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Biomedical subjects

S Izui

Publications and source records attributed to S Izui.

At least 73 records · Page 4Linked to original sources
PubMed1995

Autoimmunity following neonatal tolerance to alloantigens: role of donor I-A and I-E molecules.

The injection of semi-allogeneic F1 spleen cells into newborn mice of a parental strain induces a state of immune tolerance characterized by anti-donor CTL unresponsiveness and the appearance of a transient SLE-like autoimmune syndrome associating autoantibody production, hypergammaglobulinemia, splenomegaly and glomerulonephritis. Our previous experiments have demonstrated that host Th2-like CD4+ T lymphocytes activate donor F1 B cells persisting in the host to produce autoantibodies, and that this cellular interaction relies on the presence of alloMHC class II molecules on donor B cells. In order to investigate the role and the involvement of MHC alloantigens in the cellular T(host)-B(donor) interaction, newborn C57BL/6 (B6) mice were injected with F1 spleen cells differing from the host at the level of defined portions of the MHC class I (K) or class II (I-A and I-E) molecules. B6 mice injected at birth with spleen cells from different F1 strains were tolerant to each alloantigen (alloAg) tested, as assessed by specific anti-donor CTL unresponsiveness. However, the SLE-like autoimmune syndrome only developed in B6 mice injected at birth with F1 spleen cells differing at the level of MHC class II I-A or I-E molecules. Autoantibodies appeared later in B6 mice neonatally tolerized to I-E alloAg than those detected in B6 mice neonatally tolerized to I-A alloAg. These results show that the SLE-like autoimmune disease that develops concomitantly to neonatally-induced tolerance to alloAg is the consequence of cognate T host-B donor cellular interactions triggered by even minute differences in the MHC class II I-A or MHC class II I-E molecules.

Animals↗
PubMed1995

Lithium chloride enhances survival of NZB/W lupus mice: influence of melatonin and timing of treatment.

Daily administration of 4 mg 6LiCl to groups (15 mice/group) of female NZB/W mice starting at 8 weeks of age led to long-term survival (44 weeks of age) of 73% of the mice when injections were performed between 08:00 and 10:00 h and 67% of mice when injections were performed between 17:00 and 19:00 h. Untreated controls were dead by 34 weeks of age and the differences between untreated and treated groups was significant (P < or = 10(-4)). In contrast daily administration of melatonin (100 micrograms/mouse) did not significantly enhance survival when injections were performed between 17:00 and 19:00 h but did enhance survival when given between 08:00 and 10:00 h (P < or = 10(-3)). Differences between the two melatonin groups was also significant (P < or = 0.05). Mice treated with Li plus melatonin exhibited survival curves identical to mice treated with Li alone. Therefore, the Li effect was dominant and survival was not altered by melatonin. Cessation of treatment in long-term survivors at 44 weeks of age led to the rapid death of 80% of the mice previously treated between 17:00 and 19:00 h (Li, Li + melatonin). In contrast, only 40% of the long-term survivors in the other groups had died by 66 weeks of age (22 weeks post-treatment). Thus the p.m. groups were less protected from disease reactivation than were the a.m. groups. Neither Li, melatonin, nor Li+melatonin influenced anti-gp70 or anti-ssDNA levels in serum, but Li treatment maintained renal function as determined by proteinuria scores. These findings indicate that the effectiveness of Li is probably not related to melatonin metabolism and immunomodulating influences, but the influence of other neuroendocrine variables cannot be eliminated.

Adjuvants, Immunologic↗
PubMed1995

Induction of plasminogen activator inhibitor type 1 in murine lupus-like glomerulonephritis.

