RESUMO
The accelerated autoimmune syndrome observed in BXSB/MpJ male mice is associated with the presence on the Y chromosome of an as yet unidentified mutant gene, designated Y chromosome-linked autoimmune acceleration (Yaa). To study the mechanisms by which the Yaa gene accelerates and/or induces the production of autoantibodies, we have developed double-congenic bone marrow chimeras containing B cells from autoimmune males carrying the Yaa gene, and from nonautoimmune male or female mice lacking it and differing by the Igh allotype. The analysis of the allotype of total immunoglobulins and anti-DNA antibodies in Yaa+ male-normal female (Yaa-) chimeric mice revealed that the selective activation of B cells from autoimmune Yaa+ male mice was responsible for the hypergammaglobulinemia and autoantibody production. This phenomenon was not due to an anti-HY interaction between female T helper cells and male B cells, because first, Yaa+ B cells were selectively stimulated to produce autoantibodies in Yaa+ male-Yaa- male chimeric mice; and second, normal male and female chimeras failed to develop an autoimmune syndrome. In addition, the fact that both B cell populations in Yaa(+)-Yaa- chimeras similarly responded to a foreign antigen, human IgG, argues against the possibility that the selective activation of Yaa+ B cells may be due to their hyper-responsiveness to T helper signals. We propose that a cognate interaction of T helper cells with Yaa+ B cells, because of possible T cell recognition of a Yaa-related molecule expressed on Yaa+ B cells, may be responsible for the acceleration and/or induction of autoantibodies in BXSB/MpJ mice.
Assuntos
Autoanticorpos/biossíntese , Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Medula Óssea/imunologia , Quimera , Cromossomo Y , Animais , Anticorpos Antinucleares/análise , Doenças Autoimunes/genética , Feminino , Alótipos de Imunoglobulina/análise , Imunoglobulina G/análise , Imunoglobulina G/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Auxiliares-Indutores/imunologiaRESUMO
In vitro, collagen and collagen-like material in GBM, were demonstrated to have a particular high affinity for any DNA tested (mammalian, bacterial, viral, and plant). GBM fixed DNA 40-80 times more than HGG and BSA and 10-40 times more than bacterial LPS. GBM has a higher affinity for SSDNA than for DSDNA. This binding was inhibited at low pH, low ionic strength, and in the presence of anionic detergents, indicating that the highly negatively charged DNA may interact with the basic site on collagen or GBM by electrostatic forces. This interaction was competitively interfered with by DNA-binding proteins such as Clq. Complexes formed of DNA and anti-DNA antibodies did not exhibit the same binding property as free DNA. However, DNA which was already bound to GBM or to collagen could very efficiently bind anti-DNA antibodies and form immune complexes which would remain on these structures. The biological significance of the binding of DNA to GBM or to collagen should be particularly considered in relation to the pathogenesis of SLE. It is possible that DNA released from disrupted or degenerating cells would bind to surrounding collagen fibers or to basement membranes and then act as an immunoabsorbant for circulating anti-DNA antibodies. Some evidence for an in vivo binding of SSDNA to renal structures was obtained in mice treated with bacterial LPS 2 days before the injection of SSDNA.
Assuntos
Colágeno/metabolismo , DNA/metabolismo , Glomérulos Renais/metabolismo , Animais , Complexo Antígeno-Anticorpo , Membrana Basal/metabolismo , Sítios de Ligação , Complemento C1/metabolismo , DNA/imunologia , DNA de Cadeia Simples/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Concentração Osmolar , Ligação Proteica , Solubilidade , TemperaturaRESUMO
A single intraperitoneal injection of bacterial lipopolysaccharide (LPS) or its lipid A component induced high levels of glycoprotein, gp70, in sera of several strains of mice within 24 h. This serum gp70 response induced by LPS was independent of the activation of B cells and the presence of T cells. However, serological and immunohistochemical studies demonstrated the production of gp70 by hepatic parenchymal cells and its subsequent release into the circulating blood. The expression of gp70 in the serum was enhanced not only by LPS but also other inducers of acute phase reactants (APR) such as turpentine oil or polyriboinosinic-polyribocytidylic acid. Further, the serum gp70 response was kinetically identical to those of APR. These results strongly suggest that (a) the liver may be the major source for serum gp70, (b) serum gp70 behaves like an APR, (c) its expression may be controlled by a mechanism similar to that for other APR, and (d) this glycoprotein apparently behaves as a normal host constituent and not a product of a viral genome.
