RESUMO
BACKGROUND: In systemic lupus erythematosus patients, a strong association between the occurrence of antibodies against complement C1q (anti-C1q) and lupus nephritis can be observed. However, the predictive value of anti-C1q titres for a renal flare remains to be determined. Increasing titres of anti-C1q before the occurrence of clinical apparent nephritis might not only serve as a clinical parameter but also indicate a direct pathogenic mechanism of anti-C1q. METHODS: The aim of this study was to analyse the occurrence of anti-C1q before the onset of experimental lupus nephritis in MRL/MpJ +/+ mice and to correlate anti-C1q titres with the type and severity of glomerulonephritis (GN) developing at advanced age. RESULTS: As judged by a number of morphological and immunological analyses, GN in MRL/MpJ +/+ mice resembled human lupus nephritis and occurred in variable degrees of severity. We also observed an abundant and early presence of anti-C1q. However, anti-C1q neither correlated with overall survival nor with any histological marker of severity of GN. CONCLUSIONS: The absence of a correlation between the presence of anti-C1q and the occurrence of experimental lupus nephritis contradicts the hypothesis that anti-C1q are pathogenic. However, different pathogenic mechanisms of experimental lupus nephritis and human proliferative lupus nephritis cannot be excluded.
Assuntos
Autoanticorpos/sangue , Biomarcadores/sangue , Complemento C1q/imunologia , Glomerulonefrite/imunologia , Nefrite Lúpica/imunologia , Animais , Anticorpos Antinucleares/sangue , Feminino , Imunofluorescência , Glomerulonefrite/sangue , Glomerulonefrite/diagnóstico , Humanos , Técnicas Imunoenzimáticas , Nefrite Lúpica/sangue , Nefrite Lúpica/diagnóstico , Camundongos , Camundongos Endogâmicos BALB C , Taxa de SobrevidaRESUMO
Autoantibodies against complement C1q (anti-C1q Abs) were shown to strongly correlate with the occurrence of severe nephritis in patients with systemic lupus erythematosus (SLE), suggesting a potential pathogenic role by interfering with the complement cascade. To analyze the humoral immune response against C1q at the molecular level, we screened a bone marrow-derived IgGkappa/IgGlambda Fab phage display library from a SLE patient with high anti-C1q Ab titer against purified human C1q. Six Fabs that exhibited strong binding to C1q in ELISA were isolated. The anti-C1q Fabs recognized neoepitopes that were only exposed on bound C1q and not present on soluble C1q mapping to different regions of the collagen-like region of C1q. Analysis of the genes encoding the variable H and L chains of the IgG-derived anti-C1q Fab revealed that all the variable H and L chain regions were highly mutated, with nucleotide and amino acid homologies to the closest germline in the range of 71-97% (average 85 +/- 4) and 72-92% (average 88 +/- 6), respectively. In addition, the variable region of the Fabs exhibited high replacement to silent ratios. The six anti-C1q Fabs were shown to be of high affinity, with a K(d) ranging from of 8.4 x 10(-8) M to 1.4 x 10(-7) M, comparable to an antiviral immune response. Our data underlines the notion that the development of anti-C1q Abs in SLE is the consequence of an Ag-driven, affinity-matured immune response. Those anti-C1q Fabs are unique tools to address how complement C1q is implicated in the pathogenesis of SLE.
Assuntos
Autoanticorpos/biossíntese , Autoantígenos/fisiologia , Complemento C1q/fisiologia , Lúpus Eritematoso Sistêmico/imunologia , Sequência de Aminoácidos , Anticorpos Monoclonais/biossíntese , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Monoclonais/metabolismo , Afinidade de Anticorpos , Especificidade de Anticorpos , Proteínas Reguladoras de Apoptose/biossíntese , Proteínas Reguladoras de Apoptose/isolamento & purificação , Proteínas Reguladoras de Apoptose/metabolismo , Autoanticorpos/isolamento & purificação , Autoanticorpos/metabolismo , Autoantígenos/imunologia , Autoantígenos/metabolismo , Complemento C1q/imunologia , Complemento C1q/metabolismo , Humanos , Fragmentos Fab das Imunoglobulinas/biossíntese , Fragmentos Fab das Imunoglobulinas/isolamento & purificação , Fragmentos Fab das Imunoglobulinas/metabolismo , Dados de Sequência MolecularRESUMO
BACKGROUND: Life-threatening infections are a major cause of death after allogeneic stem cell transplantation. Complement Mannose-binding lectin is a key component of innate immunity. Functional deficiency of mannose-binding lectin due to genetic polymorphism is frequent. Previous reports showed conflicting results with respect to the influence of functional mannose-binding lectin deficiency on infectious risk after allogeneic stem cell transplantation. The aim of this study was to clarify the impact of low mannose-binding lectin levels on infectious risk in a unique cohort of very long-term survivors after stem cell transplantation. DESIGN AND METHODS: Incidence of major infections was evaluable in 43 out of 44 very long-term survivors (over ten years) and studied retrospectively in relation to mannose-binding lectin serum concentrations. RESULTS: Recipients with mannose-binding lectin levels below 1,000 ng/mL were at increased risk to suffer from one