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1.
Clin Exp Immunol ; 145(1): 155-61, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16792686

ABSTRACT

Several autoimmune diseases, mainly autoantibody-mediated, are attenuated by infusion of total IgG (IVIg). The efficacy varies widely from one patient to another. Using an experimental model of in vitro phagocytosis of autoantibody-coated erythrocytes by mouse macrophages, we analysed the possible causes for such a variability. Our results indicated that the efficacy of the phagocytosis inhibition depends upon different factors, such as the isotype and the extent of polymerization of the immunoglobulin used for the treatment as well as the genetic background of the mice and the state of macrophage activation that can be influenced by concomitant viral infection. The development of an in vitro assay for the phagocytic activity of macrophages might improve the selection of patients susceptible to benefit from IVIg treatment.


Subject(s)
Autoantibodies/immunology , Autoimmune Diseases/therapy , Erythrocytes/pathology , Immunoglobulin Isotypes/administration & dosage , Immunoglobulins, Intravenous/administration & dosage , Macrophages, Peritoneal/physiology , Animals , Autoimmune Diseases/immunology , Cells, Cultured , Female , Immunoglobulin Fc Fragments/administration & dosage , Immunoglobulin G/administration & dosage , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Models, Animal , Phagocytosis , Polymers , Species Specificity
2.
J Med Microbiol ; 52(Pt 10): 869-876, 2003 Oct.
Article in English | MEDLINE | ID: mdl-12972580

ABSTRACT

The aim of this study was the analysis of the cytokine response in BALB/c mice infected with the highly virulent RH or the weakly virulent Beverley strains of Toxoplasma gondii. Analysis of cytokine messages showed increased expression of IL12, IFN-gamma and TNF-alpha, but not IL4 mRNAs in spleen cells after infection with the T. gondii strains RH and Beverley. High levels of circulating IL12 and IFN-gamma were detected in the serum of mice infected with strain RH, although TNF-alpha levels remained low. In contrast, the same cytokines were detected at only low levels in the serum of mice infected with the Beverley strain. Administration of antibody against IL12 or IFN-gamma significantly delayed time to death of mice infected with strain RH compared to controls. T-Cell-deficient as well as normal mice were equally infected by strain RH, suggesting that T lymphocytes do not contribute to the response. Depletion of natural killer cells from the splenocyte population abolished the in vitro production of IFN-gamma. Together, our data suggest that the virulent strain RH induces in BALB/c mice a type 1 cytokine pattern with T-cell-independent overproduction of IL12 and IFN-gamma that may be involved in the pathogenesis of this micro-organism.


Subject(s)
Interferon-gamma/biosynthesis , Interleukin-12/biosynthesis , Toxoplasma/immunology , Toxoplasmosis/immunology , Animals , Enzyme-Linked Immunosorbent Assay , Female , Interferon-gamma/blood , Interferon-gamma/genetics , Interferon-gamma/immunology , Interleukin-12/blood , Interleukin-12/genetics , Interleukin-12/immunology , Mice , Mice, Inbred BALB C , Mice, SCID , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Spleen/immunology , Spleen/metabolism , Th1 Cells/immunology , Th1 Cells/metabolism , Toxoplasma/metabolism , Toxoplasma/pathogenicity , Toxoplasmosis/metabolism , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology , Tumor Necrosis Factor-alpha/metabolism , Virulence
3.
Scand J Immunol ; 57(2): 144-50, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12588660

ABSTRACT

An immunization protocol that induces antibodies (Abs) directed to cryptic epitopes of a protein antigen (Ag) reduces the efficacy of vaccines that ideally should induce Abs against native epitopes. We have shown earlier that viral infections concomitant with immunization against a protein tend to shift the Ab specificity toward cryptic epitopes and tend to induce the production of autoantibodies (autoAbs). Here, we show the effects of three adjuvants on the Ab specificity in the absence or presence of a viral infection (lactate dehydrogenase-elevating virus or LDV), with human growth hormone (hGH) being, as before, the protein Ag. Pathogen-free CBA/Ht and BALB/c mice were immunized with hGH in the presence of complete Freund's adjuvant (CFA), monophosphoryl lipid A (MPL) or alum, with the animals being either infected with LDV or not infected with LDV. Conventional and competition enzyme-linked immunosorbent assays (ELISAs) indicated that in noninfected mice, CFA induced higher titres of anti-hGH Ab than did MPL or alum, with the Ab being almost totally directed to cryptic hGH epitopes. Strikingly, CFA plus LDV infection in CBA/Ht mice shifted the specificity of the anti-hGH Ab toward native epitopes, whereas the virus decreased the Ab titre when MPL or alum was used. Our Western blot results showed that 70% of mice immunized with hGH in the presence of any adjuvant produced autoAbs against a variety of tissue Ags. The amount of autoAb and the concentration of Ab to hGH cryptic epitopes did correlate, suggesting a relationship between both kinds of Ab. Significant differences were observed in the various effects of adjuvants and the viral infection between the two mouse strains used in this work.


