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BACKGROUND: Undercarboxylated osteocalcin (ucOC) is a secreted protein produced by osteoblasts that regulates insulin secretion and insulin sensitivity in rodents. However, the significance of these effects on glucose metabolism in human remains unknown. Moreover, the pathophysiological roles of ucOC on varying degrees of glucose intolerance, including diabetes need to be elucidated. In the present study, correlations between ucOC and indices of insulin secretion and sensitivity were analyzed in normal glucose tolerance (NGT), impaired glucose metabolism (IGM), and diabetes mellitus (DM) groups. METHODS: Based on 75 g OGTT data in Japanese individuals without diabetic medication, or medications which may affect ucOC levels, individuals were classified as having normal glucose tolerance (NGT), impaired glucose metabolism (IGM), or diabetes (DM). In each group, 25 individuals were consecutively recruited [total 75 individuals, age: 65 ± 11 (mean ± SD); BMI: 24.9 ± 3.8 kg/m2]. QUICKI and Matsuda index (MI) were calculated as insulin sensitivity indices. Homeostasis model assessment (HOMA)-ß and insulinogenic index (IGI) were calculated as insulin secretion indices. UcOC was measured using ECLIA. Normally-distributed loge-transformed (ln-) values were used for ucOC, HOMA-ß, IGI, and MI. RESULTS: The ucOC was not significantly different among the three groups. The results of multiple regression analysis showed that ln-ucOC did not significantly correlate with age, sex, BMI, waist circumference, fasting plasma glucose, plasma glucose 120 min after glucose loading, fasting plasma immunoreactive insulin, ln-HOMA-ß, QUICKI, or ln-MI in any of the three groups. Interestingly, ln-ucOC correlated with ln-IGI (r = 0.422, P = 0.0354) and HbA1c (r = - 0.574, P = 0.0027) only in the DM group. There was no significant correlation between ln-IGI and age, sex, BMI, or HbA1c in the DM group. Further, the results of multiple regression analysis showed that ln-IGI could be independently predicted by BMI (ß = 0.598, P = 0.0014) and ln-ucOC (ß = 0.641, P = 0.0007) in the DM group (R2 = 0.488, P = 0.0006). CONCLUSION: In our study, ucOC positively correlated with insulin secretion independently of BMI in Japanese individuals with diabetes. These results suggest that ucOC plays more important roles in insulin secretion than in insulin sensitivity in individuals with diabetes.
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Artritis Reactiva/diagnóstico , Diabetes Mellitus/inmunología , Infecciones por Haemophilus/diagnóstico , Anciano de 80 o más Años , Ampicilina/uso terapéutico , Antibacterianos/uso terapéutico , Artritis Reactiva/etiología , Artritis Reactiva/inmunología , Caries Dental/terapia , Femenino , Infecciones por Haemophilus/complicaciones , Infecciones por Haemophilus/tratamiento farmacológico , Infecciones por Haemophilus/inmunología , Haemophilus parainfluenzae , Articulación de la Cadera/diagnóstico por imagen , Humanos , Huésped Inmunocomprometido , Faringe/microbiología , Cintigrafía , Articulación del Hombro/diagnóstico por imagen , Imagen de Cuerpo EnteroRESUMEN
