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1.
J Virol ; 93(16)2019 08 15.
Article in English | MEDLINE | ID: mdl-31142672

ABSTRACT

Previously, we reported that the absence of herpesvirus entry mediator (HVEM) decreases latency but not primary infection in ocularly infected mice. Recently, we reported that similar to the absence of HVEM, the absence of HVEM ligands (i.e., LIGHT, CD160, and B and T lymphocyte attenuator [BTLA]) also decreased latency but not primary infection. Similar to LIGHT, CD160, and BTLA, another member of tumor necrosis factor (TNF) superfamily, lymphotoxin-α (LTα), also interacts with HVEM. To determine whether LTα decreases latency in infected mice, we ocularly infected LTα-/- mice with latency-associated transcript-positive [LAT(+)] and LAT(-) viruses using similarly infected wild-type (WT) mice as controls. In contrast to WT C57BL/6 mice, LTα-/- mice were highly susceptible to ocular herpes simplex virus 1 (HSV-1) infection, independent of the presence or absence of LAT. Survival was partially restored by adoptive transfer of CD4+, CD8+, or total T cells. Infected LTα-/- mice had significantly higher corneal scarring than WT mice, and adoptive T cell transfer did not alter the severity of eye disease. In contrast to results in WT mice, the amount of latency was not affected by the absence of LAT. The amount of LAT RNA in LTα-/- mice infected with LAT(+) virus was similar to that in WT mice, and adoptive T cell transfer did not alter LAT RNA levels in LTα-/- infected mice. Increased latency in the absence of LTα correlated with upregulation of HVEM, LIGHT, CD160, and BTLA transcripts as well as with an increase in markers of T cell exhaustion. The results of our study suggest that LTα has antipathogenic and anti-inflammatory functions and may act to protect the host from infection.IMPORTANCE Recently, we evaluated the effects of HVEM and its ligands (LIGHT, CD160, and BTLA) on HSV-1 infectivity. However, the effect of LTα, another member of the TNF superfamily, on HSV-1 latency and eye disease is not known. Here, we demonstrate increased latency and corneal scarring in LTα-/- infected mice, independent of the presence of LAT. In addition, infected mice were highly susceptible to HSV-1 infection, and survival was partially but not significantly restored by adoptive T cell transfer. These results suggest that the absence of LTα affects HSV-1 infectivity differently than the absence of HVEM, LIGHT, CD160, and BTLA.


Subject(s)
Herpes Simplex/etiology , Herpes Simplex/metabolism , Herpesvirus 1, Human/physiology , Lymphotoxin-alpha/deficiency , Tumor Necrosis Factor Ligand Superfamily Member 14/metabolism , Animals , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Disease Susceptibility , Herpes Simplex/mortality , Herpes Simplex/pathology , Keratitis/virology , Lymphotoxin-alpha/genetics , Lymphotoxin-alpha/metabolism , Mice , Tumor Necrosis Factors/genetics , Tumor Necrosis Factors/metabolism , Viral Load , Viral Proteins/genetics , Virus Internalization , Virus Latency/genetics
2.
Toxicology ; 390: 100-108, 2017 09 01.
Article in English | MEDLINE | ID: mdl-28917655

ABSTRACT

BACKGROUND: Exposure to ambient fine particulate matter (PM2.5) is associated with increased cardiometabolic morbidity and mortality. This is widely believed to be attributable to PM2.5 exposure-induced pulmonary and subsequent systemic inflammation. Tumor necrosis factor alpha (TNFα), lymphotoxin α (LTα), and lymphotoxin ß (LTß) are three homologous pro-inflammatory cytokines, each with both unique and redundant activities in inflammation. Their role in PM2.5 exposure-induced inflammation and adverse cardiometabolic effects has to be determined. METHODS AND RESULTS: LTα/TNFα/LTß triple-knockout (TNF/LT KO) and wildtype (WT) mice were exposed to concentrated ambient PM2.5 (CAP) for 5 months. Lung pathological analysis revealed that TNF/LT deficiency reduced CAP exposure-induced pulmonary inflammation. However, glucose homeostasis assessments showed that TNF/LT deficiency significantly aggravated CAP exposure-induced glucose intolerance and insulin resistance. Consistent with glucose homeostasis assessments, CAP exposure significantly increased the body weight and adiposity of TNF/LT KO but not WT mice. In contrast to its body weight effects, CAP exposure reduced food intake of WT but not TNF/LT KO mice. On the other hand, CAP exposure induced marked fat droplet accumulation in brown adipose tissues of WT mice and significantly decreased their uncoupling protein 1 (UCP1) expression, and these effects were markedly exacerbated in TNF/LT KO mice. CONCLUSION: The present study suggests that TNF/LT deficiency influences PM2.5 exposure-induced response of energy metabolism through alterations in both food intake and energy expenditure.