Subject(s)
Adjuvants, Immunologic/pharmacology , Antibody Specificity/immunology , Arterivirus Infections/immunology , Epitopes/immunology , Human Growth Hormone/immunology , Lactate dehydrogenase-elevating virus/immunology , Lipid A/analogs & derivatives , Alum Compounds/pharmacology , Animals , Antibodies, Viral/blood , Autoantibodies/biosynthesis , Blotting, Western , Enzyme-Linked Immunosorbent Assay , Epitopes/metabolism , Female , Freund's Adjuvant/pharmacology , Kidney/immunology , Lipid A/pharmacology , Liver/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred CBA , Muscles/immunology , Myocardium/immunology
4.
Int Immunol ; 13(9): 1185-92, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11526099

ABSTRACT

The role of IL-6 in Ig production induced in the mouse by lactate dehydrogenase-elevating virus (LDV), Toxoplasma gondii or lipopolysaccharide (LPS) was assessed. Following infection with LDV, a strong activator of B cells, an early and transient IL-6 production was observed, that originated predominantly from macrophages. Whereas LDV-induced B lymphocyte proliferation appeared independent of IL-6, mice deficient for this cytokine showed a marked reduction in their total T-dependent IgG2a production when compared to their normal counterparts. By contrast, specific responses directed against either LDV or non-viral antigens administered at the time of infection were not decreased in the absence of IL-6. Similarly, polyclonal, but not anti-parasite IgG2a production triggered by T. gondii infection was strongly dependent on the presence of IL-6. Finally, T-independent total IgG3 secretion triggered by LPS was also markedly reduced in IL-6-deficient mice. These results suggest that IL-6 plays a major role in T-dependent and T-independent polyclonal Ig production following B lymphocyte activation by viruses, and parasites, but not in specific antibody responses induced by the same microorganisms.


Subject(s)
Antibodies, Bacterial/biosynthesis , Antibodies, Protozoan/biosynthesis , Antibodies, Viral/biosynthesis , Immunoglobulin G/biosynthesis , Interleukin-6/metabolism , Animals , Antibody Specificity , B-Lymphocytes/immunology , Escherichia coli/immunology , Female , Immunoglobulin Isotypes/biosynthesis , Lactate dehydrogenase-elevating virus/immunology , Lipopolysaccharides/immunology , Mice , Mice, Inbred BALB C , Spleen/cytology , Spleen/immunology , T-Lymphocytes/immunology , Toxoplasma/immunology
5.
Eur J Immunol ; 31(5): 1447-55, 2001 May.
Article in English | MEDLINE | ID: mdl-11465101

ABSTRACT

Western blot experiments showed that sera from mice infected with the mouse hepatitis virus strain A59 (MHV-A59) contained autoantibodies (autoAb) that bound to a 40-kDa protein present in liver and kidney extracts. No reaction was observed with extracts of the heart, muscles, spleen, brain and lung. The Ab cross-reacted with a 40-kDa protein from human, rat and sheep liver, but not with liver extracts from the silver side fish (Odontesthes bonariensis). No correlation was found between the development of the hypergammaglobulinemia that followed the viral infection and the occurrence of the autoAb. Reactive immunoglobulins pertained to the IgG1, IgG2a and IgG2b subclasses, recognized cryptic epitopes and were detected from 10 days up to 8 weeks after MHV-infection. The 40-kDa protein was purified from mouse liver extracts by ion-exchange chromatography, gel filtration and SDS-PAGE. Because the N-terminal was blocked, we digested the protein in-gel with trypsin and sequenced various peptides. Results indicated a 100% homology of sequence between the protein recognized by the autoAb and liver fumarylacetoacetate hydrolase (FAH), the enzyme that mediates the last step of tyrosine catabolism. Additionally, a second protein recognized by the autoAb was detected during FAH purification steps and was identified as liver alcohol dehydrogenase.