BACKGROUND: Recently, an integrated network analysis has revealed dysregulation in the metabolism of mannose, a glucose epimer, in severely obese individuals without diabetes. In addition, fasting plasma mannose levels (M0) are associated with insulin resistance independent of BMI. Since the association between mannose and insulin sensitivity (IS) in those with impaired glucose tolerance remains unknown, we aimed to investigate this association in individuals without severe obesity but with varying degrees of glucose tolerance. METHODS: Based on 75 g OGTT data in Japanese individuals without diabetic medication, individuals were classified as having normal glucose tolerance (NGT), impaired glucose metabolism (IGM), or diabetes (DM). In each group, 25 individuals were consecutively recruited [total 75 individuals, age: 65 ± 11 (mean ± SD); BMI: 24.9 ± 3.8 kg/m2]. QUICKI and Matsuda index (MI) were calculated as IS indices. M0 was assayed using HPLC. Normally-distributed loge-transformed (ln-) values were used for MI and leptin. RESULTS: In the simple regression analysis, ln-MI was negatively correlated with BMI (NGT: r = - 0.639, IGM: r = - 0.466, DM: r = - 0.613) and ln-leptin (NGT: r = - 0.480, IGT: r = - 0.447, DM: r = - 0.593) in all 3 groups. Ln-MI was not significantly correlated with M0 in NGT (r = 0.241, P = 0.245) and IGT (r = - 0.296, P = 0.152) groups, it was moderately and negatively correlated in the DM group (r = - 0.626, P < 0.001). Similar results were obtained, when QUICKI was used instead of MI as an index of IS. In multiple regression analysis in the DM group, QUICKI (Q) and ln-MI (M) were independently predicted by BMI (Q: ß = - 0.413; M: ß = - 0.400) and M0 (Q: ß = - 0.413, M: ß = - 0.426), accounting for 51.2% (P = 0.0004) and 51.2% (P = 0.0004) of the variability, respectively, which was larger than the prediction for BMI alone (Q: 38.4%, M: 37.6%). CONCLUSION: Fasting plasma mannose was associated with IS independent of BMI in Japanese individuals with DM.
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BACKGROUND: While the association of the prevalence of non-alcoholic fatty liver disease (NAFLD) with impaired glucose metabolism has been reported, the factors influencing glucose tolerance in NAFLD remain to be clarified. METHODS: Glucose tolerance of 131 Japanese patients diagnosed as NAFLD by histological findings of liver biopsy specimen was examined using 75 g-OGTT. According to Matteoni's classification, patients were divided to 4 groups [M1 ~ 4, M1, 2: non-alcoholic fatty liver (NAFL); and M3, 4: non-alcoholic steatohepatitis (NASH)]. Based on the OGTT data, insulinogenic index (IGI) and QUICKI were calculated as indices of insulin secretion and insulin sensitivity, respectively. Plasma glucose 120 min after glucose loading (G120) was used as the index for glucose intolerance. RESULTS: Stepwise multiple regression analysis using G120 as a dependent variable and loge-IGI, QUICKI, sex, BMI, age, NAFL/NASH as independent variables revealed that loge-IGI (ß = -0.595) and QUICKI (ß = -0.323) are significant factors predicting glucose intolerance (R2 = 0.403), indicating an important role of insulin secretion in glucose tolerance. These findings accord with glucose intolerance as high as 89.7% in patients with impaired insulin secretion defined by ≤43.2 pmol/mmol (40 µU/mg) IGI. Stepwise multiple regression analysis using QUICKI as a dependent variable and NAFL/NAFLD, sex, BMI, and age as independent variables revealed that BMI (ß = -0.469) and NAFL/NAFLD (ß = -0.204) are significant factors predicting insulin sensitivity (R2 = 0.248). CONCLUSION: Impairment of insulin secretion is the most important factor to predict glucose intolerance in NAFLD; severity of histological findings is associated with insulin sensitivity independent of adiposity in NAFLD.
