RESUMEN
Dengue fever and chikungunya are viral diseases that have spread rapidly throughout the world in recent decades. The occurrence of complications is well known, including prerenal acute kidney injury (AKI), which is usually thought to be caused by dehydration and fluid loss. Thrombotic microangiopathy (TMA) is an uncommon aggravation of dengue fever and chikungunya, with only a few cases described in the medical literature. The aim of this study is to present 3 cases of TMA associated with arboviral infection. Three patients with clinical history, laboratory test, and kidney biopsy results compatible with TMA were selected for the study, 2 of whom had a serological diagnosis of dengue fever and 1 of chikungunya. The 3 patients were followed up at the Federal University of Maranhão Hospital's Nephrology Service in 2018. A targeted gene panel sequencing (TGPS) plus multiple to atypical hemolytic uremic syndrome (aHUS) multiplex ligation-dependent probe amplification (MLPA) was performed in 2 of the patients and revealed in the patient 1 a heterozygous pathogenic variant in the gene THBD, as well as heterozygous deletions in CFH, CFHR1, and CFHR3. In the patient 2, there were heterozygous pathogenic variant in the genes CFI and CFB, in addition to heterozygous deletions in the genes CFHR1 and CFHR3. Both received treatment with eculizumab and undergone recovery of renal function. The third patient had TMA not classified as either aHUS or thrombotic thrombocytopenic purpura (TTP); he abandoned the treatment and returned to the service after 2 years for a dialysis emergency. Patients with arboviral infectious disease and changes that suggest TMA should have appropriate support to establish early diagnosis and useful treatment.
Asunto(s)
Infecciones por Arbovirus/virología , Arbovirus/aislamiento & purificación , Microangiopatías Trombóticas/virología , Adolescente , Adulto , Infecciones por Arbovirus/genética , Arbovirus/clasificación , Arbovirus/genética , Arbovirus/fisiología , Proteínas Sanguíneas/genética , Proteínas Inactivadoras del Complemento C3b/genética , Heterocigoto , Humanos , Masculino , Mutación , Microangiopatías Trombóticas/genética , Adulto JovenRESUMEN
The association of thrombotic microangiopathy (TMA) with systemic lupus erythematosus (SLE) has been described in 0.5 to 10% of cases, and patients present worse outcome. TMA is described as the association of microangiopathic hemolytic anemia, thrombocytopenia, and an organ injury, frequently the kidney. This study describes a successful case of use of eculizumab in a patient with SLE and TMA refractory to standard therapy, and provides a literature review. Case description and search in PubMed and MEDLINE using systemic lupus erythemathous and/or antiphospholipid syndrome (APS) and eculizumab retrieved 15 case reports. Eighteen-year-old female presented acute renal failure and TMA and was diagnosed with SLE. Steroids and IV cyclophosphamide were started together with plasma exchange. After 55 days, she still persisted with microangiopathic anemia, thrombocytopenia, and anuria, and eculizumab was introduced. She had rapid improvement in hematological parameters, and dialysis was discontinued 25 days after the first dose. Genetic analysis showed large heterozygous deletion encompassing the entire CFHR1 and CFHR3, a finding previously associated with patients presenting atypical hemolytic-uremic syndrome (aHUS). Twenty patients who received eculizumab with SLE and/or APS have been published to date: 11 were female and mean age at presentation was 31 years. Seven out of the 20 patients presented only SLE, 5 patients only APS and 8 patients both SLE and APS. Eighteen patients underwent plasma exchange, with a mean of 20 (4-120) sessions per patient. Thirteen patients received rituximab. Hematological response was evident in 100% and kidney recovery in 85% of patients. The terminal complement blockade with eculizumab is an optional treatment for patients with SLE and/or APS presenting TMA and refractory to current immunosuppression therapies. Genetic testing may help recognize patients with aHUS and SLE/APS and therefore help to determine length of treatment with eculizumab.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Microangiopatías Trombóticas/tratamiento farmacológico , Adolescente , Proteínas Sanguíneas/genética , Proteínas Inactivadoras del Complemento C3b/genética , Femenino , Humanos , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/genética , Eliminación de Secuencia , Microangiopatías Trombóticas/etiología , Microangiopatías Trombóticas/genética , Resultado del TratamientoAsunto(s)
Proteínas Sanguíneas/genética , Proteínas Inactivadoras del Complemento C3b/genética , Eliminación de Gen , Atrofia Geográfica/genética , Polimorfismo de Nucleótido Simple , Degeneración Macular Húmeda/genética , Anciano , Brasil , Cromosomas Humanos Par 1/genética , Factor H de Complemento/genética , Femenino , Atrofia Geográfica/diagnóstico , Humanos , Masculino , Reacción en Cadena de la Polimerasa , Degeneración Macular Húmeda/diagnósticoRESUMEN
Leptospira, the causative agent of leptospirosis, interacts with several host molecules, including extracellular matrix components, coagulation cascade proteins, and human complement regulators. Here we demonstrate that acquisition of factor H (FH) on the Leptospira surface is crucial for bacterial survival in the serum and that these spirochetes, besides interacting with FH, FH related-1, and C4b binding protein (C4BP), also acquire FH like-1 from human serum. We also demonstrate that binding to these complement regulators is mediated by leptospiral immunoglobulin-like (Lig) proteins, previously shown to interact with fibronectin, laminin, collagen, elastin, tropoelastin, and fibrinogen. Factor H binds to Lig proteins via short consensus repeat domains 5 and 20. Competition assays suggest that FH and C4BP have distinct binding sites on Lig proteins. Moreover, FH and C4BP bound to immobilized Ligs display cofactor activity, mediating C3b and C4b degradation by factor I. In conclusion, Lig proteins are multifunctional molecules, contributing to leptospiral adhesion and immune evasion.