or more major infections (P=0.002) during entire follow up. Infectious susceptibility was increased after neutrophil recovery, particularly until 24 months (Hazard Ratio 3.4) with sustained effects afterwards (Hazard Ratio 2.9). Mannose-binding lectin serum concentrations below 1,000 ng/mL were independently associated with major infections after neutrophil recovery (P=0.009). In subgroup analyses occurrence of severe herpes virus infections in particular was associated with significantly lower mannose-binding lectin levels (P=0.02). CONCLUSIONS: Our findings indicate that low mannose-binding lectin levels may predict markedly increased susceptibility to severe infections with sustained effects even late after allogeneic stem cell transplantation. Determinations of mannose-binding lectin status should therefore be included into pre-transplantation risk assessment.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Herpes Simples/sangue , Lectina de Ligação a Manose/sangue , Sobreviventes , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Herpes Simples/etiologia , Humanos , Masculino , Lectina de Ligação a Manose/genética , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Transplante HomólogoRESUMO
Autoantibodies against complement C1q (anti-C1q) strongly correlate with the occurrence of severe lupus nephritis. Recent data suggest that anti-C1q might also correlate with more severe forms of acute post-streptococcal glomerulonephritis (APSGN). Therefore, we prospectively investigated the role of anti-C1q in 50 children with newly diagnosed APSGN. Associations between anti-C1q and disease manifestations as well as serum complement concentrations were analyzed. Nineteen of the 50 children (38%) with APSGN were positive for anti-C1q compared to 0/40 healthy controls. Levels of anti-C1q correlated negatively with serum C1q and C3 concentrations. Anti-C1q positive patients had significantly higher proteinuria and serum creatinine as well as more often oliguria, hypertension and delayed resolution of the disease than patients without anti-C1q. The data point to a potential pathogenic role of anti-C1q in APSGN. Determination of anti-C1q might help to identify patients at risk for prolonged courses of the disease.
Assuntos
Autoanticorpos/sangue , Complemento C1q/imunologia , Glomerulonefrite/imunologia , Infecções Estreptocócicas/complicações , Doença Aguda , Adolescente , Autoanticorpos/imunologia , Criança , Pré-Escolar , Complemento C1q/análise , Complemento C3/análise , Complemento C3/imunologia , Complemento C4/análise , Complemento C4/imunologia , Creatinina/sangue , Feminino , Glomerulonefrite/metabolismo , Humanos , Masculino , Proteinúria/imunologia , Proteinúria/metabolismoRESUMO
BACKGROUND: Antinucleosome autoantibodies were previously described to be a marker of active lupus nephritis. However, the true prevalence of antinucleosome antibodies at the time of active proliferative lupus nephritis has not been well established. Therefore, the aim of this study is to define the prevalence and diagnostic value of autoantibodies against nucleosomes as a marker for active proliferative lupus nephritis. STUDY DESIGN: Prospective multicenter diagnostic test study. SETTING & PARTICIPANTS: 35 adult patients with systemic lupus erythematosus (SLE) at the time of the renal biopsy showing active class III or IV lupus nephritis compared with 59 control patients with SLE. INDEX TEST: Levels of antinucleosome antibodies and anti-double-stranded DNA (anti-dsDNA) antibodies. REFERENCE TEST: Kidney biopsy findings of class III or IV lupus nephritis at the time of sampling in a study population versus clinically inactive or no nephritis in a control population. RESULTS: Increased concentrations of antinucleosome antibodies were found in 31 of 35 patients (89%) with active proliferative lupus nephritis compared with 47 of 59 control patients (80%) with SLE. No significant difference between the 2 groups with regard to number of positive patients (P = 0.2) or antibody concentrations (P = 0.2) could be found. The area under the receiver operating characteristic curve as a marker of the accuracy of the test in discriminating between proliferative lupus nephritis and inactive/no nephritis in patients with SLE was 0.581 (95% confidence interval, 0.47 to 0.70; P = 0.2). Increased concentrations of anti-dsDNA antibodies were found in 33 of 35 patients (94.3%) with active proliferative lupus nephritis compared with 49 of 58 control patients (84.5%) with SLE (P = 0.2). In patients with proliferative lupus nephritis, significantly higher titers of anti-dsDNA antibodies were detected compared with control patients with SLE (P < 0.001). The area under the receiver operating characteristic curve in discriminating between proliferative lupus nephritis and inactive/no nephritis in patients with SLE was 0.710 (95% confidence interval, 0.60 to 0.82; P < 0.001). CONCLUSIONS: Antinucleosome antibodies have a high prevalence in patients with severe lupus nephritis. However, our data suggest that determining antinucleosome antibodies is of limited help in the distinction of patients with active proliferative lupus nephritis from patients with SLE without active renal disease.