Yijun Fan - Academia.edu (original) (raw)
Papers by Yijun Fan
Infection and Immunity, 1999
Chlamydia , especially Chlamydia pneumoniae , infection is closely associated with human cardiova... more Chlamydia , especially Chlamydia pneumoniae , infection is closely associated with human cardiovascular diseases. Thus far, however, few experimental studies have been carried out to investigate whether natural C. trachomatis infection can induce cardiovascular pathological changes. In this article, we report that pulmonary infection with C. trachomatis mouse pneumonitis strain (MoPn) can induce myocardial and perivascular inflammation and fibrosis in C57BL/6 mice. The pulmonary MoPn infection appeared to be disseminated systemically, because chlamydial antigens were readily detectable in multiple organs including the cardiovascular tissues. In addition, gamma interferon gene knockout mice with a C57BL/6 genetic background showed significant endocarditis and pancarditis characterized by vegetation in aortic valves, interstitial and pericardial inflammatory cellular infiltration, and growth of the organisms in the heart following respiratory tract MoPn infection. The results indicate...
Molecular medicine (Cambridge, Mass.), Jan 20, 2014
The role of interleukin-22 (IL-22) in intracellular bacterial infections is a controversial issue... more The role of interleukin-22 (IL-22) in intracellular bacterial infections is a controversial issue, although the contribution of this cytokine to host defense against extracellular bacterial pathogens has been well established. In this study, we focused on an intra-cellular bacterium, Chlamydia, and evaluated the production and function of IL-22 in host defense against chlamydial lung infection using a mouse model. We found that Chlamydia muridarum infection elicited quick IL-22 responses in the lung, which increased during infection and were reduced when bacterial loads decreased. More importantly, blockade of endogenous IL-22 using neutralizing anti-IL-22 monoclonal antibodies (mAb) resulted in more severe disease in the mice, leading to significantly higher weight loss and bacterial growth and much more severe pathological changes than treatment with isotype control antibody. Immunological analyses identified significantly lower T helper 1 (Th1) and Th17 responses in the IL-22-neu...
PLoS ONE, 2010
Background: Tuberculosis is a mycobacterial infection causing worldwide public health problems bu... more Background: Tuberculosis is a mycobacterial infection causing worldwide public health problems but the available vaccine is far from ideal. Type-1 T cell immunity has been shown to be critical for host defence against tuberculosis infection, but the role of dendritic cell (DC) subsets in pathogenesis of mycobacterial infection remains unclear. Methodology/Principal Findings: We examined the effectiveness of dendritic cell (DC) subsets in BCG-infected mice in generating immune responses beneficial for pathogen clearance and reduction of pathological reactions in the tissues following challenge infection. Our data showed that only the adoptive transfer of the subset of CD8a + DC isolated from infected mice (iCD8 + DC) generated significant protection, demonstrated by less mycobacterial growth and pathological changes in the lung and liver tissues in iCD8 + DC recipients than sham-treated control mice. The adoptive transfer of the CD8a 2 DC from the infected mice (iCD8 2 DC) not only failed to reduce bacterial growth, but enhanced inflammation characterized by diffuse heavy cellular infiltration. Notably, iCD8 2 DC produced significantly higher levels of IL-10 than iCD8 + DC and promoted more Th2 cytokine responses in in vitro DC-T cell co-culture and in vivo adoptive transfer experiments. Conclusions/Significance: The data indicate that in vivo BCG-primed CD8 + DC is the dominant DC subset in inducing protective immunity especially for reducing pathological reactions in infected tissues. The finding has implications for the rational improvement of the prophylactic and therapeutic approaches for controlling tuberculosis infection and related diseases.
The Journal of Immunology, 2011
Dendritic cells (DC) play a key role in establishing protective adaptive immunity in intracellula... more Dendritic cells (DC) play a key role in establishing protective adaptive immunity in intracellular bacterial infections, but the cells influencing DC function in vivo remain unclear. In this study, we investigated the role of NK cells in modulating the function of DC using a murine Chlamydia infection model. We found that the NK cell-depleted mice showed exacerbated disease after respiratory tract Chlamydia muridarum infection, which was correlated with altered T cell cytokine profile. Furthermore, DC from C. muridarum-infected NK-depleted mice (NK−DC) exhibited a less mature phenotype compared with that of DC from the infected mice without NK depletion (NK+DC). NK−DC produced significantly lower levels of both IL-12 and IL-10 than those of NK+DC. Moreover, NK−DC showed reduced ability to direct primary and established Ag-specific Th1 CD4+ T cell responses in DC–T coculture systems. More importantly, adoptive transfer of NK−DC, in contrast to NK+DC, failed to induce type 1 protectiv...
The Journal of Immunology, 2009
Although their contribution to host defense against extracellular infections has been well define... more Although their contribution to host defense against extracellular infections has been well defined, IL-17 and Th17 are generally thought to have limited impact on intracellular infections. In this study, we investigated the role and mechanisms of IL-17/Th17 in host defense against Chlamydia muridarum, an obligate intracellular bacterium, lung infection. Our data showed rapid increase in IL-17 production and expansion of Th17 cells following C. muridarum infection and significant detrimental impact of in vivo IL-17 neutralization by anti-IL-17 mAb on disease course, immune response, and dendritic cell (DC) function. Specifically, IL-17-neutralized mice exhibited significantly greater body weight loss, higher organism growth, and much more severe pathological changes in the lung compared with sham-treated control mice. Immunological analysis showed that IL-17 neutralization significantly reduced Chlamydia-specific Th1 responses, but increased Th2 responses. Interestingly, the DC isola...
