Systemic lupus erythematosus pathophysiology: Difference between revisions

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==Overview==
==Overview==
The pathophysiology of systemic lupus erythematosus involves the [[immune system]]. There are other factors like [[genetic]] factors, [[hormonal]] abnormalities, and environmental factors that play some roles as well. The most prominent events involving immune abnormalities are related to persistent activation of [[B cells]] and [[Plasma cell|plasma cells]] that make [[Autoantibody|auto-antibodies]] during disease progression. The most prominent events involving hormonal abnormalities are due to [[prolactin]] and [[estrogen]]. The most important environmental factors related to disease progression are [[ultraviolet]] (UV) light and some infections. On microscopic [[histopathological]] analysis, [[apoptotic]] [[Keratinocyte|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.
The pathophysiology of systemic lupus erythematosus involves the [[immune system]]. There are other factors like [[genetic]] factors, [[hormonal]] abnormalities, and environmental factors that play some roles as well. The most prominent events involving [[immune]] abnormalities are related to persistent activation of [[B cells]] and [[Plasma cell|plasma cells]] that make [[Autoantibody|auto-antibodies]] during disease progression. The most prominent events involving [[hormonal]] abnormalities are due to [[prolactin]] and [[estrogen]]. The most important environmental factors related to disease progression are [[ultraviolet]] (UV) light and some [[infections]]. On microscopic [[histopathological]] analysis, [[apoptotic]] [[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 SLE nephritis.


==Pathogenesis==
==Pathogenesis==
The progression of systemic lupus erythematosus (SLE) involves the immune system. Nearly all of the pathological manifestation of SLE are 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 will deposit in different body tissues and vessels, which may lead to [[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]] manifestation of SLE are 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 will deposit in different body tissues and [[vessels]], which may lead to [[complement]] activation and more organ damage. There are other factors like [[genetic]] factors, hormonal abnormalities, and environmental factors that play some roles as well.


=== Immune abnormalities ===
=== Immune abnormalities ===
Development of systemic lupus erythematosus (SLE) is the due to activation of different mechanisms that may result in [[auto-immune|auto-immunity]]. As a result, body tissues lose their self-tolerance. Affected patients are no longer entirely tolerant to all of their [[Antigens|self-antigens]], consequently progress to an [[Autoimmunity|autoimmune]] disease and develop auto [[antibodies]] as a response. During disease progression, [[B cell|B cells]] and [[Plasma cell|plasma cells]] that make auto-antibodies are more persistently activated and thus make more auto antibodies. These auto antibodies are targeted predominantly to [[intracellular]] [[nucleoprotein]] particles.<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>
Development of systemic lupus erythematosus (SLE) is the due to activation of different mechanisms that may result in [[auto-immune|auto-immunity]]. As a result, body tissues lose their self-tolerance. Affected patients are no longer entirely tolerant to all of their [[Antigens|self-antigens]], consequently progress to an [[Autoimmunity|autoimmune]] disease and develop auto [[antibodies]] as a response. During disease progression, [[B cell|B cells]] and [[Plasma cell|plasma cells]] that make [[Autoantibody|autoantibodies]] are more persistently activated and thus 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>
<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 auto antibody production and persistence is supposed to be down-regulated by anti-idiotypic [[antibodies]] or regulatory immune cells, but the massive immunologic response in SLE prevents this down-regulation to take place. 
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]] to take place. 