Three major components of the plasminogen activators (PA)/plasmin system are synthesized physiologically in glomeruli, and can be involved in glomerular proteolysis and extracellular matrix metabolism: tissue-type PA (tPA), urokinase (uPA) and PA inhibitor type 1 (PAI-1). To explore the possible role of a dysregulation of the plasmin protease system in the development and progression of lupus-like glomerulonephritis, we studied the expression of the renal plasmin protease components during the course of the disease, either acute, induced by IgG3 monoclonal cryoglobulins, or chronic, occurring spontaneously in three different lupus-prone mice: (NZBxNZW)F1, BXSB and MRL-lpr/lpr. RNase protection assays and in situ hybridizations revealed a marked glomerular induction of PAI-1 mRNA abundance without any significant changes in renal tPA and uPA mRNA levels in the two different types of lupus-like glomerulonephritis. The overexpression of PAI-1 mRNA occurred in parallel with a significant decrease in glomerular tPA-catalyzed enzymatic activity as determined by zymographic analysis. In addition, a concomitant increase in glomerular expression of transforming growth factor beta 1 (TGF-beta 1) mRNA was observed. The demonstration of a close correlation between the PAI-1 and TGF-beta 1 mRNA levels and the severity of lupus-like glomerular lesions suggests that a pertubation of the glomerular PA/PAI balance, resulting from a marked TGF-beta 1-mediated induction of PAI-1 gene expression, plays an important role in the progression of lupus-like glomerular lesions, leading to glomerulosclerosis.

Animals↗
PubMed1995

cDNA sequence analysis and characterization of a cytokine-inducing monoclonal antibody derived from autoimmune MRL/MP-lpr/lpr mouse.

We have previously reported that a monoclonal antibody 1D11 derived from an autoimmune MRL/Mp-lpr/lpr (MRL/lpr) mouse induced synthesis or increased production of IL-3, IL-6, and TNF-alpha in the IL-3-dependent bone marrow-derived cell line FDC-P2/185-4. In this report, we analyzed a sequence of cDNA encoding the V region of 1D11, and found that VH and VL segments of 1D11 belonged to the J558 and V kappa 21 family, respectively. The nucleotide sequence of 1D11 in the VH segment was highly homologous to that of AM9, a monoclonal RF derived from MRL/lpr mouse, and the only difference was the replacement of 3 nucleotides in the framework region 1 (FR1). However, the deduced amino acid sequence of 1D11 was identical to that of AM9. In contrast with the VH segment, the sequences of the VL regions of these two antibodies were quite different from each other; 1D11 showed a 3 base deletion in the FR2 and a 24 base insertion in the FR3 compared with AM9. At present, the mechanisms of such insertions or deletions in the FRs of autoantibodies are almost unknown. It is generally accepted that the differences in specificity and affinity of these autoantibodies depend on differences of CDR sequence. However, it is possible that not only CDRs but also FRs of autoantibodies play a critical role in pathogenicity and/or specificity in autoimmune diseases.

Amino Acid Sequence↗
PubMed1995

Immunopathogenesis of lupus nephritis: new insights from experimental models.

Genetic analysis of systemic lupus erythematosus (SLE) in several lupus-prone mice has revealed that multiple, unlinked genes are required for the expression of various autoimmune manifestations, and that several, quite distinct genetic backgrounds are compatible with this disease. Although the nature of these genetic components has not been fully defined, it is becoming clear that certain genes such as the major histocompatibility complex class II genes and the genes regulating apoptosis apparently play a major role in the development of autoimmune responses characteristic in SLE. Analysis of the nephritogenic potential of monoclonal autoantibodies underlines the importance of qualitative features of autoantibodies in the pathogenesis of lupus nephritis. Strikingly, "wire-loop" glomerular lesions characteristic in human lupus nephritis can be induced by the direct localization of murine IgG3 antibodies with cryoglobulin activity without the involvement of immune complex formation. The remarkable correlation of IgG3 production with the development and acceleration of murine lupus nephritis, in association with enhanced activation of the TH1 subset which can lead to an increase in IgG3 production, is highly significant. The production process of more pathogenic autoantibodies appears to be genetically regulated. Further identification of the genetic defects present in lupus-prone mice, but lacking in mice with non-autoimmune backgrounds, is of paramount importance for the understanding of the immunopathogenetic mechanism of lupus nephritis and for the development of new therapeutic approaches for SLE.

Animals↗
PubMed1994

Lack of association of V beta 8+ T cells with lupus-like syndrome in MRL-lpr/lpr mice.

