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1.
Sci Rep ; 12(1): 152, 2022 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-34996983

RESUMEN

The gut microbiota (GM) exerts a strong influence over the host immune system and dysbiosis of this microbial community can affect the clinical phenotype in chronic inflammatory conditions. To explore the role of the GM in lupus nephritis, we colonized NZM2410 mice with Segmented Filamentous Bacteria (SFB). Gut colonization with SFB was associated with worsening glomerulonephritis, glomerular and tubular immune complex deposition and interstitial inflammation compared to NZM2410 mice free of SFB. With SFB colonization mice experienced an increase in small intestinal lamina propria Th17 cells and group 3 innate lymphoid cells (ILC3s). However, although serum IL-17A expression was elevated in these mice, Th17 cells and ILC3s were not detected in the inflammatory infiltrate in the kidney. In contrast, serum and kidney tissue expression of the macrophage chemoattractants MCP-1 and CXCL1 were significantly elevated in SFB colonized mice. Furthermore, kidney infiltrating F4/80+CD206+M2-like macrophages were significantly increased in these mice. Evidence of increased gut permeability or "leakiness" was also detected in SFB colonized mice. Finally, the intestinal microbiome of SFB colonized mice at 15 and 30 weeks of age exhibited dysbiosis when compared to uncolonized mice at the same time points. Both microbial relative abundance as well as biodiversity of colonized mice was found to be altered. Collectively, SFB gut colonization in the NZM2410 mouse exacerbates kidney disease, promotes kidney M2-like macrophage infiltration and overall intestinal microbiota dysbiosis.


Asunto(s)
Bacterias/crecimiento & desarrollo , Microbioma Gastrointestinal , Intestinos/microbiología , Riñón/inmunología , Nefritis Lúpica/microbiología , Macrófagos/inmunología , Animales , Bacterias/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Disbiosis , Femenino , Inmunidad Innata , Mediadores de Inflamación/metabolismo , Intestinos/inmunología , Intestinos/metabolismo , Intestinos/patología , Riñón/metabolismo , Riñón/patología , Nefritis Lúpica/inmunología , Nefritis Lúpica/metabolismo , Nefritis Lúpica/patología , Macrófagos/metabolismo , Macrófagos/patología , Ratones Endogámicos C57BL , Fenotipo , Células Th17/inmunología , Células Th17/metabolismo
2.
Immunohorizons ; 6(1): 36-46, 2022 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-35039434

RESUMEN

MRL/lpr mice have been extensively used as a murine model of lupus. Disease progression in MRL/lpr mice can differ among animal facilities, suggesting a role for environmental factors. We noted a phenotypic drift of our in-house colony, which was the progeny of mice obtained from The Jackson Laboratory (JAX; stocking number 000485), that involved attenuated glomerulonephritis, increased splenomegaly, and reduced lymphadenopathy. To validate our in-house mice as a model of lupus, we compared these mice with those newly obtained from JAX, which were confirmed to be genetically identical to our in-house mice. Surprisingly, the new JAX mice exhibited a similar phenotypic drift, most notably the attenuation of glomerulonephritis. Interestingly, our in-house colony differed from JAX mice in body weight and kidney size (both sexes), as well as in splenic size, germinal center formation, and level of anti-dsDNA auto-IgG in the circulation (male only). In addition, we noted differential expression of microRNA (miR)-21 and miR-183 that might explain the splenic differences in males. Furthermore, the composition of gut microbiota was different between in-house and new JAX mice at early time points, which might explain some of the renal differences (e.g., kidney size). However, we could not identify the reason for attenuated glomerulonephritis, a shared phenotypic drift between the two colonies. It is likely that this was due to certain changes of environmental factors present in both JAX and our facilities. Taken together, these results suggest a significant phenotypic drift in MRL/lpr mice in both colonies that may require strain recovery from cryopreservation.


