The role of dectin-1 expressing dendritic cells in the pathogenesis of systemic lupus erythematosus

Background: The adaptor protein Src homology 3 domain-binding protein 2 (SH3BP2) is widely expressed in immune cells. It controls intracellular signaling pathways. The present study was undertaken to investigate the role of SH3BP2 in a murine systemic lupus erythematosus model. Methods: For the lupus model, we used Faslpr/lpr mice. Clinical and immunological phenotypes were compared between Faslpr/lpr and SH3BP2-deficient Faslpr/lpr mice. Splenomegaly and renal involvement were assessed. Lymphocyte subsets in the spleen were analyzed by flow cytometry. To examine the role of SH3BP2 in specific cells, B cell-specific SH3BP2-deficient lupus mice were analyzed; T cells and bone marrow-derived dendritic cells and macrophages were analyzed in vitro. Results: SH3BP2 deficiency significantly reduced lupus-like phenotypes, presented as splenomegaly, renal involvement, elevated serum anti-dsDNA antibody, and increased splenic B220+CD4−CD8− T cells. Notably, SH3BP2 deficiency in B cells did not rescue the lupus-like phenotypes. Furthermore, SH3BP2 deficiency did not substantially affect the characteristics of T cells and macrophages in vitro. Interestingly, SH3BP2 deficiency suppressed the differentiation of dendritic cells in vitro and reduced the number of dendritic cells in the spleen of the lupus-prone mice. Conclusions: SH3BP2 deficiency ameliorated lupus-like manifestations. Modulating SH3BP2 expression could thus provide a novel therapeutic approach to autoimmune diseases.

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Analysis of the Expression and Function of Immunoglobulin-Like Transcript 4 (ILT4, LILRB2) in Dendritic Cells from Patients with Systemic Lupus Erythematosus

Journal of Immunology Research ◽

10.1155/2016/4163094 ◽

2016 ◽

Vol 2016 ◽

pp. 1-13 ◽

Cited By ~ 4

Author(s):

Paola del Carmen Guerra-de Blas ◽

Yael Sebastián Villaseñor-Talavera ◽

Daniela de Jesús Cruz-González ◽

Lourdes Baranda ◽

Lesly Doníz-Padilla ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Dendritic Cells ◽

Lupus Erythematosus ◽

Inhibitory Effect ◽

Healthy Controls ◽

Inhibitory Receptor ◽

Systemic Lupus ◽

Tolerogenic Function ◽

And Function

Dendritic cells (DC) play an important role in the development and maintenance of immune tolerance. Although the inhibitory receptor ILT4/LILRB2 has been related with the tolerogenic phenotype of DC, the possible role of this receptor in the breakdown of DC tolerogenic function in systemic lupus erythematosus (SLE) has not been elucidated. In this study, we analyzed the expression and function of the inhibitory receptor ILT4 in DC from SLE patients. We found that the percentage of ILT4 positive plasmacytoid DC and myeloid DC is significantly diminished in SLE patients. Interestingly, ligation of ILT4 did not affect the maturation or immunogenic capability of DC in healthy controls. In contrast, in SLE patients we observed an inhibitory effect of ILT4 on the immunogenic capability of DC. ILT4 was shown not to have a crucial role in regulating the maturation and function of DC from healthy controls but is partially involved in the maturation process and immunogenic capability of DC from SLE patients, suggesting that other inhibitory receptors, involved in the regulation of DC tolerogenic function, may be impaired in this autoimmune disease.

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Abstract P214: Isolevuglandins Mediate Inflammatory Gene Expression And Immune Activation In Hypertension And Systemic Lupus Erythematosus

Hypertension ◽

10.1161/hyp.78.suppl_1.p214 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Nestor de la Visitacion ◽

Charles D Smart ◽

Jaya Krishnan ◽

David G Harrison ◽

David M Patrick

Keyword(s):

