Etiopathogenesis of systemic lupus erythematosus

doi:10.1016/S0167-5699(00)01675-3

Immunology Today

Volume 21, Issue 9, 1 September 2000, Pages 424-426

Immunology Today

https://doi.org/10.1016/S0167-5699(00)01675-3 Get rights and content

Abstract

Martin Herrmann and colleagues briefly discuss how autoimmunity might be initiated and maintained in the systemic autoimmune disease systemic lupus erythematosus.

Section snippets

Genetic defects

Deficiency of the complement component C1q is associated with recurrent infections and a high prevalence of SLE; indeed, C1q deficiency represents the genetic defect with the highest risk for SLE (Ref. 1). Mice with a targeted deletion of C1qa show glomerulonephritis with immune deposits and apoptotic cells in the glomeruli, suggesting that the autoimmune disorder is associated with impaired clearance of apoptotic cells². Furthermore, mice with a targeted deletion of Serum amyloid P component

Characteristics of monoclonal human anti-dsDNA autoantibodies

The low-affinity anti-DNA antibodies that occur normally in healthy individuals are usually of immunoglobulin (Ig)M isotype, encoded by unmutated germline sequences, and display a wide crossreactivity. By contrast, the SLE-specific high-affinity anti-double-stranded DNA antibodies (anti-dsDNA) have frequently been shown to be of IgG isotype and carry somatic mutations with a frequent bias towards arginine and asparagine in their antigen-binding sites6, 7. Therefore, the IgG anti-dsDNA in SLE

T-cell involvement

Affinity maturation, isotype switching and memory formation are T-cell-dependent processes that take place in germinal centres of secondary lymphoid organs. The isolation of autoreactive T cells from SLE patients recognizing DNA-binding proteins8, 9 led to the hypothesis that DNA–protein complexes¹⁰ may serve as a source for autoantigens¹¹. In the case of the anti-nucleosome response, B-cell-specific epitopes are located on the DNA, whereas histones may provide T-cell epitopes. Consequently,

Phagocytosis of apoptotic and necrotic cells

Under normal circumstances, apoptotic cells are efficiently engulfed by macrophages in the early phase of apoptotic cell death without inducing either inflammation or an immune response12, 13, 14. Recent reports have suggested an impaired clearance of dying cells as a major event in the etiopathogenesis of SLE (2, 15). When macrophages from a subgroup of SLE patients were differentiated in vitro, they displayed markedly impaired phagocytosis of apoptotic cells, leading to the accumulation of

Concluding remarks

On the basis of recent research, the following mechanisms can be proposed for the etiopathogenesis of (at least a subset of) SLE (Fig. 1). First, impaired clearance of dying cells results in the accumulation of cellular debris. DCs, rather than macrophages, now acquire autoantigens from these dying, late-apoptotic cells. These modified autoantigens activate autoreactive T cells, which provide help for B cells recognizing nuclear autoantigens and result in the B-cell secretion of autoantibodies.

References (25)

F. Petry
Molecular basis of hereditary C1q deficiency
Immunobiology
(1998)
G. Melino et al.
‘Tissue’ transglutaminase in cell death: a downstream or a multifunctional upstream effector?
FEBS Lett.
(1998)
K.D. Moudgil
Modulation of the immunogenicity of antigenic determinants by their flanking residues
Immunol. Today
(1998)
M. Botto
Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies
Nat. Genet.
(1998)
M.C. Bickerstaff
Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity
Nat. Med.
(1999)
K. Manger
Fcγ receptor IIa polymorphism in Caucasian patients with systemic lupus erythematosusassociation with clinical symptoms
Arthritis Rheum.
(1998)
R. Clynes
Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis
Science
(1998)
J.H. van Es
Somatic mutations in the variable regions of a human IgG anti-double-stranded DNA autoantibody suggest a role for antigen in the induction of systemic lupus erythematosus
J. Exp. Med.
(1991)
T.H. Winkler
Analysis of immunoglobulin variable region genes from human IgG anti-DNA hybridomas
Eur. J. Immunol.
(1992)
A. Desai-Mehta
Structure and specificity of T cell receptors expressed by potentially pathogenic anti-DNA autoantibody-inducing T cells in human lupus
J. Clin. Invest.
(1995)

R.E. Voll

Histone-specific Th0 and Th1 clones derived from systemic lupus erythematosus patients induce double-stranded DNA antibody production

Arthritis Rheum.

(1997)

K. Andreassen

T cell lines specific for polyomavirus T-antigen recognize T-antigen complexed with nucleosomesa molecular basis for anti-DNA antibody production

Eur. J. Immunol.