Asunto(s)
Microbioma Gastrointestinal/genética , Nefritis Lúpica/genética , MicroARNs/genética , Animales , Modelos Animales de Enfermedad , Femenino , Riñón/patología , Nefritis Lúpica/microbiología , Nefritis Lúpica/patología , Masculino , Ratones , Ratones Endogámicos MRL lpr , ARN Ribosómico 16S/análisis , Bazo/patología
3.
Eur J Pharmacol ; 884: 173421, 2020 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-32721450

RESUMEN

Emerging evidences indicated that the dysbiosis of microbiota was related to the onset of systemic lupus erythematosus (SLE). Bacteroides fragilis (B. fragilis) ATCC 25285, a human commensal, was discovered to improve inflammatory diseases. However, whether B. fragilis (ATCC 25285) has the beneficial effects on the treatment of lupus nephritis has still remained elusive. In the present study, oral treatment with B. fragilis (ATCC 25285) ameliorated the activity of MRL/lpr mice, including decreased levels of autoantibodies and symptoms of lupus nephritis. Furthermore, we demonstrated that treatment with B. fragilis (ATCC 25285) could promote CD1d expression in B cells by Est-1 pathway, while inhibit CD86 expression via SHP-2 signaling pathway to repair the immune response of B cells in MRL/lpr mice. In addition, our findings revealed a possible role of treatment with B. fragilis (ATCC 25285) in relieving intestinal inflammation in MRL/lpr mice. Meanwhile, it was uncovered that B. fragilis (ATCC 25285) restored the Th17/Treg balance in MRL/lpr mice that was consistent with the role of B. fragilis in other autoimmune diseases. Overall, the current study may highlight the potential application of B. fragilis (ATCC 25285) to treat manifestations of SLE in high-risk individuals.


Asunto(s)
Antígenos CD1d/metabolismo , Linfocitos B/microbiología , Antígeno B7-2/metabolismo , Bacteroides fragilis/fisiología , Nefritis Lúpica/terapia , Probióticos , Animales , Antígenos CD1d/inmunología , Autoanticuerpos/sangre , Linfocitos B/inmunología , Linfocitos B/metabolismo , Antígeno B7-2/inmunología , Modelos Animales de Enfermedad , Femenino , Nefritis Lúpica/inmunología , Nefritis Lúpica/metabolismo , Nefritis Lúpica/microbiología , Ratones Endogámicos C57BL , Ratones Endogámicos MRL lpr , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Proteína Proto-Oncogénica c-ets-1/metabolismo , Transducción de Señal , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/microbiología , Células Th17/inmunología , Células Th17/metabolismo , Células Th17/microbiología
4.
Ann Rheum Dis ; 78(7): 947-956, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30782585

RESUMEN

BACKGROUND/PURPOSE: To search for a transmissible agent involved in lupus pathogenesis, we investigated the faecal microbiota of patients with systemic lupus erythematosus (SLE) for candidate pathobiont(s) and evaluated them for special relationships with host immunity. METHODS: In a cross-sectional discovery cohort, matched blood and faecal samples from 61 female patients with SLE were obtained. Faecal 16 S rRNA analyses were performed, and sera profiled for antibacterial and autoantibody responses, with findings validated in two independent lupus cohorts. RESULTS: Compared with controls, the microbiome in patients with SLE showed decreased species richness diversity, with reductions in taxonomic complexity most pronounced in those with high SLE disease activity index (SLEDAI). Notably, patients with SLE had an overall 5-fold greater representation of Ruminococcus gnavus (RG) of the Lachnospiraceae family, and individual communities also displayed reciprocal contractions of a species with putative protective properties. Gut RG abundance correlated with serum antibodies to only 1/8 RG strains tested. Anti-RG antibodies correlated directly with SLEDAI score and antinative DNA levels, but inversely with C3 and C4. These antibodies were primarily against antigen(s) in an RG strain-restricted pool of cell wall lipoglycans. Novel structural features of these purified lipoglycans were characterised by mass spectrometry and NMR. Highest levels of serum anti-RG strain-restricted antibodies were detected in those with active nephritis (including Class III and IV) in the discovery cohort, with findings validated in two independent cohorts. CONCLUSION: These findings suggest a novel paradigm in which specific strains of a gut commensal may contribute to the immune pathogenesis of lupus nephritis.