The Journal of Immunology, 2007
Although the essential role of TNF-α in the control of intracellular pathogens including Leishman... more Although the essential role of TNF-α in the control of intracellular pathogens including Leishmania major is well established, it is uncertain whether the related cytokine lymphotoxin αβ2 (LTα1β2, membrane lymphotoxin) plays any role in this process. In this study, we investigated the contribution of membrane lymphotoxin in host response to L. major infection by using LTβ-deficient (LTβ−/−) mice on the resistant C57BL/6 background. Despite mounting early immune responses comparable to those of wild-type (WT) mice, LTβ−/− mice developed chronic nonhealing cutaneous lesions due to progressive and unresolving inflammation that is accompanied by uncontrolled parasite proliferation. This chronic disease was associated with striking reduction in IL-12 and Ag-specific IFN-γ production by splenocytes from infected mice. Consistent with defective cellular immune response, infected LTβ−/− mice had significantly low Ag-specific serum IgG1 and IgG2a levels compared with WT mice. Although admini...
The Journal of Immunology, 2007
We previously identified follicular dendritic cell secreted protein (FDC-SP), a small secreted pr... more We previously identified follicular dendritic cell secreted protein (FDC-SP), a small secreted protein of unknown function expressed in human tonsillar germinal centers (GC). To assess potential in vivo activities of FDC-SP, transgenic mice were generated to constitutively express FDC-SP in lymphoid tissues. FDC-SP transgenic mice show relatively normal development of immune cell populations, with the exception of a small increase in mature follicular B cells, and normal lymphoid tissue architecture. Upon immunization with a T-dependent Ag, FDC-SP transgenic mice were capable of producing an Ag-specific Ab; however, the titers of Ag-specific IgG2a and IgE were significantly reduced. GC responses after immunization were markedly diminished, with transgenic mice showing decreased numbers and sizes of GCs but normal development of follicular dendritic cell networks and normal positioning of GCs. FDC-SP transgenic mice also showed reduced production of Ag-specific IgG3 Ab after immuniza...
Journal of Cellular Physiology, 2005
Liver disease associated with cystic fibrosis (CF) has been increasingly diagnosed and recognized... more Liver disease associated with cystic fibrosis (CF) has been increasingly diagnosed and recognized as one of the major causes of death in CF during recent years. The autosomal-recessive disorder of CF results from mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) that encodes the CFTR protein. Due to its existence and multifunction in biliary epithelial, over- or less-expression of CFTR in the liver may play an important role in the development of CF liver disease (CFLD). The aim of current study is to investigate the expression of CFTR in the liver of common bile duct ligated (BDL) rats. After BDL, there was an increase in the abundance of CFTR mRNA and protein. Immunohistochemical staining also demonstrated an increased intensity of CFTR staining in the liver tissue section. In conclusion, there is an increased expression of CFTR in the liver after common BDL.
International Immunology, 2011
Inducible co-stimulator ligand (ICOSL) is a rather newly defined co-stimulatory molecule, which, ... more Inducible co-stimulator ligand (ICOSL) is a rather newly defined co-stimulatory molecule, which, through interaction with ICOS expressed on T cells, plays an important role in T-cell activation, differentiation and function. T h 2-type immune responses are critical for the development and maintenance of allergic responses including asthma. Using knockout (KO) mice, we have assessed the role of ICOSL in allergic airway inflammation and responsiveness using a standard mouse asthma model induced by ovalbumin (OVA) sensitization and challenge. Our data show that OVA-treated ICOSL KO mice exhibit significantly less lung eosinophilic infiltration, histopathology, mucus production and virtually no airway hyperresponsiveness in contrast to wild-type (Wt) counterparts. Serum antibody analysis showed that antigen-specific IgG1, IgG2a and IgE titers in ICOSL KO mice were significantly lower than those of Wt controls. Also, CD4 1 T cells isolated from ICOSL KO mice produced less T h 2 cytokines (IL-4, IL-5, IL-10 and IL-13) but more T h 1 (IFN-g) and IL-17 than their Wt controls. Taken together, we conclude that ICOSL plays an important role in predisposing individuals to allergic airway hyperresponsiveness by enhancing IgE antibody class switching and T h 2 cytokine production and diminishing the T h 17 response and airway eosinophilia.
Immunology, 2002
SummaryOur previous studies, as well as those of others, have demonstrated that local or systemic... more SummaryOur previous studies, as well as those of others, have demonstrated that local or systemic Mycobacterium bovis bacille Calmette–Gue´rin (BCG) infection can inhibit de novo allergen‐induced asthma‐like reactions, but the effect of this infection on established allergic responses is unknown. The aim of this study was therefore to examine the effect of mycobacterial infection on established allergy in a murine model of asthma‐like reaction. Mice were sensitized with ovalbumin (OVA) in alum followed by infection with BCG and subsequent intranasal challenge with the same allergen. In some experiments, mice were sensitized with OVA followed by intranasal challenge with OVA and then given BCG infection with subsequent rechallenge with OVA. Mice without BCG infection but treated with OVA in the same manner, were used as a control. The mice were examined for immunoglobulin E (IgE) response and eosinophilic inflammation, mucus production, cytokine/chemokine patterns and adhesion molecu...