Subject(s)
Autoantibodies/immunology , Autoantigens/chemistry , Autoantigens/immunology , Coronavirus Infections/immunology , Liver/enzymology , Liver/immunology , Murine hepatitis virus/physiology , Alcohol Dehydrogenase/chemistry , Alcohol Dehydrogenase/immunology , Alcohol Dehydrogenase/isolation & purification , Amino Acid Sequence , Animals , Autoantigens/isolation & purification , Blotting, Western , Cell Extracts/chemistry , Cell Extracts/immunology , Chromatography, High Pressure Liquid , Coronavirus Infections/complications , Coronavirus Infections/virology , Cross Reactions/immunology , Epitopes/chemistry , Epitopes/immunology , Humans , Hydrolases/chemistry , Hydrolases/immunology , Hydrolases/isolation & purification , Hypergammaglobulinemia/complications , Hypergammaglobulinemia/immunology , Hypergammaglobulinemia/virology , Liver/chemistry , Liver/cytology , Mice , Mice, Inbred Strains , Molecular Sequence Data , Molecular Weight , Rats , Rats, Wistar , Sequence Alignment
6.
Am J Respir Cell Mol Biol ; 24(4): 368-75, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11306428

ABSTRACT

We examined the effect of interleukin (IL)-9, a cytokine active on B and T lymphocytes and associated with bronchial asthma, on the development of lung fibrosis induced by crystalline silica particles. Therefore, we compared the response to silica (1 and 5 mg/animal, intratracheally) in transgenic mice that constitutively express high levels of IL-9 (Tg5) and their wild-type counterparts (FVB). At 2 and 4 mo after treatment with silica, histologic examination and measurement of lung hydroxyproline content showed that the severity of fibrosis was significantly less important in Tg5 mice than in their wild-type counterparts. Intraperitoneal injection of IL-9 in C57BL/6 mice also reduced the amplitude of silica-induced lung fibrosis. The reduction of lung fibrosis by IL-9 was associated with a significant expansion of the B-lymphocyte population, both in bronchoalveolar lavage (BAL) and in the pulmonary parenchyma. In wild-type animals, silica-induced fibrosis correlated with markers of a T helper 2-like response such as upregulation of IL-4 levels in lung tissue and an increased immunoglobulin (Ig) G1/IgG2a ratio in BAL. Immunohistochemical studies demonstrated that the upregulation of IL-4 associated with the development of fibrosis was mainly localized in inflammatory alveolar macrophages. In transgenic mice, the level of IL-4 in lung homogenates was not significantly affected by silica treatment, and a reduced IgG1/IgG2a ratio was observed upon treatment with silica. The levels of interferon-gamma were significantly decreased after silica treatment in both strains. Together, these observations point to an antifibrotic effect of IL-9 in pulmonary fibrosis associated with a limitation of the type 2 polarization which accompanies lung fibrosis.


Subject(s)
Interleukin-9/genetics , Interleukin-9/immunology , Pulmonary Fibrosis/immunology , Th2 Cells/immunology , Animals , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/immunology , Crystallization , Disease Models, Animal , Flow Cytometry , Gene Expression/immunology , Hydroxyproline/analysis , Immunoglobulin G/analysis , Interferon-gamma/biosynthesis , Interferon-gamma/immunology , Interleukin-4/biosynthesis , Interleukin-4/immunology , Interleukin-9/pharmacology , Lung/chemistry , Lung/immunology , Macrophages, Alveolar/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Pulmonary Fibrosis/chemically induced , Recombinant Proteins/pharmacology , Silicon Dioxide/chemistry , Silicon Dioxide/pharmacology , Th1 Cells/immunology
7.
J Virol ; 74(13): 6045-9, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10846087

ABSTRACT

Strong enhancement of the pathogenicity of an antierythrocyte monoclonal antibody was observed after infection of mice with lactate dehydrogenase-elevating virus. While injection of the antierythrocyte antibody alone induced only moderate anemia, concomitant infection with this virus, which is harmless in most normal mice, led to a dramatic drop in the hematocrit and to death of infected animals. In vitro and in vivo analyses showed a dramatic increase in the ability of macrophages from infected mice to phagocytose antibody-coated erythrocytes. These results indicate that viruses can trigger the onset of autoimmune disease by enhancing the pathogenicity of autoantibodies. They may explain how unrelated viruses could be implicated in the etiology of autoantibody-mediated autoimmune diseases.


