RESUMO
In the present study, DNA sequencing of the genes SRGN, ARF6, AP3B1, and SH2D1A was performed in a well defined cohort of 18 families with familial hemophagocytic lymphohistiocytosis (FHL). A heterozygous nucleotide change (C > T) in the 3'untranslated region of the SRGN gene and a monoallelic 3-base pair deletion (c.2409_2411delGAA) in exon 21 of the AP3B1 gene were observed in two different families. Additionally, two novel polymorphisms, one in intron 17 of AP3B1 and another in intron 2 of SH2D1A were identified. We conclude that mutations in SRGN, ARF6, and AP3B1 are not likely to be common in patients fulfilling the FHL criteria.
Assuntos
Fatores de Ribosilação do ADP/genética , Complexo 3 de Proteínas Adaptadoras/genética , Subunidades beta do Complexo de Proteínas Adaptadoras/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Linfo-Histiocitose Hemofagocítica/genética , Polimorfismo Genético/genética , Proteoglicanas/genética , Proteínas de Transporte Vesicular/genética , Regiões 3' não Traduzidas/genética , Fator 6 de Ribosilação do ADP , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Éxons/genética , Feminino , Humanos , Lactente , Masculino , Mutação/genética , Proteína Associada à Molécula de Sinalização da Ativação LinfocitáriaRESUMO
Erythema Toxicum, a rash frequently present in the healthy newborn infant is an innate, immune response to the first commensal micro flora. Flushing and urtication are seen in this manifestation suggesting mast cell (MC) activation and MC derived mediator release. It has recently become evident that MCs participate in the protective, innate immune response against microbes also by secreting products toxic to pathogens such as cathelicidin peptide antibiotics. We hypothesized that MCs contribute to the process of inflammation in Erythema Toxicum and that skin MCs of human newborns express the cathelicidin peptide antibiotic LL-37. Skin sections were immunostained for MC tryptase. Double immunofluorescence was performed by staining LL-37 in combination with tryptase. We studied ultra structure of skin MCs with transmission (TEM) and immunoelectron microscopy (IEM). Seven infants with and six infants without the rash, as well as three adults were included. We found numerous tryptase-expressing MCs recruited around the hair follicles in the lesions of Erythema Toxicum. TEM analysis of MCs exhibited signs of degranulation in the lesion. Neither skin MCs from newborns nor adults did express LL-37 as judged by confocal and IEM. MCs participate in the inflammatory responses of Erythema Toxicum by taking an active part in the immune system of the hair follicle. However, their immunological activity is not linked to the expression of the cathelicidin antimicrobial peptide LL-37. A pivotal role of MCs in the innate, inflammatory response at the site of pathogen invasion during the critical time of perinatal colonization is suggested.
Assuntos
Eritema/imunologia , Folículo Piloso/imunologia , Mastócitos/imunologia , Pele/imunologia , Triptases/metabolismo , Urticária/imunologia , Adulto , Peptídeos Catiônicos Antimicrobianos/análise , Catelicidinas , Eritema/metabolismo , Feminino , Humanos , Recém-Nascido , Masculino , Mastócitos/enzimologia , Mastócitos/ultraestrutura , Microscopia Eletrônica de Transmissão , Microscopia Imunoeletrônica , Pele/metabolismo , Pele/ultraestrutura , Urticária/metabolismoRESUMO
Hemophagocytic lymphohistiocytosis (HLH) is a rare condition with high mortality. We report an extremely premature girl, born in the 24th gestational week (BW 732 g), that during her second month developed a severe HLH subsequent to a Serratia marcescens septicemia, with hepatosplenomegaly, cytopenias, hyperbilirubinemia (mostly conjugated, total bilirubin 916 mumol/L), hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia (21266 mug/L), and elevated sIL-2 receptor levels. Genetic analysis revealed no PRF1, STX11 or UNC13D gene mutations. Treatment was provided according to the HLH-2004 protocol with etoposide, dexamethasone, and immunoglobulin, but no cyclosporin because of immature kidneys. She recovered fully from the HLH but developed a severe retinopathy as well as green teeth secondary to the hyperbilirubinemia. We conclude that secondary, bacteria-associated HLH can develop in premature infants, and that HLH can be treated with cytotoxic therapy also in premature infants. It is important to be aware of HLH in premature infants, since it is treatable.