Assuntos
Proteínas Sanguíneas/imunologia , Glicoproteínas/sangue , Animais , Colchicina/farmacologia , Feminino , Glicoproteínas/biossíntese , Glicoproteínas/farmacologia , Haptoglobinas/metabolismo , Lipopolissacarídeos/farmacologia , Fígado/metabolismo , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Endogâmicos NZB , Poli I-C/farmacologia , Quimera por Radiação , Terebintina/farmacologiaRESUMO
The effects of five distinct bacterial lipopolysaccharides (LPS) on the induction of polyclonal IgM and IgG antibodies, including polyclonal autoantibody formation, were investigated in several strains of mice. Injections of most LPS preparations that contained polysaccharide transiently induced only IgM polyclonal antibodies. However, LPS from Salmonella minnesota R595 (R595 LPS), which had a particularly high content of lipid A but lacked O-antigen polysaccharide, induced a markedly prolonged IgM and IgG polyclonal antibody response in mice, including athymic nude mice, but not in LPS-unresponsive C3H/HeJ mice. Polyclonal IgM and IgG production peaked in sera on day 8 and day 15, respectively, and remained higher than control values 2 mo after the injection. The IgG induced by R595 LPS was strictly restricted to IgG2b and Igg3 subclasses in normal mice. In contrast, in athymic nude mice which have normally lower levels of IgG1 and IgG2a than normal mice, R595 LPS stimulated the production of all the IgG subclasses and reconstituted serum levels of IgG1 and IgG2a up to, but not higher than, control values of normal mice. These findings suggest that different mechanisms regulate production of each IgG subclass after stimulation with LPS.
Assuntos
Formação de Anticorpos , Imunoglobulina G , Lipídeo A/administração & dosagem , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/farmacologia , Animais , Relação Dose-Resposta Imunológica , Imunoglobulina G/classificação , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Nus , CoelhosRESUMO
Both sexes of the (NZW x BXSB)F1 mice developed an early systemic lupus erythematosus-like disease. In males, the disease resembled that in the BXSB male parent and was not affected by sex hormonal manipulation. In females, the disease duplicated that of (NZB x NZW)F1 females by virtue of a delayed onset and estrogen dependence. Autoantibody production, circulating Ig-bound gp 70 immune complexes, and deposition of Ig and gp 70 in the affected glomeruli were demonstrated in both males and females. The abnormally high incidence of degenerative coronary vascular disease with myocardial infarction, particularly in these F1 males, provides a useful model for the investigation of a possible immunologic component in coronary vascular disease.
Assuntos
Doença das Coronárias/imunologia , Cruzamentos Genéticos , Lúpus Eritematoso Sistêmico/imunologia , Infarto do Miocárdio/imunologia , Doença Aguda , Animais , Anticorpos , Doenças Autoimunes/complicações , Castração , Doença das Coronárias/complicações , Doença das Coronárias/genética , DNA de Cadeia Simples/imunologia , Feminino , Glomerulonefrite/complicações , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Infarto do Miocárdio/complicações , Infarto do Miocárdio/genéticaRESUMO
Endogenous retroviral gp70 was investigated as a participant in the pathogenesis of a lupus-like disease that spontaneously develops in four kinds of mice (NZB, NZB x W MRL/1, and male BXSB). Sera from these strains contain a heavy form of gp 70 that varies in sedimentation rates from 9S to 19S in sucrose density gradient analysis and appears with the onset of disease and persists throughout its course. Immunologically normal strains of mice do not develop rapidly sedimenting gp70 by 8-10 mo of life. The fact that the heavy gp70 is selectively absorbed with anti-IgG antibodies or with Staphylococcus aureus protein A suggests that it is complexed with antibodies. The incidence and quantities of these gp70 ICs rise with the progression of disease in all strains with lupus. These findings suggest that Ig-complexed heavy gp70 may be involved in the pathogenesis of glomerulonephritis of mice with SLE.