Subject(s)
Gene Silencing , Glucose Metabolism Disorders/chemically induced , Lymphotoxin-alpha/deficiency , Lymphotoxin-beta/deficiency , Obesity/chemically induced , Particulate Matter/toxicity , Pneumonia/prevention & control , Tumor Necrosis Factor-alpha/deficiency , Adipose Tissue, Brown/drug effects , Adipose Tissue, Brown/metabolism , Adipose Tissue, Brown/physiopathology , Adipose Tissue, White/drug effects , Adipose Tissue, White/metabolism , Adipose Tissue, White/physiopathology , Adiposity/drug effects , Animals , Biomarkers/blood , Blood Glucose/drug effects , Blood Glucose/metabolism , Eating/drug effects , Energy Metabolism/drug effects , Genotype , Glucose Metabolism Disorders/genetics , Glucose Metabolism Disorders/metabolism , Insulin/blood , Insulin Resistance , Lipid Droplets/drug effects , Lipid Droplets/metabolism , Lymphotoxin-alpha/genetics , Lymphotoxin-beta/genetics , Mice, Inbred C57BL , Mice, Knockout , Obesity/genetics , Obesity/metabolism , Obesity/physiopathology , Particle Size , Phenotype , Pneumonia/chemically induced , Pneumonia/genetics , Pneumonia/metabolism , Time Factors , Tumor Necrosis Factor-alpha/genetics , Uncoupling Protein 1/metabolism
3.
J Virol ; 87(1): 524-30, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23097456

ABSTRACT

Rotavirus is a major cause of pediatric diarrheal illness worldwide. To explore the role of organized intestinal lymphoid tissues in infection by and immunity to rotavirus, lymphotoxin alpha-deficient (LTα(-/-)) mice that lack Peyer's patches and mesenteric lymph nodes were orally infected with murine rotavirus. Systemic rotavirus was cleared within 10 days in both LTα(-/-) and wild-type mice, and both strains developed early and sustained serum antirotavirus antibody responses. However, unlike wild-type mice, which resolved the intestinal infection within 10 days, LTα(-/-) mice shed fecal virus for approximately 50 days after inoculation. The resolution of fecal virus shedding occurred concurrently with induction of intestinal rotavirus-specific IgA in both mouse strains. Induction of intestinal rotavirus-specific IgA in LTα(-/-) mice correlated with the (late) appearance of IgA-producing plasma cells in the small intestine. This, together with the absence of rotavirus-specific serum IgA, implies that secretory rotavirus-specific IgA was produced locally. These findings indicate that serum IgG responses are insufficient and imply that local intestinal IgA responses are important for the clearance of rotavirus from intestinal tissues. Furthermore, they show that while LTα-dependent lymphoid tissues are important for the generation of IgA-producing B cells in the intestine, they are not absolutely required in the setting of rotavirus infection. Moreover, the induction of local IgA-producing B cell responses can occur late after infection and in an LTα-independent manner.


Subject(s)
Immunity, Mucosal , Immunoglobulin A/immunology , Lymphotoxin-alpha/deficiency , Rotavirus Infections/immunology , Rotavirus/immunology , Animals , Antibodies, Viral/blood , Antibodies, Viral/immunology , B-Lymphocytes/immunology , Feces/virology , Female , Immunoglobulin A/blood , Intestine, Small/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Plasma Cells/immunology , Time Factors , Virus Shedding
4.
Nat Immunol ; 13(10): 947-53, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22922363

ABSTRACT

Microbiota are essential for weight gain in mouse models of diet-induced obesity (DIO), but the pathways that cause the microbiota to induce weight gain are unknown. We report that mice deficient in lymphotoxin, a key molecule in gut immunity, were resistant to DIO. Ltbr(-/-) mice had different microbial community composition compared to their heterozygous littermates, including an overgrowth of segmented filamentous bacteria (SFB). Furthermore, cecal transplantation conferred leanness to germ-free recipients. Housing Ltbr(-/-) mice with their obese siblings rescued weight gain in Ltbr(-/-) mice, demonstrating the communicability of the obese phenotype. Ltbr(-/-) mice lacked interleukin 23 (IL-23) and IL-22, which can regulate SFB. Mice deficient in these pathways also resisted DIO, demonstrating that intact mucosal immunity guides diet-induced changes to the microbiota to enable obesity.


Subject(s)
Immunity, Mucosal , Lymphotoxin beta Receptor/physiology , Lymphotoxin-alpha/physiology , Obesity , Animals , Bacteria/growth & development , Bacteria/immunology , Cecum/microbiology , Cecum/transplantation , Diet , Energy Metabolism , Germ-Free Life , Interleukin-23/deficiency , Interleukin-23/physiology , Interleukins/deficiency , Interleukins/physiology , Lymphotoxin beta Receptor/genetics , Lymphotoxin-alpha/deficiency , Lymphotoxin-alpha/genetics , Metagenome , Mice , Mice, Knockout , Obesity/etiology , Obesity/immunology , Obesity/metabolism , Weight Gain/immunology , Interleukin-22
5.
PLoS One ; 7(3): e33106, 2012.
Article in English | MEDLINE | ID: mdl-22427961