Food Science and Technology Research, 2012
In this study, we obtained water-soluble nucleotide-extract from six kinds of edible fungi (Agroc... more In this study, we obtained water-soluble nucleotide-extract from six kinds of edible fungi (Agrocybe chaxingu, Lentinus edodes, Coprinus comatus gray, Agaricus bisporus, Armillariella mellea, Flammulina velutipes), and the extract from Agrocybe Chaxingu sporocarp exhibited the highest total reducing power and the most remarkable scavenging activity on 2,2′-azino-di(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), which had a good dose-response relationship with the concentration of water-soluble nucleotide. When the concentration of the nucleotide was 20 mg/mL, the ABTS scavenging rate could be 90%. The nucleotide-extract was also found to exhibit remarkable scavenging activity on hydroxyl radicals (EC 50 = 18.5 mg/mL), superoxide anion radicals (EC 50 = 38.4 mg/mL) and lipid peroxidation inhibition activity (EC 50 = 8.1 mg/mL). Moreover, the main nucleotides in the nucleotide-extract were identified by HPLC, which were respectively AMP, CMP, GMP, UMP, ADP, GDP and GTP in a molar ratio of 1:2.17:3.49:1.7 6:0.75:4.18:1.67. These results indicated that the nucleotide would be a new antioxidant with wonderful prospects.
European Journal of Immunology, 2009
It has been long proposed that exposure to environmental factors early in life may have an educat... more It has been long proposed that exposure to environmental factors early in life may have an educating effect on the development of immune regulatory functions. However, experimental studies on this issue are limited and the related molecular and cellular basis remains unclear. Here we report that neonatal exposure to killed bacteria (Chlamydia muridarum, originally called Chlamydia trachomatis mouse pneumonitis (MoPn)) changed the pattern of the hosts' immune responses to a model allergen (OVA) in adulthood. This was associated with altered phenotype and function of DC. We found that DC from adult mice treated neonatally with UV‐killed MoPn exhibited distinct patterns of surface marker and TLR expression and cytokine production from control mice (DC from adult mice neonatally treated with vehicle, (Sham‐DC)). More importantly, DC from adult mice treated neonatally with UV‐killed MoPn induced significantly lower type‐2 antigen‐specific T‐cell responses than Sham‐DC shown in DC:T c...
European Journal of Immunology, 2011
The hygiene hypothesis has suggested an inhibitory effect of infections on allergic diseases, but... more The hygiene hypothesis has suggested an inhibitory effect of infections on allergic diseases, but the related mechanism remains unclear. We recently reported that DCs played a critical role in Mycobacterium bovis Bacille Calmette-Gué rin (BCG)-mediated inhibition of allergy, which depended on IL-12 and IL-10-related mechanisms. Here, we tested the hypothesis that BCG infection could modulate the function of DC subsets, which might in turn inhibit allergic responses through different mechanisms. We sorted CD8a 1 and CD8a À DCs from BCG-infected mice and tested their ability to modulate Th2-cell responses to ovalbumin (OVA) using in vitro and in vivo approaches. We found that both DC subsets could inhibit the allergic Th2-cell response in both a DC:T-cell co-culture system and after adoptive transfer. These subsets exhibited different co-stimulatory marker expression and cytokine production patterns and were different in inducing Th1 and Treg cells. Specifically, we found that CD8a 1 DCs produced higher IL-12, inducing higher Th1 cell response, while CD8a À DCs expressed higher ICOS-L and produced higher IL-10, inducing CD4 1 CD25 1 FoxP3 1 Treg cells with IL-10 production and membrane-bound TGF-b expression. The finding suggests that one infection may inhibit allergy by both immune deviation and regulation mechanisms through modulation of DC subsets.
European Journal of Immunology, 2004
Although NKT cells have been found to be capable of modulating immune responses in several model ... more Although NKT cells have been found to be capable of modulating immune responses in several model systems, the role of NKT cells in allergy remains unclear. Using CD1 gene knockout (KO) mice, which lack NKT cells, we examined the function of NKT cells in the development of allergic inflammation induced by a common airborne human allergen, ragweed. The data showed that airway eosinophilia and mucus overproduction induced by ragweed were significantly reduced in CD1 KO mice, which was correlated with significantly lower allergendriven IL-4 production and lower eotaxin responses in the airways of CD1 KO mice. Moreover, both ragweed-specific and total serum IgE levels in CD1 KO mice were significantly lower than those in control BALB/c mice. The reduced allergic reaction in CD1 KO mice is not due to intrinsic deficiency because they showed normal levels of immune cells and function. In addition, in vivo stimulation of NKT cells using their natural ligand, §galactosylceramide, enhanced ragweed-induced airway eosinophilia, IL-4, and eotaxin production in control, but not CD1 KO mice. These data provide in vivo evidence for the involvement of NKT cells in the allergic mechanisms responsible for allergen-driven cytokine and chemokine production and airway inflammation.