Assuntos
Anticorpos Antivirais , Complexo Antígeno-Anticorpo , Antígenos Virais , Gammaretrovirus/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Proteínas Virais/imunologia , Animais , Feminino , Glicoproteínas/imunologia , Masculino , Camundongos , Camundongos Endogâmicos , Vírus Rauscher/imunologia , Especificidade da EspécieRESUMO
The effect of pharmacologic quantities of prostaglandin E1 (PGE) was investigated in three strains of mice (NZB X NZW, MRL/1, and BXSB) that spontaneously develop lupus-like glomerulonephritis. PGE-treatment prolonged survival and retarded the glomerular deposition of immune complex (IC) and the development of glomerulonephritis in NZB X NZW and MRL/1 mice, but did not similarly protect BXSB mice. Changes in the responsive strains correlated well with reduced amounts of circulating gp70 complexed with anti-gp70 antibodies compared with untreated controls, although total concentrations of gp70 (free and complexed) detectable in sera were similar in both groups of mice. The results strongly suggest that: (a) PGE selectively suppressed the immune response to retroviral gp70, (b) PGe had little effect on the quantity or quality of anti-DNA antibodies but did reduce the deposition of anti-DNA containing IC in the kidneys, and (c) gp70 IC appear to play an important role in the pathogenesis of glomerulonephritis in murine systemic lupus erythematosus.
Assuntos
Complexo Antígeno-Anticorpo , Lúpus Eritematoso Sistêmico/imunologia , Prostaglandinas E/farmacologia , Proteínas Virais/imunologia , Animais , Anticorpos Antinucleares/análise , Modelos Animais de Doenças , Feminino , Glomerulonefrite/imunologia , Glomerulonefrite/prevenção & controle , Glicoproteínas/imunologia , Tolerância Imunológica , Masculino , Camundongos , Prostaglandinas E/uso terapêuticoRESUMO
We have evaluated the therapeutic activity of rIL-3, in comparison with recombinant granulocyte-macrophage CSF (rGM-CSF) and recombinant erythropoietin (rEpo), on a lethal form of acute anemia induced by a single injection of a monoclonal IgG1 anti-mouse RBC (MRBC) autoantibody. Continuous perfusion of rIL-3 before the administration of anti-MRBC mAb prevented animals from the death due to anemia with a rapid recovery in greater than 90% of the cases, while only partial protection (one third of the cases) was obtained by rEpo perfusion, and no protection by rGM-CSF. Since the anti-MRBC mAb induced a marked agglutination of RBC in spleens and livers, and subsequent hemodynamic failure may be an additional contributing factor to the animals' death, the activation of Fc gamma receptor-dependent phagocytosis by rIL-3, as well as the increased number of monocytes/macrophages resulting from rIL-3 perfusion, may also facilitate rapid elimination of these agglutinated RBC, resulting in the further amelioration of the animals' survival. Our results suggest that the therapeutic effect of rIL-3 on anti-MRBC autoantibody-induced anemia is achieved by: (a) its activity to promote the growth and differentiation of erythroid progenitors responsive to Epo and of monocyte/macrophage lineage; and (b) its activity to enhance the phagocytic activity of macrophages to efficiently eliminate agglutinated RBC in spleens and livers.