ABSTRACT

Graft-versus-host disease (GVHD) is a major barrier to successful allogeneic hematopoietic cell transplantation and is largely mediated by activated donor lymphocytes. Lymphotoxin (LT)-α is expressed by subsets of activated T and B cells, and studies in preclinical models demonstrated that targeted depletion of these cells with a mouse anti-LT-α monoclonal antibody (mAb) was efficacious in inhibiting inflammation and autoimmune disease. Here we demonstrate that LT-α is also upregulated on activated human donor lymphocytes in a xenogeneic model of GVHD and targeted depletion of these donor cells ameliorated GVHD. A depleting humanized anti-LT-α mAb, designated MLTA3698A, was generated that specifically binds to LT-α in both the soluble and membrane-bound forms, and elicits antibody-dependent cellular cytotoxicity (ADCC) activity in vitro. Using a human peripheral blood mononuclear cell transplanted SCID (Hu-SCID) mouse model of GVHD, the anti-human LT-α mAb specifically depleted activated LT-expressing human donor T and B cells, resulting in prolonged survival of the mice. A mutation in the Fc region, rendering the mAb incapable of mediating ADCC, abolished all in vitro and in vivo effects. These data support a role for using a depleting anti-LT-α antibody in treating immune diseases such as GVHD and autoimmune diseases.


Subject(s)
Antibodies, Monoclonal/pharmacology , Antibody-Dependent Cell Cytotoxicity/drug effects , Graft vs Host Disease/immunology , Graft vs Host Disease/prevention & control , Lymphocytes/immunology , Lymphotoxin-alpha/deficiency , Transplantation, Homologous/adverse effects , Animals , Antibodies, Monoclonal/immunology , Antibody-Dependent Cell Cytotoxicity/immunology , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Humans , Lymphotoxin-alpha/immunology , Mice , Mice, SCID , Surface Plasmon Resonance , Transplantation, Homologous/immunology
6.
Blood ; 116(12): 2173-82, 2010 Sep 23.
Article in English | MEDLINE | ID: mdl-20566898

ABSTRACT

Lymphotoxin-α (LTα), lymphotoxin-ß (LTß), and tumor necrosis factor-α (TNFα) are inflammatory mediators that play crucial roles in lymphoid organ development. We demonstrate here that LTα also contributes to the function of lymphatic vessels and to lymphangiogenesis during inflammation. LTα(-/-) mice exhibited reduced lymph flow velocities and increased interstitial fluid pressure. Airways of LTß(-/-) mice infected with Mycoplasma pulmonis had significantly more lymphangiogenesis than wild type (WT) or LTα(-/-) mice, as did the skin draining immunization sites of LTß(-/-) mice. Macrophages, B cells, and T cells, known sources of LT and TNFα, were apparent in the skin surrounding the immunization sites as were LTα, LTß, and TNFα mRNAs. Ectopic expression of LTα led to the development of LYVE-1 and Prox1-positive lymphatic vessels within tertiary lymphoid organs (TLOs). Quantification of pancreatic lymphatic vessel density in RIPLTαLTß(-/-) and WT mice revealed that LTα was sufficient for inducing lymphangiogenesis and that LTß was not required for this process. Kidneys of inducible LTα transgenic mice developed lymphatic vessels before the appearance of obvious TLOs. These data indicate that LTα plays a significant role in lymphatic vessel function and in inflammation-associated lymphangiogenesis.


Subject(s)
Lymphangiogenesis , Lymphotoxin-alpha/physiology , Animals , Immunization , Inflammation , Kidney/immunology , Lymphatic Vessels , Lymphotoxin-alpha/deficiency , Lymphotoxin-alpha/genetics , Lymphotoxin-beta , Mice , Mice, Knockout , Mycoplasma Infections/pathology , Mycoplasma pulmonis , Skin
7.
Am J Pathol ; 176(1): 198-204, 2010 Jan.
Article in English | MEDLINE | ID: mdl-20008132

ABSTRACT

Recent evidence points to lung draining lymph nodes as the site that initiates the immune response in mice infected with aerosolized Mycobacterium tuberculosis. Here we expanded these studies and showed that infection of mice that lack lymph nodes with aerosolized M. tuberculosis results in a massive mononuclear cell infiltrate in the lungs within 14 days postinfection. This infiltration clearly resembles an expansion of the bronchus-associated lymphoid tissue. As expected, no bronchus-associated lymphoid tissue was observed in M. tuberculosis-infected wild-type control mice. Importantly, acquired specific immune response to M. tuberculosis antigens could be detected in lung lymphocytes harvested from mice lacking lymph nodes as early as 14 days postinfection. In addition, the bacterial burden in these mice was indistinguishable from that observed in wild-type C57BL/6 control mice. These results indicate that in the absence of lymph nodes, priming of the immune response occurs in the lung tissues after infection of mice with aerosolized M. tuberculosis and clearly illustrate the enormous plasticity of the immune system to develop resistance to foreign pathogens.