Subject(s)
Anemia, Hemolytic, Autoimmune/immunology , Anemia, Hemolytic, Autoimmune/virology , Autoantibodies/immunology , Erythrocytes/immunology , Lactate dehydrogenase-elevating virus/immunology , Anemia, Hemolytic, Autoimmune/etiology , Anemia, Hemolytic, Autoimmune/physiopathology , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/immunology , Autoantibodies/administration & dosage , Cells, Cultured , Female , Macrophages, Peritoneal/cytology , Macrophages, Peritoneal/immunology , Mice , Mice, Inbred BALB C , Phagocytosis/immunology
8.
J Neurovirol ; 6(1): 89-93, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10787001

ABSTRACT

Development of polioencephalomyelitis in mice infected with lactate dehydrogenase-elevating virus (LDV) requires expression of N-tropic ecotropic MuLV retroviruses. 129/Sv mice are resistant to N-tropic MuLV expression and therefore do not develop LDV-induced polioencephalomyelitis. The Fv1 gene determines the susceptibility to retrovirus replication. We sequenced the open reading frame of the Fv1nr allele of 129/Sv mice. It differs by only one nucleotide, modifying one amino acid in the encoded protein, from the Fv1n allele of susceptible AKR and C58 animals. We excluded that the resistance of 129/Sv mice to LDV-induced polioencephalomyelitis resulted from the absence of endogenous N-tropic retrovirus, by infecting (129/Sv x C58/J) F1 animals. Therefore it is possible that the amino acid that defines the Fv1nr allele is responsible for resistance of 129/Sv mice to N-tropic MuLV expression and to LDV-induced polioencephalomyelitis.


Subject(s)
Alleles , Arterivirus Infections/genetics , Cell Cycle Proteins , Genetic Predisposition to Disease , Lactate dehydrogenase-elevating virus/genetics , Neoplasm Proteins , Poliomyelitis/etiology , Proteins/genetics , Animals , Lactate dehydrogenase-elevating virus/pathogenicity , Leukemia Virus, Murine/genetics , Leukemia Virus, Murine/pathogenicity , Mice , Mice, Inbred Strains , Molecular Sequence Data
9.
Int Immunol ; 12(2): 223-30, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10653858

ABSTRACT

After infection with some viruses and intracellular parasites, antibody production is restricted to IgG2a. We first observed that, whereas live viruses such as lactate dehydrogenase-elevating virus (LDV) or mouse adenovirus induced mostly an IgG2a response, a large proportion of antibodies produced against killed viruses were IgG1. This IgG1 antiviral response was suppressed when live virions were added to inactivated viral particles. These results indicate that the IgG2a preponderance is related to the infectious process itself rather than to the type of antigen involved. Since IFN-gamma is known to stimulate IgG2a production by activated B lymphocytes and to be secreted after infection, we examined the role of this cytokine in the antibody isotypic distribution caused by LDV. Most IgG2a responses were relatively unaffected in mice deficient for the IFN-gamma receptor or treated with anti-IFN-gamma antibody. A similar IFN-gamma-independent IgG2a secretion was observed after infection with the parasites Toxoplasma gondii and Trypanosoma cruzi. However, the IFN-gamma-independent IgG2a production triggered by infection still required the presence of functional T(h) lymphocytes. Therefore, signal(s) other than IFN-gamma secretion may explain the T(h)-dependent isotypic bias in antibody secretion triggered by viruses and parasites.


Subject(s)
Immunoglobulin G/biosynthesis , Interferon-gamma/pharmacology , Protozoan Infections/immunology , Virus Diseases/immunology , Adenoviridae/immunology , Adenoviridae Infections/immunology , Animals , Antibodies, Protozoan/biosynthesis , Antibodies, Protozoan/blood , Antibodies, Viral/biosynthesis , Antibodies, Viral/blood , Arterivirus Infections/immunology , Chagas Disease/immunology , Female , Immunoglobulin G/blood , Lactate dehydrogenase-elevating virus/immunology , Mice , Mice, Inbred CBA , Spleen/immunology , Toxoplasma/immunology , Toxoplasmosis, Animal/immunology , Trypanosoma cruzi
10.
Am J Respir Cell Mol Biol ; 20(4): 561-72, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10100987

ABSTRACT

Interleukin (IL)-12 is a cytokine produced principally by activated macrophages which is involved in control of the T-helper 1/T-helper 2 cell (Th1/Th2) polarization of immune responses. To examine its potential involvement in the development of lung fibrosis, we examined the expression (protein, messenger RNA [mRNA]) of IL-12 (p70) and of its subunits (p40 and p35) in lung homogenates, bronchoalveolar lavage fluid (BALF), and bronchoalveolar lavage (BAL) cell cultures in mouse models of resolutive alveolitis (RA) and fibrosing alveolitis (FA) induced by inorganic particles (manganese dioxide [MnO2] and crystalline silica, respectively). The administration of tungsten carbide (WC), which behaved as an innocuous dust for the lung, served as a negative control condition. The FA was specifically accompanied by a Th2-like polarization characterized by high levels of immunoglobulin (Ig)G1 in BALF and by a protracted overproduction of both p40 protein and mRNA, but not by the biologically active form of IL-12 (p70). In the RA model, the p40 response was only transient, and a Th1-like response was reflected by increased levels of interferon (IFN)-gamma and dominant levels of IgG2a in BALF. Taken together, these findings suggest that production of the p40 subunit of IL-12 and Th2 polarization play important roles in lung inflammatory and fibrotic responses to inhaled inorganic particles.