Asunto(s)
Proteínas Bacterianas/metabolismo , Proteínas Sanguíneas/metabolismo , Proteínas Inactivadoras del Complemento C3b/metabolismo , Antígenos de Histocompatibilidad/metabolismo , Leptospira/patogenicidad , Leptospirosis/inmunología , Adhesión Bacteriana , Proteínas Bacterianas/genética , Sitios de Unión , Clonación Molecular , Complemento C3b/metabolismo , Proteína de Unión al Complemento C4b/metabolismo , Factor H de Complemento/metabolismo , Regulación Bacteriana de la Expresión Génica , Humanos , Evasión Inmune , Inmunoglobulinas/química , Leptospira/genética , Leptospira/metabolismo , Leptospirosis/microbiología , PlásmidosRESUMEN
We identified a 4-year-old Brazilian boy from a family of Japanese descent and history of consanguinity, who suffered from severe recurrent pneumonia. He carries factor H (FH) deficiency associated with reduced levels of component C9 and low serum levels of C3 and factor B. His mother also presented low levels of these proteins and factor I, while his father and sister had only lower levels of FH. Western blot assays confirmed the complete absence of FH and FHL-1 polypeptides in this patient. Sequencing of the proband's FH cDNA revealed a homozygous G453A substitution, encoding an Arg(127)His change. His mother, father and sister are heterozygous for this substitution. Despite the absence of FH in the plasma, this protein was detected in the patient's fibroblasts, suggesting that Arg(127) may be important for FH secretion. Low concentrations of C9 were detected in the proband serum but no mutations in the patient's C9 gene or promoter have been identified, suggesting that this is a consequence of uncontrolled complement activation and high C9 consumption.
Asunto(s)
Trastornos de la Coagulación Sanguínea Heredados/sangre , Trastornos de la Coagulación Sanguínea Heredados/genética , Complemento C9/análisis , Factor H de Complemento/deficiencia , Factor H de Complemento/genética , Secuencia de Bases , Trastornos de la Coagulación Sanguínea Heredados/fisiopatología , Western Blotting , Preescolar , Activación de Complemento/fisiología , Proteínas Inactivadoras del Complemento C3b , Complemento C9/genética , Proteínas del Sistema Complemento/análisis , Consanguinidad , Ensayo de Inmunoadsorción Enzimática , Femenino , Fibroblastos/metabolismo , Humanos , Masculino , Microscopía Confocal , Mutación , Linaje , Neumonía/etiología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
La evaluación de la actividad de anti-C3d en reactivos de Coombs poliespecíficos, con los procedimientos clásicos presenta, según la experiencia de los autores, dificultades técnicas y falta de reproductibilidad. El objetivo de este trabajo fue describir una técnica para controlar la actividad de los reactivos antiglobulina humana (AGH) poliespecíficos y monoespecíficos anti-C3d, utilizando glóbulos rojos de carnero (GRc) sensibilizados con fragmentos de complemento (C). La obtención de GRc sensibilizados con C3d, se evaluó con reactivos de calidad certificada por la firma comercial. Se obtuvieron reacciones de aglutinación francamente positivas con reactivos de Coombs poliespecíficos y con reactivos anti-C3d, -C3d monoespecíficos. La sensibilidad, especificidad y sencillez de esta técnica induce a proponerla dentro del protocolo de Control de Calidad de los antisueros AGH poliespecíficos y anti-C3d, -C3d, utilizados de rutina en los Servicios de Medicina Transfusional (AU)
Asunto(s)
Humanos , Técnicas In Vitro , Prueba de Coombs/métodos , Proteínas Inactivadoras del Complemento C3b/análisis , Control de Calidad , Ensayo de Actividad Hemolítica de Complemento/métodos , Factor D del Complemento/análisis , Proteínas del Sistema Complemento , Complemento C3d/análisis , Bancos de Sangre/tendencias , Prueba de Coombs/métodos , Anticuerpos Antiidiotipos/análisisRESUMEN