Subject(s)
Adaptive Immunity/immunology , Lung/immunology , Lung/microbiology , Lymph Nodes/microbiology , Lymph Nodes/pathology , Mycobacterium tuberculosis/immunology , Aerosols , Animals , Immunohistochemistry , Lung/pathology , Lymph Nodes/immunology , Lymphotoxin-alpha/deficiency , Lymphotoxin-alpha/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Splenectomy , Tuberculosis, Pulmonary/immunology , Tuberculosis, Pulmonary/microbiology
8.
Eur J Immunol ; 38(12): 3290-303, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19009523

ABSTRACT

2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol hydrochloride (FTY720) suppresses T-cell egress from LN, thereby preventing pathogenic T cells from migrating toward disease sites. However, little is known about whether FTY720 could control the trafficking of T cells without the presence of lymphoid tissues. Here we demonstrate that FTY720 treatment suppresses the recirculation of CD4(+) T cells in splenectomized (SPX) lymphotoxin-alpha(-/-) (LT-alpha(-/-)) mice that lack LN and spleen, as shown by peripheral blood (PB) lymphopenia in FTY720-treated SPX LT-alpha(-/-) mice. In a short-term transfer experiment, the cell number of transferred Ly5.1(+)CD4(+) T cells recovered from host FTY720-treated SPX LT-alpha(-/-) mice (Ly5.2(+)) was markedly decreased in PB, but conversely increased in BM. Notably, FTY720 treatment prevented the development of colitis that is otherwise induced in untreated SPX LT-alpha(-/-) x RAG-2(-/-) mice upon transfer of colitic lamina propria CD4(+) T cells. In such mice, the number of CD4(+) T cells in PB or lamina propria of FTY720-treated SPX LT-alpha(-/-) x RAG-2(-/-) recipients was significantly reduced, but that in the BM was significantly increased as compared with untreated control mice. Altogether, the present results indicate that FTY720 treatment may offer an additional role to direct trafficking of CD4(+) T cells in BM, resulting in the prevention of colitis.


Subject(s)
Bone Marrow/drug effects , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , Colitis/immunology , Colitis/prevention & control , Lymphoid Tissue/immunology , Propylene Glycols/pharmacology , Sphingosine/analogs & derivatives , Animals , Apoptosis/drug effects , Bone Marrow/immunology , CD4-Positive T-Lymphocytes/drug effects , Cell Movement/drug effects , Colitis/metabolism , Colitis/pathology , Cytokines/biosynthesis , Fingolimod Hydrochloride , Lymph Node Excision , Lymphoid Tissue/surgery , Lymphotoxin-alpha/deficiency , Lymphotoxin-alpha/genetics , Lymphotoxin-alpha/metabolism , Mice , Mice, Inbred C57BL , Sphingosine/pharmacology , Splenectomy
9.
Eur J Clin Invest ; 37(9): 737-41, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17696964

ABSTRACT

BACKGROUND: The endogenous mediators playing a role in the sensing of fatigue and cessation of exercise are yet to be characterized. We hypothesized that proinflammatory cytokines, in particular tumour necrosis factor-alpha (TNFalpha) and lymphotoxin-alpha (LT) transmit signals leading to fatigue. MATERIALS AND METHODS: Mice were placed in a cage with a freely rotating exercise wheel and allowed to adapt for 24 h. The running distance was measured for two additional periods of 24 h. The effects of the administration of intravenous anti-TNF antibodies, intracerebral recombinant TNF, or intravenous lipopolysaccharide (LPS) were also determined. RESULTS: Compared to normal littermates, the voluntary daily running distance was 1.8-fold greater in mice with a disruption of the gene for TNFalpha, and 3-fold greater in mice with a gene disruption for both TNFalpha and LT. Intravenous administration of a monoclonal antibody against murine TNFalpha did not affect the running distance of wild-type mice, whereas administration of TNF intracerebrally reduced by 4-fold the voluntary running distance of the animals. This demonstrates that fatigue is mediated by TNFalpha expressed in the central nervous system (CNS) and not by increased peripheral TNFalpha concentrations. TNFalpha and LT are strong inducers of prostaglandins, but mice with disrupted prostaglandin or prostacyclin receptors exhibited running distances not significantly different from their wild-type littermates. Thus, signalling molecules other than prostaglandins mediate the effect of TNFalpha and LT on exercise capacity. CONCLUSIONS: Our finding that exercise capacity is controlled by TNFalpha is the first to define the endogenous mediators of fatigue, and may have important implications for diseases with impaired exercise tolerance.