The most important immune abnormalities that are related to SLE development and progression are: 
The most important [[immune]] abnormalities that are related to SLE development and progression are: 
* Increase in circulating [[plasma cells]] and memory B cells that is associated with SLE activity.
* Increase in circulating [[plasma cells]] and [[Memory B cell|memory B cells]] that is associated with SLE activity
* Decrease in [[cytotoxic T cells]], decrease in [[suppressor T cells|suppressor T cell]]'s function, and impaired generation of polyclonal T-cell cytolytic activity.
* Decrease in [[cytotoxic T cells]], decrease in [[suppressor T cells|suppressor T cell]]'s function, and impaired generation of [[T-cell|polyclonal T-cell]] cytolytic activity
* Increased number and activity of [[T helper cell|helper T cells]].
* Increased number and activity of [[T helper cell|helper T cells]]
* [[Polyclonal antibody|Polyclonal]] activation of [[B cell|B cells]] and abnormal B-cell receptor signaling.
* [[Polyclonal antibody|Polyclonal]] activation of [[B cell|B cells]] and abnormal [[B-cell receptor]] signaling
* Increase in [[B cell|B cells]] life span
* Increase in [[B cell|B cells]] life span
* Signaling abnormalities of T and B [[Lymphocyte|lymphocytes]], which include:
* Signaling abnormalities of T and B [[Lymphocyte|lymphocytes]], which include:
** Cellular hyperactivity
** Cellular hyperactivity
** Hyper responsiveness
** Hyper responsiveness
* Increased expression of [[interferon alpha]] (IFN-α) inducible [[RNA]] transcripts by [[Mononuclear cells|mononuclear]] cells leads to elevated levels of IFN-α.<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> Increased availability of stimulatory [[nucleic acids]] would implicate [[Interferon type I|IFN-I]] production and activation of IFIGs as an underlying and chronic/recurrent mechanism which generates an immune system that is “primed” to respond to additional triggers with further immune activation and inflammation.
* Increased expression of [[interferon alpha]] (IFN-α) inducible [[RNA]] transcripts by [[Mononuclear cells|mononuclear]] cells leads to elevated levels of [[IFN-α]].<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> Increased availability of stimulatory [[nucleic acids]] would implicate [[Interferon type I|IFN-I]] production, that is responsible for [[chronic]] and recurrent characteristics of the SLE.  
* Increased expression of specific genetic factors that may be associated with promoting autoimmunity.
* Increased expression of specific [[Genetic|genetic factors]] that may be associated with promoting [[autoimmunity]]
* Dysfunctional signaling in T and [[B cell|B cells]] that may be due to:
* Dysfunctional signaling in [[T-Cells|T]] and [[B cell|B cells]] that may be due to:
** Increased [[calcium]] responses to [[antigen]] stimulation
** Increased [[calcium]] responses to [[antigen]] stimulation
** [[Hyperphosphorylation]] of [[cytosolic]] protein substrates
** [[Hyperphosphorylation]] of [[cytosolic]] [[protein]] substrates
** Decreased nuclear factor kB
** Decreased nuclear factor kB
** Abnormal voltage-gated [[potassium]] channels, these channels facilitate excessive calcium entry into [[T cells]]
** Abnormal [[Potassium channels|voltage-gated potassium channels]], these channels facilitate excessive [[calcium]] entry into [[T cells]]
* Increased level of microparticles (MPs):
* Increased level of microparticles (MPs):
** Microparticles are small, membrane-bound vesicles enclose [[DNA]], [[RNA]], [[nuclear]] proteins, cell-adhesion molecules, [[Growth factor|growth factors]], and [[Cytokine|cytokines]].
** Microparticles are small, membrane-bound vesicles enclose [[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
** They are shed from cells during [[apoptosis]] or activation
** Microparticles can drive inflammation and [[autoimmunity]] by their derivatives.<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>
** Microparticles can drive [[inflammation]] and [[autoimmunity]] by their derivatives<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>
* Elevated levels of circulating [[TNF-alpha]] correlate with active disease, and [[TNF]] is expressed in renal tissue in [[lupus nephritis]].
* Elevated levels of circulating [[TNF-alpha]] correlate with active disease, and [[TNF]] is expressed in [[Kidney|renal tissue]] in [[lupus nephritis]]
* Abnormally high levels of C4d on erythrocytes (E-C4d) and low levels of erythrocyte complement receptor type one (E-CR1) are characteristic of SLE, and combined measurement of the 2 molecules has high diagnostic sensitivity and specificity for lupus.
* Abnormally high levels of [[CD4]] on [[erythrocytes]] (E-CD4) and low levels of erythrocyte complement receptor type one (E-CR1) are characteristic of SLE, and combined measurement of the 2 molecules has high diagnostic sensitivity and specificity for lupus
* Increased number of circulating [[neutrophils]] undergoing NETosis (NET=neutrophil extracellular traps), a form of [[apoptosis]] specific for neutrophils, releases DNA bound to protein in protein nets, which stimulates anti-DNA and IFN-alpha production
* Increased 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>
* 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.
** [[thrombus]] formation
** Increased disease activity and renal disease and thus can be used even as a disease activity marker.
** 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.
** [[endothelial cells|Endothelial cell]] damage and [[inflammation]] in [[Atherosclerosis|atherosclerotic]] [[plaques]], which may contribute to accelerated [[atherosclerosis]] in systemic lupus erythematosus


