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Biomedical subjects

S Izui

Publications and source records attributed to S Izui.

At least 145 records · Page 8Linked to original sources
PubMed1987

Cryoglobulinemia induced by monoclonal immunoglobulin G rheumatoid factors derived from autoimmune MRL/MpJ-lpr/lpr mice.

A MRL strain bearing the autosomal recessive mutant gene, lpr (lymphoproliferation), spontaneously develops, in addition to a lupus-like syndrome, unique serological and pathological manifestations. Production of high titers of IgG rheumatoid factors (RF) may be related to the formation of extremely large amounts of cryoglobulins and the development of tissue lesions such as necrotizing polyarteritis, arthritis, and glomerulonephritis. To analyze more directly the relationship of IgG RF to the development of cryoglobulins and tissue injuries, we have established four monoclonal IgG RF secreting hybridomas from unimmunized MRL-lpr/lpr mice and determined their pathogenic effects in normal strains of mice. All the monoclonal IgG RF obtained in this study were of the IgG3 subclass and generated cryoglobulins. However, the fact that not only IgG3 Rf monoclonals but also four of five non-RF IgG3 monoclonals were able to form cryoglobulins, which were composed exclusively of each IgG3 monoclonal, indicates that the IgG3 molecule has a unique physicochemical property to self-associate via nonimmunological interaction and the ability to form cryoglobulins. When the in vivo pathogenic activities of these IgG3 RF and non-RF monoclonals were examined, three of IgG3 RF monoclonals with the specificity to IgG2a were able to induce extensive pathologic manifestations including peripheral vasculitis and glomerulonephritis characteristic of patients with cryoglobulinemia. Our results indicate that the IgG3 itself, independently of its specificity, could be a potential source of cryoglobulins and IgG3 RF, combined with its activity of cryoglobulin formation, may play a significant role in the development of glomerulonephritis and cutaneous vascular lesions of ears and foot pads observed frequently in aged MRL-lpr/lpr mice.

Animals↗
PubMed1987

Quantitation of retroviral gp70 antigen, autoantibodies, and immune complexes in extravascular space in arthritic MRL-lpr/lpr mice. Use of a subcutaneously implanted tissue cage model.

MRL-lpr/lpr (MRL/l) mice spontaneously develop a disease that is characterized by glomerulonephritis, diffuse vasculitis, and arthritis associated with high levels of autoantibodies that include IgG rheumatoid factor (RF). To define the immunopathogenic mechanisms that lead to the development of extravascular lesions such as arthritis, we implanted a tissue cage subcutaneously in arthritic MRL/l mice and compared components of the tissue cage fluid, which resembles the extravascular fluid, with those of sera. When compared with those of sera, tissue cage fluids from arthritic MRL/l mice had similar levels of RF and one-third the amount of C1q immune complexes. In contrast, anti-DNA activities in tissue cage fluids corresponded to only 10% of the serum activities and, most strikingly, nephritogenic retroviral gp70-anti-gp70 immune complexes were almost undetectable in tissue cage fluids. This was also the case for another strain of autoimmune mice, (New Zealand black X New Zealand white)F1 mice, although they did not produce RF. The absence of gp70 immune complexes in tissue cage fluids could be due to markedly limited diffusion of gp70 antigen in these fluids. These results strongly suggest that serum proteins, including autoantigen and autoantibodies, appear in extravascular fluid in a selective manner, depending on their size and charge. Their specific properties in sera or extravascular fluid could partly account for the different manifestations of vascular and extravascular lesions observed in autoimmune mice.

Animals↗
PubMed1987

Interstitial pneumonitis and hepatitis after transfer of bone marrow cells bearing the lpr gene to irradiated recipients: a disease due to large granular leucocytes?