(1999)

Cited by (123)

Cytokines and autoantibodies profile during systemic lupus erythematosus and psoriasis diseases in Egypt
2022, Journal of King Saud University - Science
Citation Excerpt :
Furthermore, blood abnormalities in SLE patients include lymphopenia, leucopenia, thrombocytopenia and complement deficiency (C1q, C2, and C4) (Patrikiou et al., 2020). Autoantibodies and immune complex deposition are the main causes of SLE; where the development of excessive levels of autoantibodies is caused by the increased apoptosis along with the poor clearance of apoptotic cells (Herrmann et al., 2000). The immune dysfunction is exacerbated by dysregulated cytokine production, which also plays a role in tissue inflammation and organ damage (Budagyan et al., 1998).
Cytokine, a small secreted protein, is secreted from one cell types to exert a particular effect on other cell types and/or on itself. Cytokines are characterized by their redundancy in the function; they are secreted in a cascade and can work synergistically and/or antagonistically. Cytokines have an important role in the pathogenesis of autoimmune diseases like systemic lupus erythematosus (SLE) and psoriasis (PS). Due to their crucial roles in the immune cells’ development, differentiation and regulation; any dysregulation in their production and/or action can lead to the development of autoimmune diseases. The study population was composed of healthy control volunteers, SLE patients that were diagnosed as lupus nephritis (LN) patients or non-LN patients with developed atherosclerosis (As), and psoriasis patients that were diagnosed as psoriasis patients without arthritis (Ps) or psoriatic arthritis patients (PsA).
The current study aimed to measure and compare the levels of T helper (h)1, Th2 and Th17 cytokines (IFN-γ, TNF-α, IL-17, -1β, -12, -10, -4, -2, -23, -18, -34 and -6) among Egyptian SLE and Ps patients. In addition, the pathway and type of Th cells involved in autoimmune-mediated tissue injury was examined. Detection of autoantibodies (ANA, anti-dsDNA, anti-sm, anti-histone, anti-ribosomal, APLA and anti-Ro/SSA) was performed to find if there is a relation between disease development and their presence.
Detection of autoantibodies and complement proteins were beneficial in the diagnosis of SLE and psoriasis. ANA and anti-dsDNA autoantibodies were a good marker for the diagnosis of SLE and monitoring disease activity; however, other autoantibodies like APLA, anti-sm, anti-histone and anti-ribosomal can be used to indicate the disease activity.
Cytokines can be used to determine the disease activity and autoimmune-mediated tissue injured in both SLE and psoriasis. Where, IL-17 recorded the highest level in LN and PsA patients; while the highest levels of IL-34, -23 and -6 were recorded in PsA patients and IL-1β was a characteristic cytokine in As patients.
Genes and genetics in human SLE
2020, Systemic Lupus Erythematosus: Basic, Applied and Clinical Aspects
It is generally agreed that disease features of systemic lupus erythematosus (SLE) manifest in genetically predisposed individuals after encountering environmental triggers. Genome wide association studies provide an unbiased approach to screening hundreds of thousands of single nucleotide polymorphisms and have enhanced the discovery of genetic risk loci associated with SLE. Further advancements in the field (large-scale replication studies, meta-analysis, next generation sequencing, fine mapping of disease characteristics, and functional studies) have led a rapid increase in the discovery of SLE risk variants, approaching 150 loci identified. Although functions of a number of identified loci remain unknown, most risk gene products participate in various aspects of the immune system, including the clearance of immune complexes, type I interferon and NFkB pathways, B and T cell signaling, and transcriptional regulation, which are highlighted herein. Updated progress in lupus genetics, the identification of new causal variants, the discovery of novel pathways and regulatory mechanisms, and advances in utilizing SLE-risk loci to predict disease susceptibility and therapeutic strategies are reviewed. Here we emphasize the progress made in the last few years that has greatly enhanced our understanding of SLE pathogenesis, which will serve to guide the development of novel therapies to treat the disease.
ATP signaling and NTPDase in Systemic Lupus Erythematosus (SLE)
2019, Immunobiology
Systemic lupus erythematosus (SLE) is an autoimmune and inflammatory disease with periods of exacerbation and remission. SLE is characterized by the irreversible breakdown of immunological self-tolerance, where there is deregulation of multiple aspects of the immune system. SLE immune dysfunction is characterized by activation of autoreactive T lymphocytes, and hyperactivity of B lymphocytes with consequent production of several autoantibodies. ATP is a purinergic mediator released into the extracellular space in response to cell and tissue damage which operates as a danger signal to modulate immune and inflammatory responses. ATP binds to P2 receptors and its levels are regulated by NTPDase (CD39). SLE patients exhibit increased levels of ATP which binds to P2X receptors resulting in activation of the inflammasome and consequent release of IL-1β and IL-18, cytokines associated with disease pathogenesis. CD39 is upregulated in SLE representing an important immunoregulatory mechanism by controlling inflammation and favoring the production of adenosine. The aim of this review is to clarify the effects of ATP on the modulation of the inflammatory process and immune responses via P2 receptors as well as the role of NTPDase in the immunopathogenesis of SLE.
Genes and Genetics in Human Systemic Lupus Erythematosus
2016, Systemic Lupus Erythematosus: Basic, Applied and Clinical Aspects
The complex etiology of systemic lupus erythematosus (SLE) could be attributed to a combination of genetic predispositions, epigenetic changes, and environmental exposures. The genome-wide association study (GWAS) that screens hundreds of thousands of single nucleotide polymorphisms across the genome based on a hypothesis-free approach has accelerated discovery of genetic variants predisposing individuals to SLE. After the initial GWAS discovery, subsequent large-scale replication studies and meta-analyses have identified and confirmed over 50 SLE-risk loci that most are shared in multiple ancestries. We review recent progress toward identifying causative variants at the SLE-risk loci, highlighting genes with functions in innate and adaptive immune responses that contribute to disease susceptibility and specific manifestations or end organ damage in SLE. These findings have enhanced our understanding of SLE pathogenesis to the molecular level and will guide the development of new therapeutic interventions in the near future.
Dynamic expression of microRNAs in M2b polarized macrophages associated with systemic lupus erythematosus
2014, Gene
Macrophage polarization contributes to the initiation and perpetuation of systemic lupus erythematosus (SLE). Our previous study demonstrated that M2b polarized macrophages induced by activated lymphocyte-derived DNA (ALD-DNA) have a crucial function in the initiation and progress of SLE disease. Accumulated data suggest that microRNAs (miRNAs) serve as critical regulators to control macrophage polarization. To investigate miRNA regulation during macrophage M2b polarization of SLE, miRNA microarrays of murine bone marrow derived macrophages (BMDMs) were performed following stimulation with ALD-DNA for 6 and 36 h. Over 11% of the 1111 analyzed miRNAs appeared differentially expressed during ALD-DNA triggered macrophage M2b polarization. Cluster analysis revealed certain patterns in miRNA expression that are closely linked to ALD-DNA induced macrophage M2b polarization. Analysis of the network structure showed that the predicted functions of the differentially regulated miRNAs at 6 h are significantly associated with inflammatory response and disease. Differentially regulated miRNAs identified at 36 h were determined to be significantly related to cell proliferation by biological network analysis. In this study, dynamic miRNA expression patterns and network analysis are described for the first time during ALD-DNA induced macrophage M2b polarization. The data not only provide a better understanding of miRNA-mediated macrophage polarization but also demonstrate the future therapeutic potential of targeting miRNAs in SLE patients.
Decreased interleukin 35 and CD4+EBI3+ T cells in patients with active systemic lupus erythematosus
2014, American Journal of the Medical Sciences
Interleukin 35 (IL-35) is likely to contribute to the development of autoimmune diseases, as the Epstein-Barr virus- induced gene protein 3 (EBI3) is the specificity subunit of IL-35. Nevertheless, until recently, no studies have evaluated its role in systemic lupus erythematosus (SLE) in humans. The objective of this study was to investigate the serum IL-35 level and the percentage of CD4⁺EBI3⁺ T cells in the peripheral blood of patients with SLE and explore the roles of double-positive T cells and IL-35 in the pathogenesis of SLE and the effects of glucocorticoid on these roles.
Fifty-five hospitalized patients with SLE were recruited, and 20 volunteers were enrolled as healthy controls. Serum IL-35 levels were measured by enzyme-linked immunosorbent assay, and the percentage of CD4⁺EBI3⁺ T cells was analyzed by flow cytometry.
The serum IL-35 level and the percentage of CD4⁺EBI3⁺ T cells were significantly decreased in patients with active SLE compared with healthy controls and patients with inactive SLE. The serum IL-35 level and the percentage of CD4⁺EBI3⁺ T cells were negatively correlated with the SLE disease activity index. The percentages of CD4⁺EBI3⁺ T cells and serum IL-35 levels in 10 untreated patients with active SLE were increased at days l, 3, and 7 after the treatment with methylprednisolone (0.8 mg-kg^− 1-d^− 1) compared with the percentages before the treatment.
These results demonstrate that abnormalities in IL-35 and CD4⁺EBI3⁺ T cells may play important roles in the pathogenesis of SLE; the percentage of double-positive T cells and the level of IL-35 are parameters for the evaluation of SLE activity and severity.

