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B7-H3 Promotes Pathogenesis of Autoimmune Disease and Inflammation by Regulating the Activity of Different T Cell Subsets.

Luo L, Zhu G, Xu H, Yao S, Zhou G, Zhu Y, Tamada K, Huang L, Flies AD, Broadwater M, Ruff W, van Deursen JM, Melero I, Zhu Z, Chen L - PLoS ONE (2015)

Bottom Line: Here, we demonstrate that B7-H3 KO mice have significantly less inflammation, decreased pathogenesis, and limited disease progression in both EAE and CIA mouse models when compared with littermates; these results were accompanied by a decrease in IFN-γ and IL-17 production.Our results suggest B7-H3 has a costimulatory function on Th1/Th17 but a coinhibitory function on Th2 responses.Our studies reveal that B7-H3 could affect different T cell subsets which have important implications for regulating pathogenesis and disease progression in human autoimmune disease.

View Article: PubMed Central - PubMed

Affiliation: Institute of Immunotherapy, Sun Yat-Sen University, Guangzhou, Guangdong, China.

ABSTRACT
B7-H3 is a cell surface molecule in the immunoglobulin superfamily that is frequently upregulated in response to autoantigens and pathogens during host T cell immune responses. However, B7-H3's role in the differential regulation of T cell subsets remains largely unknown. Therefore, we constructed a new B7-H3 deficient mouse strain (B7-H3 KO) and evaluated the functions of B7-H3 in the regulation of Th1, Th2, and Th17 subsets in experimental autoimmune encephalomyelitis (EAE), experimental asthma, and collagen-induced arthritis (CIA); these mouse models were used to predict human immune responses in multiple sclerosis, asthma, and rheumatoid arthritis, respectively. Here, we demonstrate that B7-H3 KO mice have significantly less inflammation, decreased pathogenesis, and limited disease progression in both EAE and CIA mouse models when compared with littermates; these results were accompanied by a decrease in IFN-γ and IL-17 production. In sharp contrast, B7-H3 KO mice developed severe ovalbumin (OVA)-induced asthma with characteristic infiltrations of eosinophils in the lung, increased IL-5 and IL-13 in lavage fluid, and elevated IgE anti-OVA antibodies in the blood. Our results suggest B7-H3 has a costimulatory function on Th1/Th17 but a coinhibitory function on Th2 responses. Our studies reveal that B7-H3 could affect different T cell subsets which have important implications for regulating pathogenesis and disease progression in human autoimmune disease.

No MeSH data available.


Related in: MedlinePlus

B7-H3 KO mice are resistant to CIA.(A) The arthritis score in CIA mice. 5–10 mice per group per experiment and data shown are representative of 3 independent experiments with similar results. (B) Representative images of hind paws from wild type (left) and B7-H3 KO (right) CIA mice on 40 days after primary immunization. (C) Representative hematoxylin and eosin—stained sections of toe and talus joints (original magnification ×4 and ×10, respectively) from wild type and B7-H3 KO CIA mice. (D) Serum anti-type II collagen Ab (IgG) levels (100 units is approximately 0.1 mg IgG antibody/ml). Data shown are representative of 3 independent experiments. (E) Staining for B7-H3 in normal and arthritic joints. Hind toe joints from normal, CIA-wild type, and B7-H3 KO mice (Original magnification ×10). (F) Splenocytes from wild type and B7-H3 KO CIA mice were restimulated with chicken CII protein in various concentrations. 5 mice per group each experiment. Cell proliferation was determined by 3H-TdR incorporation. Data shown are representative of 3 independent experiments. (G) Th1/Th2/Th17 Cytokine concentrations of cultured supernatants from chicken CII protein (20 μg/ml)-restimulated splenocytes (mixed 5 individual cells per group) after 1 and 2 days were assessed using mouse Th1/Th2/Th17 Cytokine kits (CBA); data were analyzed using FCAP Array V2.0. Data shown are representative of two independent experiments. Data are shown as mean ± SEM, *p<0.05, **p<0.01, ***p<0.001, versus control.
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pone.0130126.g006: B7-H3 KO mice are resistant to CIA.(A) The arthritis score in CIA mice. 5–10 mice per group per experiment and data shown are representative of 3 independent experiments with similar results. (B) Representative images of hind paws from wild type (left) and B7-H3 KO (right) CIA mice on 40 days after primary immunization. (C) Representative hematoxylin and eosin—stained sections of toe and talus joints (original magnification ×4 and ×10, respectively) from wild type and B7-H3 KO CIA mice. (D) Serum anti-type II collagen Ab (IgG) levels (100 units is approximately 0.1 mg IgG antibody/ml). Data shown are representative of 3 independent experiments. (E) Staining for B7-H3 in normal and arthritic joints. Hind toe joints from normal, CIA-wild type, and B7-H3 KO mice (Original magnification ×10). (F) Splenocytes from wild type and B7-H3 KO CIA mice were restimulated with chicken CII protein in various concentrations. 5 mice per group each experiment. Cell proliferation was determined by 3H-TdR incorporation. Data shown are representative of 3 independent experiments. (G) Th1/Th2/Th17 Cytokine concentrations of cultured supernatants from chicken CII protein (20 μg/ml)-restimulated splenocytes (mixed 5 individual cells per group) after 1 and 2 days were assessed using mouse Th1/Th2/Th17 Cytokine kits (CBA); data were analyzed using FCAP Array V2.0. Data shown are representative of two independent experiments. Data are shown as mean ± SEM, *p<0.05, **p<0.01, ***p<0.001, versus control.