Subject(s)
Lymphotoxin-alpha/deficiency , Tumor Necrosis Factor-alpha/deficiency , Animals , Fatigue/physiopathology , Lipopolysaccharide Receptors/administration & dosage , Lipopolysaccharide Receptors/adverse effects , Lipopolysaccharide Receptors/metabolism , Lymphotoxin-alpha/metabolism , Mice , Physical Conditioning, Animal/physiology , Tumor Necrosis Factor-alpha/metabolism
10.
J Hepatol ; 47(4): 571-9, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17644211

ABSTRACT

BACKGROUND/AIMS: Studies in animal models and humans suggest a link between endotoxemia and non-alcoholic steatohepatitis. Since Kupffer cells are responsible for clearing endotoxin and are activated via endotoxin interaction with Toll-like receptor 4 (TLR-4), we examined the relationship between hepatic TLR-4 expression and Kupffer cell content during the genesis of steatohepatitis. METHODS: Male C57BL/6, C3H/HouJ and TLR-4 mutant C3H/HeJ mice were fed control or methionine/choline-deficient diet (MCDD). In one group of C57BL/6 mice, Kupffer cells were depleted by weekly intraperitoneal injections of clodronate liposomes. After 3 weeks, serum ALT activity and portal endotoxin levels were measured. Real-time PCR was used to examine mRNA expression of TLR-4, TLR-2, CD14, MD-2, TGFbeta, TNFalpha, CD36, PPAR-alpha, liver fatty acid binding protein (L-FABP) and collagen alpha1. RESULTS: We observed histological evidence typical of steatohepatitis, portal endotoxemia and enhanced TLR-4 expression in wild type mice fed MCDD. In contrast, injury and lipid accumulation markers were significantly lower in TLR-4 mutant mice. Destruction of Kupffer cells with clodronate liposomes blunted histological evidence of steatohepatitis and prevented increases in TLR-4 expression. CONCLUSIONS: These findings demonstrate the importance of TLR-4 signaling and underscore a direct link between TLR-4 and Kupffer cells in the pathogenesis of steatohepatitis.


Subject(s)
Endotoxemia/complications , Fatty Liver/etiology , Hepatitis, Animal/etiology , Kupffer Cells/physiology , Toll-Like Receptor 4/physiology , Animals , Choline Deficiency , Clodronic Acid/pharmacology , Collagen Type I/deficiency , Collagen Type I, alpha 1 Chain , Diet , Endotoxemia/genetics , Fatty Liver/pathology , Hepatitis, Animal/pathology , Kupffer Cells/drug effects , Lymphotoxin-alpha/deficiency , Methionine/deficiency , Mice , Mice, Mutant Strains , PPAR alpha/metabolism , Signal Transduction , Toll-Like Receptor 4/genetics , Triglycerides/analysis
11.
Proc Natl Acad Sci U S A ; 104(12): 5026-31, 2007 Mar 20.
Article in English | MEDLINE | ID: mdl-17360402

ABSTRACT

Infiltration of lymphocytes into the thyroid gland and formation of lymph node-like structures is a hallmark of Hashimoto's thyroiditis. Here we demonstrate that lymphatic vessels are present within these infiltrates. Mice overexpressing the chemokine CCL21 in the thyroid (TGCCL21 mice) developed similar lymphoid infiltrates and lymphatic vessels. TGCCL21 mice lacking mature T and B cells (RAGTGCCL21 mice) did not have cellular infiltrates or increased number of lymphatic vessels compared with controls. Transfer of CD3(+)CD4(+) T cells into RAGTGCCL21 mice promoted the development of LYVE-1(+)podoplanin(+)Prox-1(+) vessels in the thyroid. Genetic deletion of lymphotoxin beta receptor or lymphotoxin alpha abrogated development of lymphatic vessels in the inflamed areas in the thyroid but did not affect development of neighboring lymphatics. These results define a model for the study of inflammatory lymphangiogenesis in the thyroid and implicate lymphotoxin beta receptor signaling in this process.


Subject(s)
Lymphangiogenesis/immunology , Lymphotoxin beta Receptor/metabolism , Signal Transduction , Thyroid Gland/pathology , Animals , CD4-Positive T-Lymphocytes/immunology , Cell Separation , Chemokine CCL21 , Chemokines, CC/metabolism , Hashimoto Disease/immunology , Hashimoto Disease/pathology , Humans , Inflammation , Lymphatic Vessels/immunology , Lymphatic Vessels/pathology , Lymphoid Tissue/immunology , Lymphoid Tissue/pathology , Lymphotoxin beta Receptor/deficiency , Lymphotoxin-alpha/deficiency , Mice , Mice, Transgenic , Thyroid Gland/immunology
12.
J Immunol ; 178(6): 3757-66, 2007 Mar 15.
Article in English | MEDLINE | ID: mdl-17339474