Subject(s)
Interleukin-12/genetics , Lung/immunology , Pulmonary Fibrosis/immunology , Silicon Dioxide , Th2 Cells/immunology , Animals , Antibody Formation , Bronchoalveolar Lavage Fluid/immunology , Cells, Cultured , Female , Gene Expression Regulation/immunology , Immunoglobulin G/biosynthesis , Immunoglobulin G/genetics , Lung/pathology , Macromolecular Substances , Manganese Compounds , Mice , Mice, Inbred Strains , Oxides , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/pathology , RNA, Messenger/genetics , Transcription, Genetic , Tungsten Compounds
11.
Adv Exp Med Biol ; 440: 569-74, 1998.
Article in English | MEDLINE | ID: mdl-9782331

ABSTRACT

Expression of Bgp1a, a glycoprotein that serves as receptor for mouse hepatitis virus-A59 has been analyzed in various mouse tissues and correlated with the pathogenicity that this virus induces in the corresponding organs. Expression of Bgp1a was observed in many cells of epithelial origin, including hepatocytes and endothelial cells. It was also shown on macrophages and B lymphocytes. Bgp1a localization may easily explain infection and lysis of some cell types like hepatocytes. In contrast, other cell types that express the viral receptor are not infected after in vivo inoculation with mouse hepatitis virus-A59, which may be due to inaccessibility of the receptor to the virus during mouse infection, or to resistance to this virus in some cell types. This may account for the ability of the blood-brain barrier to prevent mouse hepatitis virus-A59 spreading into the central nervous system. In other organs, the virus may induce pathogenesis indirectly, resulting in the destruction of cells that do not express Bgp1a, like thymic lymphocytes, or else impair cell functions such as cytokine and immunoglobulin production by macrophages and B lymphocytes, respectively.


Subject(s)
Coronavirus Infections/virology , Glycoproteins/physiology , Murine hepatitis virus/pathogenicity , Receptors, Virus/physiology , Animals , Antigens, CD , B-Lymphocytes/metabolism , Blood-Brain Barrier , Cell Adhesion Molecules , Cell Death , Coronavirus Infections/immunology , Cytokines/biosynthesis , Glycoproteins/biosynthesis , Lymphocyte Activation , Macrophages/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred CBA , Rabbits , Receptors, Virus/biosynthesis , Thymus Gland
12.
Proc Soc Exp Biol Med ; 218(4): 349-56, 1998 Sep.
Article in English | MEDLINE | ID: mdl-9714079

ABSTRACT

The effect of LCMV on CD4+ T lymphocytes was analyzed in C3HeB/FeJ mice after infection with the Docile strain of this virus. Our results indicated that LCMV triggers: i) an inhibition of Th2 lymphocyte differentiation induced by concomitant immunization with a nonviral protein antigen; ii) a depression of T helper-dependent antibody responses elicited by such an immunization; and iii) a CD4+ cell-mediated proliferation of spleen cells leading to increased interleukin-4 and interferon-gamma message expression and IgG2a-restricted total immunoglobulin secretion. Taken together, these results indicate that LCMV profoundly affects CD4+ cell-mediated immune responses in infected animals. Such modulations of T-helper functions may explain the preponderance of IgG2a in the antierythrocyte autoimmune response induced by the virus in C3HeB/FeJ mice.