To evaluate the role of V beta 8+ T cells in the development of lupus-like autoimmune syndrome in MRL-lpr/lpr mice, we treated them with the F23.1 anti-V beta 8 monoclonal antibody (mAb) from birth to 4 months of age. Here we report that almost complete depletion of V beta 8+ T cells by the F23.1 mAb treatment neither inhibited nor delayed the development of hypergammaglobulinemia, autoantibody production and autoimmune glomerulonephritis in MRL-lpr/lpr mice. In addition, the F23.1 mAb treatment did not prevent the development of lymphadenopathy and the generation of a CD4-CD8- double-negative T cell subset, characteristically accumulating in lpr lymph nodes. Our results strongly argue against the idea that the V beta 8+ T cells play a critical role in the development of lupus-like autoimmune syndrome in MRL-lpr/lpr mice.

Animals↗
PubMed1994

Hyperprolactinemia in male NZB/NZW (B/W) F1 mice: accelerated autoimmune disease with normal circulating testosterone.

It has been proposed that the immunostimulatory hormone, prolactin, is associated with flares of systemic lupus erythematosus (SLE). In autoimmune female NZB/NZW F1 (B/W) mice with accelerated lupus-like disease, hyperprolactinemia accelerated autoimmunity. The current study explored effects of moderate and severe hyperprolactinemia in male B/W mice, which have late-onset SLE. Autoimmune disease in B/W males was assessed by measurement of anti-DNA antibodies (anti-DNA), gp70-anti-gp70 immune complexes (gp70IC), IgM, IgG, and renal function. Serum testosterone concentrations were assayed serially. All mice were necropsied when moribund. Hyperprolactinemic B/W males were characterized by premature appearance of anti-DNA and gp70IC and elevation of IgM and IgG. Hyperprolactinemia accelerated mortality with vasculitis and renal disease compared to control mice. Serum testosterone concentrations were not suppressed. In male B/W mice, chronic hyperprolactinemia stimulated autoimmune disease activity; the deleterious effects of prolactin were not mediated through suppression of the immunoprotective hormone, testosterone. This observation supports the proposed association between elevated prolactin levels and exacerbations of SLE.

Animals↗
PubMed1994

A CD8+ T-lymphocyte-mediated and CD4+ T-lymphocyte-independent autoimmune diabetes of early onset in transgenic mice.

While transgenic mice expressing tumour necrosis factor-alpha under the control of the beta-cell-specific insulin promoter display a marked lymphocytic infiltration of the islets, they never develop insulin-dependent diabetes mellitus (IDDM). In striking contrast, "double" transgenic mice whose beta cells express both tumour necrosis factor-alpha as well as the co-stimulatory B7-1 molecule all develop IDDM at an early age. Furthermore, administration of anti-CD8 but not anti-CD4 immunoglobulins prevents diabetes onset. These results indicate that while tumour necrosis factor-alpha induced lymphocytic infiltration is not sufficient to effect beta-cell destruction, locally co-stimulated islet-infiltrating CD8+ T lymphocytes could play a critical role in the development of IDDM.

Animals↗
PubMed1994

Autoimmune hemolytic anemia.

Autoimmune hemolytic anemia (AHA) is characterized by the production of Coombs' antibodies, which are responsible for the destruction of red blood cells (RBCs). Analysis of both monoclonal anti-RBC autoantibodies derived from autoimmune New Zealand black mice and transgenic mice expressing a pathogenic IgM anti-RBC autoantibody has considerably improved our understanding of the B-cell responses involved in AHA, although our knowledge of T-cell immunity in AHA is still limited. The identification of the major T-cell epitope in the context of MHC class II molecules would be of paramount importance in helping to elucidate the cellular and molecular basis central to the development of AHA.

Anemia, Hemolytic, Autoimmune↗
PubMed1994

Glomerulopathy induced by IgG3 anti-trinitrophenyl monoclonal cryoglobulins derived from non-autoimmune mice.