ABSTRACT

Following oral exposure, some transmissible spongiform encephalopathy (TSE) agents accumulate first upon follicular dendritic cells (FDCs) in the GALT. Studies in mice have shown that this accumulation is obligatory for the efficient delivery of the TSE agent to the brain. However, which GALTs are crucial for disease pathogenesis is uncertain. Mice deficient in specific GALT components were used here to determine their separate involvement in scrapie agent neuroinvasion from the intestine. In the combined absence of the GALTs and FDCs (lymphotoxin (LT)alpha(-/-) mice and LTbeta(-/-) mice), scrapie agent transmission was blocked. When FDC maturation was induced in remaining lymphoid tissues, mice that lacked both Peyer's patches (PPs) and mesenteric lymph nodes (wild-type (WT)-->LTalpha(-/-) mice) or PPs alone (WT-->LTbeta(-/-) mice) remained refractory to disease, demonstrating an important role for the PPs. Although early scrapie agent accumulation also occurs within the mesenteric lymph nodes, their presence in WT-->LTbeta(-/-) mice did not restore disease susceptibility. We have also shown that isolated lymphoid follicles (ILFs) are important novel sites of TSE agent accumulation in the intestine. Mice that lacked PPs but contained numerous FDC-containing mature ILFs succumbed to scrapie at similar times to control mice. Because the formation and maturation status of ILFs is inducible and influenced by the gut flora, our data suggest that such factors could dramatically affect susceptibility to orally acquired TSE agents. In conclusion, these data demonstrate that following oral exposure TSE agent accumulation upon FDCs within lymphoid tissue within the intestine itself is critically required for efficient neuroinvasion.


Subject(s)
Dendritic Cells, Follicular/immunology , Intestines/immunology , Lymphotoxin-beta/immunology , Peyer's Patches/immunology , PrPSc Proteins/pharmacology , Scrapie/immunology , Administration, Oral , Animals , Dendritic Cells, Follicular/pathology , Immunity, Mucosal/drug effects , Immunity, Mucosal/genetics , Intestines/pathology , Lymphotoxin-alpha/deficiency , Lymphotoxin-alpha/immunology , Lymphotoxin-beta/deficiency , Mice , Mice, Knockout , Peyer's Patches/pathology , PrPSc Proteins/immunology , Scrapie/genetics , Scrapie/transmission
13.
Immunol Lett ; 109(1): 64-71, 2007 Mar 15.
Article in English | MEDLINE | ID: mdl-17292972

ABSTRACT

Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases that affect humans and animals. Diseases include scrapie in sheep and Creutzfeldt-Jakob disease in humans. Following peripheral exposure, TSE agents usually accumulate on follicular dendritic cells (FDCs) in lymphoid tissues before neuroinvasion. Studies in mice have shown that TSE exposure through scarified skin is an effective means of transmission. Following inoculation by this route TSE agent accumulation upon FDCs is likewise essential for the subsequent transmission of disease to the brain. However, which lymphoid tissues are crucial for TSE pathogenesis following inoculation via the skin was not known. Mice were therefore created that lacked the draining inguinal lymph node (ILN), but had functional FDCs in remaining lymphoid tissues such as the spleen. These mice were inoculated with the scrapie agent by skin scarification to allow the role of draining ILN in scrapie pathogenesis to be determined. We show that following inoculation with the scrapie agent by skin scarification, disease susceptibility was dramatically reduced in mice lacking the draining ILN. These data demonstrate that following inoculation by skin scarification, scrapie agent accumulation upon FDCs in the draining lymph node is critical for the efficient transmission of disease to the brain.


Subject(s)
Dendritic Cells, Follicular/immunology , Lymph Nodes/immunology , PrPSc Proteins/pathogenicity , Skin Diseases, Infectious/immunology , Animals , Drainage , Lymphotoxin-alpha/deficiency , Lymphotoxin-alpha/immunology , Mice , Mice, Inbred C57BL , PrPSc Proteins/immunology , PrPSc Proteins/metabolism , Prion Diseases/etiology , Prion Diseases/immunology , Scrapie/etiology , Scrapie/immunology , Skin Diseases, Infectious/etiology
14.
Parasite Immunol ; 29(3): 153-8, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17266742

ABSTRACT

Tumour necrosis factor (TNF) plays important roles in the pathogenesis of severe malaria, as well as in the generation of immune responses against malaria parasites. However, far less is known about the role of the closely related TNF family member lymphotoxin alpha (LTalpha) during malaria. We have used mice deficient in either TNF or LTalpha, as well as chimeric mice generated using donor bone marrow from these animals, to study the roles of these cytokines following Plasmodium chabaudi chabaudi AS infection. TNF and LTalpha were not required for the resolution of P. chabaudi chabaudi AS blood-stage infection. However, LTalpha, but not TNF, was necessary for early IFNgamma production and the regulation of IFNgamma production later in infection. A similar delay to that found for IFNgamma production was also observed for TNF production in LTalpha-deficient mice, compared with control mice. These results identify divergent roles for TNF and LTalpha in the regulation of host immune responses during P. chabaudi chabaudi AS infection.