Assuntos
Anemia/terapia , Anticorpos Monoclonais , Autoanticorpos/imunologia , Fatores Estimuladores de Colônias/uso terapêutico , Eritrócitos/imunologia , Eritropoetina/uso terapêutico , Substâncias de Crescimento/uso terapêutico , Interleucina-3/uso terapêutico , Doença Aguda , Anemia/imunologia , Anemia/patologia , Animais , Endocitose , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Hematócrito , Interleucina-3/administração & dosagem , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos , Perfusão , Receptores Fc/fisiologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Baço/patologiaRESUMO
Acute thrombocytopenia and megakaryocyte infection have been investigated during the preleukemic phase of the disease induced by the Rauscher murine leukemia virus (RMuLV) in mice. Injection of RMuLV, either intravenously or intraperitoneally, rapidly induced thrombocytopenia, possibly as a result of direct interaction between platelets and viral particles. The susceptibility to this acute thrombocytopenia was genetically controlled and was inherited as a dominant trait. Murine strains with H-2d or H-2k haplotype, which are susceptible to the induction of leukemia by RMuLV, developed thrombocytopenia, whereas leukemia-resistant H-2b and H-2q strains of mice failed to develop thrombocytopenia. Using B10 H-2-congenic and intra-H-2-recombinant mice, it was shown that the susceptibility to RMuLV-induced thrombocytopenia was controlled by gene(s) in or closely linked to the D region of the H-2 complex. Megakaryocytes may be one of the first sites for the replication of RMuLV. Indeed, among bone marrow cells, only megakaryocytes expressed viral antigens gp70 and p30 during the initial phase of RMuLV infection. In addition, megakaryocytes from infected mice were able to transfer preleukemic thrombocytopenia as well as leukemia in syngeneic mice. The infection of megakaryocytes by RMuLV appears to be genetically controlled in a manner similar to the induction of thrombocytopenia, since only the megakaryocytes from mice developing thrombocytopenia were infected by RMuLV. These results indicate that the gene(s) governing the induction of thrombocytopenia by RMuLV may be the same gene(s) (or closely linked to the gene) that controls the susceptibility to leukemogenesis, and would be consistent with the expression of the gene product, presumably a receptor-like molecule for RMuLV, on platelet and megakaryocyte membranes.
Assuntos
Leucemia Experimental/genética , Megacariócitos/imunologia , Trombocitopenia/genética , Doença Aguda , Animais , Antígenos Virais/análise , Antígenos Virais/genética , Células da Medula Óssea , Suscetibilidade a Doenças , Feminino , Antígenos H-2/genética , Antígenos H-2/imunologia , Cinética , Leucemia Experimental/etiologia , Leucemia Experimental/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Vírus Rauscher/imunologia , Trombocitopenia/etiologia , Trombocitopenia/imunologia , Proteínas do Envelope Viral , Proteínas Virais/análiseRESUMO
Retroviral gp70 and anti-gp70 antibodies were isolated from circulating immune complexes (IC) of 7-10-mo-old (NZB X NZW)F1 mice, after which the nature and origin of this gp70 (IC-gp70) and the immunologic characteristics of these anti-gp70 antibodies (IC-anti-gp70) were investigated. Immunochemical and structural analyses of IC-gp70 demonstrated that among multiple immunologically related gp70 expressed in all mice, the IC-gp70 had characteristics similar to those of NZB xenotropic viral gp70 (NZB-X1 gp70) that is commonly present in sera of virtually all strains of mice. The study of binding by IC-anti-gp70 antibodies to retroviral gp70 from various sources showed that the IC-anti-gp70 were primarily directed to NZB-X1 gp70 as well as serum gp70. These data strongly suggest that the abnormality of murine strains with systemic lupus erythematosus causing them to produce antibodies to their own xenotropic viral gp70 and to form IC with serum gp70 is not based on their expression of an unusual type of gp70, but rather their ability to make an antibody to NZB-X1 gp70, probably as a result of their immunologic dysfunction.
Assuntos
Anticorpos Antivirais/análise , Complexo Antígeno-Anticorpo/análise , Glicoproteínas/imunologia , Retroviridae/imunologia , Animais , Glicoproteínas/isolamento & purificação , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Camundongos Endogâmicos NZBRESUMO
Interleukin-4 (IL-4) provides support for humoral immune responses through upregulation of T helper (Th) type 2 cell differentiation, but it is not known whether IL-4 promotes antibody-mediated autoimmune diseases such as systemic lupus erythematosus (SLE). Here, we show that the constitutive expression of an IL-4 transgene by B cells completely prevents the development of lethal lupus-like glomerulonephritis in the (NZW x C57BL/6.Yaa)F1 murine model of SLE. This was associated with marked changes in the serum levels of IgG subclasses, rather than in the total levels of anti-DNA antibodies, with a lack of IgG3, a decrease of IgG2a, and an increase in IgG1 subclasses, and by a strong reduction in the serum levels of gp70-anti-gp70 immune complexes. This effect of the transgene appears to result from a modulation of the Th1 versus Th2 autoimmune response, since the protected mice displayed comparably modified IgG2a and IgG3 antibody response against exogenous T cell-dependent antigen, but not against T cell-independent antigens. Thus, IL-4 prevents the development of this lupus-like autoimmune disease, most likely by downregulating the appearance of Th1-mediated IgG subclasses of autoantibodies such as the IgG3 autoantibodies which have been shown to be especially nephritogenic.