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AIMS/INTRODUCTION: Mannose is a monosaccharide constituent of glycoproteins and glycolipids. Experiments in rats have shown previously that the plasma mannose level decreases after glucose load, but does not decrease in diabetic rats, and that hepatic glycogenolysis is a source of this plasma mannose; however, these results are not fully elucidated in humans. Plasma mannose levels before/after glucose loading in humans with various degrees of glucose intolerance were examined to analyze their association with clinical factors. MATERIALS AND METHODS: The 75-g oral glucose tolerance test was carried out in Japanese individuals not taking diabetes medications. Participants were classified into normal glucose tolerance, impaired glucose metabolism and diabetes mellitus groups. Insulinogenic index as an index of insulin secretion, and Matsuda Index as an index of insulin sensitivity were calculated. Mannose was assayed by the established method using high-performance liquid chromatography after labeling. RESULTS: After glucose load, the plasma mannose level decreased gradually in the normal glucose tolerance group, but did not decrease in the diabetes mellitus group. Plasma mannose changes during 120 min from baseline (M120 -M0 ) were significantly different among the three groups (normal glucose tolerance: -16.7 ± 1.7; impaired glucose metabolism: -9.0 ± 1.9; diabetes mellitus: -1.4 ± 1.8 µmol/L [n = 25 in each group], P < 0.0001). Plasma glucose 120 min after glucose loading (R2 = 0.412) or loge -insulinogenic index, loge -Matsuda Index and age (R2 = 0.230) were determinants of M120 -M0 in multiple regression analyses. CONCLUSIONS: We clarified the relationship between plasma mannose level and glucose tolerance in humans. The present results are compatible with those using rats, in which mannose derived from glycogenolysis plays an important role in the alteration of mannose levels after glucose loading.
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Intolerancia a la Glucosa , Glucogenólisis , Manosa/sangre , Anciano , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Masculino , Persona de Mediana Edad , Análisis de RegresiónAsunto(s)
Pabellón Auricular/diagnóstico por imagen , Enfermedades del Oído/diagnóstico por imagen , Policondritis Recurrente/diagnóstico por imagen , Anciano , Quimioterapia Combinada , Pabellón Auricular/patología , Enfermedades del Oído/tratamiento farmacológico , Enfermedades del Oído/patología , Glucocorticoides/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Masculino , Metotrexato/uso terapéutico , Policondritis Recurrente/tratamiento farmacológico , Policondritis Recurrente/patología , Prednisolona/uso terapéutico , UltrasonografíaRESUMEN
OBJECTIVE: Systemic lupus erythematosus (SLE) is characterized by loss of B cell tolerance and by the presence of polyclonal B cell activation. Syndecan-1 (CD138) is expressed on plasma cells derived from B cells, and is suspected to play a role in SLE. We evaluated the level of soluble CD138 (sCD138) and cell surface expression of CD138 in patients with active SLE, and also examined correlations among the serum levels of BAFF, a proliferation-inducing ligand (APRIL), and CD138 in these patients. METHODS: Peripheral blood samples were obtained from 22 SLE patients in an active disease state and 14 normal controls. The levels of serum sCD138, sBAFF, and sAPRIL were measured using ELISA, and cell surface CD138 was analyzed by flow cytometry. The levels of CD138 mRNA were analyzed by RT-PCR. Blood samples were obtained longitudinally when the patients were in an inactive disease state. RESULTS: The levels of circulating CD138, CD138 mRNA in PBMC, and the numbers of CD20(- )CD38(+)CD138(+) plasma cells were increased in patients with active SLE in comparison with normal controls. Furthermore, the serum sCD138 level in SLE patients was found to correlate with the proportion of CD20(- )CD38(+)CD138(+) plasma cells. On the other hand, patients with active SLE showed a reduced level of sCD138, and this was inversely correlated with the serum level of sAPRIL. CONCLUSIONS: These results suggest that sCD138 may be applicable as a surrogate marker of disease activity, and that syndecan-1/APRIL signaling may be a potential therapeutic target for patients with active SLE.