Subject(s)
Lymphotoxin-alpha/immunology , Malaria/immunology , Plasmodium chabaudi/immunology , Tumor Necrosis Factor-alpha/immunology , Animals , Enzyme-Linked Immunosorbent Assay , Female , Immunoglobulin G/blood , Immunoglobulin M/blood , Interferon-gamma/biosynthesis , Lymphotoxin-alpha/deficiency , Mice , Mice, Inbred C57BL , Time Factors , Tumor Necrosis Factor-alpha/deficiency
15.
Blood ; 109(4): 1602-10, 2007 Feb 15.
Article in English | MEDLINE | ID: mdl-17018858

ABSTRACT

Lymphocytes from lymphotoxin (LT) alpha-deficient mice, which lack segregation of their B- and T-cell areas, acquire normal organization following adoptive transfer into RAG-deficient recipients, identifying a non-B non-T cell in the segregation process. Here we show that a CD4+CD3- accessory cell is tightly associated with discrete VCAM-1-expressing stromal cells in B- and T-cell areas of the mouse spleen. CD4+CD3- cells express high levels of LTalpha, LTbeta, and tumor necrosis factor (TNF) alpha, which are the ligands for the LTbeta receptor and TNFR1 expressed by stromal cells. The expression of these ligands is functional, as transferring CD4+CD3- cells derived from either embryonic or adult tissues into LTalpha-deficient mice organizes B/T segregation and up-regulates CCL21 protein expression in areas where T cells are segregated from B cells. We propose that the function of CD4+CD3- cells is to form a link between primed CD4 T cells and the underlying stromal elements, creating distinct microenvironments in which they enable effector responses.


Subject(s)
CD3 Complex , CD4 Antigens , Spleen/cytology , Stromal Cells/cytology , T-Lymphocytes/cytology , Adoptive Transfer , Animals , B-Lymphocytes/cytology , CD4-Positive T-Lymphocytes , Cell Communication/immunology , Lymphotoxin-alpha/deficiency , Mice , Mice, Knockout , Spleen/immunology
16.
Histol Histopathol ; 22(3): 235-50, 2007 03.
Article in English | MEDLINE | ID: mdl-17163398

ABSTRACT

Traumatic brain injury causes progressive tissue atrophy and consequent neurological dysfunction, resulting from neuronal cell death in both animal models and patients. Fas (CD95) and Fas ligand (FasL/CD95L) are important mediators of apoptosis. However, little is known about the relationship between Fas and FasL and neuronal cell death in mice lacking the genes for inflammatory cytokines. In the present study, double tumor necrosis factor/lymphotoxin-alpha knockout (-/-) and interleukin-6-/- mice were subjected to closed head injury (CHI) and sacrificed at 24 hours or 7 days post-injury. Consecutive brain sections were evaluated for Fas and FasL expression, in situ DNA fragmentation (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling; TUNEL), morphologic characteristics of apoptotic cell death and leukocyte infiltration. A peak incidence of TUNEL positive cells was found in the injured cortex at 24 hours which remained slightly elevated at 7 days and coincided with maximum Fas expression. FasL was only moderately increased at 24 hours and showed maximum expression at 7 days. A few TUNEL positive cells were also found in the ipsilateral hippocampus at 24 hours. Apoptotic, TUNEL positive cells mostly co-localized with neurons and Fas and FasL immunoreactivity. The amount of accumulated polymorphonuclear leukocytes and CD11b positive cells was maximal in the injured hemispheres at 24 hours. We show strong evidence that Fas and FasL might be involved in neuronal apoptosis after CHI. Furthermore, Fas and FasL upregulation seems to be independent of neuroinflammation since no differences were found between cytokine-/- and wild-type mice.


Subject(s)
Brain Injuries/metabolism , Brain/metabolism , Fas Ligand Protein/metabolism , Wounds, Nonpenetrating/metabolism , fas Receptor/metabolism , Animals , Apoptosis , Brain/pathology , Brain Injuries/pathology , CD11b Antigen/metabolism , Disease Models, Animal , Fluorescent Antibody Technique, Indirect , Immunoenzyme Techniques , In Situ Nick-End Labeling , Interleukin-6/deficiency , Interleukin-6/genetics , Lymphotoxin-alpha/deficiency , Lymphotoxin-alpha/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neurons/metabolism , Neurons/pathology , Neutrophils/pathology , Specific Pathogen-Free Organisms , Tumor Necrosis Factor-alpha/deficiency , Tumor Necrosis Factor-alpha/genetics , Up-Regulation , Wounds, Nonpenetrating/pathology
18.
Blood ; 109(6): 2339-45, 2007 Mar 15.
Article in English | MEDLINE | ID: mdl-17119110

ABSTRACT

We have recently demonstrated that IgD(hi) B cells can occupy an extravascular perisinusoidal niche in the bone marrow in addition to the well-established follicular niche in conventional secondary lymphoid organs. The spleen has long been considered to be the site at which newly formed B lymphocytes mature into IgD(hi) naive recirculating B cells, but the existence of mutant mice that have selectively lost mature B cells in the bone marrow prompted an examination of B-cell maturation at this latter site. Following a single pulse of BrdU in intact mice, sequential labeling of more mature B-cell populations in the bone marrow suggested ongoing maturation at this site. Further evidence for B-cell maturation in the bone marrow was obtained from analyses of transitional B cells in splenectomized lymphotoxin alpha-deficient mice that lack all secondary lymphoid organs. In these mice, antibody-secreting cells recognizing multivalent antigens were also observed in the bone marrow following an intravenous microbial challenge. These data suggest that newly formed B cells mature into IgD(hi) B cells simultaneously in the spleen and the bone marrow and establish in a stringent manner that humoral immune responses can be initiated in situ in the bone marrow.