Assuntos
Linfócitos B/imunologia , Interleucina-4/biossíntese , Nefrite Lúpica/genética , Nefrite Lúpica/prevenção & controle , Animais , Anticorpos Antinucleares/biossíntese , Anticorpos Antinucleares/sangue , Formação de Anticorpos , Diferenciação Celular , Elementos Facilitadores Genéticos , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunoglobulina G/sangue , Cadeias Pesadas de Imunoglobulinas/genética , Interleucina-4/genética , Nefrite Lúpica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Transgênicos , Regiões Promotoras Genéticas , Linfócitos T/imunologia , Células Th2/citologia , Células Th2/imunologiaRESUMO
The bcl-2 protooncogene has been shown to provide a survival signal to self-reactive B cells, but it fails to override their developmental arrest after encounter with antigen. Furthermore, constitutive expression of bcl-2 in B cells does not promote the development of autoimmune disease in most strains of mice, indicating that signals other than those conferred by bcl-2 are required for long-term survival and differentiation of self-reactive B cells in vivo. To further examine the factors that are required for the pathogenesis of autoimmune disease, we have assessed the effect of bcl-2 overexpression on the development of host-versus-graft disease, a self-limited model of systemic autoimmune disease. In this model, injection of spleen cells from (C57BL/6 x BALB/c)F1 hybrid mice into BALB/c newborn parental mice induces immunological tolerance to donor tissues and activation of autoreactive F1 donor B cells through interactions provided by allogeneic host CD4+ T cells. BALB/c newborns injected with spleen cells from (C57BL/6 x BALB/c)F1 mice expressing a bcl-2 transgene in B cells developed high levels of anti-single-stranded DNA and a wide range of pathogenic autoantibodies that were not or barely detectable in mice injected with nontransgenic spleen cells. In mice injected with transgenic B cells, the levels of pathogenic autoantibodies remained high during the course of the study and were associated with long-term persistence of donor B cells, development of a severe autoimmune disease, and accelerated mortality. These results demonstrate that bcl-2 can provide survival signals for the maintenance and differentiation of autoreactive B cells, and suggest that both increased B cell survival and T cell help play critical roles in the development of certain forms of systemic autoimmune disease.
Assuntos
Envelhecimento/imunologia , Linfócitos B/imunologia , Antígenos H-2/imunologia , Tolerância Imunológica , Isoantígenos/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Proteínas Proto-Oncogênicas/biossíntese , Proto-Oncogenes , Animais , Animais Recém-Nascidos , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Cruzamentos Genéticos , Morte , Proteínas de Ligação ao GTP/biossíntese , Heterozigoto , Lúpus Eritematoso Sistêmico/patologia , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-bcl-2 , Baço/imunologia , Baço/patologiaRESUMO
After injection of lipopolysaccharides (LPS) in mice, there is first a release of DNA into plasma and secondly an induction of anti-DNA antibodies. The circulating DNA was purified from plasma and physico-immunochemically characterized. This DNA has a similar density to mammalian cellular DNA,is 4--6S insize, and probably represents a mixture of single-stranded DNA (SSDNA) and double-stranded DNA (DSDNA) or DSDNA with some single-stranded regions. This purified DNA was shown to react with anti-DNA antibodies which appeared as early as 3 days after a single injection of LPS in mice. In serum, DNA-anti-DNA complexes were not detected, although unidentified circulating immune complex-like material was demonstrated 5-8 days after the injection of LPS. In tissues, particularly in renal glomeruli, fine granular immune complex-type immunoglobulin deposits appeared along the glomerular capillary walls and in the mesangium 3 days after the injection of LPS. There is a direct correlation between the level of anti-DNA antibodies and the intensity of glomerular deposits and about 40% of immunoglobulins eluted from kidneys are anti-DNA antibodies, indicating that some of the immune complexes localized in kidneys are DNA-anti-DNA complexes. Based on these observations, the following hypothetical mechanism for the glomerular localization of DNA-anti-DNA complexes after the injection of LPS in mice is proposed. First, DNA, which has been released in circulating blood after injection of LPS, might bind to renal glomeruli, probably on glomerular basement membranes (GBM) through a high affinity of GBM for DNA; secondly, circulating anti-DNA antibodies, which appear later, might react with the glomerular-bound DNA and form immune complexes independently of circulating immune complexes. However, the possibility of direct deposition of immune complexes is not ruled out.
