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. 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:
Signaling abnormalities
- Protein kinases are responsible for intracellular cytokine signal. Intracellular signaling is leading to various types of cell response, such as:
- Cell migration
- Cell proliferation
- Inflammatory response
- Cell signaling abnormalities will lead to:
- T and B lymphocytes cellular hyperactivity
- T and B lymphocytes hyper responsiveness
- Persistence of autoreactive T cells that would otherwise have been deleted
- Signaling abnormalities of T and B lymphocytes, 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
General
- Increased expression of specific genetic factors that may be associated with promoting autoimmunity
- Increased expression of interferon alpha (IFN-α) inducible RNA transcripts by mononuclear cells leads to elevated levels of IFN-α.[3] Increased availability of stimulatory nucleic acids would implicate IFN-I production, that is responsible for chronic and recurrent characteristics of the SLE.
- Elevated levels of circulating TNF-alpha correlate with active disease, and TNF is expressed in renal tissue in lupus nephritis
- 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
Neutrophil
- 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 neutrophil extracellular trap leads to: [4]
- thrombus formation
- Increased disease activity and renal disease and thus can be used even as a disease activity marker
- Endothelial cell damage and inflammation in atherosclerotic plaques, which may contribute to accelerated atherosclerosis in systemic lupus erythematosus
Microparticles
- Increased level 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[5]
- Increase in circulating plasma cells and memory B cells that is associated with SLE activity
- Polyclonal activation of B cells and abnormal B-cell receptor signaling
- Increase in B cells life span
- Decrease in cytotoxic T cells, decrease in suppressor T cell's function, and impaired generation of polyclonal T-cell cytolytic activity
- Increased number and activity of helper T cells
- 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
- Antiphospholipid antibodies
- These changes promote the production of antinuclear antibodies
Hormonal abnormalities
The following evidence is suggestive of the hormonal predisposition to SLE:
- Sexual predilection for females, shows the relationship of female hormones and the onset of SL
- Significantly increased risk for SLE in:[6]
- Early age of menarche
- Early age at menopause or surgical menopause
- Women that are treated with estrogen-containing regimens such as oral contraceptives or postmenopausal hormone replacement therapies
Hormones that are related to disease progression:[7]
- Prolactin:
- Stimulates the immune system and is elevated in SLE
- Exogenous estrogen - including oral contraceptive use and postmenopausal hormone replacement therapy: [7][8]
- Stimulates the type 1 IFN pathway
- Stimulates thymocytes, CD8+ and CD4+ T cells, B cells, macrophages, and causes the release of certain cytokines (eg, IL-1)
- Prompt maturation of B cells, especially those that have a high affinity to anti-DNA antibodies by decreasing the apoptosis of self-reactive B-cells[9]
- 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
- Down-regulates T-cell proliferation and increases the number of CD8 cells
- Both progesterone and high levels of estrogen promote a Th2 response, which favors autoantibody production
Environmental factors
- Infections can stimulate some antigen specific cells and lead to SLE:
- Epstein-Barr virus (EBV): May induce anti-DNA antibodies or even lupus-like symptoms. It is associated with higher risk of SLE and also triggering the active course of disease in children.
- Trypanosomiasis or mycobacterial infections may have the same effect as EBV.
- SLE flares may follow bacterial infections as well.
- Ultraviolet (UV) light:
- 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.
Lupus nephritis
In the initial phase of the disease, the immune deposits and/or autoantibodies induce cytokine production in renal resident cells, leading to further inflammatory cytokine/chemokine expression and leukocyte infiltration and activation. Then, infiltrate leukocytes, such as macrophages (Mφ) and dendritic cells (DCs), secrete a variety of cytokines and activate naïve T cells, leading the cytokine profile towards T helper (Th)1, Th2, and/or Th17.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 |
HLA-DR2 and HLA-DR3 confer an overall 2-to-3-fold increased risk for SLE
HLA-DQ and –DR alleles show strong associations with SLE autoantibodies |
| Non-HLA | Mannose binding lectin polymorphisms
CR1 Immunoglobulin Gm and Km FcγRIIA (IgG Fc receptor) FcγRIIIA (IgG Fc receptor) PARP (poly-ADP ribose polymerase) Humhr 3005 |
|
| Complement System | C2, C4, C1q |
Associated Conditions
- Homozygous deficiencies of the components of complement especially C1q are associated with developing immunologic diseases especially SLE or a lupus-like disease.[11]
- 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. [12]
- Women treated with estrogen-containing regimens such as oral contraceptives or 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.
- Anti-Ro, anti-La, anti sm, and anti RNP antibodies have been associated with mucocutaneous involvement and less severe nephropathy.
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:
- Hyperkeratosis
- Epidermal atrophy
- Dermal mucin deposition
- Liquefactive degeneration of the basal layer of the epidermis and vacuolization
- Thickening of the basement membrane
- Pigment incontinence
- Mononuclear cell infiltration at dermo-epidermal junction
- Superficial, perivascular, and perifollicular areas (due to mononuclear cell inflammatory infiltrate)
| SLE dermatitis subtype | Specific microscopic findings |
|---|---|
| Acute cutaneous lupus erythematosus |
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| Subacute cutaneous lupus erythematosus |
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| Chronic cutaneous lupus erythematosus |
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Glomerulonephritis histopathology:
| Class | SLE nephritis subtype | Light microscopy findings | Electron microscopy/Immunofluorescence findings |
|---|---|---|---|
| I | Minimal mesangial lupus nephritis | - |
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| II | Mesangial proliferative lupus nephritis |
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| III | Focal lupus nephritis |
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| IV | Diffuse lupus nephritis |
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| V | Lupus membranous nephropathy |
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| VI | Advanced sclerosing lupus nephritis |
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Synovial involvement histopathology
- Nonspecific histopathologic findings
- Superficial fibrin-like material
- Local or diffuse synovial cell lining proliferation
- Vascular changes:
- Perivascular mononuclear cells
- Lumen obliteration
- Enlarged endothelial cells
- Thrombi
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
- Deposition of immunoglobulin and complement at the dermal-epidermal junction
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References
- ↑ Elkon K (1995). "Autoantibodies in systemic lupus erythematosus". Curr Opin Rheumatol. 7 (5): 384–8. PMID 8519610.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 7.0 7.1 Lahita RG (1999). "The role of sex hormones in systemic lupus erythematosus". Curr Opin Rheumatol. 11 (5): 352–6. PMID 10503654.
- ↑ 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.
- ↑ 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.
- ↑ Sullivan KE (2000). "Genetics of systemic lupus erythematosus. Clinical implications". Rheum. Dis. Clin. North Am. 26 (2): 229–56, v–vi. PMID 10768211.
- ↑ 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.
- ↑ 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.
- ↑ 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.