Asunto(s)
Anticuerpos Antibacterianos/inmunología , Autoanticuerpos/inmunología , Heces/microbiología , Lupus Eritematoso Sistémico/microbiología , Nefritis Lúpica/inmunología , Adulto , Anticuerpos Antibacterianos/sangre , Autoanticuerpos/sangre , Estudios de Casos y Controles , Clostridiales/inmunología , Clostridiales/aislamiento & purificación , Estudios Transversales , Femenino , Humanos , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/inmunología , Nefritis Lúpica/microbiología , ARN Ribosómico 16S/análisis , Índice de Severidad de la Enfermedad
5.
Medicine (Baltimore) ; 96(42): e8211, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-29049207

RESUMEN

RATIONALE: Mucormycosis is a rare fungal infection but life-threatening, especially in lupus nephritis (LN). Mucormycosis may manifest as rhino-orbital-cerebral, pulmonary, cutaneous, gastrointestinal, renal, or disseminated forms. PATIENT CONCERNS: We report a case of a 52-year-old woman with cutaneous mucormycosis infection who was admitted because of LN. DIAGNOSES: Histopathological analysis of the lesion confirmed the Rhizopus microspores from the family Mucoraceae. INTERVENTIONS AND OUTCOMES: The mortality of mucormycosis remains unacceptably high. Our patient died at last even with standard therapy (aggressive surgical debridement and anti-mucormycosis drugs). LESSONS: It is difficult to diagnose because lacking of specific clinical features, it is necessary to identify the susceptible patients, and then make diagnosis rapidly through tissue biopsy. Despite the outcome is poor, aggressive surgical debridement and Amphotericin B/Posaconazole can be effective.


Asunto(s)
Dermatomicosis/microbiología , Nefritis Lúpica/microbiología , Mucormicosis/microbiología , Resultado Fatal , Femenino , Humanos , Persona de Mediana Edad , Rhizopus/aislamiento & purificación
6.
Microbiome ; 5(1): 73, 2017 07 11.
Artículo en Inglés | MEDLINE | ID: mdl-28697806

RESUMEN

BACKGROUND: Systemic lupus erythematosus, characterized by persistent inflammation, is a complex autoimmune disorder with no known cure. Immunosuppressants used in treatment put patients at a higher risk of infections. New knowledge of disease modulators, such as symbiotic bacteria, can enable fine-tuning of parts of the immune system, rather than suppressing it altogether. RESULTS: Dysbiosis of gut microbiota promotes autoimmune disorders that damage extraintestinal organs. Here we report a role of gut microbiota in the pathogenesis of renal dysfunction in lupus. Using a classical model of lupus nephritis, MRL/lpr, we found a marked depletion of Lactobacillales in the gut microbiota. Increasing Lactobacillales in the gut improved renal function of these mice and prolonged their survival. We used a mixture of 5 Lactobacillus strains (Lactobacillus oris, Lactobacillus rhamnosus, Lactobacillus reuteri, Lactobacillus johnsonii, and Lactobacillus gasseri), but L. reuteri and an uncultured Lactobacillus sp. accounted for most of the observed effects. Further studies revealed that MRL/lpr mice possessed a "leaky" gut, which was reversed by increased Lactobacillus colonization. Lactobacillus treatment contributed to an anti-inflammatory environment by decreasing IL-6 and increasing IL-10 production in the gut. In the circulation, Lactobacillus treatment increased IL-10 and decreased IgG2a that is considered to be a major immune deposit in the kidney of MRL/lpr mice. Inside the kidney, Lactobacillus treatment also skewed the Treg-Th17 balance towards a Treg phenotype. These beneficial effects were present in female and castrated male mice, but not in intact males, suggesting that the gut microbiota controls lupus nephritis in a sex hormone-dependent manner. CONCLUSIONS: This work demonstrates essential mechanisms on how changes of the gut microbiota regulate lupus-associated immune responses in mice. Future studies are warranted to determine if these results can be replicated in human subjects.