La evaluación de la actividad de anti-C3d en reactivos de Coombs poliespecíficos, con los procedimientos clásicos presenta, según la experiencia de los autores, dificultades técnicas y falta de reproductibilidad. El objetivo de este trabajo fue describir una técnica para controlar la actividad de los reactivos antiglobulina humana (AGH) poliespecíficos y monoespecíficos anti-C3d, utilizando glóbulos rojos de carnero (GRc) sensibilizados con fragmentos de complemento (C'). La obtención de GRc sensibilizados con C3d, se evaluó con reactivos de calidad certificada por la firma comercial. Se obtuvieron reacciones de aglutinación francamente positivas con reactivos de Coombs poliespecíficos y con reactivos anti-C3d, -C3d monoespecíficos. La sensibilidad, especificidad y sencillez de esta técnica induce a proponerla dentro del protocolo de Control de Calidad de los antisueros AGH poliespecíficos y anti-C3d, -C3d, utilizados de rutina en los Servicios de Medicina Transfusional
Asunto(s)
Humanos , Proteínas Inactivadoras del Complemento C3b/análisis , Prueba de Coombs , Técnicas In Vitro , Anticuerpos Antiidiotipos/análisis , Bancos de Sangre/tendencias , Complemento C3d/análisis , Factor D del Complemento/análisis , Proteínas del Sistema Complemento , Prueba de Coombs , Ensayo de Actividad Hemolítica de Complemento/métodos , Control de CalidadRESUMEN
The third component of complement, the central protein of the complement cascade, occurs in two principal allotypes, C3S and C3F. An excess frequency of the F allotype has been implicated in a number of disease states, including some forms of glomerulonephritis. These associations have been explained by functional differences between C3S and C3F. We examined several complement functions, using purified preparations of C3S or C3F. The C3S allotype was 1.3 times more efficient than C3F in a hemolytic assay employing sensitized sheep erythrocytes; this difference was shown to arise from a slightly more efficient deposition of C3F on the cell surface. These differences are trivial and of much less magnitude than the functional differences between C4A and C4B. There were no differences between allotypes in their ability to be converted to inactive C3b (C3bi) by complement factors H and I or by CR1 and factor I. No significant differences were seen between the allotypes and their ability to support solubilization of preformed immune complexes.
Asunto(s)
Complemento C3/genética , Polimorfismo Genético , Animales , Complejo Antígeno-Anticuerpo/genética , Proteínas Sanguíneas/análisis , Bovinos , Complemento C3/análisis , Proteínas Inactivadoras del Complemento C3b/farmacología , Complemento C4/análisis , Factor H de Complemento , Factor I de Complemento , Eritrocitos/inmunología , Hemólisis/genética , Humanos , Fenotipo , Conejos , Serina Endopeptidasas/farmacología , Ovinos , SolubilidadRESUMEN
Serum or plasma concentrations of components of the classical (C1q, C4) and alternative (C3, factor B) pathways, regulatory protein factor H, and one of the C3 products of degradation, C3d, were determined in 19 patients with amebic liver abscess (ALA). Patients were divided into two groups. Thirteen patients that recovered under medical treatment who had a significantly shorter clinical course on admission (P less than 0.05) (group 1) exhibited either normal (C1q; C4; factor B; C3d) or increased levels of these components (C3, P less than 0.001; factor B, P less than 0.01). On the other hand, 16 patients that recovered after medical treatment and abscess drainage (group 2) exhibited significantly diminished serum levels of C1q (P less than 0.05), C3 (P less than 0.001), factor B (P less than 0.01) and factor H (P less than 0.05), and normal levels of C4, and C3d as compared to the control group. The relationships among the complement components studied were suggestive of activation of the complement system through the classical pathway in patients within group 1 and through both pathways in group 2. Sera of 3 out of the 5 patients who initially exhibited low plasma levels of C3d showed an increase during convalescence. Plasma levels of C3d were demonstrated to show a direct correlation with serum albumin and SGOT in this group of patients. Possible implications of the complement system in the immunopathogenesis of ALA are discussed.