Accelerated Pathological and Clinical Nephritis in Systemic Lupus Erythematosus-Prone New Zealand Mixed 2328 Mice Doubly Deficient in TNF Receptor 1 and TNF Receptor 2 via a Th17-Associated Pathway

Jacob, Noam; Huang, Yang; Pricop, Luminita; Liu, Yi; Gao, Xiaoping; Zheng, Song Guo; Wang, Juhua; Gao, Hua; Putterman, Chaim; Koss, Michael N.; Stohl, William; Jacob, Chaim O.

doi:10.4049/jimmunol.0802948

Cited by 94 publications

(88 citation statements)

References 66 publications

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“…The induction of SLE following TNF blockade reported in this study is further highlighted by the recent results of Jacob, et al 23 in the lupus-prone NZM 2328 mouse model, which show that abrogating the effects of TNF by deleting both TNF receptors leads to a heightened and distinct inflammatory pathway that accelerates onset of disease, supporting the notion that anti-TNF may be contraindicated in the treatment of SLE.…”

Section: Rheumatologysupporting

confidence: 60%

On Anti-Tumor Necrosis Factor-induced Systemic Lupus Erythematosus

Jacob¹,

Jacob²

2009

J Rheumatol

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Section: Rheumatologysupporting

confidence: 60%

On Anti-Tumor Necrosis Factor-induced Systemic Lupus Erythematosus

Jacob¹,

Jacob²

2009

J Rheumatol

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“…A number of studies have indicated that Th17 is involved in the pathogenesis of a variety of inflammatory diseases, including rheumatoid arthritis, asthma, inflammatory bowel diseases [38][39][40], and lupus nephritis [41,42]. Further studies should be performed to identify the effects of anti-P on the production of IL-17 in PBMC from healthy donors.…”

Section: Discussionmentioning

confidence: 96%

Anti-ribosomal P protein antibody induces Th1 responses by enhancing the production of IL-12 in activated monocytes

2010

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Autoantibodies to ribosomal P proteins (anti-P) are detected in 12-16% of patients with systemic lupus erythematosus (SLE), and have been found to be associated with some manifestations, including lupus psychosis, nephritis and hepatitis. We have recently disclosed that anti-P react with activated human peripheral blood monocytes, and enhance their production of tumor necrosis factor-α and interleukin (IL)-6. It is also possible that anti-P might regulate other monocyte functions, including the regulation of T helper (Th) responses. The current study was therefore undertaken to explore the effects of anti-P on the induction of Th1 responses. Peripheral blood mononuclear cells (PBMC) from healthy donors were cultured with affinity-purified anti-P or control IgG. Highly purified monocytes were cultured with interferon (IFN)-γ in the presence of anti-P or normal IgG. Anti-P significantly enhanced the production of IFN-γ by PBMC. Of note, anti-IL-12 monoclonal antibodies almost completely abrogated the anti-P-mediated upregulation of the IFN-γ production of PBMC. Accordingly, anti-P significantly enhanced the production of IL-12 by activated monocytes. These results indicate that anti-P induce Th1 responses by upregulating the production of IL-12 by activated monocytes. The data therefore suggest that anti-P play an important role in the pathogenesis of SLE through the promotion of Th1 responses.

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“…Expression of Stat3, which is also driven by oxidative stress [24], is increased in both lupus T [25] and B cells [13]. Stat3-dependent signals play a key role in the differentiation of Th17 cells [26], which appear to mediate nephritis in patients with SLE [27,28]. …”

Section: T Cell Dsyfunction In-systemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

Systems biology of lupus: Mapping the impact of genomic and environmental factors on gene expression signatures, cellular signaling, metabolic pathways, hormonal and cytokine imbalance, and selecting targets for treatment

Perl

2009

Autoimmunity

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Systemic lupus erythematosus (SLE) is characterized by the dysfunction of T cells, B cells, and dendritic cells, the release of pro-inflammatory nuclear materials from necrotic cells, and the formation of antinuclear antibodies (ANA) and immune complexes of ANA with DNA, RNA, and nuclear proteins. Activation of the mammalian target of rapamycin (mTOR) has recently emerged as a key factor in abnormal activation of Tand B cells in SLE. In T cells, increased production of nitric oxide and mitochondrial hyperpolarization (MHP) were identified as metabolic checkpoints upstream of mTOR activation. mTOR controls the expression T-cell receptor-associated signaling proteins CD4 and CD3ζ through increased expression of the endosome recycling regulator Rab5 and HRES-1/Rab4 genes, enhances Ca2+ fluxing and skews the expression of tyrosine kinases both in T and B cells, and blocks the expression of Foxp3 and the generation of regulatory T cells. MHP, increased activity of mTOR, Rab GTPases, and Syk kinases, and enhanced Ca2+ flux have emerged as common Tand B cell biomarkers and targets for treatment in SLE.

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Accelerated Pathological and Clinical Nephritis in Systemic Lupus Erythematosus-Prone New Zealand Mixed 2328 Mice Doubly Deficient in TNF Receptor 1 and TNF Receptor 2 via a Th17-Associated Pathway

Cited by 94 publications

References 66 publications

On Anti-Tumor Necrosis Factor-induced Systemic Lupus Erythematosus

On Anti-Tumor Necrosis Factor-induced Systemic Lupus Erythematosus

Anti-ribosomal P protein antibody induces Th1 responses by enhancing the production of IL-12 in activated monocytes

Systems biology of lupus: Mapping the impact of genomic and environmental factors on gene expression signatures, cellular signaling, metabolic pathways, hormonal and cytokine imbalance, and selecting targets for treatment

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