Subject(s)
Anemia, Hemolytic/immunology , Autoimmune Diseases/immunology , Lymphocytic Choriomeningitis/immunology , Lymphocytic choriomeningitis virus/immunology , T-Lymphocytes, Helper-Inducer/immunology , Animals , Antigens/administration & dosage , Autoimmune Diseases/virology , Cell Line , Dogs , Female , Hemocyanins/administration & dosage , Hemocyanins/immunology , Immunization , Kidney , Lymphocyte Activation , Mice , Mice, Inbred C3H , Mice, Inbred CBA , Mollusca/immunology , T-Lymphocytes, Helper-Inducer/virology
13.
Infect Immun ; 66(6): 2991-5, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9596779

ABSTRACT

Murine antibody responses to soluble proteins are generally restricted to the immunoglobulin G1 (IgG1) isotype. When mice were infected with Toxoplasma gondii Beverley and concomitantly immunized with a soluble unrelated protein antigen, a modification in the isotypic distribution of antibodies directed against this nonparasite antigen was observed, with a preferential production of IgG2a. Interestingly, when mice were immunized with a soluble protein antigen during the chronic phase (day 40) of infection with T. gondii Beverley, a similar modification in the isotypic distribution of antiprotein antibodies was observed.


Subject(s)
Toxoplasmosis, Animal/immunology , Acute Disease , Animals , Antibodies, Protozoan/blood , Chronic Disease , Cytokines/biosynthesis , Cytokines/genetics , Female , Immunoglobulin Isotypes/blood , Interleukin-12/immunology , Lactoferrin/immunology , Mice , Mice, Inbred BALB C , RNA, Messenger/analysis , Spleen/immunology
14.
Histol Histopathol ; 13(1): 181-99, 1998 01.
Article in English | MEDLINE | ID: mdl-9476648

ABSTRACT

Mouse hepatitis virus, strain A59 (MHV-A59), is a coronavirus that triggers in susceptible mice a wide variety of pathologies, including hepatitis, thymus involution, B lymphocyte polyclonal activation and, after intra-cerebral inoculation, transient demyelination. One receptor that mediates entry of the virus into target cells has been identified: it is a glycoprotein of the carcinoembryonic antigen family, called Bgp1a. The availability of antibodies recognizing this molecule permits the analysis of its cellular expression and of the relationship between receptor expression and pathology induced by the virus. Bgp1a is found on epithelial and endothelial cells as well as on B lymphocytes and macrophages. In the liver, Bgp1a expression correlates well with infection of hepatocytes and endothelial cells, leading to the development of hepatitis. However, other cells expressing this molecule, such as central nervous system endothelial cells, are not infected by the virus. This observation may explain how the blood-brain barrier prevents dissemination of MHV-A59 from the general circulation into the brain. Thymic atrophy results from apoptosis of immature double-positive T lymphocytes which might be caused indirectly by infection of a small proportion of thymus epithelial cells that express Bgp1a rather than by infection of T cells that do not express the receptor. Finally, polyclonal activation of B lymphocytes, leading to increased secretion of antibodies of the IgG2a isotype, involves a cascade of events, including cytokine secretion, that may result from the interaction of MHV-A59 with B cells and macrophages that express Bgp1a. Therefore, after viral infection, cellular expression of Bgp1a may have different results: cell lysis; alteration of cellular functions that may lead to indirect death of other cell types, or resistance to infection.


Subject(s)
Coronavirus Infections/metabolism , Murine hepatitis virus , Receptors, Virus/biosynthesis , Animals , Antigens, CD , Cell Adhesion Molecules , Coronavirus Infections/pathology , Glycoproteins/metabolism , Mice , Models, Biological , Murine hepatitis virus/pathogenicity
15.
J Immunol ; 159(6): 2616-23, 1997 Sep 15.
Article in English | MEDLINE | ID: mdl-9300680

ABSTRACT

We focused on the role of IL-4 in the regulation of the Th2 cytokine IL-9. In vivo, IL-9 mRNA was detected in lymph nodes after immunization with soluble Ags. IL-9 expression preceded that of IL-4, and was not affected in IL-4 knockout mice. In contrast, a significant decrease of IL-9 message was observed in IL-10-deficient mice, indicating a role for this cytokine in the induction of IL-9 production. Treatment with anti-CD4 Ab and analysis of purified CD4 cells confirmed that IL-9 was produced by CD4+ cells. Moreover, similarly to what has been reported for IL-4, IL-9 message induction was strongly decreased by infection with lactate dehydrogenase-elevating virus. IL-9 mRNA was also detected after in vivo stimulation with anti-CD3 Ab. In this model, IL-9 expression followed that of IL-4, but was not reduced in IL-4-deficient mice. This contrasts with in vitro stimulation in which, as reported in humans, IL-9 expression in lymphocytes incubated with anti-CD3 Ab and costimulatory molecules appeared as a late event, and was partly dependent on IL-4. In vitro IL-9 secretion was reduced significantly by addition of anti-IL-4 Ab, as well as in lymphocytes from IL-4 gene-deficient mice. Taken together, our results indicate that the Th2 cytokine IL-9 can be expressed by both IL-4-dependent and -independent pathways.