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Lupus Eritematoso Sistémico/sangre , Sindecano-1/sangre , Adulto , Factor Activador de Células B/sangre , Femenino , Regulación de la Expresión Génica , Humanos , Leucocitos Mononucleares/metabolismo , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/metabolismo , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , Índice de Severidad de la Enfermedad , Sindecano-1/genética , Sindecano-1/metabolismo , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/sangre , Adulto JovenRESUMEN
FTY720 is a novel investigational agent targeting the sphingosine 1-phosphate (S1P) receptors with an ability to cause immunosuppression by inducing lymphocyte sequestration in lymphoid organs. Systemic lupus erythematosus (SLE) is refractory autoimmune disease characterized by the production of a wide variety of autoantibodies and immune complex (IC)-mediated lupus nephritis. Among several SLE-prone strains of mice, BXSB is unique in terms of the disease-associated monocytosis in periphery and the reduced frequency of marginal zone B (MZ B) cells in spleen. In the present study, we examined the effect of FTY720 on lupus nephritis of BXSB mice. FTY720 treatment resulted in a marked decrease in lymphocytes, but not monocytes, in peripheral blood, and caused relocalization of marginal zone B (MZ B) cells into the follicle in the spleen. These changes did not affect the production of autoantibodies, thus IgG and C3 were deposited in glomeruli in FTY720-treated mice. Despite these IC depositions, FTY720-treated mice showed survival advantage with the improved proteinuria. Histological analysis revealed that FTY720 suppressed mesangial cell proliferation and inflammatory cell infiltration. These results suggest that FTY720 ameliorates lupus nephritis by inhibiting the end-stage inflammatory process following IC deposition in glomeruli.
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Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Nefritis Lúpica/prevención & control , Células Mesangiales/efectos de los fármacos , Glicoles de Propileno/uso terapéutico , Esfingosina/análogos & derivados , Animales , Anticuerpos Antinucleares/sangre , Clorhidrato de Fingolimod , Recuento de Leucocitos , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/mortalidad , Nefritis Lúpica/sangre , Nefritis Lúpica/patología , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Células Mesangiales/patología , Ratones , Monocitos/efectos de los fármacos , Monocitos/inmunología , Esfingosina/uso terapéutico , Bazo/efectos de los fármacos , Bazo/inmunologíaRESUMEN
The development of systemic lupus is accelerated by the Yaa (Y-linked autoimmune acceleration) mutation, which is the consequence of a translocation of the telomeric end containing the Tlr7 gene from the X chromosome onto the Y chromosome. However, the loss of marginal zone (MZ) B cells, one of the Yaa-linked cellular abnormalities, has previously been shown to be unrelated to the Tlr7 gene duplication, and the present study therefore aimed to investigate the mechanism responsible for MZ B-cell loss. Analyses of Yaa and non-Yaa C57BL/6 male mice expressing an MD4 anti-HEL IgM transgene or those deficient in fms-like tyrosine kinase 3 ligand (FL) revealed that the proportion of MZ B cells in these Yaa mice was comparable to that of the respective non-Yaa control mice. Notably, the activation of MZ B cells was compromised in both of these transgenic model systems, due to the absence of cognate antigens or the impaired development of dendritic cells, respectively. These results contrasted with the loss of MZ B cells in non-Yaa mice treated with FL and the lack of accumulation of MZ B cells in Yaa mice treated with a B-cell survival factor, BAFF. Taken together, our results suggest that the persistent and enhanced activation of Yaa-bearing hyperactive MZ B cells by dendritic cells is responsible for the loss of this B-cell subset in Yaa mice.
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Linfocitos B/patología , Células Dendríticas/inmunología , Genes Ligados a Y/genética , Activación de Linfocitos , Glicoproteínas de Membrana/genética , Receptor Toll-Like 7/genética , Translocación Genética , Animales , Subgrupos de Linfocitos B , Lupus Eritematoso Sistémico/patología , Tejido Linfoide/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , MutaciónRESUMEN
The autoimmune-type Fcgr2b with deletion polymorphism in AP-4-binding site in the promoter region is suggested to be one most plausible susceptibility gene for systemic lupus erythematosus (SLE). We previously found that there is a strong epistatic interaction between the autoimmune-type Fcgr2b polymorphism and Y chromosome-linked autoimmune acceleration (Yaa) mutation, thus severe SLE observed in BXSB males neither develops in BXSB females nor in the congenic BXSB.IIB(B6) males carrying wild C57BL/6-type Fcgr2b. Present studies examined whether the wild-type Fcgr2b could suppress SLE in mice carrying Yaa-unrelated SLE susceptibility genes. Comparison of disease features between SLE-prone (NZW x BXSB) F1 females and the congenic (NZW x BXSB.IIB(B6)) F1 females carrying wild-type Fcgr2b showed that, as compared with findings in the former, SLE features including activation/proliferation of not only B cells but also T cells and monocytes/macrophages were all inhibited in the latter. It was concluded that the autoimmune-type Fcgr2b promotes and the wild-type inhibits SLE through mechanisms that promote and suppress activation/proliferation of a wide variety of immune cells, respectively. Thus, the Fcgr2b polymorphism is a key genetic element for not only Yaa-related but also Yaa-unrelated lupus.
