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. 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. 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:
  • 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

B-Cell related

• 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

T-Cell related

• 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:
  • 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.

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.

The current paradigm is that LN results from immune complex deposition in the renal glomeruli leading to complement activation, chronic inflammation and renal insufficiency defined by histopathology and the presence of proteinuria and cellular casts.

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:

• 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

Classification	Gene subtype	Function	Pathological effect
HLA	HLA class2 12867584	contain genes encoding glycoproteins that process and present peptides for recognition by T cells (Antigen presentig cells)	HLA-DR2 and HLA-DR3 confer an overall 2-to-3-fold increased risk for SLE More in European and Asian HLA-DQ and –DR alleles show strong associations with SLE autoantibodies
	HLA class3 11079100	the class III region containing other important immune genes The complement system, through opsonization, facilitates the clearance of apoptotic debris and cellular fragments that might contain nuclear antigens, which are targets for SLE-associated autoantibodies C4A and C4B code for complement C4-A and complement C4-B proteins, respectively, which have different functional characteristics; complement C4-A has a higher affinity for immune complexes (ICs) circulating complement C4 proteins function in the clearance of ICs.	Individuals that are homozygous deficient in C1q (very rare disease) develop a severe and early onset form of SLE with severe glomerulonephritis and skin manifestations Complete C2 and C4 deficiencies are rare: mild form of SLE that affects mostly the joints and skin C4A have stronger genetic evidence for an association with SLE than complement C4-B circulating complement C4 proteins deficiency will promote autoimmunity.
Non-HLA	Interferon (IFN) regulatory factor 5 20080916	a pivotal transcription factor in the type I IFN pathway regulates the expression of IFN-dependent genes, inflammatory cytokines and 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 pro-inflammatory cytokines such as TNFα, IL-12 and IL-6 specific combinations of several polymorphisms in the IRF5 region interact to increase disease risk
	STAT4  18579578 19109131 18516230 18803832	encodes the signal transducer and activator of transcription 4 protein (STAT4) and has been found to associate with SLE	associated with a more- severe SLE phenotype that is characterized by disease-onset at a young age (<30 years), a high frequency of nephritis, the presence of antibodies towards double-stranded DNA, and an increased sensitivity to IFN-α signaling in peripheral blood mononuclear cells
	PTPN22 19302045	encodes tyrosine-protein phosphatase non- receptor type 22 (PTPN22), a lymphoid-specific phosphatase that inhibits T-cell activation	risk of developing multiple auto-immune diseases including SLE In European-derived populations increases the intrinsic lymphoid-specific phosphatase activity which reduces the threshold for T-cell receptor (TCR) signaling and promotes autoimmunity
	FcγR genes 10413210	recognize immune complexes and are involved in antibody-dependent responses	mutation associated with low affinity for IgG2-opsonized particles and reduced clearance of ICs
	C1q genes	through opsonization, facilitates the clearance of apoptotic debris and cellular fragments that might contain nuclear antigens, which are targets for SLE-associated autoantibodies.	Individuals that are homozygous deficient in C1q (very rare disease) develop a severe and early onset form of SLE with severe glomerulonephritis and skin manifestations 11079100 Complete C2 and C4 deficiencies are rare: mild form of SLE that affects mostly the joints and skin C4A and C4B code for complement C4-A and complement C4-B proteins, respectively, which have different functional characteristics; complement C4-A has a higher affinity for immune complexes (ICs) and stronger genetic evidence for an association with SLE than complement C4-B. circulating complement C4 proteins function in the clearance of ICs. Their deficiency will promote autoimmunity.
	The IRAK1-MECP2 region	IL-1 receptor-associated kinase 1 is a serine–threonine protein kinase, regulates multiple pathways in both innate and adaptive immune responses by linking several immune-receptor-complexes to TNF receptor-associated factor 6. a critical role in the transcriptional suppression of methylation-sensitive genes.
	TREX1	encodes 3′ repair exonuclease 1, a major 3′–5′ DNA exonuclease. This enzyme proofreads DNA polymerase and potentially also functions as a DNA-degrading enzyme in granzyme-A-mediated apoptosis and as a cytosolic DNA sensor	impairs DNA damage repair, leading to the accumulation of endogenous retroelement-derived DNA. Defective clearance of this DNA induces IFN production and an immune-mediated inflammatory response, promoting systemic autoimmunity.
	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+type 1 regulatory T cells, but induces B-cell activation and differentiation, as well as IL-17 production predispose to SLE either by augmenting the interaction between T cells and antigen-presenting cells, or by influencing the functional consequences of T-cell activation
	IL-10	encodes IL-10 an important regulatory cytokine with both immunosuppressive and immunostimulatory properties	Increased IL-10 production by peripheral blood B cells and monocytes from patients with SLE is known to correlate with disease activity,98 demon strating that IL-10 has an important role in the pathogenesis of SLE.
Regulators of IFNα	TNFAIP3 and TNIP1	key regulators of the NFκB signaling pathway (Figure 1b), and modulate cell activation, cytokine signaling and apoptosis.
	PHRF1	encodes an elongation factor	SLE-associated autoantibodies with elevated IFN-α activity
Regulators of Lymphocytes	BLK 19180478	encodes tyrosine-protein kinase Blk, a member of the Src family of kinases, which mediates intra-cellular signaling and influences the proliferation, differentiation and tolerance of B cells	in Chinese and Japanese populations
	BANK1	a B-cell adaptor protein, regulates direct coupling between the Src family of tyrosine kinases and the calcium channel IP3R, and facilitates the release of intracellular calcium, altering the B-cell activation threshold	sustained activation of B-cell receptors and the subsequent B-cell hyperactivity that is commonly observed in SLE
	LYN	mediates B-cell activation by phosphorylating the immunoreceptor tyrosine-based activation motif of the B-cell-receptor-associated Igα/β signaling molecules, or mediates B-cell inhibition by phosphorylating inhibitory receptors such as CD22
	ETS1	negatively regulates the differentiation of B cells and type 17 T-helper cells.  regulates these cells by inhibiting the function of an important transcription factor in plasma cells
	IKZF1	lymphoid-restricted zinc finger transcription factor that regulates lymphocyte differentiation and proliferation, as well as 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	This integrin adhesion molecule binds the complement cleavage fragment of C3b, and also a myriad of other ligands that are potentially relevant to SLE	contributed to SLE susceptibility

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

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References