We have previously shown that murine IgG3 monoclonal autoantibodies with cryoglobulin activity, derived from lupus-prone mice, are able to induce glomerular lesions resembling the "wire-loop" lesion typically described for human lupus nephritis. In the present study, we have further assessed the nephritogenic potential of four IgG3 anti-hapten, trinitrophenyl (TNP), monoclonal antibodies (mAb) obtained from non-autoimmune mice immunized with TNP-conjugated foreign antigens. Our results showed that two of four IgG3 anti-TNP monoclonal cryoglobulins were capable of inducing glomerular lesions, characterized by voluminous intracapillary thrombi and mesangial deposition of PAS-positive materials, which differed from "wire-loop" lesions generated by IgG3 monoclonal cryoglobulins with autoantibody activities. These anti-TNP monoclonal cryoglobulins, however, failed to induce glomerular lesions when mice were kept at 37 degrees C after the mAb administration. This finding formally proves that the cryoglobulin activity is critically involved in the development of glomerular lesions induced by IgG3 anti-TNP mAb. In addition, we have demonstrated a remarkable difference in the nephritogenic activities of two IgG3 anti-TNP mAb, which exhibit a marked sequence homology in the variable regions of their heavy and light chains (91.5% and 99.1% at the amino acid level, respectively) and an identical isoelectric point. Our results indicate first, that IgG3 monoclonal cryoglobulins are able to generate two different kinds of glomerular lesions, and second, that a subtle difference in variable region sequences may determine not only the nephritogenic activities, but also the type of glomerular lesions mediated by IgG3 cryoglobulins.

Animals↗
PubMed1994

The Yaa gene abrogates the major histocompatibility complex association of murine lupus in (NZB x BXSB)F1 hybrid mice.

To investigate the specific contribution of select MHC class II genes on the development of murine lupus, H-2 congenic (NZB x BXSB)F1 hybrid mice bearing either H-2b/b, H-2d/b, or H-2d/d haplotypes were generated. We compared the clinical development (autoantibody production and glomerulonephritis) of systemic lupus erythematosus (SLE) in these three F1 hybrids in the presence or absence of the mutant gene, Yaa (Y chromosome-linked autoimmune acceleration), which normally accelerates the progression of murine SLE. (NZB x BXSB)F1 hybrid female mice bearing either the H-2b/b or H-2d/b haplotype developed a rapid course of severe SLE, while the appearance of disease was markedly delayed in H-2d/d hybrid females. However, in the presence of the Yaa gene, H-2d/d F1 males developed SLE as severe as H-2b/b and H-2d/b F1 males. These data indicate that (a) the conventional H-2b is a haplotype leading to susceptibility for murine SLE, while H-2d is a relatively resistant haplotype; (b) the H-2b haplotype exhibits a dominant effect on autoimmune responses, similar to the classical MHC-linked Ir gene effect; and (c) most strikingly, the Yaa gene totally abrogates the MHC effect on murine lupus in (NZB x BXSB)F1 hybrid mice.

Animals↗
PubMed1994

Molecular and cellular basis for pathogenicity of autoantibodies.

Using two different kinds of monoclonal autoantibodies, anti-mouse RBC (MRBC) autoantibodies and IgG3 rheumatoid factor (RF) cryoglobulins, we have attempted to better define the molecular and cellular basis of the pathogenicity of autoantibodies. Among eight anti-MRBC monoclonal antibodies (mAbs) obtained from NZB mice, only five of them are able to cause anemia. The distinct differences in specificity between pathogenic and non-pathogenic anti-MRBC mAbs emphasize the importance of autoantibody specificity for the pathogenesis of autoimmune hemolytic anemia. Histological examination has revealed that Fc gamma receptor-mediated erythrophagocytosis and sequestration of agglutinated RBC in spleens and livers are the major pathogenic mechanisms of hemolytic anemia. This indicates that the affinity of autoantibodies for the Fc gamma receptors of phagocytes and/or the ability to cause hemagglutination, both of which vary among immunoglobulin isotypes, are additional factors determining the pathogenic activity of anti-MRBC autoantibodies. Studies on a panel of anti-IgG2a RF mAbs derived from MRL-lpr/lpr mice have demonstrated that only the IgG3 isotypes of RF mAb are able to generate cryoglobulins and to induce skin leukocytoclastic vasculitis and glomerulonephritis in normal mice. Although the cryoglobulin activity of RF mAb associated with the IgG3 isotype has been shown to be solely responsible for the generation of glomerular lesions (both RF and cryoglobulin activities are necessary for cutaneous vascular lesions), the absence of nephritogenic activity by some IgG3 monoclonal cryoglobulins supports the idea that qualitative features of cryoglobulins are critical to determine their pathogenic activities. Of interest, IgG3 autoantibodies lacking the cryoglobulin activity may not be harmful, but even protective against the development of IgG3 cryoglobulin-mediated tissue lesions, because they inhibit the cryoglobulin formation of pathogenic IgG3 autoantibodies as a result of their nonspecific IgG3 Fc-Fc interaction. Our results on monoclonal autoantibodies clearly indicate the importance of certain subpopulations of autoantibodies in the pathogenesis of autoantibody-mediated cellular and tissue injuries.