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Epistasis Genética/inmunología , Lupus Eritematoso Sistémico/genética , Polimorfismo Genético , Regiones Promotoras Genéticas/genética , Receptores de IgG/genética , Animales , Autoinmunidad/genética , Femenino , Predisposición Genética a la Enfermedad , Masculino , Ratones , Receptores Fc/genéticaRESUMEN
OBJECTIVE: Lupus-prone BXSB mice develop monocytosis characterized by selective accumulation of the Gr-1- monocyte subset. The aim of this study was to explore the possible role of activating IgG Fc receptors (FcgammaR) in the development of monocytosis and to characterize the functional phenotype of the Gr-1- subset that accumulates in lupus-prone mice bearing the NZB-type defective Fcgr2b allele for the inhibitory FcgammaRIIB. METHODS: The development of monocytosis was analyzed in BXSB and anti-IgG2a rheumatoid factor-transgenic C57BL/6 mice deficient in activating FcgammaR. Moreover, we assessed the expression levels of activating FcgammaR and inhibitory FcgammaRIIB on Gr-1+ and Gr-1- monocyte subsets in C57BL/6 mice bearing the C57BL/6-type or the NZB-type Fcgr2b allele. RESULTS: We observed monocytosis with expansion of the Gr-1- subset in anti-IgG2a-transgenic C57BL/6 mice expressing IgG2a, but not in those lacking IgG2a. Moreover, monocytosis barely developed in BXSB and anti-IgG2a-transgenic C57BL/6 mice deficient in activating FcgammaR. The Gr-1- subset that accumulated in lupus-prone mice displayed a unique hyperactive phenotype. It expressed very low levels of inhibitory FcgammaRIIB, due to the presence of the NZB-type Fcgr2b allele, but high levels of activating FcgammaRIV. This was in contrast to high levels of FcgammaRIIB expression and no FcgammaRIV expression on the Gr-1+ subset. CONCLUSION: Our results demonstrated a critical role of activating FcgammaR in the development of monocytosis and in the expansion of a Gr-1-FcgammaRIIB(low)FcgammaRIV+ hyperactive monocyte subset in lupus-prone mice. Our findings further highlight the importance of the NZB-type Fcgr2b susceptibility allele in murine lupus, the presence of which induces increased production of hyperactive monocytes as well as dysregulated activation of autoreactive B cells.