Asunto(s)
Microbioma Gastrointestinal , Riñón/fisiopatología , Lactobacillus/fisiología , Nefritis Lúpica/microbiología , Nefritis Lúpica/terapia , Animales , Modelos Animales de Enfermedad , Femenino , Inmunoglobulina G/sangre , Interleucina-10/biosíntesis , Interleucina-10/sangre , Interleucina-6/biosíntesis , Riñón/inmunología , Riñón/patología , Lactobacillus/clasificación , Lactobacillus/crecimiento & desarrollo , Lactobacillus/aislamiento & purificación , Nefritis Lúpica/inmunología , Nefritis Lúpica/fisiopatología , Masculino , Ratones , Ratones Endogámicos MRL lpr , Orquiectomía , Factores Sexuales , Linfocitos T Reguladores
7.
Clin Exp Immunol ; 181(2): 323-37, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25703185

RESUMEN

Environmental factors, including microbes and diet, play a key role in initiating autoimmunity in genetically predisposed individuals. However, the influence of gut microflora in the initiation and progression of systemic lupus erythematosus (SLE) is not well understood. In this study, we have examined the impact of drinking water pH on immune response, disease incidence and gut microbiome in a spontaneous mouse model of SLE. Our results show that (SWR × NZB) F1 (SNF1 ) mice that were given acidic pH water (AW) developed nephritis at a slower pace compared to those on neutral pH water (NW). Immunological analyses revealed that the NW-recipient mice carry relatively higher levels of circulating autoantibodies against nuclear antigen (nAg) as well as plasma cells. Importantly, 16S rRNA gene-targeted sequencing revealed that the composition of gut microbiome is significantly different between NW and AW groups of mice. In addition, analysis of cytokine and transcription factor expression revealed that immune response in the gut mucosa of NW recipient mice is dominated by T helper type 17 (Th17) and Th9-associated factors. Segmented filamentous bacteria (SFB) promote a Th17 response and autoimmunity in mouse models of arthritis and multiple sclerosis. Interestingly, however, not only was SFB colonization unaffected by the pH of drinking water, but also SFB failed to cause a profound increase in Th17 response and had no significant effect on lupus incidence. Overall, these observations show that simple dietary deviations such as the pH of drinking water can influence lupus incidence and affect the composition of gut microbiome.


Asunto(s)
Agua Potable/administración & dosificación , Tracto Gastrointestinal/microbiología , Nefritis Lúpica/microbiología , Microbiota/inmunología , Animales , Anticuerpos Antinucleares/biosíntesis , Bacteroides/clasificación , Bacteroides/inmunología , Clostridium/clasificación , Clostridium/inmunología , Cruzamientos Genéticos , Cianobacterias/clasificación , Cianobacterias/inmunología , Citocinas/biosíntesis , Progresión de la Enfermedad , Femenino , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/patología , Predisposición Genética a la Enfermedad , Concentración de Iones de Hidrógeno , Lactobacillus/clasificación , Lactobacillus/inmunología , Nefritis Lúpica/dietoterapia , Nefritis Lúpica/inmunología , Nefritis Lúpica/patología , Masculino , Ratones , Ratones Endogámicos NZB , Células Plasmáticas/efectos de los fármacos , Células Plasmáticas/inmunología , Células Plasmáticas/microbiología , Células Plasmáticas/patología , ARN Ribosómico 16S/genética , Células Th17/efectos de los fármacos , Células Th17/inmunología , Células Th17/microbiología , Células Th17/patología , Factores de Tiempo
8.
J Immunol ; 177(10): 6880-8, 2006 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-17082602

