RESUMO
Deficiencies in early complement components are associated with the development of systemic lupus erythematosus (SLE) and therefore early complement components have been proposed to influence B lymphocyte activation and tolerance induction. A defect in apoptosis is a potential mechanism for breaking of peripheral B cell tolerance, and we hypothesized that the lack of the early complement component C4 could initiate autoimmunity through a defect in peripheral B lymphocyte apoptosis. Previous studies have shown that injection of a high dose of soluble antigen, during an established primary immune response, induces massive apoptotic death in germinal centre B cells. Here, we tested if the antigen-induced apoptosis within germinal centres is influenced by early complement components by comparing complement C4-deficient mice with C57BL/6 wild-type mice. We demonstrate that after the application of a high dose of soluble antigen in wild-type mice, antibody levels declined temporarily but were restored almost completely after a week. However, after antigen-induced apoptosis, B cell memory was severely limited. Interestingly, no difference was observed between wild-type and complement C4-deficient animals in the number of apoptotic cells, restoration of antibody levels and memory response.
Assuntos
Apoptose/imunologia , Linfócitos B/imunologia , Complemento C4/deficiência , Complemento C4/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Animais , Antígenos/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Centro Germinativo/imunologia , Tolerância Imunológica , Memória Imunológica , Camundongos , Camundongos Endogâmicos C57BL , Nitrofenóis/imunologia , FenilacetatosRESUMO
A 58-year-old woman presented with hemolysis and thrombocytopenia 2 weeks after receiving a kidney graft. Hemolytic uremic syndrome was initially suspected, because in addition to hematological changes the graft function was missing. Unexpectedly, the results of the direct antiglobulin test became positive (4+), which is not normally observed in the hemolytic uremic syndrome. Differentiation of the eluted antibodies revealed anti-rhesus D specificity, which had to be interpreted either as an autoantibody of patient's origin or, hypothetically, as a "graft versus host" antibody of donor origin. Gm- and Km allotyping of these antibodies demonstrated a pattern which differed from the patient's but was identical to that of the kidney donor. Therefore hemolysis could be explained unambiguously by "graft versus host" antibodies. Whether the thrombocytopenia was also due to an immune process was not clear, although some evidence favors this hypothesis. Immunosuppressive treatment remained unchanged and several red blood cell transfusions were necessary before reactivity of the direct antiglobulin test diminished and became negative 7 weeks after kidney transplantation. The occurrence of hemolysis in the early posttransplantation period should thus draw attention to the possibility of "graft versus host" antibodies directed against red cells. Concomitant thrombocytopenia may occur. Donor screening for irregular erythrocyte antibodies should be performed whenever solid organ transplantation is intended.
Assuntos
Anemia Hemolítica/diagnóstico , Anemia Hemolítica/etiologia , Transplante de Rim/efeitos adversos , Linfócitos B/imunologia , Teste de Coombs , Diagnóstico Diferencial , Eritrócitos/imunologia , Feminino , Humanos , Isoanticorpos/análise , Transplante de Rim/imunologia , Pessoa de Meia-Idade , Sistema do Grupo Sanguíneo Rh-Hr/imunologia , Doadores de TecidosRESUMO
We describe the identification and molecular characterization of a novel variant O(1) allele of the ABO blood group locus. The allele was found in a young child and by analyzing the maternal DNA we were able to show that a meiotic recombination event between the maternal O(1v-3) and B(1-1) alleles recreated a O(1)/B hybrid allele. Further characterization of intron 6 sequences delineated the putative recombination breakpoint between nucleotide position 42 and 163 of the intron. We propose that the novel O(1variant) allele should be named O(1v-7) and is a combination of exon 6 from a O(1v-3) allele and exon 7 from a B(1-1) allele.
