Fc Gamma Receptor IIB Deficient Mice

Ondee, Thunnicha; Surawut, Saowapha; Taratummarat, Sujittra; Hirankarn, Nattiya; Palaga, Tanapat; Pisitkun, Prapaporn; Pisitkun, Trairak; Leelahavanichkul, Asada

doi:10.1097/shk.0000000000000796

Cited by 40 publications

(73 citation statements)

References 34 publications

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“…B cells express only the inhibitory receptor FcγRIIb. It has been reported that FcγRIIB-deficient mice display an increased frequency of autoreactive B cells and lupus-like manifestations (25,26). Although monocyte/macrophage abnormalities play a pivotal role in the pathogenesis of SLE, the role of macrophages in spleen inflammation and splenomegaly is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Predominant Role of Immunoglobulin G in the Pathogenesis of Splenomegaly in Murine Lupus

et al. 2020

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Systemic lupus erythematosus (SLE) is characterized by high levels of autoantibodies and multiorgan tissue damage. The pathogenesis of splenomegaly in SLE remains unknown. In this study, the role of immunoglobulin G (IgG) generation and deposition in the inflammation of the spleen and associated dysfunction in SLE was investigated. In the lupus mice, we observed the development of spontaneous splenomegaly, and we found that lupus serum IgG is an important pathological factor involved in the initiation of inflammation and further germinal center (GC) and plasma cell formation. We discovered that macrophages of the splenic marginal zone are dispensable for the GC response induced by lupus IgG, but red pulp macrophages are important for GC responses. Furthermore, we found that pathogenic lupus IgG promotes inflammation and GC formation through the macrophage-mediated secretion of TNF-α. Syk inhibitor treatment suppressed the changes in the histopathology of the spleen induced by lupus IgG. This study will contribute to the understanding of the pathogenesis of splenomegaly in lupus and promote the development of an effective therapeutic strategy for SLE.

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Section: Introductionmentioning

confidence: 99%

Predominant Role of Immunoglobulin G in the Pathogenesis of Splenomegaly in Murine Lupus

et al. 2020

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“…We have previously reported the overwhelming response to endotoxin (LPS) followed by the prominent immune exhaustion in FcGRIIb−/− mice [10]. Similarly, patients with lupus are susceptible to infection and this susceptibility towards infection is increased in patients with immune exhaustion [11,12,13,14].…”

Section: Introductionmentioning

confidence: 99%

Decreased Protein Kinase C-β Type II Associated with the Prominent Endotoxin Exhaustion in the Macrophage of FcGRIIb−/− Lupus Prone Mice is Revealed by Phosphoproteomic Analysis

Ondee

Jaroonwitchawan

Pisitkun

et al. 2019

IJMS

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Dysfunction of FcGRIIb, the only inhibitory receptor of the FcGR family, is commonly found in the Asian population and is possibly responsible for the extreme endotoxin exhaustion in lupus. Here, the mechanisms of prominent endotoxin (LPS) tolerance in FcGRIIb−/− mice were explored on bone marrow-derived macrophages using phosphoproteomic analysis. As such, LPS tolerance decreased several phosphoproteins in the FcGRIIb−/− macrophage, including protein kinase C-β type II (PRKCB), which was associated with phagocytosis function. Overexpression of PRKCB attenuated LPS tolerance in RAW264.7 cells, supporting the role of this gene in LPS tolerance. In parallel, LPS tolerance in macrophages and in mice was attenuated by phorbol 12-myristate 13-acetate (PMA) administration. This treatment induced several protein kinase C families, including PRKCB. However, PMA attenuated the severity of mice with cecal ligation and puncture on LPS tolerance preconditioning in FcGRIIb−/− but not in wild-type cells. The significant reduction of PRKCB in the FcGRIIb−/− macrophage over wild-type cell possibly induced the more severe LPS-exhaustion and increased the infection susceptibility in FcGRIIb−/− mice. PMA induced PRKCB, improved LPS-tolerance, and attenuated sepsis severity, predominantly in FcGRIIb−/− mice. PRKCB enhancement might be a promising strategy to improve macrophage functions in lupus patients with LPS-tolerance from chronic infection.