RESUMEN

TLR4 is the receptor for the Gram-negative bacterial cell wall component LPS. TLR4 signaling is controlled by both positive and negative regulators to balance optimal immune response and potential sepsis. Unchecked TLR4 activation might result in autoimmune diseases, a hypothesis that has not been formally resolved. In this study, we found that TLR4 signaling to LPS can be positively enforced by expressing gp96 on cell surfaces through the chaperone function of, but not the direct signaling by, gp96; TLR4 as well as the commensal flora are essential for the production of anti-dsDNA Ab and the immune complex-mediated glomerulonephritis in transgenic mice that express surface gp96. Moreover, a similar constellation of autoimmunity was evident in mice that encode multiple copies of tlr4 gene. Our study has revealed that increased TLR4 signaling alone without exogenous insult can break immunological tolerance. It provides a strong experimental evidence for TLR4 dysregulation as an etiology of lupus-like renal disease.


Asunto(s)
Nefritis Lúpica/genética , Nefritis Lúpica/inmunología , Glicoproteínas de Membrana/fisiología , Receptor Toll-Like 4/biosíntesis , Receptor Toll-Like 4/genética , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunología , Animales , Bacterias/inmunología , Línea Celular , Membrana Celular/genética , Membrana Celular/inmunología , Membrana Celular/metabolismo , Femenino , Amplificación de Genes/inmunología , Humanos , Tolerancia Inmunológica/genética , Lipopolisacáridos/toxicidad , Nefritis Lúpica/microbiología , Nefritis Lúpica/patología , Masculino , Glicoproteínas de Membrana/biosíntesis , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Chaperonas Moleculares/biosíntesis , Chaperonas Moleculares/genética , Chaperonas Moleculares/fisiología , Solubilidad , Receptor Toll-Like 4/deficiencia , Receptor Toll-Like 4/fisiología
9.
Pediatr Nephrol ; 20(12): 1750-5, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16133037

RESUMEN

Infection is the major complication of cyclophosphamide therapy in patients with lupus nephritis. The objectives of this study were to report and compare the rate of infection between children with lupus nephritis who had received intravenous pulse cyclophosphamide (IVCY) and those who had received oral cyclophosphamide (OCY) and to determine the risk factors for infection during treatment with cyclophosphamide in these groups. Records of nine patients who had received IVCY from the beginning [pure intravenous cyclophosphamide (PIVCY) group], 11 patients who had received prior oral cyclophosphamide and later switched to IVCY [combined intravenous cyclophosphamide (CIVCY) group] and 41 patients who had received OCY were reviewed. Infection occurred in 21 of 61 patients (34%). In the PIVCY group, four episodes of infection occurred in three of nine patients (33%). In the CIVCY group, six episodes of infection occurred in four of 11 patients (36%). In the OCY group, 18 episodes of infection occurred in 14 of 41 patients (34%). The rate of infection between these groups was not different (P=0.99). None of the following parameters were risk factors for infection: cumulative dose of cyclophosphamide, leukopenia and neutropenia. On the contrary, white blood cell (WBC) count and polymorphonuclear cell (PMN) count were significantly less in the no-infection group (P=<0.001, P<0.001, respectively), with odds ratios for leukopenia (WBCs <4,000 mm(3)) and neutropenia (PMNs <1,500 mm(3)) between the infection and the no-infection group equal to 0.18 (95%CI 0.05-0.63) and 0 (95%CI 0-0.19), respectively. Most of the patients who had infection received prednisolone at a dosage of more than 0.5 mg/kg per day (67% of the PIVCY group, 50% of the CIVCY group and 83% of the OCY group). Fatal infections occurred in two patients who had concomitant active systemic lupus erythematosus (SLE). Although lymphopenia (lymphocyte count <1,500/mm(3)) was not the risk factor for infection, it was observed that six of seven patients with herpes zoster had lymphopenia. Herpes zoster seemed to occur more frequently in the OCY group (15%) than in the whole IVCY group (5%), but there was no statistical difference (P=0.41). We conclude that the rate of infection in the IVCY and OCY group was not different. Infection is likely to occur in patients receiving a concomitant high dose of prednisolone. The occurrence of fatal infection in patients with active disease should be noted. No single risk factor was detected in this study.