Mice bearing the 'auto-immune' lpr gene develop a lympho-proliferative disease associated with the production of various antibodies. Lethally irradiated recipients were grafted with bone marrow cells (BMC) from syngeneic mice with or without the lpr gene. After 6 months, the survivors were 0/24 and 16/20 for the recipients of lpr and normal BMC respectively. The mortality rate was independent of the presence of T lymphocytes among the BMC. Histological evaluation showed that hepatitis, interstitial pneumonitis, and sclerosis of lymphohaemopoietic organs were the major causes of death for the recipients of lpr BMC. Hepatitis was associated with an increase in the number of liver interstitial cells (LIC) from about 2 X 10(6) up to about 10(7) cells per liver. The LIC associated with the hepatitis were composed of polymorphonuclear leucocytes and large mononuclear leucocytes, showing phenotypic (i.e. Thy.1+, asialo GM1, presence of cytoplasmic granules) and functional (i.e. non-phagocytic and cytolytic) properties of NK cells. The disease can be distinguished both from the spontaneous disease of the lpr mice (by the absence of 'lpr cells' and of anti-DNA antibodies) and from graft versus host disease by the absence of cutaneous and intestinal lesions. It may represent a model of tissue injury mediated by large granular leucocytes.

Animals↗
PubMed1986

Autoimmunity after induction of neonatal tolerance to alloantigens: role of B cell chimerism and F1 donor B cell activation.

BALB/c mice rendered tolerant by the neonatal injection of semiallogeneic (C57BL/6 X BALB/c)F1 spleen cells develop features of autoimmune disease. The possible mechanisms involved in autoantibody production, particularly anti-DNA antibodies, were investigated. In the first 5 wk, there was polyclonal B cell activation, as indicated by marked hypergammaglobulinemia, with a predominance of IgG1 and an increased production of antihapten antibodies. IgG1 anti-SSDNA and anti-DSDNA antibodies were detected with similar kinetics, but at higher titers than the anti-hapten antibodies. Also, there was a correlation between the effective induction of tolerance, as evaluated by the measurement of alloantigen-specific cytolytic T lymphocyte precursors, the persistence of B cell chimerism, and the production of anti-DNA antibodies. Anti-DNA antibodies were observed only in mice exhibiting a persistence of immunoglobulins bearing the donor's allotype. To determine the origin of anti-DNA antibodies, experiments were conducted whereby newborn BALB/c (Igh-1a) mice were injected with F1 cells from mice resulting from a crossing between Igh congenic BALB/c mice bearing the IgCHb allotype and conventional C57BL/6 mice (Igh-1b). All anti-DNA and anti-hapten antibodies exhibited the Igb allotype and thus were produced by the F1 donor B cells. The initial phase of tolerance induction was apparently associated with an allogeneic helper effect, because DNP-KLH-primed F1 donor cells transferred to newborn BALB/c could be stimulated after challenge with DNP-BGG. The triggering of persisting auto-reactive F1 donor B cells may reflect an activation by "incompletely" tolerant semiallogeneic T cells.

Animals↗
PubMed1986

Pathogenesis of the delayed phase of Rauscher virus-induced thrombocytopenia.

BALB/c (H-2d) mice infected with Rauscher murine leukemia virus (RMuLV) developed two phases of thrombocytopenia: an acute phase, probably due to direct virus-platelet interactions, and a delayed phase, starting 2 to 3 wk after virus injection, which was associated with the infection of megakaryocytes by RMuLV and with the expression of RMuLV gp70 and p30 antigens on platelet membranes. This study was concerned with the pathogenesis of this second phase of thrombocytopenia. During this period, the number of marrow megakaryocytes was increased. A peripheral platelet destruction was further indicated by reduced platelet life span. It was shown that radiolabeled platelets, either normal or infected, were submitted to a more rapid clearance in infected recipients than in normal recipients. This might be due to the splenomegaly observed in infected recipients. However, the immediate clearance of gp70+ platelets was more accelerated in infected recipients with high titers of serum anti-gp70 antibodies than in infected recipients without detectable serum anti-gp70 antibodies. In addition, the passive transfer of anti-RMuLV serum to normal BALB/c mice induced a rapid and specific clearance of previously injected radiolabeled platelets expressing RMuLV antigens. In H-2d mice, viral gp70 antigen expression on platelets correlated with the development of delayed thrombocytopenia; but H-2k strains of mice, although susceptible to RMuLV and expressing RMuLV-related antigens on their platelets, did not develop any anti-RMuLV antibodies nor any delayed thrombocytopenia. These results suggest that specific clearance of gp70+ platelets in the presence of significant amounts of serum antiviral antibodies and nonspecific hypersplenism play a role in the development of delayed thrombocytopenia in RMuLV-infected mice.