Subject(s)
Gene Expression Regulation , Interleukin-4/metabolism , Interleukin-9/biosynthesis , T-Lymphocytes, Helper-Inducer/metabolism , Animals , Interleukin-4/genetics , Interleukin-4/immunology , Mice , Mice, Knockout , T-Lymphocytes, Helper-Inducer/immunology
16.
Scand J Immunol ; 46(2): 168-74, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9583997

ABSTRACT

Infection with lactate dehydrogenase-elevating virus (LDV) modifies the isotypic distribution of antibodies (Ab) directed to several antigenic proteins with a preferential production of IgG2a. Because it was not known whether the virus could also affect the Ab specificity, the authors addressed this point using human growth hormone (hGH) as a model antigen. Anti-hGH monoclonal antibodies (MoAb) were used as probes to study the occurrence of Ab to three native hGH epitopes (3C11, F11 and 10D6) in sera from LDV-infected CBA/Ht and BALB/c mice immunized with hGH. Competition ELISA was used to determine the extent of Ab directed to cryptic hGH epitopes, i.e. antigenic determinants hidden in the native hormone. Results indicated that in LDV-infected CBA/Ht mice the titres of anti-hGH Ab were lower than in controls, although a consistent isotypic shift to IgG2a subclass was observed. Concurrently, the presence of Ab to epitopes 3C11, F11 and/or 10D6 were markedly reduced in infected animals and most anti-hGH Ab were directed to hGH cryptic epitopes. By contrast, LDV infection increased the amount of anti-KLH Ab elicited by CBA/Ht mice and did not affect Ab specificity, whilst control and LDV-infected BALB/c mice showed similar concentrations of anti-hGH Ab. Furthermore, the proportion of Ab to cryptic hGH epitopes did not change in infected animals even though an important shift to IgG2a was detected. Thus, data presented herein suggest that LDV infection modifies Ab specificity depending on the mice genetic background and on the antigenic characteristics of the immunogen.


Subject(s)
Antibody Specificity/immunology , Arterivirus Infections/immunology , Hemocyanins/immunology , Human Growth Hormone/immunology , Lactate dehydrogenase-elevating virus/immunology , Animals , Antibodies, Monoclonal , Binding, Competitive , Enzyme-Linked Immunosorbent Assay , Epitopes/immunology , Female , Immunoglobulin G/analysis , Immunoglobulin Isotypes/analysis , Mice , Mice, Inbred BALB C , Mice, Inbred CBA
17.
Immunology ; 91(2): 239-45, 1997 Jun.
Article in English | MEDLINE | ID: mdl-9227323

ABSTRACT

C3HeB/FeJ mice infected with the docile strain of lymphocytic choriomeningitis virus (LCMV-d) develop a persistent infection with a transient haemolytic anaemia. Immunoglobulin can be eluted from the red blood cells (RBC) of these mice but it cannot be detected on the RBC by a conventional antiglobulin test. The present study demonstrates that RBC from such mice bear erythrocyte autoantibodies which are predominantly of the IgG2a subclass, with lower levels of autoantibodies of the IgG1, IgG2b and IgG3 subclasses. To identify the target antigen the autoantibodies were eluted from the RBC of LCMV-infected mice. The eluted autoantibody bound to intact normal RBC and precipitated a 105000 MW component that corresponds to murine Band 3 protein. A monoclonal antibody derived from mice infected with LCMV-d also precipitated mouse Band 3, and reacted specifically by enzyme-linked immunosorbent assay against a purified preparation of Band 3. This study has shown that in C3H mice infected with LCMV-d which develop autoimmune haemolytic anaemia, the target autoantigen is erythrocyte membrane Band 3.


Subject(s)
Anion Exchange Protein 1, Erythrocyte/immunology , Autoantibodies/biosynthesis , Lymphocytic Choriomeningitis/immunology , Anemia, Hemolytic, Autoimmune/immunology , Anemia, Hemolytic, Autoimmune/virology , Animals , Antibody Specificity , Autoantigens/immunology , Erythrocytes/immunology , Female , Immunoglobulin G/biosynthesis , Mice , Mice, Inbred C3H , Precipitin Tests
18.
J Neurovirol ; 3(6): 428-34, 1997 Dec.
Article in English | MEDLINE | ID: mdl-9475114

