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 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 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, as by their effect, disinhibited cellular apoptosis chain may start. This apoptosis step is the first step in the lupus pathogenesis.

• 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 (EBV)
    • Trypanosomiasis
    • Mycobacterial infections
    • SLE flares may follow bacterial infections
• 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

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. 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):

• Microparticles are small, membrane-bound vesicles enclosing 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

Pro-inflammatory cytokines

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

• Increased expression of interferon alpha (IFN-α) inducible RNA transcripts by mononuclear cells 
• Increased 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 renal tissue in lupus nephritis) correlate with active disease

Signaling abnormalities

Protein kinases are responsible for intracellular cytokine signals. 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

B-Cell role

• Increase in circulating plasma cells and memory B cells that are associated with SLE activity
• Polyclonal activation of B cells and abnormal B-cell receptor signaling
• Increase in B cells' life span

T-Cell role

• Decrease in cytotoxic T cells, decrease in suppressor T cell 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 vessel vasculopathy with perivascular accumulation of mononuclear cells, without destruction of the blood vessel
  • Antiphospholipid antibodies
• These changes promote the production of antinuclear antibodies

Neutrophil role

• 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

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 include:

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

Genetics

Systemic lupus erythematosus is transmitted in polygenic inheritance pattern. Genes involved in the pathogenesis of systemic lupus erythematosus include HLA class 2 especially DR2 nd DR3, HLA class 3 especially complement genes include C2 and C4 genes, IFNRF5 gene, and other genes related to immunologic system. The following evidence is also suggestive of the genetic predisposition of SLE:

• 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	Contains genes encoding glycoproteins that process and present peptides for recognition by T cells (antigen presenting cells) The most important related genes: HLA-DR2 HLA-DR3	Associated with an overall 2 to 3 fold increase in the risk of SLE More in European and Asian people HLA-DQ and HLA-DR alleles: Strong association with SLE autoantibodies
Immune complex dependent response	HLA class 3	Contains important immune genes including: C2 gene C4 gene Encode complement proteins The complement system acts through opsonization: Facilitates the clearance of 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 complexes	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	The complement system acts through opsonization: Facilitates the clearance of 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
Innate response	Interferon (IFN) regulatory factor 5	Codes a transcription factor in the type 1 interferon pathway Regulates: Expression of IFN-dependent genes Inflammatory cytokines Genes involved in apoptosis	The most strongly and consistently SLE-associated loci outside the MHC region Upon activation, IRF5 activates transcription of type I IFN and proinflammatory cytokines such as TNFα, IL-12 and IL-6 Specific combinations of several polymorphisms in the IRF5 region interact to increase disease risk
	STAT4	Encodes the signal transducer and activator of transcription 4 protein	Associated with a more severe SLE phenotype: Disease-onset at a young age (<30 years) High frequency of nephritis Associated with the presence of antibodies towards double-stranded DNA Mutation lead to an increased sensitivity to IFN-α signaling in peripheral blood mononuclear cells
	The IRAK1-MECP2 region	Encodes a protein kinase: Regulates multiple pathways in both innate and adaptive immune responses by linking several immune-receptor-complexes to TNF receptor-associated factor 6 Critical role in the transcriptional suppression of methylation-sensitive genes	The exact pathogenetics is not completely known
	FcγR genes	Encode proteins that: Recognize immune complexes Are involved in antibody-dependent responses	Mutation associated with: Low affinity for IgG2-opsonized particles Reduced clearance of immune complexes
Cell apoptosis regulators	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 production An immune-mediated inflammatory response Systemic autoimmunity
	IL-10	Encodes IL-10 An important regulatory cytokine with both immunosuppressive and immunostimulatory properties	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	The exact pathogenetics is not completely known
	PHRF1	Encodes an elongation factor	Related to SLE-associated autoantibodies and elevated IFN-α activity
Regulators of Lymphocytes	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 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 activation
	BLK	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
	PTPN22	Encodes a lymphoid-specific phosphatase that inhibits T-cell activation	Associated with a higher risk of developing multiple autoimmune diseases More seen in European populations Mutation increases the intrinsic lymphoid-specific phosphatase activity that lead to: Reduction of T-cell receptor (TCR) signaling threshold Promotion of autoimmunity
	BANK1	Encodes a B-cell adaptor protein Facilitates the release of intracellular calcium Alters the B-cell activation threshold	Mutations lead to hyperctivation of B-cell receptors and the subsequent B-cell hyperactivity that is commonly observed in SLE
	LYN	Mediates B-cell activation Mediates B-cell inhibition
	ETS1	Negatively regulates the differentiation of B cells and type 17 T-helper cells Regulates lymphocytes by inhibiting the function of an important transcription factor in plasma cells	The exact pathogenetics is not completely known
	IKZF1	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
Genes involved in immune complex clearance	ITGAM	Encodes a protein that binds the complement cleavage fragment of C3b	Contributes to SLE susceptibility

Associated Conditions

• Homozygous deficiencies of the components of complement, especially C1q, are associated with developing immunologic diseases, particularly 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 the most important characteristic findings are:

• Kidney: Bilateral pallor and hypertrophy
• Brain: Infarct regions and hemorrhages
• Heart: Cardiomegaly and valvular vegetation
• Lung: Peural fibrosis and pleural effusion

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:

• 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	Preview
Acute cutaneous lupus erythematosus	Lymphohistiocytic infiltrate in the superficial dermis	Adapted from Librepathology
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: Consists 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	Light microscopy previews	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	Adapted from Librepathology	Isolated subepithelial or subendothelial deposits
III	Focal lupus nephritis	Active or inactive endocapillary or extracapillary segmental glomerulonephritis Involvement of glomeruli < 50%	Adapted from Librepathology	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%	Adapted from Librepathology	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%	Adapted from Librepathology	Global or segmental subepithelial immune deposits

Synovial 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 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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