* As an example of immune abnormalities and their complications, nervous system involvement in SLE is due to:
* As an example of immune abnormalities and their complications, nervous system involvement in SLE is due to:
**Small to moderate sized vessels vasculopathy with perivascular accumulation of [[mononuclear cells]], without destruction of the blood vessel
**Small to moderate sized [[vessels]] [[Vasculopathies|vasculopathy]] with [[Perivascular cell|perivascular]] accumulation of [[mononuclear cells]], without destruction of the [[blood vessel]]
**[[Antiphospholipid antibodies]]
**[[Antiphospholipid antibodies]]
*These changes promote the production of [[antinuclear antibodies]]
*These changes promote the production of [[antinuclear antibodies]]


=== Hormonal abnormalities ===
=== Hormonal abnormalities ===
The following evidence is suggestive of the hormonal predisposition to SLE:
The following evidence is suggestive of the [[Hormone|hormonal]] predisposition to SLE:
* Sexual predilection for females, shows the relationship of female hormones and the onset of SLE.
* Sexual predilection for females, shows the relationship of female hormones and the onset of SL
* 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>
* 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 therapy|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 disease progression:<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>
Hormones that are related to disease progression:<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>
* [[Prolactin]]:
* [[Prolactin]]:
** Stimulates the immune system and is elevated in SLE.
** Stimulates the [[immune system]] and is elevated in SLE


* Exogenous [[estrogen]] - 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>
* Exogenous [[estrogen]] - 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>
** Stimulates the type 1 [[IFN]] pathway.
** Stimulates the type 1 [[IFN]] pathway
** 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]]).
** 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]])
** 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>
** 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>
** Stimulate expression of [[HLA]] and [[endothelial cell]] adhesion molecules ([[VCAM-1|VCAM]], [[ICAM-1|ICAM]]).
** Stimulate expression of [[HLA]] and [[endothelial cell]] [[Adhesion molecule|adhesion molecules]] ([[VCAM-1|VCAM]], [[ICAM-1|ICAM]])
** Increases [[macrophage]] [[proto-oncogene]] expression.
** Increases [[macrophage]] [[proto-oncogene]] expression
** Enhanced adhesion of peripheral [[mononuclear cells]] to [[endothelium]].
** Enhanced adhesion of peripheral [[mononuclear cells]] to [[endothelium]]


* [[Progesterone]]:
* [[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.
** 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]]
** Down-regulates [[T cell|T-cell]] proliferation and increases the number of [[CD8 cytotoxic lymphocyte|CD8 cells]]
* Both progesterone and high levels of [[estrogen]] promote a [[Th2]] response, which favors [[autoantibody]] production
* Both [[progesterone]] and high levels of [[estrogen]] promote a [[Th2]] response, which favors [[autoantibody]] production


=== Environmental factors ===
=== Environmental factors ===
* Infections can stimulate some antigen specific cells and lead to SLE:
* Infections can stimulate some [[antigen]] specific cells and lead to SLE:
** [[Epstein Barr virus|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.
** [[Epstein Barr virus|Epstein-Barr virus (EBV)]]: May induce anti-DNA [[antibodies]] or even lupus-like symptoms. It is associated with higher risk of SLE and also triggering the active course of disease in children.
** [[Trypanosomiasis]] or [[mycobacterial]] infections may have the same effect as [[EBV]].
** [[Trypanosomiasis]] or [[mycobacterial]] infections may have the same effect as [[EBV]].
** SLE flares may follow bacterial infections as well.
** SLE flares may follow [[bacterial infections]] as well.
* [[Ultraviolet|Ultraviolet (UV)]] light:  
* [[Ultraviolet|Ultraviolet (UV)]] light:  
** Can stimulate [[B-cells]] to produce more [[antibodies]].  
** Can stimulate [[B-cells]] to produce more [[antibodies]].  
** It can also interfere with antigen processing by activation of [[macrophages]] and hence increase the degree of [[autoimmunity]].
** It can also interfere with [[antigen processing]] by activation of [[macrophages]] and hence increase the degree of [[autoimmunity]].


==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 system]] related genes, and other genes related to immunologic system as well.
Systemic lupus erythematosus is transmitted in [[polygenic inheritance]] pattern. [[Genes]] involved in the [[pathogenesis]] of systemic lupus erythematosus include [[HLA]] class [[polymorphism]], [[complement system]] related [[genes]], and other genes related to [[Immune systems|immunologic system]] as well.