Mentions: CIA is the most widely used mouse model for rheumatoid arthritis, a common autoimmune disease. The CIA model is thought to be an auto-reactive T and B cell-dependent arthritis, and recent studies have suggested that Th17 cells play a central role in the pathogenesis of CIA. Therefore, we tested the effect of B7-H3 in the development of CIA. B7-H3 KO mice exhibited a later onset, an attenuated severity of arthritis based on the assigned arthritis score (Fig 6A), and a decreased severity in joint swelling (Fig 6B) compared with wt mice. Clinical observation was further verified by histological examination. H&E staining of arthritic paw joints from wt mice revealed severe synovial hyperplasia, infiltration of inflammatory cells, and destructive cartilage and bone. In contrast, the levels of inflammation, infiltration, and cartilage erosion were markedly alleviated in B7-H3 KO mice (Fig 6C). In addition, CII-specific IgG levels in sera from B7-H3 KO mice were significantly lower than those from wild type mice, as determined by ELISA 20 days after primary immunization (Fig 6D). Our results indicate that B7-H3 KO mice have significantly decreased symptoms of CIA.


B7-H3 Promotes Pathogenesis of Autoimmune Disease and Inflammation by Regulating the Activity of Different T Cell Subsets.

Luo L, Zhu G, Xu H, Yao S, Zhou G, Zhu Y, Tamada K, Huang L, Flies AD, Broadwater M, Ruff W, van Deursen JM, Melero I, Zhu Z, Chen L - PLoS ONE (2015)

B7-H3 KO mice are resistant to CIA.(A) The arthritis score in CIA mice. 5–10 mice per group per experiment and data shown are representative of 3 independent experiments with similar results. (B) Representative images of hind paws from wild type (left) and B7-H3 KO (right) CIA mice on 40 days after primary immunization. (C) Representative hematoxylin and eosin—stained sections of toe and talus joints (original magnification ×4 and ×10, respectively) from wild type and B7-H3 KO CIA mice. (D) Serum anti-type II collagen Ab (IgG) levels (100 units is approximately 0.1 mg IgG antibody/ml). Data shown are representative of 3 independent experiments. (E) Staining for B7-H3 in normal and arthritic joints. Hind toe joints from normal, CIA-wild type, and B7-H3 KO mice (Original magnification ×10). (F) Splenocytes from wild type and B7-H3 KO CIA mice were restimulated with chicken CII protein in various concentrations. 5 mice per group each experiment. Cell proliferation was determined by 3H-TdR incorporation. Data shown are representative of 3 independent experiments. (G) Th1/Th2/Th17 Cytokine concentrations of cultured supernatants from chicken CII protein (20 μg/ml)-restimulated splenocytes (mixed 5 individual cells per group) after 1 and 2 days were assessed using mouse Th1/Th2/Th17 Cytokine kits (CBA); data were analyzed using FCAP Array V2.0. Data shown are representative of two independent experiments. Data are shown as mean ± SEM, *p<0.05, **p<0.01, ***p<0.001, versus control.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4465912&req=5