European Journal of Immunology, 2004
Our previous study has shown that Chlamydia lung infection can inhibit local eosinophilic inflamm... more Our previous study has shown that Chlamydia lung infection can inhibit local eosinophilic inflammation induced by allergen sensitization and challenge, which is correlated with altered cytokine production. In the present study, we examined the role played by dendritic cells (DC) in chlamydial infection‐mediated modulation of allergic responses. The results showed that DC freshlyisolated from Chlamydia‐infected mice (iIDC), unlike those from naive control mice (iNDC), could efficiently modulate immune responses to ovalbumin in vitro and in vivo. Co‐culture of freshly isolated DC with naive CD4 cells from T cell receptor transgenic mice (DO11.10) showed that iIDC directed Th1‐dominant, while iNDC directed Th2‐dominant, allergen‐specific CD4 T cell responses. Moreover, adoptive transfer of iIDC, but not iNDC, could inhibit systemic and local eosinophilia induced by allergen exposure. The reduction of eosinophilia was associated with a decrease in IL‐5 receptor expression on bone marrow...
Clinical Immunology, 2002
While much progress has been achieved in controlling infectious diseases, there is a startling in... more While much progress has been achieved in controlling infectious diseases, there is a startling increase in the prevalence of allergic disorders in developed countries. Previous studies using experimental murine models of asthma have demonstrated that mycobacterial infections are capable of suppressing asthma-like reactions induced by ovalbumin (OVA). Using a different intracellular bacterium, Chlamydia trachomatis mouse pneumonitis (MoPn), we examined the effect of infection on the development of allergic responses to a common natural airborne allergen, ragweed (RW). The data showed that airway eosinophilia induced by ragweed sensitization/challenge was significantly reduced in MoPn-infected mice. MoPn-infected mice also exhibited significantly lower levels of allergen-driven Th2 cytokine production, namely IL-4, IL-5, IL-10, and IL-13, following ragweed exposure in comparison with those treated with ragweed only. Additionally, the production of eotaxin, a CC chemokine for eosinophil chemoattraction following RW exposure, was significantly reduced in the lungs of MoPninfected mice. However, MoPn infection did not reduce the levels of RW-specific IgE and IgG1 production in the sera, nor did it diminish the level of total serum IgE. These data provide evidence that the suppression of the allergic airway inflammation induced by a common environmental allergen is attainable through intracellular bacterial infection.
American Journal of Respiratory and Critical Care Medicine, 2008
Rationale: We previously showed an important role of natural killer T cells (NKT) in skewing the ... more Rationale: We previously showed an important role of natural killer T cells (NKT) in skewing the adaptive T cell immunity to Chlamydia pneumoniae (Cpn), an intracellular bacterial lung infection, but the mechanism remains unclear. Objectives: To investigate the underlying mechanism by which NKT modulate T cell responses in chlamydial pneumonia. Methods: We examined the effect of NKT activation in modulating DC function, especially in generating protective immunity against Cpn infection using combination of NKT knockout (KO) mice and specific NKT activation approaches. Measurements and Main Results: We found that NKT activation in vivo after Cpn infection induces phenotypic and functional changes in dendritic cells (DC). DC from NKT-deficient mice showed reduced CD40 expression and IL-12 production, whereas enhancing NKT activation using a-GalCer increased CD40 expression and IL-12 production. Co-culture of DC with NKT enhanced bioactive IL-12p70 production by DC in a CD40L-, IFN-g-, and cell-cell contactdependent manner. Further, co-culture of T cells with DC isolated from infected wild-type (WT) and NKT-deficient mice induced type-1 and type-2 responses, respectively, while DC from a-GalCertreated, infected mice led to enhanced type-1 responses. Moreover, upon adoptive transfer, DC from infected WT mice induced strong type-1 immunity, whereas those from knockout mice induced type-2 responses and increased disease severity upon challenge infection. Conclusions: Our results provide direct evidence of the critical role of NKT activation in the functional modulation of DC for the development of protective immunity in a clinically relevant respiratory infection.
The Journal of Immunology, 2006
Our previous study has shown that the adoptive transfer of dendritic cells (DCs) freshly isolated... more Our previous study has shown that the adoptive transfer of dendritic cells (DCs) freshly isolated from Chlamydia-infected mice (iIDCs), unlike those from control naive mice (iNDCs), can inhibit systemic and cutaneous eosinophilia induced by OVA exposure. In the present study, we examined the mechanism by which iIDC inhibits allergen-specific Th2 cell differentiation in vitro and in vivo. The study revealed that iIDCs exhibited higher surface expression of CD8α and the ICOS ligand (ICOS-L), as well as higher IL-10 and IL-12 production than iNDCs. In vitro DC:CD4+ T cell coculture experiments showed that iIDCs could inhibit allergen-specific Th2 cell differentiation and that the inhibitory effect could be abolished by the blockage of IL-10 or IL-12 activity. More interestingly, the coblockade of IL-10 and the ICOS-L showed synergistic effect in enhancing allergen-driven Th2 cytokine production. Furthermore, adoptive transfer of iIDCs, but not iNDCs, to OVA sensitized mice significantl...