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:<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>
* Increase of disease occurrence in identical twins
* Increase of disease occurrence in [[identical twins]]
* Increased disease frequency among first degree relatives
* Increased disease frequency among first degree relatives
* The increased risk of developing the disease in siblings of SLE patients
* The increased risk of developing the disease in siblings of SLE patients
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|-  
|-  
!Non-HLA   
!Non-HLA   
| colspan="1" rowspan="1" |Mannose binding lectin polymorphisms
| colspan="1" rowspan="1" |Mannose binding lectin [[polymorphisms]]
Tumour necrosis factor α
[[TNF-α|Tumour necrosis factor α]]


T cell receptor
[[T cell receptor]]


Interleukin 6
[[Interleukin 6]]


CR1
CR1
Line 122: Line 122:
PARP (poly-ADP ribose polymerase)
PARP (poly-ADP ribose polymerase)


Heat shock protein 70
[[Heat shock protein 70 (Hsp70) internal ribosome entry site (IRES)|Heat shock protein 70]]


Humhr 3005  
Humhr 3005  
Line 132: Line 132:
==Associated Conditions==
==Associated Conditions==
* [[Homozygous]] deficiencies of the components of [[complement]] especially C1q are associated with developing immunologic diseases especially 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>
* [[Homozygous]] deficiencies of the components of [[complement]] especially C1q are associated with developing immunologic diseases especially 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>
* 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.
* Women treated with [[estrogen]]-containing regimens such as oral [[contraceptives]] or [[HRT|postmenopausal hormone replacement therapies]] are more predisposed to SLE.
* Annular or psoriasiform skin lesions are associated with anti-Ro (SS-A) and anti-La (SS-B) antibodies.
* 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.
* 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 of kidney, bilateral [[pallor]], and [[Hypertrophy (medical)|hypertrophy]] of kidneys are characteristic findings of systemic lupus erythematosus.
On gross pathology of [[kidney]], bilateral [[pallor]], and [[Hypertrophy (medical)|hypertrophy]] of [[kidneys]] are characteristic findings of systemic lupus erythematosus.


On gross pathology of brain, [[infarct]] regions and [[hemorrhages]] are characteristic findings of systemic lupus erythematosus.
On gross pathology of [[brain]], [[infarct]] regions and [[hemorrhages]] are characteristic findings of systemic lupus erythematosus.


On gross pathology of cardiac valves, [[cardiomegaly]] and [[valvular]] vegetations are characteristic findings of systemic lupus erythematosus.
On gross pathology of [[Cardiac valve|cardiac valves]], [[cardiomegaly]] and [[valvular]] vegetation are characteristic findings of systemic lupus erythematosus.


On gross pathology of [[pleura]], [[pleuritis]] and [[pleural fibrosis]] are characteristic findings of systemic lupus erythematosus.
On gross pathology of [[pleura]], [[pleuritis]] and [[pleural fibrosis]] are characteristic findings of systemic lupus erythematosus.


== Microscopic Pathology ==
== Microscopic Pathology ==
On microscopic [[histopathological]] analysis, [[apoptotic]] [[keratinocytes]], [[vacuolization]] of the [[basement membrane]], and dermal mucin deposition are characteristic findings of SLE [[dermatitis]], and active or inactive endocapillary or extracapillary segmental [[glomerulonephritis]] are characteristic findings of SLE nephritis.
On microscopic [[histopathological]] analysis, [[apoptotic]] [[keratinocytes]], [[vacuolization]] of the [[basement membrane]], and dermal mucin [[Deposition (chemistry)|deposition]] are characteristic findings of SLE [[dermatitis]], and active or inactive [[Endocapillary proliferative glomerulonephritis|endocapillary]] or extracapillary segmental [[glomerulonephritis]] are characteristic findings of SLE nephritis.


=== Skin involvement histopathology: ===
=== Skin involvement histopathology: ===

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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. There are other factors like genetic factors, hormonal abnormalities, and environmental factors that play some roles as well. The most prominent events involving immune abnormalities are related to persistent activation of B cells and plasma cells that make auto-antibodies during disease progression. The most prominent events involving hormonal abnormalities are due to prolactin and estrogen. The most important environmental factors related to disease progression are ultraviolet (UV) light and some infections. On microscopic histopathological analysis, apoptotic keratinocytes, vacuolization of the basement membrane, and dermal mucin deposition are characteristic findings of SLE dermatitis, and active or inactive endocapillary or extracapillary segmental glomerulonephritis are characteristic findings of SLE nephritis.

Pathogenesis

The progression of systemic lupus erythematosus (SLE) involves the immune system. Nearly all of the pathological manifestation of SLE are 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 will deposit in different body tissues and vessels, which may lead to complement activation and more organ damage. There are other factors like genetic factors, hormonal abnormalities, and environmental factors that play some roles as well.