Gene Expression ◽

Systemic Lupus Erythematosus ◽

Dendritic Cells ◽

Lupus Erythematosus ◽

Inflammatory Cells ◽

Neutrophil Infiltration ◽

Ang Ii ◽

Systemic Lupus ◽

Inflammatory Gene Expression

Justification: Hypertension and systemic lupus erythematosus (SLE) share similarities including elevations of blood pressure, proteinuria, inflammation and renal dysfunction and both involve formation of isoLG adducts. We hypothesized that isoLG scavenging would modulate overlapping gene pathways in inflammatory cells in these two conditions. Methods: We performed 10 X genomics single cell sequencing on splenocytes of C57Bl/6 mice with angiotensin II (Ang II)-induced hypertension, Ang II co-treatment with the isoLG scavenger 2HOBA, and 24-week-old B6.SLE123 mice with or without 6-weeks of 2HOBA. Matched C57Bl/6 females were used as controls for the B6.SLE123 mice. Results: Both models exhibited myeloid expansion and genes associated with neutrophil infiltration compared to their respective controls and 2HOBA attenuated this ( Table 1 ). Hypertension was associated with neutrophil expansion whereas SLE was associated an expansion of neutrophils, monocytes, and dendritic cells. In SLE, 2HOBA predominantly modulated gene expression in dendritic cells. Gene ontology revealed 2HOBA downregulated genes governing inflammation including Il1 β (Avglog2(fold change) = -1.6, P adj = 0.002) in both hypertension and SLE. Conclusions: In a mouse model of SLE, scavenging of isoLGs with 2HOBA downregulates inflammatory genes specifically in DCs. In models of both hypertension and SLE, scavenging of isoLG prevents neutrophil expansion. Combined these data describe a shared role of isoLGs in hypertension and SLE and suggest a specific role of DCs and neutrophil activation in the pathogenesis of both conditions. Table 1. Percentage of myeloid derived cells in all groups.

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SH3BP2 Deficiency Ameliorates Murine Systemic Lupus Erythematosus

10.21203/rs.3.rs-74861/v1 ◽

2020 ◽

Author(s):

Kyoko Kawahara ◽

Tomoyuki Mukai ◽

Masanori Iseki ◽

Akiko Nagasu ◽

Hajime Nagasu ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Dendritic Cells ◽

Lupus Erythematosus ◽

Renal Involvement ◽

Systemic Lupus ◽

Dsdna Antibody ◽

Murine Systemic Lupus Erythematosus

Abstract Background: The adaptor protein Src homology 3 domain-binding protein 2 (SH3BP2) is widely expressed in immune cells, such as myeloid cells, B cells, and T cells. It controls intracellular signaling pathways, including Syk and Src. The present study was undertaken to investigate the role of SH3BP2 in a murine systemic lupus erythematosus model.Methods: For the lupus model, we used Faslpr/lpr mice (C57BL/6 background). Clinical and immunological phenotypes were compared between Faslpr/lpr and SH3BP2-deficient Faslpr/lpr mice. Splenomegaly and renal involvement were assessed in 35-week-old mice. Serum levels of anti-dsDNA antibody and rheumatoid factor were determined using ELISA. Lymphocyte subsets in the spleen were analyzed by flow cytometry. To examine the role of SH3BP2 in specific cells, B cell-specific SH3BP2-deficient lupus mice were generated and analyzed; T cells and bone marrow-derived dendritic cells and macrophages were analyzed in vitro. Results: SH3BP2 deficiency significantly reduced lupus-like phenotypes, presented as splenomegaly, renal involvement, elevated serum anti-dsDNA antibody and rheumatoid factor, and increased splenic B220+CD4-CD8- T cells. Notably, SH3BP2 deficiency in B cells did not rescue the lupus-like phenotypes. Furthermore, SH3BP2 deficiency did not substantially affect the characteristics of T cells and macrophages in vitro. Interestingly, SH3BP2 deficiency suppressed the differentiation of dendritic cells in vitro and reduced the number of dendritic cells in the spleen of the lupus-prone mice.Conclusions: SH3BP2 deficiency ameliorated clinical and immunological manifestations in lupus-prone mice, possibly via targeting dendritic cell differentiation. Modulating SH3BP2 expression could thus provide a novel therapeutic approach to autoimmune diseases.

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