RESUMO
Inborn errors of immunity are a group of genetic disorders caused by mutations that affect the development and/or function of several compartments of the immune system, predisposing patients to infections, autoimmunity, allergy and malignancies. In this regard, mutations that affect proteins involved in trafficking, priming, docking, or membrane fusion will impair the exocytosis of lytic granules of effector NK and cytotoxic T lymphocytes. This may predispose patients to hemophagocytic lymphohistiocytosis, a life-threatening immune disorder characterized by systemic lymphocyte and macrophage activation, and increased levels of cytokines, which lead to an uncontrolled hyperinflammation state and progressive multiorgan damage. In this review, we will describe a clinical case and recent advances in inborn errors of immunity predisposing to hemophagocytic lymphohistiocytosis. Summary sentence: Review of recent advances in inborn errors of immunity predisposing to hemophagocytic lymphohistiocytosis.
Assuntos
Linfo-Histiocitose Hemofagocítica , Criança , Citocinas/genética , Humanos , Linfo-Histiocitose Hemofagocítica/genética , Mutação , Linfócitos T CitotóxicosRESUMO
BACKGROUND: Histiocytic sarcoma is a very rare monocyte/macrophage-derived hematopoietic system tumor with a poor prognosis whose diagnosis is pathologically challenging due to its extreme rarity and histological overlap with various mimicking entities in which histiocytes also predominate. CASE: We report the case of a 33-year-old male patient with hemophagocytic lymphohistiocytosis, purpuric syndrome, and significant splenomegaly. The patient underwent splenectomy; subsequent macroscopic examination revealed a spleen weighing 2065 grams with hyperemic red pulp and multiple infarcts at the periphery. The histological and immunohistochemical study established a diagnosis of primary splenic histiocytic sarcoma with frequent hemophagocytosis. Next-generation sequencing demonstrated mutations in FLT3, NOTCH2, and KMT2A, microsatellite stability, and a tumor mutational burden of 2 mut/Mb. The patient's condition deteriorated clinically from the appearance of the first symptoms and he died 6 months later from multi-organ failure. CONCLUSION: Primary splenic histiocytic sarcoma is one of the rarest tumors of the hematopoietic system. We report the first case with mutations in FLT3, NOTCH2, and KMT2A, and associated hemophagocytic lymphohistiocytosis.
Assuntos
Sarcoma Histiocítico , Linfo-Histiocitose Hemofagocítica , Adulto , Sequenciamento de Nucleotídeos em Larga Escala , Histiócitos/patologia , Sarcoma Histiocítico/complicações , Sarcoma Histiocítico/diagnóstico , Sarcoma Histiocítico/genética , Humanos , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/genética , Masculino , Mutação , Receptor Notch2/genética , Baço/patologia , Baço/cirurgia , Tirosina Quinase 3 Semelhante a fmsRESUMO
INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is an exaggerated activation of the immune system which can be either primary (familial) or secondary. Familial hemophagocytic lymphohistiocytosis type 3 (FHL-3) is a severe immune disorder, caused by mutations in the UNC13D gene, which codes for a protein crucial to the cytotoxic function of lymphocytes. OBJECTIVE: To describe the diagnostic relevance of next-generation sequencing in the approach of a patient with suspected FHL and to demonstrate the effectiveness of bone marrow transplantation as the only curative measure. CLINICAL CASE: 4-year-old preschool male, previously healthy, who presented with mononucleosis syndrome and positive IgM for Epstein Barr virus, developing hepatosplenomegaly and progressive clinical de terioration. A lymphoproliferative syndrome was suspected, which was ruled out by bone marrow aspiration, finding evidence of active hemophagocytosis. The patient met the criteria for hemophago cytic syndrome (bone marrow aspiration, pancytopenia, elevated ferritin, and hypertriglyceridemia) and, given the lack of response to first-line management, including antiviral treatment, a possible primary etiology was considered. A molecular study was completed with NGS that was positive for FHL-3. Due to the progressive clinical deterioration, a bone marrow transplantation was performed, presenting successful results after the first year had elapsed. CONCLUSION: NGS is an indispensable tool in the diagnosis of FHL, mainly when the response to standard treatment is not adequate and facilitates the timely implementation of the necessary therapeutic measures.
