RESUMO
High blood pressure exerts its deleterious effects on health largely through acceleration of end-organ diseases. Among these, progressive loss of renal function is particularly important, not only for the direct consequences of kidney damage but also because loss of renal function is associated with amplification of other adverse cardiovascular outcomes. Genetic susceptibility to hypertension and associated end-organ disease is non-Mendelian in both humans and in a rodent model, the spontaneously hypertensive rat (SHR). Here, we report that hypertensive end-organ disease in the inbred SHR-A3 line is attributable to genetic variation in the immunoglobulin heavy chain on chromosome 6. This variation coexists with variation in a 10 Mb block on chromosome 17 that contains genetic variation in 2 genes involved in immunoglobulin Fc receptor signaling. Substitution of these genomic regions into the SHR-A3 genome from the closely related, but injury-resistant, SHR-B2 line normalizes both biomarker and histological measures of renal injury. Our findings indicate that genetic variation leads to a contribution by immune mechanisms hypertensive end-organ injury and that, in this rat model, disease is influenced by differences in germ line antibody repertoire.
Assuntos
Animais Congênicos/imunologia , Cromossomos de Mamíferos , Hipertensão Renal , Hipertensão , Fragmentos Fc das Imunoglobulinas , Rim , Nefrite , Receptores Fc , Animais , Anticorpos/sangue , Biomarcadores/sangue , Mapeamento Cromossômico , Modelos Animais de Doenças , Predisposição Genética para Doença , Humanos , Hipertensão/diagnóstico , Hipertensão/genética , Hipertensão Renal/genética , Hipertensão Renal/imunologia , Hipertensão Renal/patologia , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/imunologia , Rim/imunologia , Rim/patologia , Nefrite/genética , Nefrite/imunologia , Nefrite/patologia , Prognóstico , Locos de Características Quantitativas , Ratos , Ratos Endogâmicos SHR , Receptores Fc/genética , Receptores Fc/imunologiaRESUMO
Systems of antigen delivery into antigen-presenting cells represent an important novel strategy in chicken vaccine development. In this study, we verified the ability of Rous sarcoma virus (RSV) antigens fused with streptavidin to be targeted by specific biotinylated monoclonal antibody (anti-CD205) into dendritic cells and induce virus-specific protective immunity. The method was tested in four congenic lines of chickens that are either resistant or susceptible to the progressive growth of RSV-induced tumors. Our analyses confirmed that the biot-anti-CD205-SA-FITC complex was internalized by chicken splenocytes. In the cytokine expression profile, several significant differences were evident between RSV-challenged progressor and regressor chicken lines. A significant up-regulation of IL-2, IL-12, IL-15, and IL-18 expression was detected in immunized chickens of both regressor and progressor groups. Of these cytokines, IL-2 and IL-12 were most up-regulated 14 days post-challenge (dpc), while IL-15 and IL-18 were most up-regulated at 28 dpc. On the contrary, IL-10 expression was significantly down-regulated in all immunized groups of progressor chickens at 14 dpc. We detected significant up-regulation of IL-17 in the group of immunized progressors. LITAF down-regulation with iNOS up-regulation was especially observed in the progressor group of immunized chickens that developed large tumors. Based on the increased expression of cytokines specific for activated dendritic cells, we conclude that our system is able to induce partial stimulation of specific cell types involved in cell-mediated immunity.
Assuntos
Antígenos Virais/imunologia , Galinhas/virologia , Citocinas/fisiologia , Células Dendríticas/imunologia , Vírus do Sarcoma de Rous/imunologia , Sarcoma Aviário/prevenção & controle , Vacinas Virais/imunologia , Animais , Animais Congênicos/imunologia , Animais Congênicos/virologia , Anticorpos Biespecíficos/imunologia , Antígenos CD/imunologia , Galinhas/imunologia , Células Dendríticas/virologia , Imunidade Celular/imunologia , Lectinas Tipo C/imunologia , Antígenos de Histocompatibilidade Menor/imunologia , Receptores de Superfície Celular/imunologia , Sarcoma Aviário/imunologiaRESUMO
Introgression of a New Zealand Black (NZB) chromosome 13 interval onto a C57BL/6 (B6) background (B6.NZBc13) is sufficient to produce many hallmarks of lupus, including high-titre anti-chromatin antibody production, abnormal B- and T-cell activation, and renal disease. In this study we sought to characterize the immune defects leading to these abnormalities. By generating hematopoietic chimeras and BCR transgenic mice, we show that the congenic autoimmune phenotype can be transferred by BM cells and requires the presence of autoreactive B cells. Using the hen egg white lysozyme immunoglobulin transgenic mouse model, we demonstrate that B-cell anergy, deletion, and receptor editing are intact. Nevertheless, congenic B cells exhibit altered peripheral B-cell selection, as demonstrated by enhanced survival and activation of endogenous B cells with autoreactivity to chromatin and Sm/ribonucleoprotein. Given the autoantibody specificities to nuclear antigens, TLR signalling was assessed. B6.NZBc13 B cells were hyper-responsive to poly(I:C), a TLR3 ligand, demonstrating enhanced proliferation and survival as compared to B6 B cells. Our findings indicate the presence of an intrinsic B-cell defect on NZB chromosome 13 that results in hyper-responsiveness to a dsRNA analogue and implicates its potential supporting role in the generation of autoimmunity in B6.NZBc13 mice.
