I, Svenungsson E, Sturfelt G, Bengtsson AA, Jönsen A, Truedsson L, Rantapää-Dahlqvist S, Eriksson C, Alm G, Göring HH, Pastinen T, Syvänen AC, Rönnblom L (2008). "A risk haplotype of STAT4 for systemic lupus erythematosus is over-expressed, correlates with anti-dsDNA and shows additive effects with two risk alleles of IRF5". Hum. Mol. Genet. 17 (18): 2868–76. doi:10.1093/hmg/ddn184. PMC 2525501. PMID 18579578.
  15. ↑ Kariuki SN, Kirou KA, MacDermott EJ, Barillas-Arias L, Crow MK, Niewold TB (2009). "Cutting edge: autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-alpha in lupus patients in vivo". J. Immunol. 182 (1): 34–8. PMC 2716754. PMID 19109131.
  16. ↑ Taylor KE, Remmers EF, Lee AT, Ortmann WA, Plenge RM, Tian C, Chung SA, Nititham J, Hom G, Kao AH, Demirci FY, Kamboh MI, Petri M, Manzi S, Kastner DL, Seldin MF, Gregersen PK, Behrens TW, Criswell LA (2008). "Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus". PLoS Genet. 4 (5): e1000084. doi:10.1371/journal.pgen.1000084. PMC 2377340. PMID 18516230.
  17. ↑ Kawasaki A, Ito I, Hikami K, Ohashi J, Hayashi T, Goto D, Matsumoto I, Ito S, Tsutsumi A, Koga M, Arinami T, Graham RR, Hom G, Takasaki Y, Hashimoto H, Behrens TW, Sumida T, Tsuchiya N (2008). "Role of STAT4 polymorphisms in systemic lupus erythematosus in a Japanese population: a case-control association study of the STAT1-STAT4 region". Arthritis Res. Ther. 10 (5): R113. doi:10.1186/ar2516. PMC 2592800. PMID 18803832.
  18. ↑ Yap SN, Phipps ME, Manivasagar M, Tan SY, Bosco JJ (1999). "Human Fc gamma receptor IIA (FcgammaRIIA) genotyping and association with systemic lupus erythematosus (SLE) in Chinese and Malays in Malaysia". Lupus. 8 (4): 305–10. doi:10.1191/096120399678847876. PMID 10413210.
  19. ↑ Ito I, Kawasaki A, Ito S, Hayashi T, Goto D, Matsumoto I, Tsutsumi A, Hom G, Graham RR, Takasaki Y, Hashimoto H, Ohashi J, Behrens TW, Sumida T, Tsuchiya N (2009). "Replication of the association between the C8orf13-BLK region and systemic lupus erythematosus in a Japanese population". Arthritis Rheum. 60 (2): 553–8. doi:10.1002/art.24246. PMID 19180478.
  20. ↑ Gregersen PK, Olsson LM (2009). "Recent advances in the genetics of autoimmune disease". Annu. Rev. Immunol. 27: 363–91. doi:10.1146/annurev.immunol.021908.132653. PMC 2992886. PMID 19302045.
  21. ↑ Yokoyama K, Su Ih IH, Tezuka T, Yasuda T, Mikoshiba K, Tarakhovsky A, Yamamoto T (2002). "BANK regulates BCR-induced calcium mobilization by promoting tyrosine phosphorylation of IP(3) receptor". EMBO J. 21 (1–2): 83–92. doi:10.1093/emboj/21.1.83. PMC 125810. PMID 11782428.
  22. ↑ Kozyrev SV, Abelson AK, Wojcik J, Zaghlool A, Linga Reddy MV, Sanchez E, Gunnarsson I, Svenungsson E, Sturfelt G, Jönsen A, Truedsson L, Pons-Estel BA, Witte T, D'Alfonso S, Barizzone N, Barrizzone N, Danieli MG, Gutierrez C, Suarez A, Junker P, Laustrup H, González-Escribano MF, Martin J, Abderrahim H, Alarcón-Riquelme ME (2008). "Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus". Nat. Genet. 40 (2): 211–6. doi:10.1038/ng.79. PMID 18204447.
  23. ↑ Harley JB, Alarcón-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL, Tsao BP, Vyse TJ, Langefeld CD, Nath SK, Guthridge JM, Cobb BL, Mirel DB, Marion MC, Williams AH, Divers J, Wang W, Frank SG, Namjou B, Gabriel SB, Lee AT, Gregersen PK, Behrens TW, Taylor KE, Fernando M, Zidovetzki R, Gaffney PM, Edberg JC, Rioux JD, Ojwang JO, James JA, Merrill JT, Gilkeson GS, Seldin MF, Yin H, Baechler EC, Li QZ, Wakeland EK, Bruner GR, Kaufman KM, Kelly JA (2008). "Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci". Nat. Genet. 40 (2): 204–10. doi:10.1038/ng.81. PMC 3712260. PMID 18204446.
  24. ↑ Moisan J, Grenningloh R, Bettelli E, Oukka M, Ho IC (2007). "Ets-1 is a negative regulator of Th17 differentiation". J. Exp. Med. 204 (12): 2825–35. doi:10.1084/jem.20070994. PMC 2118518. PMID 17967903.
  25. ↑ 25.0 25.1 Gateva V, Sandling JK, Hom G, Taylor KE, Chung SA, Sun X, Ortmann W, Kosoy R, Ferreira RC, Nordmark G, Gunnarsson I, Svenungsson E, Padyukov L, Sturfelt G, Jönsen A, Bengtsson AA, Rantapää-Dahlqvist S, Baechler EC, Brown EE, Alarcón GS, Edberg JC, Ramsey-Goldman R, McGwin G, Reveille JD, Vilá LM, Kimberly RP, Manzi S, Petri MA, Lee A, Gregersen PK, Seldin MF, Rönnblom L, Criswell LA, Syvänen AC, Behrens TW, Graham RR (2009). "A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus". Nat. Genet. 41 (11): 1228–33. doi:10.1038/ng.468. PMC 2925843. PMID 19838195.
  26. ↑ Wojcik H, Griffiths E, Staggs S, Hagman J, Winandy S (2007). "Expression of a non-DNA-binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis". Eur. J. Immunol. 37 (4): 1022–32. doi:10.1002/eji.200637026. PMID 17357110.
  27. ↑ Petry F, Botto M, Holtappels R, Walport MJ, Loos M (2001). "Reconstitution of the complement function in C1q-deficient (C1qa-/-) mice with wild-type bone marrow cells". J. Immunol. 167 (7): 4033–7. PMID 11564823.
  28. ↑ Li R, Peng H, Chen GM, Feng CC, Zhang YJ, Wen PF, Qiu LJ, Leng RX, Pan HF, Ye DQ (2014). "Association of FCGR2A-R/H131 polymorphism with susceptibility to systemic lupus erythematosus among Asian population: a meta-analysis of 20 studies". Arch. Dermatol. Res. 306 (9): 781–91. doi:10.1007/s00403-014-1483-5. PMID 24997134.
  29. ↑ Sepehr A, Wenson S, Tahan SR (2010). "Histopathologic manifestations of systemic diseases: the example of cutaneous lupus erythematosus". J. Cutan. Pathol. 37 Suppl 1: 112–24. doi:10.1111/j.1600-0560.2010.01510.x. PMID 20482683.

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