Assuntos
Transplante de Medula Óssea , Linfo-Histiocitose Hemofagocítica/cirurgia , Exame de Medula Óssea , Pré-Escolar , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linfo-Histiocitose Hemofagocítica/genética , Masculino , Proteínas de Membrana/genética , Resultado do TratamentoRESUMO
Objective: To highlight a novel, treatable syndrome, we report 4 patients with CNS-isolated inflammation associated with familial hemophagocytic lymphohistiocytosis (FHL) gene mutations (CNS-FHL). Methods: Retrospective chart review. Results: Patients with CNS-FHL are characterized by chronic inflammation restricted to the CNS that is not attributable to any previously described neuroinflammatory etiology and have germline mutations in known FHL-associated genes with no signs of systemic inflammation. Hematopoietic stem cell transplantation (HCT) can be well tolerated and effective in achieving or maintaining disease remission in patients with CNS-FHL. Conclusions: Early and accurate diagnosis followed by treatment with HCT can reduce morbidity and mortality in CNS-FHL, a novel, treatable syndrome. Classification of evidence: This study provides Class IV evidence that HCT is well tolerated and effective in treating CNS-FHL.
Assuntos
Doenças do Sistema Nervoso Central/diagnóstico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Doenças do Sistema Nervoso Central/genética , Criança , Pré-Escolar , Feminino , Mutação em Linhagem Germinativa , Humanos , Linfo-Histiocitose Hemofagocítica/genéticaRESUMO
Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperferritinemic systemic inflammatory disorders. Although profound cytotoxic impairment causes familial HLH (fHLH), the mechanisms driving non-fHLH and MAS are largely unknown. MAS occurs in patients with suspected rheumatic disease, but the mechanistic basis for its distinction is unclear. Recently, a syndrome of recurrent MAS with infantile enterocolitis caused by NLRC4 inflammasome hyperactivity highlighted the potential importance of interleukin-18 (IL-18). We tested this association in hyperferritinemic and autoinflammatory patients and found a dramatic correlation of MAS risk with chronic (sometimes lifelong) elevation of mature IL-18, particularly with IL-18 unbound by IL-18 binding protein, or free IL-18. In a mouse engineered to carry a disease-causing germ line NLRC4T337S mutation, we observed inflammasome-dependent, chronic IL-18 elevation. Surprisingly, this NLRC4T337S-induced systemic IL-18 elevation derived entirely from intestinal epithelia. NLRC4T337S intestines were histologically normal but showed increased epithelial turnover and upregulation of interferon-γ-induced genes. Assessing cellular and tissue expression, classical inflammasome components such as Il1b, Nlrp3, and Mefv predominated in neutrophils, whereas Nlrc4 and Il18 were distinctly epithelial. Demonstrating the importance of free IL-18, Il18 transgenic mice exhibited free IL-18 elevation and more severe experimental MAS. NLRC4T337S mice, whose free IL-18 levels were normal, did not. Thus, we describe a unique connection between MAS risk and chronic IL-18, identify epithelial inflammasome hyperactivity as a potential source, and demonstrate the pathogenicity of free IL-18. These data suggest an IL-18-driven pathway, complementary to the cytotoxic impairment of fHLH, with potential as a distinguishing biomarker and therapeutic target in MAS.
