Levels of Transforming Growth Factor-β Are Low in Systemic Lupus Erythematosus Patients with Active Disease

Becker-Merok, Andrea; Eilertsen, Gro Østli; Nossent, Jiri

doi:10.3899/jrheum.100180

Cited by 82 publications

(69 citation statements)

References 54 publications

(58 reference statements)

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“…Consumption in the kidney may reflect lower circulating levels of TGF␤1, which seem to be associated with severe disease, kidney involvement, and worse outcome in SLE (35,36). Additionally, an elevated total plasma level of TGF␤1 in SLE has been shown in some studies, and TGF␤1-transgenic mice develop a glomerulonephritis resembling immune complex-mediated glomerular injury (22).…”

Section: Discussionmentioning

confidence: 99%

Pathogenic Mechanisms in Lupus Nephritis: Nucleosomes Bind Aberrant Laminin β1 With High Affinity and Colocalize in the Electron‐Dense Deposits

Olin

Mörgelin

Truedsson

et al. 2014

Arthritis & Rheumatology

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Objective. Apoptotic nucleosomes are structurally and immunologically involved in lupus nephritis. The purpose of this study was to examine the expression and function of laminins and their interactions with nucleosomes in the kidneys of patients with lupus nephritis, using surface plasmon resonance (SPR) analysis.Methods. SPR interaction analysis was used to quantify the strength of laminin-nucleosome interactions. Electron microscopy techniques were used to determine in vivo colocalization of IgG, chromatin, and laminin ␤1, as well as to characterize nucleosomelaminin interactions in vitro.Results. Nucleosomes were found to possess high affinity for laminin ␤1-containing laminins and to have the potential to form stable molecular complexes with these structures. In vivo, laminin ␤1 was aberrantly expressed in the glomerular basement membrane (GMB) of lupus nephritis patients, and in situ, it acted as a nucleosome ligand, selectively colocalizing with nucleosomes within electron-dense deposits (EDDs). Normal adult laminin 11, which contains laminin ␤2, did not bind nucleosomes, and it did not colocalize in vivo with the nucleosomes in the nephritic GBM. In addition, TGF␤1 was expressed by the glomerular mesangium, glomerular endothelial cells, and by podocytes in patients with lupus nephritis. It was trapped in situ within EDDs by an as-yet-unknown ligand. As was recently described in a transgenic mouse model, paracrine kidney glomerular TGF␤1 may thereby contribute to the development of glomerulopathy via the induction of laminin ␤1 incorporation in the GBM, whereas systemic blood vessel-derived TGF␤1 could be trapped during filtration.Conclusion. Our findings of the specific highaffinity binding of nucleosomes to aberrantly expressed laminin ␤1 in the GBM and their colocalization in the GBM may explain important features of the initial steps in the pathogenesis of lupus nephritis, the planted antigen hypothesis.

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Section: Discussionmentioning

confidence: 99%

Pathogenic Mechanisms in Lupus Nephritis: Nucleosomes Bind Aberrant Laminin β1 With High Affinity and Colocalize in the Electron‐Dense Deposits

Olin

Mörgelin

Truedsson

et al. 2014

Arthritis & Rheumatology

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“…Although serum TGF-ß levels reflect the total production from many cellular sources, Becker-Merok, et al have demonstrated that decreased TGF-ß production correlated with decreased CD4+, CD8+, and NK cell frequency, implicating the reduction of these cell subsets as responsible for the decreased level of this cytokine 3 . Recent studies have also revealed that CD4+CD25+Foxp3+ regulatory/suppressor (Treg) cells may be another important source for the TGF-ß expression and/or production.…”

Section: Transforming Growth Factor-ß Level: Indicator For Severity Omentioning

confidence: 99%

“…However, in their study in this issue of The Journal, Becker-Merok, et al provide new evidence that lower serum TGF-ß1 levels may be the most consistent cytokine abnormality in SLE. They found that a lower TGF-ß1 level correlates with disease activity, a reduction in CD4+, CD8+ and NK cell numbers, and severe organ damage in active SLE 3 . The authors also demonstrated that decreased TGF-ß1 level seems to be an intrinsic defect, since corticosteroid treatment did not interfere with its production in patients with active SLE.…”

Section: Transforming Growth Factor-ß Level: Indicator For Severity Omentioning

confidence: 99%

Transforming Growth Factor-β Level: Indicator for Severity of Disease and Organ Damage in Patients with Systemic Lupus Erythematosus: Figure 1.