pone.0130126.g006: B7-H3 KO mice are resistant to CIA.(A) The arthritis score in CIA mice. 5–10 mice per group per experiment and data shown are representative of 3 independent experiments with similar results. (B) Representative images of hind paws from wild type (left) and B7-H3 KO (right) CIA mice on 40 days after primary immunization. (C) Representative hematoxylin and eosin—stained sections of toe and talus joints (original magnification ×4 and ×10, respectively) from wild type and B7-H3 KO CIA mice. (D) Serum anti-type II collagen Ab (IgG) levels (100 units is approximately 0.1 mg IgG antibody/ml). Data shown are representative of 3 independent experiments. (E) Staining for B7-H3 in normal and arthritic joints. Hind toe joints from normal, CIA-wild type, and B7-H3 KO mice (Original magnification ×10). (F) Splenocytes from wild type and B7-H3 KO CIA mice were restimulated with chicken CII protein in various concentrations. 5 mice per group each experiment. Cell proliferation was determined by 3H-TdR incorporation. Data shown are representative of 3 independent experiments. (G) Th1/Th2/Th17 Cytokine concentrations of cultured supernatants from chicken CII protein (20 μg/ml)-restimulated splenocytes (mixed 5 individual cells per group) after 1 and 2 days were assessed using mouse Th1/Th2/Th17 Cytokine kits (CBA); data were analyzed using FCAP Array V2.0. Data shown are representative of two independent experiments. Data are shown as mean ± SEM, *p<0.05, **p<0.01, ***p<0.001, versus control.
Mentions: CIA is the most widely used mouse model for rheumatoid arthritis, a common autoimmune disease. The CIA model is thought to be an auto-reactive T and B cell-dependent arthritis, and recent studies have suggested that Th17 cells play a central role in the pathogenesis of CIA. Therefore, we tested the effect of B7-H3 in the development of CIA. B7-H3 KO mice exhibited a later onset, an attenuated severity of arthritis based on the assigned arthritis score (Fig 6A), and a decreased severity in joint swelling (Fig 6B) compared with wt mice. Clinical observation was further verified by histological examination. H&E staining of arthritic paw joints from wt mice revealed severe synovial hyperplasia, infiltration of inflammatory cells, and destructive cartilage and bone. In contrast, the levels of inflammation, infiltration, and cartilage erosion were markedly alleviated in B7-H3 KO mice (Fig 6C). In addition, CII-specific IgG levels in sera from B7-H3 KO mice were significantly lower than those from wild type mice, as determined by ELISA 20 days after primary immunization (Fig 6D). Our results indicate that B7-H3 KO mice have significantly decreased symptoms of CIA.

Bottom Line: Here, we demonstrate that B7-H3 KO mice have significantly less inflammation, decreased pathogenesis, and limited disease progression in both EAE and CIA mouse models when compared with littermates; these results were accompanied by a decrease in IFN-γ and IL-17 production.Our results suggest B7-H3 has a costimulatory function on Th1/Th17 but a coinhibitory function on Th2 responses.Our studies reveal that B7-H3 could affect different T cell subsets which have important implications for regulating pathogenesis and disease progression in human autoimmune disease.

View Article: PubMed Central - PubMed

Affiliation: Institute of Immunotherapy, Sun Yat-Sen University, Guangzhou, Guangdong, China.

ABSTRACT
B7-H3 is a cell surface molecule in the immunoglobulin superfamily that is frequently upregulated in response to autoantigens and pathogens during host T cell immune responses. However, B7-H3's role in the differential regulation of T cell subsets remains largely unknown. Therefore, we constructed a new B7-H3 deficient mouse strain (B7-H3 KO) and evaluated the functions of B7-H3 in the regulation of Th1, Th2, and Th17 subsets in experimental autoimmune encephalomyelitis (EAE), experimental asthma, and collagen-induced arthritis (CIA); these mouse models were used to predict human immune responses in multiple sclerosis, asthma, and rheumatoid arthritis, respectively. Here, we demonstrate that B7-H3 KO mice have significantly less inflammation, decreased pathogenesis, and limited disease progression in both EAE and CIA mouse models when compared with littermates; these results were accompanied by a decrease in IFN-γ and IL-17 production. In sharp contrast, B7-H3 KO mice developed severe ovalbumin (OVA)-induced asthma with characteristic infiltrations of eosinophils in the lung, increased IL-5 and IL-13 in lavage fluid, and elevated IgE anti-OVA antibodies in the blood. Our results suggest B7-H3 has a costimulatory function on Th1/Th17 but a coinhibitory function on Th2 responses. Our studies reveal that B7-H3 could affect different T cell subsets which have important implications for regulating pathogenesis and disease progression in human autoimmune disease.

No MeSH data available.


Related in: MedlinePlus