Infection and Immunity, 1999
Chlamydia , especially Chlamydia pneumoniae , infection is closely associated with human cardiova... more Chlamydia , especially Chlamydia pneumoniae , infection is closely associated with human cardiovascular diseases. Thus far, however, few experimental studies have been carried out to investigate whether natural C. trachomatis infection can induce cardiovascular pathological changes. In this article, we report that pulmonary infection with C. trachomatis mouse pneumonitis strain (MoPn) can induce myocardial and perivascular inflammation and fibrosis in C57BL/6 mice. The pulmonary MoPn infection appeared to be disseminated systemically, because chlamydial antigens were readily detectable in multiple organs including the cardiovascular tissues. In addition, gamma interferon gene knockout mice with a C57BL/6 genetic background showed significant endocarditis and pancarditis characterized by vegetation in aortic valves, interstitial and pericardial inflammatory cellular infiltration, and growth of the organisms in the heart following respiratory tract MoPn infection. The results indicate...
Molecular medicine (Cambridge, Mass.), Jan 20, 2014
The role of interleukin-22 (IL-22) in intracellular bacterial infections is a controversial issue... more The role of interleukin-22 (IL-22) in intracellular bacterial infections is a controversial issue, although the contribution of this cytokine to host defense against extracellular bacterial pathogens has been well established. In this study, we focused on an intra-cellular bacterium, Chlamydia, and evaluated the production and function of IL-22 in host defense against chlamydial lung infection using a mouse model. We found that Chlamydia muridarum infection elicited quick IL-22 responses in the lung, which increased during infection and were reduced when bacterial loads decreased. More importantly, blockade of endogenous IL-22 using neutralizing anti-IL-22 monoclonal antibodies (mAb) resulted in more severe disease in the mice, leading to significantly higher weight loss and bacterial growth and much more severe pathological changes than treatment with isotype control antibody. Immunological analyses identified significantly lower T helper 1 (Th1) and Th17 responses in the IL-22-neu...
PLoS ONE, 2010
Background: Tuberculosis is a mycobacterial infection causing worldwide public health problems bu... more Background: Tuberculosis is a mycobacterial infection causing worldwide public health problems but the available vaccine is far from ideal. Type-1 T cell immunity has been shown to be critical for host defence against tuberculosis infection, but the role of dendritic cell (DC) subsets in pathogenesis of mycobacterial infection remains unclear. Methodology/Principal Findings: We examined the effectiveness of dendritic cell (DC) subsets in BCG-infected mice in generating immune responses beneficial for pathogen clearance and reduction of pathological reactions in the tissues following challenge infection. Our data showed that only the adoptive transfer of the subset of CD8a + DC isolated from infected mice (iCD8 + DC) generated significant protection, demonstrated by less mycobacterial growth and pathological changes in the lung and liver tissues in iCD8 + DC recipients than sham-treated control mice. The adoptive transfer of the CD8a 2 DC from the infected mice (iCD8 2 DC) not only failed to reduce bacterial growth, but enhanced inflammation characterized by diffuse heavy cellular infiltration. Notably, iCD8 2 DC produced significantly higher levels of IL-10 than iCD8 + DC and promoted more Th2 cytokine responses in in vitro DC-T cell co-culture and in vivo adoptive transfer experiments. Conclusions/Significance: The data indicate that in vivo BCG-primed CD8 + DC is the dominant DC subset in inducing protective immunity especially for reducing pathological reactions in infected tissues. The finding has implications for the rational improvement of the prophylactic and therapeutic approaches for controlling tuberculosis infection and related diseases.
The Journal of Immunology, 2011
Dendritic cells (DC) play a key role in establishing protective adaptive immunity in intracellula... more Dendritic cells (DC) play a key role in establishing protective adaptive immunity in intracellular bacterial infections, but the cells influencing DC function in vivo remain unclear. In this study, we investigated the role of NK cells in modulating the function of DC using a murine Chlamydia infection model. We found that the NK cell-depleted mice showed exacerbated disease after respiratory tract Chlamydia muridarum infection, which was correlated with altered T cell cytokine profile. Furthermore, DC from C. muridarum-infected NK-depleted mice (NK−DC) exhibited a less mature phenotype compared with that of DC from the infected mice without NK depletion (NK+DC). NK−DC produced significantly lower levels of both IL-12 and IL-10 than those of NK+DC. Moreover, NK−DC showed reduced ability to direct primary and established Ag-specific Th1 CD4+ T cell responses in DC–T coculture systems. More importantly, adoptive transfer of NK−DC, in contrast to NK+DC, failed to induce type 1 protectiv...
The Journal of Immunology, 2009
Although their contribution to host defense against extracellular infections has been well define... more Although their contribution to host defense against extracellular infections has been well defined, IL-17 and Th17 are generally thought to have limited impact on intracellular infections. In this study, we investigated the role and mechanisms of IL-17/Th17 in host defense against Chlamydia muridarum, an obligate intracellular bacterium, lung infection. Our data showed rapid increase in IL-17 production and expansion of Th17 cells following C. muridarum infection and significant detrimental impact of in vivo IL-17 neutralization by anti-IL-17 mAb on disease course, immune response, and dendritic cell (DC) function. Specifically, IL-17-neutralized mice exhibited significantly greater body weight loss, higher organism growth, and much more severe pathological changes in the lung compared with sham-treated control mice. Immunological analysis showed that IL-17 neutralization significantly reduced Chlamydia-specific Th1 responses, but increased Th2 responses. Interestingly, the DC isola...