Assuntos
Anticorpos Antinucleares , Complexo Antígeno-Anticorpo , DNA/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Polissacarídeos Bacterianos/imunologia , Animais , Antígenos , Modelos Animais de Doenças , Glomérulos Renais/imunologia , Lúpus Eritematoso Sistêmico/etiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Salmonella typhimuriumRESUMO
In vivo, prolonged polyclonal activation of B cells by the nonantigenic but potent mitogenic lipid A portion of lipopolysaccharide (LPS-R595) resulted in acceleration of the late life systemic lupus erythematosus disease of female MRL/n, BXSB, and NZW mice, mimicking the time, form, and histopathological features characteristic of their early life disease counterparts, i.e., MRL/l females, BXSB males, and (NZB X NZW)F1 females. Similar polyclonal B cell activation of "immunologically normal" mice has less effect and led to a limited expression of autoimmune disease. This R595-induced autoimmunity and immune complex-mediated disease seemed to be the direct result of activation of the immune system and not from other effects of endotoxin since C3H/HeJ, a strain lacking lymphocyte receptors for LPS-R595, had neither serological nor histological evidence of autoimmune disease despite identical treatment.
Assuntos
Doenças Autoimunes/etiologia , Linfócitos B/imunologia , Ativação Linfocitária , Animais , Células Produtoras de Anticorpos/imunologia , Autoanticorpos/biossíntese , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Coagulação Sanguínea/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Doença Crônica , Feminino , Glomerulonefrite/imunologia , Técnica de Placa Hemolítica , Heparina/administração & dosagem , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BLRESUMO
Males from the BXSB murine strain (H-2b) spontaneously develop an autoimmune syndrome with features of systemic lupus erythematosus (SLE), which results in part from the action of a mutant gene (Yaa) located on the Y chromosome. Like other H-2b mice, the BXSB strain does not express the class II major histocompatibility complex antigen, I-E. Here we report that the expression of I-E (E alpha dE beta b) in BXSB males bearing an E alpha d transgene prevents hypergammaglobulinemia, autoantibody production, and subsequent autoimmune glomerulonephritis. These transgenic mice bear on the majority of their B cells not only I-E molecules, but also an I-E alpha chain-derived peptide presented by a higher number of I-Ab molecules, as recognized by the Y-Ae monoclonal antibody. The I-E+ B cells appear less activated in vivo than the I-E- B cells, a minor population. This limited activation of the I-E+ B cells does not reflect a functional deficiency of this cell population, since it can be stimulated to IgM production in vitro by lipopolysaccharides at an even higher level than the I-E- B cell population. The development of the autoimmune syndrome in the transgenic and nontransgenic bone marrow chimeric mice argues against the possibility that the induction of regulatory T cells or clonal deletion of potential autoreactive T cells as a result of I-E expression is a mechanism of the protection conferred by the E alpha d transgene. We propose a novel mechanism by which the E alpha d transgene protects BXSB mice against SLE: overexpression of I-E alpha chains results in the generation of excessive amounts of a peptide displaying a high affinity to the I-Ab molecule, thereby competing with pathogenic autoantigen-derived peptides for presentation by B lymphocytes and preventing their excessive stimulation.