Assuntos
Autoimunidade/imunologia , Linfócitos B/imunologia , Cromossomos de Mamíferos/genética , Animais , Animais Congênicos/imunologia , Anticorpos Antinucleares/imunologia , Anticorpos Antinucleares/metabolismo , Subpopulações de Linfócitos B/citologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Linfócitos B/citologia , Linfócitos B/metabolismo , Transplante de Medula Óssea , Contagem de Células , Diferenciação Celular/imunologia , Proliferação de Células , Sobrevivência Celular/imunologia , Anergia Clonal/imunologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Feminino , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NZB , Camundongos Transgênicos , Muramidase/imunologia , Poli I-C/imunologia , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Transdução de Sinais/imunologia , Baço/imunologia , Baço/patologia , Linfócitos T/citologia , Linfócitos T/imunologia , Receptor 3 Toll-Like/metabolismo , Quimeras de Transplante/imunologiaRESUMO
Genetic variation in the major histocompatibility complex (MHC) influences susceptibility and immune responses to Mycobacterium tuberculosis in mice and humans, but connections among the severity of tuberculosis (TB), dynamic changes in T cell responses to mycobacteria, and MHC genetic polymorphisms are poorly characterized. The overall effect of the MHC genes on TB susceptibility and cellular responses to mycobacteria is moderate; thus, such studies provide reliable results only if congenic mouse strains bearing a variety of H2 haplotypes on an identical genetic background are analyzed. Using a panel of H2-congenic strains on the B10 background, we demonstrate that T cells from mice of three different strains, which are resistant to TB infection, readily respond by proliferation to repeated stimulations with mycobacterial sonicate, whereas T cells from three susceptible mouse strains die after the second stimulation with antigen. This difference is specific, as T cells from TB-susceptible and -resistant mouse strains do not differ in response to irrelevant antigens. The CD4/CD8 ratio in immune lymph nodes correlates strongly and inversely with TB susceptibility, being significantly lower in resistant mice as a result of an increased content of CD8+ cells. These differences between the two sets of mouse strains correlate with an elevated level of activation-induced T cell apoptosis in TB-susceptible mice and a higher proportion of activated CD44+ CD62 ligand- T cells in TB-resistant mice. These results may shed some light on the nature of the cellular basis of MHC-linked differences in susceptibility to TB.
Assuntos
Antígenos de Bactérias/imunologia , Apoptose/imunologia , Antígenos H-2/imunologia , Imunidade Inata/imunologia , Linfócitos T/imunologia , Tuberculose Pulmonar/imunologia , Animais , Animais Congênicos/imunologia , Relação CD4-CD8 , Modelos Animais de Doenças , Feminino , Haplótipos , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/imunologiaRESUMO
Major histocompatibility complex (MHC) genes in mammals (H-2 in mice) play a major role in regulating immune function. They also bestow individuality in the form of a chemical signature or odortype. At present, the respective contributions of the olfactory epithelium and the vomeronasal organ (VNO) in the recognition of individual odortypes are not well defined. We examined a possible role for the VNO in the recognition of MHC odortypes in mice by first removing the organ (VNX) and then training the mice to distinguish the odors of two congenic strains of mice that differed only in their MHC type. C57BL/6J mice (bb at H-2) and C57BL/6J-H-2(k) (kk at H-2) provided urine for sensory testing. Eight VNX and six sham-operated mice were trained to make the discrimination. Neither the number of training trials-to-criterion nor the rate of learning differed significantly for VNX and sham-operated mice. We conclude that the VNO is not necessary for learning to discriminate between MHC odortypes.