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“…Lupus characteristics as determined by serum creatinine, proteinuria, and anti-dsDNA in FcγRIIb-/- mice after 24-week-old is previously described ( Ondee et al, 2017 ; Surawut et al, 2017 ). Hence, HP administration in 24-week-old mice represents HP infection in patients with symptomatic lupus.…”

Section: Resultsmentioning

confidence: 99%

“…Macrophages were derived from the bone marrow (BM) ( Ondee et al, 2017 ) and phagocytosis assay was performed following an established protocol ( Chmiela et al, 1997 ; Miliukene et al, 2007 ). In short, 1 × 10 9 cell/ml heat-killed HP (60°C for 30 min) was incubated with 100 μg/ml fluorescein isothiocyanate (FITC) (Sigma, United States) in PBS at 35°C for 30 min for FITC-labeling.…”

Section: Methodsmentioning

confidence: 99%

Helicobacter pylori Infection Increased Anti-dsDNA and Enhanced Lupus Severity in Symptomatic FcγRIIb-Deficient Lupus Mice

et al. 2018

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The defect on Fc gamma receptor IIb (FcγRIIb), the only inhibitory FcγR, has been identified as one of the genetic factors increasing susceptibility to lupus. The prevalence of Helicobacter pylori (HP) and FcγRIIb dysfunction-polymorphisms are high among Asians, and their co-existence is possible. Unfortunately, the influence of HP against lupus progression in patients with lupus is still controversial. In this study, the interactions between these conditions were tested with HP infection in 24-week-old FcγRIIb-/- mice (symptomatic lupus). HP induced failure to thrive, increased stomach bacterial burdens and stomach injury (histology and cytokines) in both wild-type and FcγRIIb-/- mice. While the severity of HP infection, as determined by these parameters, was not different between both strains, antibodies production (anti-HP, anti-dsDNA and serum gammaglobulin) were higher in FcγRIIb-/- mice compared to wild-type. Accordingly, HP infection also accelerated the severity of lupus as determined by proteinuria, serum creatinine, serum cytokines, renal histology, and renal immune complex deposition. Although HP increased serum cytokines in both wild-type and FcγRIIb-/- mice, the levels were higher in FcγRIIb-/- mice. As such, HP also increased spleen weight and induced several splenic immune cells responsible for antibody productions (activated B cell, plasma cell and follicular helper T cell) in FcγRIIb-/- mice, but not in wild-type. These data describe the different systemic responses against localized HP infection from diverse host genetic background. In conclusion, the mutual interactions between HP and lupus manifestations of FcγRIIb-/-mice were demonstrated in this study. With the prominent immune responses from the loss of inhibitory signaling in FcγRIIb-/- mice, HP infection in these mice induced intense chronic inflammation, increased antibody production, and enhanced lupus severity. Thus, the increased systemic inflammatory responses due to localized HP inducing gastritis in some patients with lupus may enhance lupus progression. More studies are needed.

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Fc Gamma Receptor IIB Deficient Mice

Cited by 40 publications

References 34 publications

Predominant Role of Immunoglobulin G in the Pathogenesis of Splenomegaly in Murine Lupus

Predominant Role of Immunoglobulin G in the Pathogenesis of Splenomegaly in Murine Lupus

Decreased Protein Kinase C-β Type II Associated with the Prominent Endotoxin Exhaustion in the Macrophage of FcGRIIb−/− Lupus Prone Mice is Revealed by Phosphoproteomic Analysis

Helicobacter pylori Infection Increased Anti-dsDNA and Enhanced Lupus Severity in Symptomatic FcγRIIb-Deficient Lupus Mice

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