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TrendsEtiopathogenesis of systemic lupus erythematosus

Abstract

Section snippets

Genetic defects

Characteristics of monoclonal human anti-dsDNA autoantibodies

T-cell involvement

Phagocytosis of apoptotic and necrotic cells

Concluding remarks

Immunobiology

FEBS Lett.

Immunol. Today

Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies

Nat. Genet.

Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity

Nat. Med.

Fcγ receptor IIa polymorphism in Caucasian patients with systemic lupus erythematosusassociation with clinical symptoms

Arthritis Rheum.

Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis

Science

Somatic mutations in the variable regions of a human IgG anti-double-stranded DNA autoantibody suggest a role for antigen in the induction of systemic lupus erythematosus

J. Exp. Med.

Analysis of immunoglobulin variable region genes from human IgG anti-DNA hybridomas

Eur. J. Immunol.

Structure and specificity of T cell receptors expressed by potentially pathogenic anti-DNA autoantibody-inducing T cells in human lupus

J. Clin. Invest.

Histone-specific Th0 and Th1 clones derived from systemic lupus erythematosus patients induce double-stranded DNA antibody production

Arthritis Rheum.

T cell lines specific for polyomavirus T-antigen recognize T-antigen complexed with nucleosomesa molecular basis for anti-DNA antibody production

Eur. J. Immunol.

Trends
Etiopathogenesis of systemic lupus erythematosus