Asunto(s)
Ciclofosfamida/administración & dosificación , Infecciones/complicaciones , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/microbiología , Quimioterapia por Pulso , Administración Oral , Adolescente , Edad de Inicio , Niño , Femenino , Estudios de Seguimiento , Herpes Zóster/complicaciones , Herpes Zóster/microbiología , Humanos , Inmunosupresores/uso terapéutico , Infecciones/microbiología , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/microbiología , Lupus Eritematoso Sistémico/mortalidad , Nefritis Lúpica/complicaciones , Nefritis Lúpica/diagnóstico , Nefritis Lúpica/epidemiología , Nefritis Lúpica/mortalidad , Masculino , Registros Médicos , Prednisolona/uso terapéutico , Estudios Retrospectivos , Factores de Riesgo , Tailandia/epidemiología , Factores de Tiempo , Resultado del Tratamiento
10.
Lupus ; 10(9): 606-11, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-11678448

RESUMEN

Inducing and maintaining remission in patients with lupus nephritis may be difficult. Current treatments have significant toxicity. Mycophenolate mofetil (MMF) limits damage in murine models of lupus nephritis. We have assessed the efficacy and tolerability of MMF in the treatment of patients with long-standing or resistant lupus nephritis. We have treated 13 patients with biopsy proven lupus nephritis (two membranous nephropathy, four membranous nephropathy with superimposed proliferative changes, seven with proliferative glomerulonephritis). All patients had relapsed on conventional treatment or there were pressing indications to minimise steroid dosage or avoid alkylating agents. Nine out of 13 were treated with MMF and prednisolone, 3/10 with MMF alone and 1/10 with MMF, prednisolone and cyclosporine. Thirteen patients were treated with MMF for up to 37 months (median 25 months). Three patients were withdrawn from MMF during the first 8 months of treatment. The remainder tolerated MMF (median dose 1 g/day). Serological improvements were observed in 9/13 and steroid dosage was reduced in 8/10 patients. Infections occurred in 3/13. One patient relapsed. MMF significantly reduced the rate of decline of renal function. MMF should be considered in the treatment of long-standing or resistant lupus nephritis. Controlled clinical trials are required to confirm these findings.


Asunto(s)
Inmunosupresores/administración & dosificación , Nefritis Lúpica/tratamiento farmacológico , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/administración & dosificación , Corticoesteroides/administración & dosificación , Adulto , Presión Sanguínea , Femenino , Estudios de Seguimiento , Humanos , Inmunosupresores/efectos adversos , Infecciones , Fallo Renal Crónico/tratamiento farmacológico , Fallo Renal Crónico/microbiología , Nefritis Lúpica/microbiología , Persona de Mediana Edad , Ácido Micofenólico/efectos adversos , Pacientes Desistentes del Tratamiento , Proyectos Piloto , Proteinuria/tratamiento farmacológico , Proteinuria/microbiología , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
11.
Clin Immunol Immunopathol ; 86(3): 271-9, 1998 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-9557160