Anemia, Hemolytic, Autoimmune↗
PubMed1994

The role of the Yaa gene in lupus syndrome.

The BXSB/MpJ (BXSB) murine strain (H-2b) spontaneously develops an autoimmune syndrome with features of systemic lupus erythematosus (SLE) that affects males much earlier than females. A mutant gene located on the BXSB Y chromosome, designated Yaa (Y chromosome-linked autoimmune acceleration), is responsible for the acceleration of the disease observed in male BXSB mice. Studies on H-2 congenic and I-E transgenic mice have clearly demonstrated that the MHC class II genes play a crucial role in the development or protection of SLE. However, the MHC effect can be completely masked by the presence of the Yaa gene in mice with certain genetic backgrounds. It is intriguing that the Yaa gene effect is selective on autoimmune responses, varying in different lupus-prone mice. Studies on immune responses against foreign antigens have shown that the Yaa gene potentiates immune responses only against antigens to which mice are genetically (H-2-linked) low-responding, but not high-responding. Thus, the selective immune enhancing activity of the Yaa gene may be related to differences in the capacity of T helper cells specific for given antigens. Moreover, studies on Yaa(+)-Yaa- bone marrow cell chimeric mice have suggested that a specific cognate interaction of T helper cells with Yaa+ B cells is responsible for a selective enhancing effect of immune responses to foreign antigens as well as autoantigens. It is significant that unlike the lpr mutation, whose abnormality is associated with the capacity of the Fas antigen to mediate apoptosis, the Yaa gene by itself is unable to induce significant autoimmune responses in mice without apparent SLE background. This suggests that the molecular defect of the Yaa gene is likely to differ from that of the lpr gene, and that the Yaa gene effect requires the abnormal autosomal genome present in lupus-prone mice. Based on these findings, a possible molecular nature of the Yaa gene abnormality will be discussed.

Animals↗
PubMed1994

An autoimmune MRL/Mp-Ipr/Ipr mouse-derived monoclonal IgG antibody stimulates cytokine production in bone-marrow-derived cell line by cross-linking of a cell surface antigen and Fc receptor.

An IgG1 mAb 1G10 derived from an autoimmune MRL/Mp-Ipr/Ipr (MRL/Ipr) mouse has previously been shown to induce IL-3, TNF-alpha and IL-6 production, and autocrine growth in an IL-3-dependent myeloid cell line, FDC-P2/185-4. In the present study, we have attempted to further define the molecular mechanism responsible for the 1G10-induced activation of FDC-P2/185-4 cells. We have shown that 1G10 lacked anti-IgG1 rheumatoid factor activity, failing to generate self-associated immune complexes. Since 1G10 stimulated cells in an Fc gamma R-dependent manner, it seems likely that cross-linking of a cell surface antigen and Fc gamma R by 1G10 antibody is responsible for the stimulation of FDC-P2/185-4 cells. Among several mAb specific to surface antigens expressed on FDC-P2/185-4 cells (MHC class I, LFA-1, and Fc gamma R), only a mAb specific to the alpha chain of LFA-1 alpha was able to induce the IL-3 and Fc gamma R-dependent proliferation of FDC-P2/185-4 cells, similar to that induced by 1G10. Immunoprecipitation analysis revealed that 1G10 recognized a polypeptide with a molecular mass of 140 kilodaltons (p140), which differed from Fc gamma R and from LFA-1 alpha chain. These results suggest that cross-linking of not general but particular cell surface antigens and Fc gamma R stimulates FDC-P2/185-4 cells to produce cytokines resulting in their proliferation.

Animals↗