Background
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with severe organ damage involving both the innate and adaptive immune systems. Currently, it is believed that apoptosis and clearance defects of necrotic cells may play an important role in the pathogenesis of SLE. The nuclear substances released by these cells stimulate the immune system as autoantigens. In this process, dysregulation of multiple immune pathways, secretion of pro-inflammatory cytokines, production of autoantibodies and activation of complement system lead to loss of autoimmune tolerance. Many autoantibodies are hallmarks of the serologic features of SLE, and autoantibodies such as anti-dsDNA, anti-ribonucleoprotein (RNP), and anti-nuclear (ANA) are detected in the serum of SLE patients.
Anti-dsDNA antibodies bind directly to DNA antigens or cross-reactive antigens in renal cells and indirectly form anti-dsDNA antibody-containing immune complexes (ICs) in the renal parenchyma. This triggers a complement cascade, accompanied by infiltration of immune cells and cytokine release, which induces kidney inflammation and fibrosis processes. Anti-dsDNA IgG penetrates living cells by binding to nuclear components and internalizes autoantibodies, thereby inducing proliferation of mesenchymal stromal cells and increasing secretion of the pro-inflammatory cytokine IL-6. At the same time, DNA-containing antigens also directly activate autoreactive B cells via B cell receptors (BCRs) and Toll-like receptors (TLRs.) TLRs in SLE patients recognize BCR-mediated internalized autonucleic acids, which are critical for the loss of B cell tolerance.
Anti-dsDNA autoantibodies are a hallmark of lupus nephritis, and in this disease anti-dsDNA antibodies markedly affect renal resident cells. In addition to reacting with a variety of DNA substances, anti-dsDNA antibodies bind to mutated non-DNA antigens, including alpha-actinin, laminin, collagen, and heparan sulfate. Anti-dsDNA antibodies contribute to the inflammatory and fibrotic process by overexpressing a large number of pro-inflammatory cytokines, such as monocyte chemotactic protein 1 (MCP-1), TNF-α, interleukins, and hyaluronic acid, leading to chronic kidney injury. SLE also involves the skin, and anti-DNA antibodies can specifically bind to the dermal-epidermal junction of skin and keratinocytes, leading to apoptosis of keratinocytes through antibody-dependent cell-mediated cytotoxicity (ADCC).
Figure 1. The pathogenic mechanism of anti-dsDNA antibodies in neuropsychiatric lupus, lupus nephritis, and CLE
(Source: Wang Y, et al. 2022)
Alternative Names
Anti double stranded DNA monoclonal antibody
References
- 1. Wang Y, et al. The Therapeutic Strategies for SLE by Targeting Anti-dsDNA Antibodies. Clin Rev Allergy Immunol. 2022 Oct;63(2):152-165.
- 2. Orme ME, et al. Anti-dsDNA Testing Specificity for Systemic Lupus Erythematosus: A Systematic Review. J Appl Lab Med. 2022 Jan 5;7(1):221-239
References
Anti-dsDNA IgE induces IL-4 production from basophils, potentially involved in B-cell differentiation in systemic lupus erythematosus
Rheumatology (Oxford)
Authors: Fujimoto S, Arinobu Y, Miyawaki K, Ayano M, Mitoma H, Kimoto Y, Ono N, Akashi K, Horiuchi T, Niiro H.
Abstract
Objectives: Recently, the involvement of basophils and IgE-type autoantibodies in the pathogenesis of SLE has been elucidated using mouse models; however, few studies have been conducted in humans. In this study, the role of basophils and anti-double-stranded DNA (dsDNA) IgE in SLE was examined using human samples.
Methods: The correlation between disease activity and serum levels of anti-dsDNA IgE in SLE was evaluated using enzyme-linked immunosorbent assay. Cytokines produced by IgE-stimulated basophils from healthy subjects were assessed using RNA sequences. The interaction of basophils and B cells to promote B cell differentiation was investigated using a co-culture system. The ability of basophils from patients with SLE with anti-dsDNA IgE to create cytokines that may be involved in B cell differentiation in response to dsDNA was examined using real-time PCR.
Results: Anti-dsDNA IgE levels in the serum of patients with SLE correlated with disease activity. Healthy donor basophils produced IL-3, IL-4 and TGF-β1 after anti-IgE stimulation. Co-culture of B cells with anti-IgE-stimulated basophils increased plasmablasts which were cancelled by neutralizing IL-4. After encountering the antigen, basophils released IL-4 more quickly than follicular helper T cells. Basophils isolated from patients with anti-dsDNA IgE promoted IL-4 expression by adding dsDNA.
Conclusions: These results suggest that basophils contribute to the pathogenesis of SLE by promoting B cell differentiation via dsDNA-specific IgE in patients similar to the process described in mouse models.
Anti-histone and anti-nucleosome rather than anti-dsDNA antibodies associate with IFN-induced biomarkers in Sudanese and Swedish Systemic Lupus Erythematosus patients
Rheumatology (Oxford)
Authors: Elbagir S, Mohammed NA, Oke V, Larsson A, Nilsson J, Elshafie A, Elagib EM, Nur MAM, Gunnarsson I, Svenungsson E, Rönnelid J.
Abstract
Objectives: In SLE, anti-dsDNA can co-occur with autoantibodies against other chromatin components, like histones and nucleosomes. These antibodies induce type-1 interferon production, a hallmark of SLE. We measured antinuclear antibody (ANA) sub-specificities and investigated their associations to inflammatory biomarkers including interferon-regulated chemokines.
Methods: We included 93 Sudanese and 480 Swedish SLE patients and matched controls (N = 104 + 192). Autoantibodies targeting ANA-subspecificites: dsDNA, Sm, Sm/U1RNPcomplex, U1RNP, SSA/Ro52, SSA/Ro60, SSB/La, ribosomal P, PCNA and histones were quantified in all subjects, anti-nucleosome only in the Swedish patients, with a bead-based multiplex immunoassay. Levels of 72 plasma biomarkers were determined with Proximity Extension Assay technique or ELISA.
Results: Among Sudanese patients, the investigated antibodies significantly associated with 9/72 biomarkers. Anti-histone antibodies showed the strongest positive correlations with MCP-3 and S100A12 as well as with interferon I-inducible factors MCP-1 and CXCL10. Anti-dsDNA antibodies associated with CXCL10 and S100A12, but in multivariate analyses, unlike anti-histone, associations lost significance.Among Swedish patients, MCP-1, CXCL10, SA100A12 also demonstrated stronger associations to anti-histone and anti-nucleosome antibodies, compared with anti-dsDNA and other ANA sub-specificities. In multiple regression models, anti-histone/nucleosome retained the strongest associations. When excluding anti-histone or anti-nucleosome positive patients, the associations between MCP-1/CXCL10 and anti-dsDNA were lost. In contrast, when excluding anti-dsDNA positive patients, associations with anti-histone and anti-nucleosome remained significant.
Conclusion: In two cohorts of different ethnical origin, autoantibodies targeting chromatin correlate stronger with IFN-induced inflammatory biomarkers than anti-dsDNA or other ANA sub-specificities. Our results suggest that anti-histone/nucleosome autoantibodies may be main drivers of type-1 interferon activity in SLE.
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