Systemic lupus erythematosus pathophysiology

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

Overview

The 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 auto-antibodies are more persistently activated and thus make more auto antibodies. These auto antibodies are targeted predominantly to intracellular nucleoprotein particles.

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. 

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.
• 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.
• Polyclonal activation of B cells and abnormal B-cell receptor signaling.
• Increase in B cells life span
• Signaling abnormalities of T and B lymphocytes, which include:
  • Cellular hyperactivity
  • Hyper responsiveness
• Increased expression of interferon alpha (IFN-α) inducible RNA transcripts by mononuclear cells leads to elevated levels of IFN-α. Increased availability of stimulatory nucleic acids would implicate 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 specific genetic factors that may be associated with promoting autoimmunity.
• 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 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.
• Elevated levels of circulating TNF-alpha correlate with active disease, and TNF is expressed in 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.
• 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:
  • 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.

• 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 SLE.
• Significantly increased risk for SLE in:
  • 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:

• Prolactin:
  • Stimulates the immune system and is elevated in SLE.

• Exogenous estrogen - including oral contraceptive use and postmenopausal hormone replacement therapy:
  • 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.
  • 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.

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.

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

• 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

• Homozygous deficiencies of the components of complement especially C1q are associated with developing immunologic diseases especially SLE or a lupus-like disease.
• 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.
• 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 vegetations 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	Lymphohistiocytic infiltrate in the superficial dermis
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	Discoid lupus erythematosus : Follicular plugging Mononuclear cell infiltration near the dermal-epidermal junction, dermal blood vessels, and appendages Lupus erythematosus tumidus: Consisting of predominately CD3+/CD4+ lymphocytes Focal interface changes Lupus profundus (lupus panniculitis) : Perivascular infiltrates of mononuclear cells plus panniculitis Hyaline fat necrosis Direct immunofluorescence: Immune deposits in the dermal-epidermal junction

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%	Immune deposits in the subendothelial space of the glomerular capillary and mesangium Fibrinoid necrosis and crescents in glomeruli Tubulointerstitial or vascular abnormalities
IV	Diffuse lupus nephritis	Endocapillary glomerulonephritis Extracapillary glomerulonephritis Mesangial abnormalities Involvement of glomeruli > 50%	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%	Global or segmental subepithelial immune deposits

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
• Deposits of immunoglobulin and complement at the dermal-epidermal junction

Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

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