Animals↗
PubMed1986

Clonality of the spontaneous immune response to DNA in murine lupus.

To probe the mechanism of spontaneous formation of anti-DNA antibodies, we studied the isotype distribution of anti-DNA antibodies in the plasma of NZB/W mice with incipient, chronic, and drug-attenuated nephritis. The concentration of anti-DNA antibodies in plasma did not discriminate between the various groups of mice, and the anti-DNA activity in renal eluates was very low and did not reflect the course of nephritis. Progression of incipient to chronic nephritis was associated with increase, and drug attenuation of nephritis with decrease, in plasma concentration of all isotypes tested. Anti-DNA antibodies were detected in all classes (IgG, IgM) of antibodies studied and the anti-DNA antibodies were found to be unrestricted with respect to IgG isotypes and within a given (IgG2a) isotype. The data indicate that the spontaneous immune response to DNA in NZB/W mice reflects activation of several autoreactive clones and that, overall, anti-DNA activity in the plasma or renal eluate is a poor predictor of extent of renal disease.

Animals↗
PubMed1985

Suppression of B cell development and antibody responses in mice with polyclonal rabbit and monoclonal rat anti-IgM antibodies. I. Characterization of the suppressed state.

Mice treated from birth with polyclonal, crude or affinity purified rabbit or monoclonal rat anti-mouse IgM antibodies [b-7-6 and C-2-23: Eur. J. Immunol. 14: 753-757, 1984] were found to be heavily suppressed with respect to B-cell activities. Crude or affinity purified rabbit or monoclonal rat anti-mouse IgM gave comparable results as follows: serum IgM was below detectable levels; serum IgG was reduced to about 1-3% of normal levels; free anti-IgM was always detectable; IgM and/or kappa-light-chain positive cells as well as IgM-secreting cells were absent in various lymphoid organs; the B-cell mitogen lipopolysaccharide was unable to induce proliferative responses; primary antibody responses could not be induced against sheep red blood cells and phosphorylcholine; lymphoid organs were reduced in size and B-cell areas were not populated with lymphocytes; besides a 40% reduction in absolute lymphocyte numbers in the blood, we found increased platelet counts and a 10% eosinophilia in anti-IgM-treated mice.

Animals↗
PubMed1985

Distinct clonotypes of anti-DNA antibodies in mice with lupus nephritis.