Immune abnormalities

Development of systemic lupus erythematosus (SLE) is the due to activation of different mechanisms that may result in auto-immunity. As a result, body tissues lose their self-tolerance. Affected patients are no longer entirely tolerant to all of their self-antigens, consequently progress to 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 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 to take place. 

The most important immune abnormalities that are related to SLE development and progression are: 

Hormonal abnormalities

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

Hormones that are related to disease progression:[7]

Environmental factors

Genetics

Systemic lupus erythematosus is transmitted in polygenic inheritance pattern. Genes involved in the pathogenesis of systemic lupus erythematosus include HLA class polymorphism, complement system related genes, and other genes related to immunologic system as well.

The following evidence is also suggestive of the genetic predisposition of SLE:[10]

  • Increase of disease occurrence in identical twins
  • Increased disease frequency among first degree relatives
  • The increased risk of developing the disease in siblings of SLE patients
Gene class Gene subtype
HLA DR2, DR3, DR4, DR7, DR8, DRw12, DQw2, DQA1,

DQB1, DQ6, DQw6, DQ7, DQw7, DQw8, DQw9, B61, B8

Non-HLA Mannose binding lectin polymorphisms

Tumour necrosis factor α

T cell receptor

Interleukin 6

CR1

Immunoglobulin Gm and Km

FcγRIIA (IgG Fc receptor)

FcγRIIIA (IgG Fc receptor)

PARP (poly-ADP ribose polymerase)

Heat shock protein 70

Humhr 3005

Complement System C2, C4, C1q

Associated Conditions

Gross Pathology

On gross pathology of kidney, bilateral pallor, and hypertrophy of kidneys are characteristic findings of systemic lupus erythematosus.

On gross pathology of brain, infarct regions and hemorrhages are characteristic findings of systemic lupus erythematosus.

On gross pathology of cardiac valves, cardiomegaly and valvular vegetation are characteristic findings of systemic lupus erythematosus.

On gross pathology of pleura, pleuritis and pleural fibrosis are characteristic findings of systemic lupus erythematosus.

Microscopic Pathology

On microscopic histopathological analysis, apoptotic keratinocytes, vacuolization of the basement membrane, and dermal mucin deposition are characteristic findings of SLE dermatitis, and active or inactive endocapillary or extracapillary segmental glomerulonephritis are characteristic findings of SLE nephritis.

Skin involvement histopathology:

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

SLE dermatitis subtype Specific microscopic findings
Acute cutaneous lupus erythematosus
Subacute cutaneous lupus erythematosus
  • Less follicular plugging and hyperkeratosis in comparison with dischoid lupus erythematosus
  • Superficial appendageal and perivascular lymphocytic infiltration
  • Absence or minimal change of basement membrane thickening
Chronic cutaneous lupus erythematosus

Glomerulonephritis histopathology:

Class SLE nephritis subtype Light microscopy findings Electron microscopy/Immunofluorescence findings
I Minimal mesangial lupus nephritis -
  • Mesangial immune deposits
II Mesangial proliferative lupus nephritis
  • Mesangial hyper cellularity (of any degree)
  • Mesangial matrix expansion
  • Isolated subepithelial or subendothelial deposits
III Focal lupus nephritis
  • Active or inactive endocapillary or extracapillary segmental glomerulonephritis
  • Involvement of glomeruli < 50%
IV Diffuse lupus nephritis
  • Subendothelial deposits specially during the active phase
  • Diffuse wire loop deposits with little or no glomerular proliferation
V Lupus membranous nephropathy
  • Diffuse thickening of the glomerular capillary wall
  • Immunofluorescence or electron microscopy
  • Global or segmental subepithelial immune deposits
VI Advanced sclerosing lupus nephritis
  • Global sclerosis
  • Involvement of glomeruli > 90%

Synovial involvement histopathology

Mucosal involvement histopathology

  • Hyperkeratosis
  • Atrophy of rete processes
  • Superficial and deep inflammatory infiltrates
  • Edema in the lamina propria
  • Continuous or patchy periodic acid-Schiff (PAS)-positive deposits in the basement membrane zone
  • Deposition of intercellular mucin
  • Deposits of immunoglobulin and complement at the dermal-epidermal junction


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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. ↑ 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.
  4. ↑ 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.
  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. ↑ 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.
  12. ↑ 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.
  13. ↑ 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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