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Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Monocitos/inmunología , Receptores de IgG/biosíntesis , Receptores de IgG/genética , Animales , Recuento de Células , Proliferación Celular , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Endogamia , Lupus Eritematoso Sistémico/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/patología , Receptores de Quimiocina/genética , Receptores de Quimiocina/metabolismo , Receptores de IgG/deficiencia , Receptores de IgG/inmunologíaRESUMEN
Immune complex (IC)-mediated tissue inflammation is controlled by stimulatory and inhibitory IgG Fc receptors (FcgammaRs). Systemic lupus erythematosus is a prototype of IC-mediated autoimmune disease; thus, imbalance of these two types of FcgammaRs is probably involved in pathogenesis. However, how and to what extent each FcgammaR contributes to the disease remains unclear. In lupus-prone BXSB mice, while stimulatory FcgammaRs are intact, inhibitory FcgammaRIIB expression is impaired because of promoter region polymorphism. To dissect roles of stimulatory and inhibitory FcgammaRs, we established two gene-manipulated BXSB strains: one deficient in stimulatory FcgammaRs (BXSB.gamma(-/-)) and the other carrying wild-type Fcgr2b (BXSB.IIB(B6/B6)). The disease features were markedly suppressed in both mutant strains. Despite intact renal function, however, BXSB.gamma(-/-) had IC deposition in glomeruli associated with high-serum IgG anti-DNA Ab levels, in contrast to BXSB.IIB(B6/B6), which showed intact renal pathology and anti-DNA levels. Lymphocytes in BXSB.gamma(-/-) were activated, as in wild-type BXSB, but not in BXSB.IIB(B6/B6). Our results strongly suggest that both types of FcgammaRs in BXSB mice are differently involved in the process of disease progression, in which, while stimulatory FcgammaRs play roles in effecter phase of IC-mediated tissue inflammation, the BXSB-type impaired FcgammaRIIB promotes spontaneous activation of self-reactive lymphocytes and associated production of large amounts of autoantibodies and ICs.
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Nefritis Lúpica/genética , Nefritis Lúpica/inmunología , Receptores Fc/fisiología , Receptores de IgG/fisiología , Animales , Anticuerpos Antinucleares/sangre , Plaquetas/inmunología , ADN/inmunología , Femenino , Inmunoglobulina G/sangre , Nefritis Lúpica/sangre , Nefritis Lúpica/mortalidad , Macrófagos/inmunología , Macrófagos/patología , Masculino , Ratones , Ratones Congénicos , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Noqueados , Fagocitosis/genética , Receptores Fc/deficiencia , Receptores Fc/genética , Receptores de IgG/deficiencia , Receptores de IgG/genética , Esplenomegalia/inmunología , Esplenomegalia/patología , Trombocitopenia/sangre , Trombocitopenia/genética , Trombocitopenia/inmunologíaRESUMEN
The accelerated development of systemic lupus erythematosus (SLE) in BXSB male mice is associated with the presence of the Y-linked autoimmune acceleration (Yaa) mutation, which induces an age-dependent monocytosis. Using a cohort of C57BL/6 (B6) x (NZB x B6)F1 backcross male mice bearing the Yaa mutation, we defined the pathogenic role and genetic basis for Yaa-associated monocytosis. We observed a remarkable correlation of monocytosis with autoantibody production and subsequent development of lethal lupus nephritis, indicating that monocytosis is an additional useful indicator for severe SLE. In addition, we identified an NZB-derived locus on chromosome 1 predisposing to the development of monocytosis, which peaked at Fcgr2b encoding FcgammaRIIB and directly overlapped with the previously identified NZB autoimmunity 2 (Nba2) locus. The contribution of Nba2 to monocytosis was confirmed by the analysis of Yaa-bearing B6 mice congenic for the NZB-Nba2 locus. Finally, we observed a very low-level expression of FcgammaRIIB on macrophages bearing the NZB-type Fcgr2b allele, compared with those bearing the B6-type allele, and the development of monocytosis in FcgammaRIIB haploinsufficient B6 mice carrying the Yaa mutation. These data suggest that the Nba2 locus may play a supplementary role in the pathogenesis of SLE by promoting the development of monocytosis and the activation of effector cells bearing stimulatory FcgammaR, in addition to its implication in the dysregulated activation of autoreactive B cells.