Clonotypes of IgG anti-DNA antibodies were studied by isoelectric focusing in various autoimmune mice with or without lethal lupus nephritis. MRL/MpJ-lpr/lpr mice exhibited the most heterogeneous spectrotypes of anti-DNA antibodies in the pH range from 6.5 to 8.5, with marked variation in individual mice. Female (NZB X NZW)F1 mice expressed rather uniform DNA-binding bands composed of at least five to six distinct subgroups, having isoelectric points from 6.5 to 8.0. Male BXSB mice showed major characteristic bands confined to alkaline pH range from 7.8 to 8.5, similar to C57BL/6J-lpr/lpr mice, which showed markedly restricted bands in this region. Both AKR/J-lpr/lpr and C3H/HeJ-lpr/lpr mice expressed DNA-binding bands mostly focused between pH 6.5 and 8.2. The aging study indicated that three autoimmune mice (MRL/MpJ-lpr/lpr, [NZB X NZW]F1, and male BXSB) that developed fatal glomerulonephritis showed clonal expansion of anti-DNA antibodies throughout their life. In contrast, such age-dependent expansion of anti-DNA clonotypes was not evident in three lpr cogenic mice (C57BL/6J-lpr/lpr, AKR/J-lpr/lpr, and C3H/HeJ-lpr/lpr) that developed only mild glomerulonephritis; rather, their expression of anti-DNA spectrotypes diminished as they aged. Anti-DNA activities in renal eluates from nephritic autoimmune mice were mostly distributed in the pH range from 6.5 to 8.0, without significant concentrations in the high alkaline range of more than pH 8.0. These results suggest that there exist distinct anti-DNA clonotypes in each mouse strain and that the development of lupus nephritis does not appear to be associated with particular spectrotypes of anti-DNA antibodies. Rather, the age-dependent expansion of anti-DNA clonotypes may be a feature more characteristic of mice developing lethal lupus nephritis.

Age Factors↗
PubMed1985

Pathogenic role of anti-DNA antibodies in murine lupus nephritis.

We studied the relative role of anti-DNA antibodies in pathogenesis of murine lupus nephritis, and we used, as index of their contribution, the association between attenuation, or progression, of renal disease and decrease or increase in concentration of anti-DNA antibodies in the plasma and renal eluate of NZB/W mice. The concentration of anti-DNA antibodies in plasma did not discriminate mice with incipient or drug attenuated nephritis, who had normal renal function, from mice with progressive nephritis, who developed renal failure. Although the quantity of IgG eluted from kidneys reflected the extent of renal disease (mice with progressive nephritis greater than mice with attenuated nephritis greater than mice with incipient nephritis), the anti-DNA activity of such antibodies was negligible. The low anti-DNA activity could not be attributed to either excess DNA or DNAase in renal eluates. In fact, the eluates contained a factor that inhibited the interaction between anti-DNA antibody and DNA. The results indicate that immune complex systems other than, or in addition to, DNA-anti-DNA are likely to play a role in the pathogenesis of murine lupus nephritis.

Animals↗
PubMed1985

A fish oil diet rich in eicosapentaenoic acid reduces cyclooxygenase metabolites, and suppresses lupus in MRL-lpr mice.

Dietary supplementation of fish oil as the exclusive source of lipid suppresses autoimmune lupus in MRL-lpr mice. This marine oil diet decreases the lymphoid hyperplasia regulated by the lpr gene, prevents an increase in macrophage surface Ia expression, reduces the formation of circulating retroviral gp70 immune complexes, delays the onset of renal disease, and prolongs survival. We show that a fatty acid component uniquely present in fish oil but not in vegetable oil decreases the quantity of dienoic prostaglandin E, thromboxane B, and prostacyclin normally synthesized by multiple tissues, including kidney, lung, and macrophages, and promotes the synthesis of small amounts of trienoic prostaglandin in autoimmune mice. We suggest that this change in endogenous cyclooxygenase metabolite synthesis directly suppresses immunologic and/or inflammatory mediators of murine lupus.

Animals↗
PubMed1985

Functional analysis of T cell subsets from mice bearing the lpr gene.

The autosomal recessive lpr (lymphoproliferation) gene is responsible for a thymus-dependent massive lymphoproliferation associated with the development of lupus-like autoimmune disease. Phenotypic analysis of adult lpr/lpr lymph nodes has demonstrated accumulation of a dull Lyt-1+, Thy-1+ population that expresses neither Lyt-2 nor L3T4 antigens. With the use of a depletion method based on complement-mediated lysis with an anti-Lyt-2 monoclonal antibody (31 M) and a new anti-L3T4 monoclonal antibody (RL 172.4), we have purified the Lyt-2- L3T4- subset from lymph nodes or spleens of C57BL/6-lpr/lpr mice and determined whether they are immunologically functional in vitro. Production of neither interleukin 2 nor interferon-gamma was detected by the double-negative subset after stimulation with concanavalin A and/or phorbol myristate acetate. The frequencies of allospecific cytotoxic T lymphocyte (CTL) precursors and lectin-induced antigen-nonspecific CTL precursors were diminished to almost undetectable levels, whereas the Lyt-2+ population from lpr/lpr mice had CTL-precursor frequencies comparable with that of +/+ mice. These results show that the major cell subset of adult lpr/lpr lymph nodes or spleens is composed of lymphocytes with markedly limited potential for lymphokine production or antigenic stimulation.