ABSTRACT

BALB/c mice develop a neurologic demyelinating disease after inoculation of mouse hepatitis virus (MHV), strain A59, by the intracranial, but not by the intraperitoneal route. To determine the mechanisms that prevent virus spreading through the blood-brain barrier, we analyzed expression of MHVR, a glycoprotein that serves as receptor for mouse hepatitis virus on endothelial cells of cerebral blood vessels. Our results indicated that MHVR was strongly expressed on the endoluminal pole of these cells. In addition, a direct virus binding assay showed that mouse hepatitis virus was able to bind endothelial cells via this receptor. Despite this expression of a functional viral receptor, in normal mice infected with mouse hepatitis virus by the contra-peritoneal route, no in vivo viral replication could be detected in endothelial cells from the brain, contrasting with the equivalent cells from the liver. However, shortly after i.v. administration of sodium dodecylsulfate detergent to the mice, virus infection of some cerebral endothelial cells was detected in a few mice. As a consequence of detergent treatment, virus infection was able to cross the blood-brain barrier. These results suggest that the protective role of the blood-brain barrier against spreading of mouse hepatitis virus A59 into the central nervous system is determined by a specific restriction of viral entry into the endothelial cells of cerebral origin.


Subject(s)
Blood-Brain Barrier , Demyelinating Diseases/virology , Endothelium, Vascular/physiology , Murine hepatitis virus/physiology , Receptors, Virus/physiology , Animals , Brain/virology , Female , Injections , Injections, Intraperitoneal , Mice , Mice, Inbred BALB C , Murine hepatitis virus/pathogenicity , Specific Pathogen-Free Organisms
19.
J Neurovirol ; 3(5): 380-4, 1997 Oct.
Article in English | MEDLINE | ID: mdl-9372459

ABSTRACT

Immunosuppression, occurring naturally with aging, or experimentally after cyclophosphamide treatment or irradiation, is required for the development in C58 mice infected with lactate dehydrogenase-elevating virus (LDV) of a severe polioencephalomyelitis that is caused by viral destruction of anterior horn neurons. Here it is shown that depletion of T helper lymphocytes by administration of an anti-CD4 antibody was followed by a progressive paralysis typical of polioencephalomyelitis in C58/J mice inoculated with a neurovirulent strain of LDV. Although it was clear that other cell subsets are also required to assure complete protection of genetically-susceptible mice, our results show that T helper lymphocytes play a major role in the prevention of LDV-induced polioencephalomyelitis. The mechanisms by which these cells confer this protection remain however to be determined.


Subject(s)
Arterivirus Infections/immunology , CD4-Positive T-Lymphocytes/immunology , Central Nervous System Infections/immunology , Lactate dehydrogenase-elevating virus , Animals , Antibodies , CD4-Positive T-Lymphocytes/virology , Central Nervous System Infections/virology , Female , Immunity, Innate , Mice , Mice, Inbred Strains
20.
Clin Exp Immunol ; 106(1): 103-7, 1996 Oct.
Article in English | MEDLINE | ID: mdl-8870706

ABSTRACT

In order to gain insight into the mechanisms by which the infusion of IgG can improve some autoimmune diseases, we induced haemolytic anaemia in mice by the injection of anti-erythrocyte MoAbs derived from NZB mice by S. Izui (Geneva). The IgG1 antibody 31-9D induces anaemia by erythrocyte sequestration in the spleen and liver, whereas the IgG2a antibody 34-3C triggers erythrophagocytosis (Shibata et al., Int Immunol 1990. 2:1133). Treatment of mice with pools of either human or mouse IgG clearly attenuated the anaemia induced by 34-3C, but not by 31-9D. Similar protection was obtained with human monoclonal IgGs from myeloma patients. Prior absorption by mouse erythrocytes did not affect the efficacy of the injected IgG. Treatment with Fc fragments also reduced the anaemia. In vitro experiments confirmed that 34-3C, but not 31-9D, triggered erythrocyte phagocytosis by murine macrophages. This process was completely inhibited by addition of polyclonal or myeloma IgG or of human Fc fragments. These results indicate that, in this model of autoimmune pathology, the protective effect of IgG is mediated by its interaction with the macrophage Fc receptors.


Subject(s)
Anemia, Hemolytic, Autoimmune/drug therapy , Anemia, Hemolytic, Autoimmune/etiology , Antibodies, Monoclonal/pharmacology , Erythrocytes/immunology , Immunoglobulin G/pharmacology , Immunoglobulin G/therapeutic use , Anemia, Hemolytic, Autoimmune/immunology , Animals , Antibodies, Monoclonal/blood , Autoantibodies/blood , Autoantibodies/pharmacology , Female , Humans , Immunization, Passive , Mice , Mice, Inbred BALB C , Mice, Inbred NZB
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