RESUMEN

Pristane induces a lupus-like syndrome characterized by autoantibody production and glomerulonephritis in nonautoimmune strains of mice. Although it has been suggested that this syndrome results from nonspecific immune activation, there is little evidence so far that B cells are activated nonspecifically by pristane or that this promotes autoimmunity. In this study, we examined whether polyclonal hypergammaglobulinemia occurs in pristane-induced lupus, and its relationship to the production of anti-DNA, nRNP/Sm, and Su autoantibodies. In conventionally housed mice, there was a marked increase in total IgM and IgG3 2 weeks after i.p. pristane injection, followed by increased IgG1, IgG2a, and IgG2b levels. IgM levels were higher in pristane-treated specific pathogen-free (SPF) mice than in conventionally housed mice, whereas IgG and IgA levels were reduced. Pristane induced anti-nRNP/Sm and Su autoantibodies in SPF mice, but their onset was delayed and levels were lower than those in conventionally housed mice. There was no consistent relationship between total IgG1, 2a, and 2b hypergammaglobulinemia and production of anti-nRNP/Sm and Su autoantibodies. Moreover, the total Ig levels were similar in the anti-nRNP/Sm-positive and -negative groups. In contrast, production of IgM anti-ssDNA antibodies paralleled IgM hypergammaglobulinemia in some, but not all, mice. These studies indicate that pristane-induced lupus is associated with marked hypergammaglobulinemia, the magnitude of which is influenced by the microbial environment. However, anti-nRNP/Sm and Su autoantibody production is at least partly independent of polyclonal B cell activation. The data strongly suggest that pristane-induced lupus is not exclusively the consequence of nonspecific immune stimulation. They also point to the importance of microbial stimulation in the development of hypergammaglobulinemia in this inducible lupus model.


Asunto(s)
Autoanticuerpos/biosíntesis , Hipergammaglobulinemia/etiología , Nefritis Lúpica/inmunología , Animales , Anticuerpos Antinucleares/biosíntesis , Autoantígenos , Citocinas/inmunología , Modelos Animales de Enfermedad , Femenino , Hipergammaglobulinemia/inmunología , Inmunoglobulinas/sangre , Nefritis Lúpica/inducido químicamente , Nefritis Lúpica/microbiología , Ratones , Ratones Endogámicos BALB C , Proteínas , Ribonucleoproteínas Nucleares Pequeñas/inmunología , Organismos Libres de Patógenos Específicos/inmunología , Terpenos/toxicidad , Factores de Tiempo , Proteínas Nucleares snRNP
12.
Ann N Y Acad Sci ; 475: 47-58, 1986.
Artículo en Inglés | MEDLINE | ID: mdl-2947530

RESUMEN

The investigations with the NZB X SWR model show that the development of systemic autoimmune disease is a multistep, multigene process. Severe lupus nephritis in the NZB X SWR hybrids results from the interaction of genes inherited from both the autoimmune NZB and the normal SWR parents. A similar genetic interaction occurs in the NZB X NZW hybrids, but in this model, both the parental strains are abnormal and the nature of the gene products or their mechanism of action is unknown. In the NZB X SWR model, we have been able to identify a restricted subpopulation of nephritogenic anti-DNA antibody idiotypes that are encoded by genes of the normal SWR parents. Thus, these are one set of genes that determine the development of severe lupus nephritis in the F1 hybrids. In addition, another set of genes allows for the expansion of B cells that produce such pathogenic anti-DNA idiotypes in the F1 hybrids since such B-cell clones remain dormant in the normal SWR parents. The latter category of genes, presumably specifying defects in immunoregulation, are probably inherited from the NZB parents or may be the result of complementation of genes inherited from both parents. Further investigations with the NZB X SWR model will help us define the immunoregulatory defects in SLE that are specific for the T and B cells involved in pathogenic autoantibody production.


Asunto(s)
Anticuerpos Antinucleares/inmunología , Enfermedades Autoinmunes/inmunología , Modelos Animales de Enfermedad/inmunología , Idiotipos de Inmunoglobulinas/inmunología , Nefritis Lúpica/inmunología , Ratones Endogámicos NZB/inmunología , Ratones Endogámicos/inmunología , Enfermedades de los Roedores/genética , Animales , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/microbiología , Linfocitos B/inmunología , Cruzamientos Genéticos , Modelos Animales de Enfermedad/genética , Modelos Animales de Enfermedad/microbiología , Idiotipos de Inmunoglobulinas/genética , Nefritis Lúpica/complicaciones , Nefritis Lúpica/microbiología , Ratones , Ratones Endogámicos NZB/genética , Ratones Endogámicos/genética , Retroviridae/inmunología , Enfermedades de los Roedores/inmunología , Enfermedades de los Roedores/microbiología , Linfocitos T Reguladores/inmunología
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