Subject(s)
B-Lymphocytes/cytology , B-Lymphocytes/immunology , Bone Marrow Cells/cytology , Bone Marrow Cells/immunology , Cell Differentiation , Spleen/cytology , Spleen/immunology , Animals , Antigens/immunology , B-Lymphocytes/metabolism , Bone Marrow Cells/metabolism , Immunoglobulin M/biosynthesis , Immunoglobulin M/immunology , Lymph Nodes/cytology , Lymph Nodes/immunology , Lymph Nodes/metabolism , Lymphotoxin-alpha/deficiency , Lymphotoxin-alpha/genetics , Lymphotoxin-alpha/metabolism , Mice , Spleen/metabolism , Splenectomy
19.
Eur J Immunol ; 36(9): 2504-14, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16906535

ABSTRACT

B cell-activating factor belonging to the TNF family (BAFF) is a B cell survival factor required for B cell maturation. BAFF transgenic (Tg) mice develop autoimmune disorders characterized by autoantibody production, which leads to nephritis and salivary gland destruction (sialadenitis), features reminiscent of systemic lupus erythematosus and Sjögren's syndrome (SS), respectively. Disease in BAFF Tg mice correlates with the expansion of the marginal zone (MZ) B cell compartment and the abnormal presence of MZ-like B cells in the blood, LN and inflamed salivary glands, suggesting a role for these cells in BAFF-induced autoimmunity. Lymphotoxin-beta (LTbeta)-deficient mice show disrupted splenic architecture, lack MZ B cells and some peripheral LN, and are unable to mount T cell-dependent immune responses. BAFF Tg mice lacking LTbeta (LTbetaDelta-BTg) retained these defects, yet still developed nephritis associated with the presence of B-1 B cells in the kidneys. However, in contrast to old BAFF Tg mice, aging LTbetaDelta-BTg mice no longer developed sialadenitis. Thus, autoimmune disorders in BAFF Tg mice are possibly events coordinated by MZ and B-1 B cells at separate anatomical sites.


Subject(s)
Autoimmune Diseases/immunology , B-Lymphocytes/immunology , Membrane Proteins/immunology , Nephritis/immunology , Sialadenitis/immunology , Tumor Necrosis Factor-alpha/immunology , Animals , B-Cell Activating Factor , B-Lymphocytes/cytology , Cell Differentiation/immunology , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Immunoglobulin A/analysis , Lymph Nodes/cytology , Lymph Nodes/immunology , Lymphotoxin-alpha/deficiency , Lymphotoxin-beta , Membrane Proteins/deficiency , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Transgenic , Reverse Transcriptase Polymerase Chain Reaction , Spleen/cytology , Spleen/immunology , Stem Cells/cytology , Stem Cells/immunology , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism
20.
Eur J Immunol ; 36(8): 2061-75, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16841297

ABSTRACT

Interaction of lymphotoxin alpha(1)beta(2) (LTalpha(1)beta(2)) with its receptor is key for the generation and maintenance of secondary lymphoid organ microstructure. We used mice conditionally deficient for LTbeta on different lymphocyte subsets to determine how the LTbeta-dependent lymphoid structure influences immune reactivity. All conditionally LTbeta-deficient mice mounted normal immune responses against vesicular stomatitis virus (VSV), and were protected against lymphocytic choriomeningitis virus (LCMV). In contrast, they exhibited reduced immune responses against non-replicating antigens. Completely LTbeta-deficient mice failed to retain VSV in the marginal zone and died from VSV infections, and they became virus carriers following infection with the non-cytopathic LCMV, which was correlated with defective virus replication in dendritic cells. It was ruled out that LTbeta expression on lymphocytes influenced their activation, homing capacity, or maturation. We therefore conclude that LTbeta expression influences immune reactivity at two distinct levels: (i) Expression of LTbeta on lymphocytes enhances the induction of immune responses against limiting amounts of antigen. (ii) Expression of LTbeta on non-lymphocytes governs antiviral immunity by enhancing antigen presentation on antigen-presenting cells. This prevents cytotoxic T lymphocytes exhaustion or death of the host by uncontrolled virus spread.


Subject(s)
Gene Expression , Immunity/immunology , Lymphotoxin-alpha/immunology , Lymphotoxin-alpha/metabolism , Membrane Proteins/immunology , Membrane Proteins/metabolism , Animals , B-Lymphocytes/cytology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Cell Differentiation , Cell Movement , Cells, Cultured , Immunohistochemistry , Lymphoid Tissue/abnormalities , Lymphoid Tissue/immunology , Lymphoid Tissue/metabolism , Lymphotoxin-alpha/deficiency , Lymphotoxin-alpha/genetics , Lymphotoxin-beta , Membrane Proteins/deficiency , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Rhabdoviridae Infections/immunology , Rhabdoviridae Infections/pathology , Rhabdoviridae Infections/virology , T-Lymphocytes/cytology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Vesicular stomatitis Indiana virus/immunology , Virion/immunology
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