Systemic lupus erythematosus pathophysiology

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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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