Assuntos
Sistema ABO de Grupos Sanguíneos/genética , Troca Genética , Alelos , Criança , Humanos , Meiose , Fenótipo , Reação em Cadeia da PolimeraseRESUMO
The role of complement in the maintenance of self-tolerance has been examined in two models: an immunoglobulin transgenic model of peripheral tolerance and a lupus-like murine model of CD95 (Fas) deficiency. We find that self-reactive B lymphocytes deficient in complement receptors CD21/CD35 or transferred into mice deficient in the complement protein C4 are not anergized by soluble self-antigen. In the second model, deficiency in CD21/CD35 or C4 combined with CD95 deficiency results in high titers of anti-nuclear antibodies leading to severe lupus-like disease. These findings suggest a novel role for the complement system in B cell tolerance and provide insight into the genetic association of complement deficiency with susceptibility to systemic lupus erythematosus.
Assuntos
Proteínas do Sistema Complemento/imunologia , Tolerância Imunológica/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Autoimunidade/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Anergia Clonal , Complemento C3/deficiência , Complemento C4/deficiência , Feminino , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Muramidase/metabolismo , Receptores de Complemento 3b/deficiência , Receptores de Complemento 3d/deficiência , Receptor fas/fisiologiaRESUMO
Affinity-driven selection of B lymphocytes within germinal centers is critical for the development of high-affinity memory cells and host protection. To investigate the role of the CD21/CD35 coreceptor in B cell competition for follicular retention and survival within the germinal center, either Cr2+ or Cr2null lysozyme-specific transgenic B cells were adoptively transferred into normal mice immunized with duck (DEL) or turkey (TEL) lysozyme, which bind with different affinities. In mice injected with high-affinity turkey lysozyme, Cr2null B cells responded by follicular retention; however, they could not survive within germinal centers. This suggests that CD21 provides a signal independent of antigen that is required for survival of B cells in the germinal center.
Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Receptores de Complemento 3b/imunologia , Receptores de Complemento 3d/imunologia , Transferência Adotiva , Sequência de Aminoácidos , Animais , Linfócitos B/citologia , Divisão Celular , Sobrevivência Celular , Feminino , Expressão Gênica , Centro Germinativo/citologia , Imunização , Ativação Linfocitária , Masculino , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Muramidase/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Complemento 3b/genética , Receptores de Complemento 3d/genética , Baço/imunologiaRESUMO
Mice deficient in complement components C3 (C3 -/-) and C4 (C4 -/-) were found to have a profound defect in their Ab response to a T-dependent Ag (bacteriophage (phi X174). Characterization of the deficient mice demonstrated a diminished level of peanut agglutinin+ germinal centers and a failure in isotype switching despite normal B cell signaling in vitro. The nature of the defect was found to lie at the B cell level, as the T cells were primed in C3- and C4-deficient mice as well as those in wild-type mice. These results, and the finding that the defect could be partly reversed by a 10-fold increase in Ag dose, support the hypothesis that covalent attachment of complement ligands, i.e., C3b and C3d to the Ag-Ab complex, increases its immunogenicity.
Assuntos
Linfócitos B/imunologia , Via Clássica do Complemento , Proteínas do Sistema Complemento/farmacologia , Linfócitos T/imunologia , Animais , Anticorpos Antivirais/biossíntese , Antígenos Virais/farmacologia , Linfócitos B/efeitos dos fármacos , Bacteriófago phi X 174/imunologia , Complemento C3/deficiência , Complemento C4/deficiência , Feminino , Centro Germinativo/imunologia , Ativação Linfocitária/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Baço/citologia , Baço/imunologiaRESUMO
Covalent attachment of activated products of the third component of complement to antigen enhances its immunogenicity, but the mechanism is not clear. This effect is mediated by specific receptors, mCR1 (CD35) and mCR2 (CD21), expressed primarily on B cells and follicular dendritic cells in mice. To dissect the role of mCR1 and mCR2 in the humoral response, we have disrupted the Cr2 locus to generate mice deficient in both receptors. The deficient mice (Cr2-/-) were found to have a reduction in the CD5+ population of peritoneal B-1 cells, although their serum IgM levels were within the range of normal mice. Moreover, Cr2-/- mice had a severe defect in their humoral response to T-dependent antigens that was characterized by a reduction in serum antibody titers and in the number and size of germinal centers within splenic follicles. Reconstitution of the deficient mice with bone marrow from MHC-matched Cr2+/+ donors corrected the defect, demonstrating that the defect was due to B cells themselves. These results indicate an obligatory role of B cell complement receptors in responses of the B cells to protein antigens.