Zheng¹

2010

J Rheumatol

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“…Circulating levels of IL-1b were elevated in Sjögren's syndrome (15), but not in autoimmune hemolytic anemia (16). Reported levels of IL-1b in systemic lupus erythematosus (SLE) patient serum range from undetected (17,18), decreased in SLE relative to controls (19,20), to increased in a small percentage of patients (21). IL-1b levels may be higher in subsets of patients such as those with neuropsychiatric SLE (22) or vascular damage (20).…”

mentioning

confidence: 99%

“…Reported levels of IL-1b in systemic lupus erythematosus (SLE) patient serum range from undetected (17,18), decreased in SLE relative to controls (19,20), to increased in a small percentage of patients (21). IL-1b levels may be higher in subsets of patients such as those with neuropsychiatric SLE (22) or vascular damage (20). The other cytokine produced by the inflammasome, IL-18, is elevated in the serum and glomeruli of SLE patients with lupus nephritis and is associated with localization of plasmacytoid dendritic cells to glomeruli (23,24).…”

mentioning

confidence: 99%

Deficient NLRP3 and AIM2 Inflammasome Function in Autoimmune NZB Mice

Sester

Sagulenko

Thygesen

et al. 2015

The Journal of Immunology

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Inflammasomes are protein complexes that promote caspase activation, resulting in processing of IL-1β and cell death, in response to infection and cellular stresses. Inflammasomes have been anticipated to contribute to autoimmunity. The New Zealand Black (NZB) mouse develops anti-erythrocyte Abs and is a model of autoimmune hemolytic anemia. These mice also develop anti-nuclear Abs typical of lupus. In this article, we show that NZB macrophages have deficient inflammasome responses to a DNA virus and fungal infection. Absent in melanoma 2 (AIM2) inflammasome responses are compromised in NZB by high expression of the AIM 2 antagonist protein p202, and consequently NZB cells had low IL-1β output in response to both transfected DNA and mouse CMV infection. Surprisingly, we also found that a second inflammasome system, mediated by the NLR family, pyrin domain containing 3 (NLRP3) initiating protein, was completely lacking in NZB cells. This was due to a point mutation in an intron of the Nlrp3 gene in NZB mice, which generates a novel splice acceptor site. This leads to incorporation of a pseudoexon with a premature stop codon. The lack of full-length NLRP3 protein results in NZB being effectively null for Nlrp3, with no production of bioactive IL-1β in response to NLRP3 stimuli, including infection with Candida albicans. Thus, this autoimmune strain harbors two inflammasome deficiencies, mediated through quite distinct mechanisms. We hypothesize that the inflammasome deficiencies in NZB alter the interaction of the host with both microflora and pathogens, promoting prolonged production of cytokines that contribute to development of autoantibodies.

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Levels of Transforming Growth Factor-β Are Low in Systemic Lupus Erythematosus Patients with Active Disease

Abstract: Lower TGF-β1 was the most consistent cytokine abnormality in patients with SLE. The associations with disease activity, lymphocyte subsets, and damage suggest that TGF-β1 may be a therapeutic target of interest in SLE.

Cited by 82 publications

References 54 publications

Pathogenic Mechanisms in Lupus Nephritis: Nucleosomes Bind Aberrant Laminin β1 With High Affinity and Colocalize in the Electron‐Dense Deposits

Pathogenic Mechanisms in Lupus Nephritis: Nucleosomes Bind Aberrant Laminin β1 With High Affinity and Colocalize in the Electron‐Dense Deposits

Transforming Growth Factor-β Level: Indicator for Severity of Disease and Organ Damage in Patients with Systemic Lupus Erythematosus: Figure 1.

Deficient NLRP3 and AIM2 Inflammasome Function in Autoimmune NZB Mice

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