Assuntos
Autoimunidade , Antígenos de Histocompatibilidade Classe II/fisiologia , Lúpus Eritematoso Sistêmico/prevenção & controle , Animais , Células Cultivadas , Feminino , Antígenos de Histocompatibilidade Classe II/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos TransgênicosRESUMO
Superantigens are defined by their ability to stimulate a large fraction of T cells via interaction with the T cell receptor (TCR) V beta domain. Endogenous superantigens, classically termed minor lymphocyte-stimulating (Mls) antigens, were recently identified as products of open reading frames (ORF) in integrated proviral copies of mouse mammary tumor virus (MMTV). We have described an infectious MMTV homologue of the classical endogenous superantigen Mls-1a (Mtv-7). The ORF molecules of both the endogenous Mtv-7 and the infectious MMTV(SW) interact with T cells expressing the TCR V beta 6, 7, 8.1, and 9 domains. Furthermore, the COOH termini of their ORF molecules, thought to confer TCR specificity, are very similar. Since successful transport of MMTV from the site of infection in the gut to the mammary gland depends on a functional immune system, we were interested in determining the early events after and requirements for MMTV infection. We show that MMTV(SW) infection induces a massive response of V beta 6+ CDC4+ T cells, which interact with the viral ORF. Concomitantly, we observed a B cell response and differentiation that depends on both the presence and stimulation of the superantigen-reactive T cells. Furthermore, we show that B cells are the main target of the initial MMTV infection as judged by the presence of the reverse-transcribed viral genome and ORF transcripts. Thus, we suggest that MMTV infection of B cells leads to ORF-mediated B-T cell interaction, which maintains and possibly amplifies viral infection.
Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Ativação Linfocitária , Vírus do Tumor Mamário do Camundongo/imunologia , Antígenos Secundários de Estimulação de Linfócitos/imunologia , Infecções Tumorais por Vírus/imunologia , Animais , Formação de Anticorpos , Antígenos Virais/imunologia , Linfócitos B/microbiologia , Sequência de Bases , Regulação Viral da Expressão Gênica , Genes Virais , Vírus do Tumor Mamário do Camundongo/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos/química , RNA Mensageiro/genética , RNA Viral/genética , Infecções Tumorais por Vírus/microbiologia , Proteínas Estruturais Virais/genéticaRESUMO
To assess the potency of low-affinity anti-red blood cell (RBC) autoantibodies in the induction of anemia, we generated an immunoglobulin (Ig)G2a class-switch variant of a 4C8 IgM anti-mouse RBC autoantibody, and compared its pathogenic potential with that of its IgM isotype and a high-affinity 34-3C IgG2a autoantibody. The RBC-binding activity of the 4C8 IgG2a variant was barely detectable, at least 1,000 times lower than that of its IgM isotype, having a high-binding avidity, and that of the 34-3C IgG2a monoclonal antibody (mAb). This low-affinity feature of the 4C8 mAb was consistent with the lack of detection of opsonized RBCs in the circulating blood from the 4C8 IgG2a-injected mice. However, the 4C8 IgG2a variant was highly pathogenic, as potent as its IgM isotype and the 34-3C IgG2a mAb, due to its capacity to interact with Fc receptors involved in erythrophagocytosis. In addition, our results indicated that the pentameric form of the low-affinity IgM isotype, by promoting the binding and agglutination of RBCs, is critical for its pathogenic activity. Demonstration of the remarkably high pathogenic potency of low-affinity autoantibodies, if combined with appropriate heavy chain effector functions, highlights the critical role of the Ig heavy chain constant regions, but the relatively minor role of autoantigen-binding affinities, in autoimmune hemolytic anemia.