The Journal of Immunology, 2007
Although the essential role of TNF-α in the control of intracellular pathogens including Leishman... more Although the essential role of TNF-α in the control of intracellular pathogens including Leishmania major is well established, it is uncertain whether the related cytokine lymphotoxin αβ2 (LTα1β2, membrane lymphotoxin) plays any role in this process. In this study, we investigated the contribution of membrane lymphotoxin in host response to L. major infection by using LTβ-deficient (LTβ−/−) mice on the resistant C57BL/6 background. Despite mounting early immune responses comparable to those of wild-type (WT) mice, LTβ−/− mice developed chronic nonhealing cutaneous lesions due to progressive and unresolving inflammation that is accompanied by uncontrolled parasite proliferation. This chronic disease was associated with striking reduction in IL-12 and Ag-specific IFN-γ production by splenocytes from infected mice. Consistent with defective cellular immune response, infected LTβ−/− mice had significantly low Ag-specific serum IgG1 and IgG2a levels compared with WT mice. Although admini...
The Journal of Immunology, 2007
We previously identified follicular dendritic cell secreted protein (FDC-SP), a small secreted pr... more We previously identified follicular dendritic cell secreted protein (FDC-SP), a small secreted protein of unknown function expressed in human tonsillar germinal centers (GC). To assess potential in vivo activities of FDC-SP, transgenic mice were generated to constitutively express FDC-SP in lymphoid tissues. FDC-SP transgenic mice show relatively normal development of immune cell populations, with the exception of a small increase in mature follicular B cells, and normal lymphoid tissue architecture. Upon immunization with a T-dependent Ag, FDC-SP transgenic mice were capable of producing an Ag-specific Ab; however, the titers of Ag-specific IgG2a and IgE were significantly reduced. GC responses after immunization were markedly diminished, with transgenic mice showing decreased numbers and sizes of GCs but normal development of follicular dendritic cell networks and normal positioning of GCs. FDC-SP transgenic mice also showed reduced production of Ag-specific IgG3 Ab after immuniza...
Journal of Cellular Physiology, 2005
Liver disease associated with cystic fibrosis (CF) has been increasingly diagnosed and recognized... more Liver disease associated with cystic fibrosis (CF) has been increasingly diagnosed and recognized as one of the major causes of death in CF during recent years. The autosomal-recessive disorder of CF results from mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) that encodes the CFTR protein. Due to its existence and multifunction in biliary epithelial, over- or less-expression of CFTR in the liver may play an important role in the development of CF liver disease (CFLD). The aim of current study is to investigate the expression of CFTR in the liver of common bile duct ligated (BDL) rats. After BDL, there was an increase in the abundance of CFTR mRNA and protein. Immunohistochemical staining also demonstrated an increased intensity of CFTR staining in the liver tissue section. In conclusion, there is an increased expression of CFTR in the liver after common BDL.
International Immunology, 2011
Inducible co-stimulator ligand (ICOSL) is a rather newly defined co-stimulatory molecule, which, ... more Inducible co-stimulator ligand (ICOSL) is a rather newly defined co-stimulatory molecule, which, through interaction with ICOS expressed on T cells, plays an important role in T-cell activation, differentiation and function. T h 2-type immune responses are critical for the development and maintenance of allergic responses including asthma. Using knockout (KO) mice, we have assessed the role of ICOSL in allergic airway inflammation and responsiveness using a standard mouse asthma model induced by ovalbumin (OVA) sensitization and challenge. Our data show that OVA-treated ICOSL KO mice exhibit significantly less lung eosinophilic infiltration, histopathology, mucus production and virtually no airway hyperresponsiveness in contrast to wild-type (Wt) counterparts. Serum antibody analysis showed that antigen-specific IgG1, IgG2a and IgE titers in ICOSL KO mice were significantly lower than those of Wt controls. Also, CD4 1 T cells isolated from ICOSL KO mice produced less T h 2 cytokines (IL-4, IL-5, IL-10 and IL-13) but more T h 1 (IFN-g) and IL-17 than their Wt controls. Taken together, we conclude that ICOSL plays an important role in predisposing individuals to allergic airway hyperresponsiveness by enhancing IgE antibody class switching and T h 2 cytokine production and diminishing the T h 17 response and airway eosinophilia.
Immunology, 2002
SummaryOur previous studies, as well as those of others, have demonstrated that local or systemic... more SummaryOur previous studies, as well as those of others, have demonstrated that local or systemic Mycobacterium bovis bacille Calmette–Gue´rin (BCG) infection can inhibit de novo allergen‐induced asthma‐like reactions, but the effect of this infection on established allergic responses is unknown. The aim of this study was therefore to examine the effect of mycobacterial infection on established allergy in a murine model of asthma‐like reaction. Mice were sensitized with ovalbumin (OVA) in alum followed by infection with BCG and subsequent intranasal challenge with the same allergen. In some experiments, mice were sensitized with OVA followed by intranasal challenge with OVA and then given BCG infection with subsequent rechallenge with OVA. Mice without BCG infection but treated with OVA in the same manner, were used as a control. The mice were examined for immunoglobulin E (IgE) response and eosinophilic inflammation, mucus production, cytokine/chemokine patterns and adhesion molecu...