Assuntos
Interleucina-18/imunologia , Síndrome de Ativação Macrofágica/imunologia , Transdução de Sinais/imunologia , Substituição de Aminoácidos , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/imunologia , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/imunologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/imunologia , Humanos , Inflamassomos/genética , Inflamassomos/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Interleucina-18/genética , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/patologia , Síndrome de Ativação Macrofágica/genética , Síndrome de Ativação Macrofágica/patologia , Camundongos , Camundongos Knockout , Mutação de Sentido Incorreto , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Pirina/genética , Pirina/imunologia , Transdução de Sinais/genéticaRESUMO
Chediak-Higashi syndrome (CHS) is a rare autosomal recessive immunodeficiency disease characterized by frequent infections, hypopigmentation, progressive neurologic deterioration and hemophagocytic lymphohistiocytosis (HLH), known as the accelerated phase. There is little experience in the accelerated phase of CHS treatment worldwide. Here, we present a case of a 9-month-old boy with continuous high fever, hypopigmentation of the skin, enlarged lymph nodes, hepatosplenomegaly and lung infection. He was diagnosed with CHS by gene sequencing, and had entered the accelerated phase. After 8 weeks of therapy, the boy had remission and was prepared for allogenic stem cell transplantation.
Assuntos
Síndrome de Chediak-Higashi/tratamento farmacológico , Síndrome de Chediak-Higashi/genética , Mutação da Fase de Leitura , Síndrome de Chediak-Higashi/patologia , Diagnóstico Tardio , Cabelo/patologia , Humanos , Hipopigmentação/genética , Hipopigmentação/patologia , Lactente , Linfo-Histiocitose Hemofagocítica/genética , Masculino , Pneumonia/diagnóstico por imagem , Pneumonia/genética , Pele/patologia , Resultado do TratamentoRESUMO
Chediak-Higashi syndrome (CHS) is a rare autosomal recessive immunodeficiency disease characterized by frequent infections, hypopigmentation, progressive neurologic deterioration and hemophagocytic lymphohistiocytosis (HLH), known as the accelerated phase. There is little experience in the accelerated phase of CHS treatment worldwide. Here, we present a case of a 9-month-old boy with continuous high fever, hypopigmentation of the skin, enlarged lymph nodes, hepatosplenomegaly and lung infection. He was diagnosed with CHS by gene sequencing, and had entered the accelerated phase. After 8 weeks of therapy, the boy had remission and was prepared for allogenic stem cell transplantation.
Assuntos
Humanos , Masculino , Lactente , Síndrome de Chediak-Higashi/tratamento farmacológico , Síndrome de Chediak-Higashi/genética , Mutação da Fase de Leitura , Síndrome de Chediak-Higashi/patologia , Diagnóstico Tardio , Cabelo/patologia , Hipopigmentação/genética , Hipopigmentação/patologia , Linfo-Histiocitose Hemofagocítica/genética , Pneumonia/diagnóstico por imagem , Pneumonia/genética , Pele/patologia , Resultado do TratamentoRESUMO
Familial Hemophagocytic Lymphohistiocytosis type 2 (FHL2) results from mutations in PRF1. We described two unrelated individuals who presented with FHL, in whom severely impaired NK cytotoxicity and decrease perforin expression was observed. DNA sequencing of PRF1 demonstrated that both were not only heterozygous for the p.54R > C/91A > V haplotype but also presented with the novel variant p.47G > V at the perforin protein. Perforin mRNA was found to be increased in a individual with that genotype. A carrier of the novel variant also demonstrated altered perforin mRNA and protein expression. Phylogenetic analysis and multiple alignments with perforin orthologous demonstrated a high level of conservation at Gly47. PolyPhen-2 and PROVEAN predicted p.47G > V to be "probably damaging" and "deleterious", respectively. A thermodynamic analysis showed that this variant was highly stabilizing, decreasing the protein internal energy. The ab initio perforin molecular modeling indicated that Gly47 is buried inside the hydrophobic core of the MACPF domain, which is crucial for the lytic pore formation and protein oligomerization. After the in silico induction of the p.47G > V mutation, Val47 increased the interactions with the surrounding amino acids due to its size and physical properties, avoiding a proper conformational change of the domain. To our knowledge, this is the first description supporting that p.47G > V is a pathogenic variant that in conjunction with p.54R > C/91A > V might result in the clinical phenotype of FHL2.