ABSTRACT
BACKGROUND: Increasing evidence links genetic defects affecting actin-regulatory proteins to diseases with severe autoimmunity and autoinflammation, yet the underlying molecular mechanisms are poorly understood. Dedicator of cytokinesis 11 (DOCK11) activates the small Rho guanosine triphosphatase (GTPase) cell division cycle 42 (CDC42), a central regulator of actin cytoskeleton dynamics. The role of DOCK11 in human immune-cell function and disease remains unknown. METHODS: We conducted genetic, immunologic, and molecular assays in four patients from four unrelated families who presented with infections, early-onset severe immune dysregulation, normocytic anemia of variable severity associated with anisopoikilocytosis, and developmental delay. Functional assays were performed in patient-derived cells, as well as in mouse and zebrafish models. RESULTS: We identified rare, X-linked germline mutations in DOCK11 in the patients, leading to a loss of protein expression in two patients and impaired CDC42 activation in all four patients. Patient-derived T cells did not form filopodia and showed abnormal migration. In addition, the patient-derived T cells, as well as the T cells from Dock11-knockout mice, showed overt activation and production of proinflammatory cytokines that were associated with an increased degree of nuclear translocation of nuclear factor of activated T cell 1 (NFATc1). Anemia and aberrant erythrocyte morphologic features were recapitulated in a newly generated dock11-knockout zebrafish model, and anemia was amenable to rescue on ectopic expression of constitutively active CDC42. CONCLUSIONS: Germline hemizygous loss-of-function mutations affecting the actin regulator DOCK11 were shown to cause a previously unknown inborn error of hematopoiesis and immunity characterized by severe immune dysregulation and systemic inflammation, recurrent infections, and anemia. (Funded by the European Research Council and others.).
Subject(s)
Actins , Anemia , Guanine Nucleotide Exchange Factors , Inflammation , Animals , Humans , Mice , Actins/genetics , Actins/metabolism , Anemia/etiology , Anemia/genetics , Disease Models, Animal , Guanine Nucleotide Exchange Factors/deficiency , Guanine Nucleotide Exchange Factors/genetics , Hematopoiesis , Inflammation/etiology , Inflammation/genetics , Zebrafish/genetics , Zebrafish/metabolismABSTRACT
No disponble
Subject(s)
Humans , Child , Hemoptysis/diagnosis , Hemoptysis/therapy , Bronchiolitis Obliterans/therapy , Papilloma/pathology , Larynx/pathology , Drug-Related Side Effects and Adverse Reactions , Cidofovir/adverse effects , Psychosocial Impact , Bronchoscopy/methods , Intubation, Intratracheal , Quality of LifeABSTRACT
Introduction: Development of secondary haemophagocytic lymphohistiocytosis (sHLH) in the context of typhoid fever (TF) is a very rare but serious complication. Methods: Description of the first pediatric case of typhoid fever acquired in a non-endemic area complicated by sHLH. A systematic literature review of sHLH in the context of TF was performed with extraction of epidemiological, clinical and laboratory data. Results: The literature search revealed 17 articles (22 patients). Fifteen patients were eligible for data analysis (53.4% children). All patients had fever and pancytopenia. Transaminases and LDH were frequently elevated (46.6%). Salmonella typhi was detected mainly by blood culture (64.3%). All the patients received antibiotics whereas immunomodulation (dexamethasone) was used in two cases. Conclusions: A high suspicion index for this condition is needed even in non-endemic areas. The addition of immunmodulation to standard antimicrobial therapy should be considered in selected cases
Introducción: El síndrome hemofagocítico (HLH) secundario en el contexto de fiebre tifoidea es una complicación rara pero seria. Métodos: Descripción del primer caso pediátrico de fiebre tifoidea adquirida en área no endémica complicada con síndrome hemofagocítico y revisión sistemática de la literatura de casos de HLH secundarios a fiebre tifoidea. Descripción de datos epidemiológicos, clínicos y de laboratorio, diagnóstico y manejo. Resultados: La búsqueda bibliográfica reveló 17 artículos (22 pacientes). Quince pacientes eran elegibles para el análisis (53,4% niños). La fiebre y la pancitopenia estaban siempre presentes, y las transaminasas y la LDH estaban frecuentemente elevados (46,6%). La detección de S. typhi se realizó mediante hemocultivo, principalmente (64,3%). Todos los pacientes reportados recibieron antibióticos; la dexametasona fue usada como tratamiento inmunomodulador en 2 de los casos. Conclusiones: Mantener alto el grado de sospecha de esta condición es necesario, incluso en áreas no endémicas, ya que el uso de tratamiento inmunomodulador junto al tratamiento antimicrobiano puede ser determinante para una evolución clínica favorable
Subject(s)
Humans , Male , Child , Adolescent , Lymphohistiocytosis, Hemophagocytic/etiology , Lymphohistiocytosis, Hemophagocytic/epidemiology , Typhoid Fever/complications , Typhoid Fever/epidemiology , Abdominal Pain/etiology , Age Distribution , Asia/epidemiology , Ceftriaxone/therapeutic use , Developed Countries , Diagnosis, Differential , Endemic Diseases , Fever/etiology , Lymphohistiocytosis, Hemophagocytic/drug therapy , Methylprednisolone/therapeutic useSubject(s)
Antiviral Agents/adverse effects , Cidofovir/adverse effects , Cryptogenic Organizing Pneumonia/chemically induced , Hemoptysis/chemically induced , Papillomavirus Infections/drug therapy , Respiratory Tract Infections/drug therapy , Administration, Inhalation , Adrenal Cortex Hormones/therapeutic use , Antiviral Agents/administration & dosage , Antiviral Agents/therapeutic use , Child , Cidofovir/administration & dosage , Combined Modality Therapy , Compassionate Use Trials , Drug Substitution , Female , Humans , Infant , Male , Nebulizers and Vaporizers , Papillomavirus Infections/complications , Papillomavirus Infections/surgery , Respiratory Tract Infections/complications , Respiratory Tract Infections/surgery , TracheostomyABSTRACT
INTRODUCTION: Development of secondary haemophagocytic lymphohistiocytosis (sHLH) in the context of typhoid fever (TF) is a very rare but serious complication. METHODS: Description of the first pediatric case of typhoid fever acquired in a non-endemic area complicated by sHLH. A systematic literature review of sHLH in the context of TF was performed with extraction of epidemiological, clinical and laboratory data. RESULTS: The literature search revealed 17 articles (22 patients). Fifteen patients were eligible for data analysis (53.4% children). All patients had fever and pancytopenia. Transaminases and LDH were frequently elevated (46.6%). Salmonella typhi was detected mainly by blood culture (64.3%). All the patients received antibiotics whereas immunomodulation (dexamethasone) was used in two cases. CONCLUSIONS: A high suspicion index for this condition is needed even in non-endemic areas. The addition of immunmodulation to standard antimicrobial therapy should be considered in selected cases.