Animals↗
PubMed1985

Growth and differentiation in vitro of the accumulating Lyt-2-/L3T4- subset in lpr mice.

Mice bearing the recessive gene lpr develop an autoimmune syndrome associated with a massive lymphadenopathy, both of which are age and thymus dependent. The predominant accumulating cells in lymphoid tissue of lpr/lpr mice are Thy-1+ but express neither of the mature T cell markers, Lyt-2 or L3T4. We have purified this Lyt-2-/L3T4- subset and examined its phenotype. These cells are not actively cycling, do not express interleukin-2 (IL 2) receptors nor significant levels of antigen receptor, but do express the B cell marker B220. In vitro growth conditions were examined for the lpr Lyt-2-/L3T4- subset. By using a combination of phorbol ester and IL 2, these cells acquired transient expression of IL 2 receptors and grew in an IL 2-dependent manner. Furthermore, these proliferating cells underwent differentiation to a more mature T cell phenotype, with loss of cell surface B220 and acquisition, by a portion, of antigen receptor and Lyt-2. The possible parallels with normal T cell maturation are discussed.

Animals↗
PubMed1985

Association of glycoprotein gp70 with progression or attenuation of murine lupus nephritis.

We studied the relative role of gp70-antigp70 complexes in the pathogenesis of murine lupus nephritis, and we used as an index of its contribution, the association between attenuation, or progression, of renal disease and decrease or increase in concentration of gp70 complexes and IgG in the plasma and renal eluate of NZB/W mice. The arrest or attenuation of nephritis, by immunosuppression, was associated with decreased concentrations in the plasma and renal eluates of IgG and gp70 complexes, and the relative concentration of these reagents in the eluates better reflected the extent of renal disease than did their concentration in the plasma. Neither the relative concentration of Clq-reactive materials, nor the quantity of antiDNA antibodies in the plasma, distinguished the mice whose nephritis was arrested by immunosuppression from those with terminal renal failure. The findings further support that the gp70-antigp70 system plays an important role in the pathogenesis of murine lupus nephritis.

Animals↗
PubMed1984

Self-associating IgG rheumatoid factors in MRL/l autoimmune mice.

Previous work has shown that the intermediate complexes isolated from the plasma of patients with rheumatoid arthritis are composed of self-associating IgG rheumatoid factors. Mice of the MRL/l strain develop spontaneous autoimmune disease with arthritis that is pathologically similar to human rheumatoid arthritis. Also, the sera of MRL/l mice contain autoantibodies to nuclear antigens as well as IgM and IgG rheumatoid factors. The present studies were done to determine if the IgG rheumatoid factors isolated from these mice undergo self-association. MRL/l mouse sera were categorized into groups A and B based on serum-serum precipitin interactions. Thirteen of 13 MRL/l mice sera examined contained intermediate complexes sedimenting between the 6.6S and 19S components of normal serum by sedimentation velocity ultracentrifugation. There were no differences in the level of intermediate complexes between groups A and B. IgG rheumatoid factors were isolated from the sera of 9 other mice. Upon sedimentation equilibrium ultracentrifugation, these rheumatoid factors underwent concentration-dependent self-association similar to that described for human self-associating IgG rheumatoid factors, although the precise stoichiometry of self-association could not be determined. The IgG rheumatoid factors from group B had higher energies of self-interaction than those from group A. These studies provide additional evidence that MRL/l mice may be the best available animal model for the study of human rheumatoid arthritis.