Assuntos
Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Sepse/diagnóstico , Sepse/tratamento farmacológico , Infecções por Serratia/diagnóstico , Infecções por Serratia/tratamento farmacológico , Corticosteroides/administração & dosagem , Citotoxinas/administração & dosagem , Citotoxinas/uso terapêutico , Dexametasona/administração & dosagem , Quimioterapia Combinada , Etoposídeo/administração & dosagem , Feminino , Humanos , Hiperbilirrubinemia/diagnóstico , Imunoglobulinas/administração & dosagem , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Recém-Nascido , Recém-Nascido Prematuro , Linfo-Histiocitose Hemofagocítica/microbiologia , Retinopatia da Prematuridade , Sepse/complicações , Sepse/microbiologia , Infecções por Serratia/complicações , Serratia marcescensRESUMO
Familial hemophagocytic lymphohistiocytosis (FHL) is typically an early onset, fatal disease characterized by a sepsislike illness with cytopenia, hepatosplenomegaly, and deficient lymphocyte cytotoxicity. Disease-causing mutations have been identified in genes encoding perforin (PRF1/FHL2), Munc13-4 (UNC13D/FHL3), and syntaxin-11 (STX11/FHL4). In contrast to mutations leading to loss of perforin and Munc13-4 function, it is unclear how syntaxin-11 loss-of-function mutations contribute to disease. We show here that freshly isolated, resting natural killer (NK) cells and CD8(+) T cells express syntaxin-11. In infants, NK cells are the predominant perforin-containing cell type. NK cells from FHL4 patients fail to degranulate when encountering susceptible target cells. Unexpectedly, IL-2 stimulation partially restores degranulation and cytotoxicity by NK cells, which could explain the less severe disease progression observed in FHL4 patients, compared with FHL2 and FHL3 patients. Since the effector T-cell compartment is still immature in infants, our data suggest that the observed defect in NK-cell degranulation may contribute to the pathophysiology of FHL, that evaluation of NK-cell degranulation in suspected FHL patients may facilitate diagnosis, and that these new insights may offer novel therapeutic possibilities.
Assuntos
Regulação da Expressão Gênica , Células Matadoras Naturais/citologia , Linfócitos/citologia , Linfo-Histiocitose Hemofagocítica/genética , Proteínas Qa-SNARE/genética , Adulto , Western Blotting , Proliferação de Células , Pré-Escolar , Citocinas/metabolismo , Feminino , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Células Matadoras Naturais/metabolismo , Proteínas com Domínio LIM , Proteínas com Homeodomínio LIM , Subpopulações de Linfócitos , Linfócitos/metabolismo , Linfo-Histiocitose Hemofagocítica/metabolismo , Linfo-Histiocitose Hemofagocítica/patologia , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Mutação/genética , Perforina , Proteínas Citotóxicas Formadoras de Poros/genética , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Proteínas Qa-SNARE/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Erythema toxicum neonatorum is a common rash of unknown etiology affecting healthy newborn infants. In this study, we postulated that the rash reflects a response to microbial colonization of the skin at birth, and that the hair follicle constitutes an "easily opened door" for microbes into the skin of the newborn. We collected microbial cultures from the skin of 69 healthy, 1-d-old infants with and without erythema toxicum to identify the colonizing flora and correlate culture results with clinical findings. We also analyzed biopsies from lesions of erythema toxicum with scanning and transmission electron microscopy in the search for microbes. Finally, each infant's body temperature was measured as a sign of acute phase response. We found that 84% of 1-d-old healthy infants, with and without erythema toxicum were colonized with coagulase-negative staphylococci. In all lesions of erythema toxicum, TEM identified cocci-like bacteria localized in the hair follicle epithelium and into recruited immune cells surrounding the hair follicle; morphology and dimension supported their identification as belonging to the genus Staphylococcus. SEM revealed 10 times more hair structures per skin surface unit in newborns compared with adults. Infants with erythema toxicum also had higher body temperature. In erythema toxicum, commensal microbes gain entry into the skin tissue, most probably through the hair canal. This triggers the local immune system and a systemic acute phase response, including an increase in body temperature. We speculate that early microbial exposure to the newborn may be important for the maturation of the immune system.