Food Science and Technology Research, 2012
In this study, we obtained water-soluble nucleotide-extract from six kinds of edible fungi (Agroc... more In this study, we obtained water-soluble nucleotide-extract from six kinds of edible fungi (Agrocybe chaxingu, Lentinus edodes, Coprinus comatus gray, Agaricus bisporus, Armillariella mellea, Flammulina velutipes), and the extract from Agrocybe Chaxingu sporocarp exhibited the highest total reducing power and the most remarkable scavenging activity on 2,2′-azino-di(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), which had a good dose-response relationship with the concentration of water-soluble nucleotide. When the concentration of the nucleotide was 20 mg/mL, the ABTS scavenging rate could be 90%. The nucleotide-extract was also found to exhibit remarkable scavenging activity on hydroxyl radicals (EC 50 = 18.5 mg/mL), superoxide anion radicals (EC 50 = 38.4 mg/mL) and lipid peroxidation inhibition activity (EC 50 = 8.1 mg/mL). Moreover, the main nucleotides in the nucleotide-extract were identified by HPLC, which were respectively AMP, CMP, GMP, UMP, ADP, GDP and GTP in a molar ratio of 1:2.17:3.49:1.7 6:0.75:4.18:1.67. These results indicated that the nucleotide would be a new antioxidant with wonderful prospects.
European Journal of Immunology, 2009
It has been long proposed that exposure to environmental factors early in life may have an educat... more It has been long proposed that exposure to environmental factors early in life may have an educating effect on the development of immune regulatory functions. However, experimental studies on this issue are limited and the related molecular and cellular basis remains unclear. Here we report that neonatal exposure to killed bacteria (Chlamydia muridarum, originally called Chlamydia trachomatis mouse pneumonitis (MoPn)) changed the pattern of the hosts' immune responses to a model allergen (OVA) in adulthood. This was associated with altered phenotype and function of DC. We found that DC from adult mice treated neonatally with UV‐killed MoPn exhibited distinct patterns of surface marker and TLR expression and cytokine production from control mice (DC from adult mice neonatally treated with vehicle, (Sham‐DC)). More importantly, DC from adult mice treated neonatally with UV‐killed MoPn induced significantly lower type‐2 antigen‐specific T‐cell responses than Sham‐DC shown in DC:T c...
European Journal of Immunology, 2011
The hygiene hypothesis has suggested an inhibitory effect of infections on allergic diseases, but... more The hygiene hypothesis has suggested an inhibitory effect of infections on allergic diseases, but the related mechanism remains unclear. We recently reported that DCs played a critical role in Mycobacterium bovis Bacille Calmette-Gué rin (BCG)-mediated inhibition of allergy, which depended on IL-12 and IL-10-related mechanisms. Here, we tested the hypothesis that BCG infection could modulate the function of DC subsets, which might in turn inhibit allergic responses through different mechanisms. We sorted CD8a 1 and CD8a À DCs from BCG-infected mice and tested their ability to modulate Th2-cell responses to ovalbumin (OVA) using in vitro and in vivo approaches. We found that both DC subsets could inhibit the allergic Th2-cell response in both a DC:T-cell co-culture system and after adoptive transfer. These subsets exhibited different co-stimulatory marker expression and cytokine production patterns and were different in inducing Th1 and Treg cells. Specifically, we found that CD8a 1 DCs produced higher IL-12, inducing higher Th1 cell response, while CD8a À DCs expressed higher ICOS-L and produced higher IL-10, inducing CD4 1 CD25 1 FoxP3 1 Treg cells with IL-10 production and membrane-bound TGF-b expression. The finding suggests that one infection may inhibit allergy by both immune deviation and regulation mechanisms through modulation of DC subsets.
European Journal of Immunology, 2004
Although NKT cells have been found to be capable of modulating immune responses in several model ... more Although NKT cells have been found to be capable of modulating immune responses in several model systems, the role of NKT cells in allergy remains unclear. Using CD1 gene knockout (KO) mice, which lack NKT cells, we examined the function of NKT cells in the development of allergic inflammation induced by a common airborne human allergen, ragweed. The data showed that airway eosinophilia and mucus overproduction induced by ragweed were significantly reduced in CD1 KO mice, which was correlated with significantly lower allergendriven IL-4 production and lower eotaxin responses in the airways of CD1 KO mice. Moreover, both ragweed-specific and total serum IgE levels in CD1 KO mice were significantly lower than those in control BALB/c mice. The reduced allergic reaction in CD1 KO mice is not due to intrinsic deficiency because they showed normal levels of immune cells and function. In addition, in vivo stimulation of NKT cells using their natural ligand, §galactosylceramide, enhanced ragweed-induced airway eosinophilia, IL-4, and eotaxin production in control, but not CD1 KO mice. These data provide in vivo evidence for the involvement of NKT cells in the allergic mechanisms responsible for allergen-driven cytokine and chemokine production and airway inflammation.