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Autoinmunidad/genética , Genes Ligados a Y/inmunología , Leucocitosis/inmunología , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Monocitos/inmunología , Alelos , Animales , Antígenos CD/biosíntesis , Antígenos CD/genética , Femenino , Genes Ligados a Y/genética , Leucocitosis/genética , Nefritis Lúpica/genética , Nefritis Lúpica/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Congénicos , Ratones Endogámicos C57BL , Ratones Endogámicos NZB , Ratones Noqueados , Monocitos/patología , Mutación , Receptores de IgG/biosíntesis , Receptores de IgG/genéticaRESUMEN
OBJECTIVE: Monocytosis is a unique cellular abnormality associated with the Yaa (Y-linked autoimmune acceleration) mutation. The present study was designed to define the cellular mechanism responsible for the development of monocytosis and to characterize the effect of the Yaa mutation on the development of monocyte subsets. METHODS: We produced bone marrow chimeras reconstituted with a mixture of Yaa and non-Yaa bone marrow cells bearing distinct Ly-17 alloantigens, and determined whether monocytes of Yaa origin became dominant. Moreover, we defined the 2 major inflammatory (Gr-1+,CD62 ligand [CD62L]+) and resident (Gr-1-,CD62L-) subsets of blood monocytes in aged BXSB Yaa male mice, as compared with BXSB male mice lacking the Yaa mutation. RESULTS: Analysis of the Ly17 allotype of blood monocytes in chimeric mice revealed that monocytes of both Yaa and non-Yaa origin were similarly involved in monocytosis. Significantly, the development of monocytosis paralleled a selective expansion of the resident monocyte subset compared with the inflammatory subset, and the former expressed CD11c, a marker of dendritic cells. Neither monocytosis nor the change in monocyte subpopulations, including CD11c expression, was observed in Yaa-bearing C57BL/6 mice, in which systemic lupus erythematosus (SLE) fails to develop. CONCLUSION: Our results suggest that Yaa-associated monocytosis is not attributable to an intrinsic abnormality in the growth potential of monocyte lineage cells bearing the Yaa mutation and that the Yaa mutation could lead to the expansion of dendritic cells, thereby contributing to the accelerated development of SLE.
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Autoinmunidad/genética , Antígeno CD11c/metabolismo , Células Dendríticas/metabolismo , Lupus Eritematoso Sistémico/genética , Monocitos/citología , Cromosoma Y/genética , Animales , Anticuerpos Antinucleares/análisis , Biomarcadores , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Proliferación Celular , Quimera , Modelos Animales de Enfermedad , Femenino , Leucocitosis , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/patología , Masculino , Ratones , Ratones Endogámicos NZB , Monocitos/inmunología , Monocitos/metabolismo , Cromosoma Y/inmunologíaRESUMEN
Using a cohort of C57BL/6 (B6) x (NZB x B6)F1 backcross male mice bearing the Yaa (Y-linked autoimmune acceleration) mutation, we mapped and characterized the NZB-derived susceptibility loci predisposing to the development of autoimmune hemolytic anemia (AHA). Our analysis identified 2 major loci on NZB chromosome 7 and chromosome 1 linked with Coombs antierythrocyte autoantibody production, and their contributions were confirmed by the analysis of B6.Yaa mice (B6 mice bearing the Yaa mutation) congenic for each NZB-derived susceptibility interval. A newly identified Aia3 (autoimmune anemia 3) locus present on NZB chromosome 7 selectively regulated Coombs antibody responses, while the second locus, directly overlapping with Nba2 (NZB autoimmunity 2) on chromosome 1, promoted the development of AHA, likely as part of its effect on overall production of lupus autoantibodies. A higher incidence of Coombs antibody production in B6.Aia3 congenic mice (B6 mice bearing the NZB-Aia3 locus) than B6.Nba2 mice (B6 mice bearing the NZB-Nba2 locus) indicated a major role for Aia3 in AHA. Notably, lack of expansion of B1 cells in B6.Aia3 congenic mice argued against the involvement of this subset in AHA. Finally, our analysis of BC mice also demonstrated the presence of a B6-derived H2-linked locus on chromosome 17 that apparently regulated the production of Coombs antibodies as a result of its overall autoimmune promoting effect.