Animals↗
PubMed1984

IgG rheumatoid factors and cryoglobulins in mice bearing the mutant gene lpr (lymphoproliferation).

The autosomal recessive mutant gene, lpr (lymphoproliferation), produces a massive proliferation of T cells in autoimmune MRL mice. Since the MRL strain bearing the lpr mutation is the only strain that spontaneously develops high titers of rheumatoid factors (RF), we have investigated whether non-autoimmune mice (C57BL/6, C3H/HeJ and AKR) bearing the lpr gene could produce RF. Serum levels of RF activity were assessed by a new radioimmunoassay, in which serum samples pretreated with acetate buffer were incubated with 125I-mouse IgG and precipitated with 7% polyethylene glycol. The majority of serum from 4- to 6-month-old non-autoimmune strains of mice bearing the lpr gene exhibited significant RF activity, as did MRL-lpr/lpr mice. Sucrose density-gradient analysis has revealed that all the IgG RF activity was present in a form of immune complexes, sedimenting in the intermediate position (7-19S) and fully dissociable into 7S IgG under an acid condition. This indicates that the production of IgG RF does not require a particular background genome of the MRL strain. In addition, mice bearing the lpr mutation developed extremely large amounts of cryoglobulins, which paralleled the production of RF. Analysis of components of their cryoglobulins revealed a marked enrichment of IgG3 subclass as compared to other IgG subclasses and IgM. These results suggest that IgG3-containing immune complexes represent the major source of cryoglobulins occurring in mice bearing the lpr gene.

Animals↗
PubMed1984

IgM rheumatoid factors in Guatemalan onchocerciasis.

The possible presence of IgM Rheumatoid factors (RF) and anti-DNA antibodies was investigated in sera of patients with Guatemalan onchocerciasis. The mean value of IgM RF in the patients was found to be significantly higher than that in controls and 10 out of 57 patients had increased levels of IgM RF. In addition, serum IgM levels in those 10 patients with increased levels of IgM RF were significantly elevated. In contrast, no significant increase of serum anti-single-stranded (ssDNA) and double-stranded DNA (dsDNA) antibodies were found in the patients.

Adult↗
PubMed1984

Resistance to tolerance induction is not prerequisite to development of murine SLE.

Four different SLE-prone mice, NZB, (NZB x NZW)F1, MRL/MpJ-lpr/lpr, and male BXSB/MpJ, resisted the induction of tolerance to human IgG (HGG) at 5 wk, but not before 3 wk of age. However, female F1 hybrids between NZW and BXSB mice were easily made tolerant to HGG, although they develop an acute form of typical SLE similar to that seen in (NZB x NZW)F1 hybrid females. In addition, C57BL/6 mice bearing a mutant gene, lpr (lymphoproliferation), which produced significant amounts of various autoantibodies characteristic of murine SLE, were still as susceptible to tolerance induction as control C57BL/6 mice. In contrast, both (NZW x BXSB)F1 and (C3H x BXSB)F1 hybrid males carrying the abnormal Y chromosome of BXSB mice failed to become tolerant to HGG, although the extent of resistance to tolerance induction was less significant in (C3H x BXSB)F1 males than in (NZW x BXSB)F1 males. Our results suggest that 1) the defect in tolerance induction to heterologous IgG such as HGG is not necessarily required for the development of an SLE-like syndrome in mice; 2) the induction or enhanced production of autoantibodies by the lpr gene is not related to this cellular abnormality; but 3) a Y chromosome-associated factor from BXSB mice plays a significant role in the abnormality to resist tolerance induction as well as the acceleration of SLE. Our observations are consistent with the hypothesis that SLE may be based on highly specific abnormalities of immune responses to particular autoantigens, but not on a generalized breakdown of a tolerance mechanism.

Animals↗