European Journal of Immunology, 2004
Our previous study has shown that Chlamydia lung infection can inhibit local eosinophilic inflamm... more Our previous study has shown that Chlamydia lung infection can inhibit local eosinophilic inflammation induced by allergen sensitization and challenge, which is correlated with altered cytokine production. In the present study, we examined the role played by dendritic cells (DC) in chlamydial infection‐mediated modulation of allergic responses. The results showed that DC freshlyisolated from Chlamydia‐infected mice (iIDC), unlike those from naive control mice (iNDC), could efficiently modulate immune responses to ovalbumin in vitro and in vivo. Co‐culture of freshly isolated DC with naive CD4 cells from T cell receptor transgenic mice (DO11.10) showed that iIDC directed Th1‐dominant, while iNDC directed Th2‐dominant, allergen‐specific CD4 T cell responses. Moreover, adoptive transfer of iIDC, but not iNDC, could inhibit systemic and local eosinophilia induced by allergen exposure. The reduction of eosinophilia was associated with a decrease in IL‐5 receptor expression on bone marrow...
Clinical Immunology, 2002
While much progress has been achieved in controlling infectious diseases, there is a startling in... more While much progress has been achieved in controlling infectious diseases, there is a startling increase in the prevalence of allergic disorders in developed countries. Previous studies using experimental murine models of asthma have demonstrated that mycobacterial infections are capable of suppressing asthma-like reactions induced by ovalbumin (OVA). Using a different intracellular bacterium, Chlamydia trachomatis mouse pneumonitis (MoPn), we examined the effect of infection on the development of allergic responses to a common natural airborne allergen, ragweed (RW). The data showed that airway eosinophilia induced by ragweed sensitization/challenge was significantly reduced in MoPn-infected mice. MoPn-infected mice also exhibited significantly lower levels of allergen-driven Th2 cytokine production, namely IL-4, IL-5, IL-10, and IL-13, following ragweed exposure in comparison with those treated with ragweed only. Additionally, the production of eotaxin, a CC chemokine for eosinophil chemoattraction following RW exposure, was significantly reduced in the lungs of MoPninfected mice. However, MoPn infection did not reduce the levels of RW-specific IgE and IgG1 production in the sera, nor did it diminish the level of total serum IgE. These data provide evidence that the suppression of the allergic airway inflammation induced by a common environmental allergen is attainable through intracellular bacterial infection.
American Journal of Respiratory and Critical Care Medicine, 2008
Rationale: We previously showed an important role of natural killer T cells (NKT) in skewing the ... more Rationale: We previously showed an important role of natural killer T cells (NKT) in skewing the adaptive T cell immunity to Chlamydia pneumoniae (Cpn), an intracellular bacterial lung infection, but the mechanism remains unclear. Objectives: To investigate the underlying mechanism by which NKT modulate T cell responses in chlamydial pneumonia. Methods: We examined the effect of NKT activation in modulating DC function, especially in generating protective immunity against Cpn infection using combination of NKT knockout (KO) mice and specific NKT activation approaches. Measurements and Main Results: We found that NKT activation in vivo after Cpn infection induces phenotypic and functional changes in dendritic cells (DC). DC from NKT-deficient mice showed reduced CD40 expression and IL-12 production, whereas enhancing NKT activation using a-GalCer increased CD40 expression and IL-12 production. Co-culture of DC with NKT enhanced bioactive IL-12p70 production by DC in a CD40L-, IFN-g-, and cell-cell contactdependent manner. Further, co-culture of T cells with DC isolated from infected wild-type (WT) and NKT-deficient mice induced type-1 and type-2 responses, respectively, while DC from a-GalCertreated, infected mice led to enhanced type-1 responses. Moreover, upon adoptive transfer, DC from infected WT mice induced strong type-1 immunity, whereas those from knockout mice induced type-2 responses and increased disease severity upon challenge infection. Conclusions: Our results provide direct evidence of the critical role of NKT activation in the functional modulation of DC for the development of protective immunity in a clinically relevant respiratory infection.
The Journal of Immunology, 2006
Our previous study has shown that the adoptive transfer of dendritic cells (DCs) freshly isolated... more Our previous study has shown that the adoptive transfer of dendritic cells (DCs) freshly isolated from Chlamydia-infected mice (iIDCs), unlike those from control naive mice (iNDCs), can inhibit systemic and cutaneous eosinophilia induced by OVA exposure. In the present study, we examined the mechanism by which iIDC inhibits allergen-specific Th2 cell differentiation in vitro and in vivo. The study revealed that iIDCs exhibited higher surface expression of CD8α and the ICOS ligand (ICOS-L), as well as higher IL-10 and IL-12 production than iNDCs. In vitro DC:CD4+ T cell coculture experiments showed that iIDCs could inhibit allergen-specific Th2 cell differentiation and that the inhibitory effect could be abolished by the blockage of IL-10 or IL-12 activity. More interestingly, the coblockade of IL-10 and the ICOS-L showed synergistic effect in enhancing allergen-driven Th2 cytokine production. Furthermore, adoptive transfer of iIDCs, but not iNDCs, to OVA sensitized mice significantl...