Assuntos
Aprendizagem por Discriminação/fisiologia , Complexo Principal de Histocompatibilidade/fisiologia , Olfato/imunologia , Urina/fisiologia , Órgão Vomeronasal/fisiologia , Animais , Animais Congênicos/imunologia , Feminino , Complexo Principal de Histocompatibilidade/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Odorantes , Bulbo Olfatório/fisiologia , Percepção/fisiologia , Olfato/genética , Especificidade da Espécie , Órgão Vomeronasal/cirurgiaRESUMO
OBJECTIVE: Collagen-induced arthritis (CIA) is a model of inflammatory arthritis with many similarities to rheumatoid arthritis (RA). We previously mapped in F(2) offspring of CIA-susceptible DA and CIA-resistant F344 rats, 5 quantitative trait loci (QTLs) for which F344 alleles were associated with reduced CIA severity. In the present study, we sought to characterize the independent arthritis-modulating effects of these 5 QTLs. METHODS: CIA-regulatory regions were transferred from the F344 genome to the DA background or vice versa by repeated backcrossing. The arthritis-modulating effects of the transferred alleles were determined by comparing the severity of experimentally induced arthritis in congenic rats with that in DA rats. RESULTS: Congenic lines with either the F344 major histocompatibility complex (MHC) on the DA background or the DA MHC on the F344 background were resistant to CIA, confirming both MHC and non-MHC contributions to the genetic regulation of CIA. F344 alleles at the Cia3 and Cia5 regions of chromosomes 4 and 10 reduced CIA severity relative to that observed in DA rats. F344 Cia4 and Cia6 regions of chromosomes 7 and 8 failed to significantly alter CIA severity. Arthritis-modifying effects of Cia4 and Cia6 were, however, detected in pristane-induced and/or Freund's incomplete adjuvant oil-induced arthritis. The arthritis-modifying effects of the non-MHC CIA-regulatory loci differed in males and females. CONCLUSION: These congenic lines confirmed the existence and location of genes that regulate the severity of experimental arthritis in rats. Mechanisms responsible for the sex-specificity of individual arthritis-regulatory loci may explain some of the sex differences observed in RA and other autoimmune diseases in humans.
Assuntos
Animais Congênicos/genética , Modulação Antigênica/genética , Artrite Experimental/genética , Complexo Principal de Histocompatibilidade/genética , Característica Quantitativa Herdável , Animais , Animais Congênicos/imunologia , Modulação Antigênica/imunologia , Artrite Experimental/imunologia , Artrite Experimental/fisiopatologia , Colágeno/imunologia , Colágeno/farmacologia , Modelos Animais de Doenças , Feminino , Adjuvante de Freund/imunologia , Adjuvante de Freund/farmacologia , Complexo Principal de Histocompatibilidade/imunologia , Masculino , Ratos , Ratos Endogâmicos F344 , Fatores Sexuais , Terpenos/imunologia , Terpenos/farmacologia , Fatores de TempoRESUMO
The antibody (Ab) response induced by DNA-based immunization was compared in various strains of inbred, H-2 congenic and outbred mice with different haplotypes of mouse major histocompatibility complex (H-2). Two different plasmid expression vectors encoding Aequorea victoria green fluorescent protein (GFP) or Escherichia coli, beta-galactosidase (beta-gal) were introduced into quadriceps muscle, and Ab production was examined using both enzyme-linked immunosorbent assay and immunoblot analysis. The beta-gal plasmid DNA immunization induced strong Ab production in all inbred, H-2 congenic and outbred strains at the early stages of immunization. By comparison with beta-gal peptide immunization, the degree of Ab response was H-2 haplotype-dependent. On the other hand, Ab production by GFP plasmid DNA immunization was observed in outbred strains, but not in some of the inbred and H-2 congenic strains. Also, outbred strains showed a high Ab response compared with other inbred and H-2 congenic strains by GFP peptide immunization. Reverse transcription-polymerase chain reaction analysis demonstrated the presence of GFP or beta-gal transcripts at the DNA inoculation site in all the strains studied, even in inbred and H-2 congenic strains which showed no Ab production by GFP plasmid DNA immunization. These results indicate that the difference in Ab response induced by DNA immunization as well as by peptide immunization depends upon the H-2 haplotypes of host strains.