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Anemia Hemolítica Autoinmune/genética , Mapeo Cromosómico , Predisposición Genética a la Enfermedad , Ratones Endogámicos NZB/genética , Anemia Hemolítica Autoinmune/etiología , Animales , Formación de Anticuerpos/genética , Autoanticuerpos/genética , Cromosomas de los Mamíferos , Prueba de Coombs , Ligamiento Genético , Masculino , RatonesRESUMEN
By assessing the development of Y-linked autoimmune acceleration (Yaa) gene-induced systemic lupus erythematosus in C57BL/6 (B6) x (New Zealand Black (NZB) x B6.Yaa)F(1) backcross male mice, we mapped three major susceptibility loci derived from the NZB strain. These three quantitative trait loci (QTL) on NZB chromosomes 1, 7, and 13 differentially regulated three different autoimmune traits: anti-nuclear autoantibody production, gp70-anti-gp70 immune complex (gp70 IC) formation, and glomerulonephritis. Contributions to the disease traits were further confirmed by generating and analyzing three different B6.Yaa congenic mice, each carrying one individual NZB QTL. The chromosome 1 locus that overlapped with the previously identified Nba2 (NZB autoimmunity 2) locus regulated all three traits. A newly identified chromosome 7 locus, designated Nba5, selectively promoted anti-gp70 autoantibody production, hence the formation of gp70 IC and glomerulonephritis. B6.Yaa mice bearing the NZB chromosome 13 locus displayed increased serum gp70 production, but not gp70 IC formation and glomerulonephritis. This locus, called Sgp3 (serum gp70 production 3), selectively regulated the production of serum gp70, thereby contributing to the formation of nephritogenic gp70 IC and glomerulonephritis, in combination with Nba2 and Nba5 in NZB mice. Among these three loci, a major role of Nba2 was demonstrated, because B6.Yaa Nba2 congenic male mice developed the most severe disease. Finally, our analysis revealed the presence in B6 mice of an H2-linked QTL, which regulated autoantibody production. This locus had no apparent individual effect, but most likely modulated disease severity through interaction with NZB-derived susceptibility loci.
Asunto(s)
Ligamiento Genético/inmunología , Nefritis Lúpica/genética , Nefritis Lúpica/inmunología , Ratones Endogámicos NZB/genética , Sitios de Carácter Cuantitativo/inmunología , Cromosoma Y/inmunología , Animales , Anticuerpos Antinucleares/sangre , Complejo Antígeno-Anticuerpo/sangre , Autoantígenos/sangre , Cromatina/inmunología , Cruzamientos Genéticos , Marcadores Genéticos/inmunología , Predisposición Genética a la Enfermedad , Glomerulonefritis/genética , Glomerulonefritis/inmunología , Glicoproteínas/sangre , Glicoproteínas/genética , Inmunoglobulina G/sangre , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Masculino , Ratones , Ratones Congénicos , Ratones Endogámicos C57BL , Chaperonas Moleculares/genética , Mutación , Síndrome , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunologíaRESUMEN
The accelerated development of systemic lupus erythematosus (SLE) in BXSB male mice is associated with the presence of an as yet unidentified mutant gene, Yaa (Y-linked autoimmune acceleration). In view of a possible role of marginal zone (MZ) B cells in murine SLE, we have explored whether the expression of the Yaa mutation affects the differentiation of MZ and follicular B cells, thereby implicating the acceleration of the disease. In this study, we show that both BXSB and C57BL/6 Yaa mice, including two different substrains of BXSB Yaa males that are protected from SLE, displayed an impaired development of MZ B cells early in life. Studies in bone marrow chimeras revealed that the loss of MZ B cells resulted from a defect intrinsic to B cells expressing the Yaa mutation. The lack of selective expansion of MZ B cells in diseased BXSB Yaa males strongly argues against a major role of MZ B cells in the generation of pathogenic autoantibodies in the BXSB model of SLE. Furthermore, a comparative analysis with mice deficient in CD22 or expressing an IgM anti-trinitrophenyl/DNA transgene suggests that the hyperreactive phenotype of Yaa B cells, as judged by a markedly increased spontaneous IgM secretion, is likely to contribute to the enhanced maturation toward follicular B cells and the block in the MZ B cell generation.