Assuntos
Anemia Hemolítica Autoimune/imunologia , Autoanticorpos/sangue , Eritrócitos/imunologia , Anemia Hemolítica Autoimune/sangue , Animais , Anticorpos Monoclonais , Linhagem Celular , Citometria de Fluxo , Variação Genética , Hemólise , Imunoglobulina G/sangue , Imunoglobulina G/genética , Imunoglobulina M/sangue , Imunoglobulina M/genética , Região de Troca de Imunoglobulinas , Fígado/imunologia , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Receptores Fc/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , TransfecçãoRESUMO
The effect of dietary restriction on the expression of retroviral envelope glycoprotein, gp70, and the formation of gp70-anti gp70 immune complexes was investigated in lupus-prone NZB x NZW F1 hybrid mice. Restricting total calorie intake from the usual 20 to only 10 calories per day after weaning markedly reduced serum levels of both free and antibody-complexed gp70, prevented renal disease, and increased the life spans of these mice. The reduction in serum gp70 was evident after only 2 wk of feeding these animals the low-calorie diet, and the concentration remained virtually unchanged throughout the course of 10 mon experimentation. However, serum concentrations of the major structural protein, p30, of endogenous retroviruses were not altered by restricting calories. Amounts of the serum glycoprotein, haptoglobin, decreased parallel to those of gp70 but amounts of albumin did not. These results suggest that the expression of gp70 in serum is controlled independently of the production of complete viral particles, and regulated by a mechanism similar to that for other serum glycoproteins, such as haptoglobin.
Assuntos
Dieta , Ingestão de Energia , Camundongos Endogâmicos NZB/imunologia , Retroviridae , Proteínas Virais/sangue , Animais , Formação de Anticorpos , Complexo Antígeno-Anticorpo , DNA/imunologia , Dieta/efeitos adversos , Feminino , Glomerulonefrite/etiologia , Glomerulonefrite/patologia , Haptoglobinas , Hibridização Genética , Masculino , Camundongos , Albumina Sérica , Proteínas do Envelope Viral , Proteínas Virais/imunologiaRESUMO
NZB x NZW (NZB x W) F1 hybrid mice spontaneously develop a disease most prominently characterized by immune complex glomerulonephritis (GN), which seems to be associated with both antibodies to DNA and to the serum retroviral envelope glycoprotein, gp70. To evaluate the contribution of each of these autoimmune responses to the pathogenesis of the GN, we studied NZB x W F2 mice in which the two responses appeared to segregate relatively independently. Use of this model permitted analysis of possible correlations between each response and the G.N. The presence of circulating anti-gp 70-complexed gp70 correlated significantly with the development of fatal GN and one could predict the course of renal disease by computing the rising serum levels of gp70 complexed with antibodies. In contrast, the presence of free antibodies to either double-stranded or single-stranded DNA was not significantly associated with the development of fatal GN. This association of anti-gp70 antibody production with these animals' early death from GN strongly suggests that the gene(s) governing production of antibodies to serum retroviral gp70 may be one of the major genes responsible for spontaneous renal disease segregated in NZB x W F2 generations.
Assuntos
Antígenos Virais/imunologia , Retroviridae/imunologia , Proteínas Virais/imunologia , Animais , Complexo Antígeno-Anticorpo , Feminino , Glomerulonefrite/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Camundongos Endogâmicos NZB , Proteínas do Envelope ViralRESUMO
Using three different Fcgamma receptor (FcgammaR)-deficient mouse strains, we examined the induction of autoimmune hemolytic anemia by each of the four immunoglobulin (Ig)G isotype-switch variants of a 4C8 IgM antierythrocyte autoantibody and its relation to the contributions of the two FcgammaR, FcgammaRI, and FcgammaRIII, operative in the phagocytosis of opsonized particles. We found that the four IgG isotypes of this antibody displayed striking differences in pathogenicity, which were related to their respective capacity to interact in vivo with the two phagocytic FcgammaRs, defined as follows: IgG2a > IgG2b > IgG3/IgG1 for FcgammaRI, and IgG2a > IgG1 > IgG2b > IgG3 for FcgammaRIII. Accordingly, the IgG2a autoantibody exhibited the highest pathogenicity, approximately 20-100-fold more potent than its IgG1 and IgG2b variants, respectively, while the IgG3 variant, which displays little interaction with these FcgammaRs, was not pathogenic at all. An unexpected critical role of the low-affinity FcgammaRIII was revealed by the use of two different IgG2a anti-red blood cell autoantibodies, which displayed a striking preferential utilization of FcgammaRIII, compared with the high-affinity FcgammaRI. This demonstration of the respective roles in vivo of four different IgG isotypes, and of two phagocytic FcgammaRs, in autoimmune hemolytic anemia highlights the major importance of the regulation of IgG isotype responses in autoantibody-mediated pathology and humoral immunity.