Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 26
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
2.
Front Immunol ; 10: 297, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941118

RESUMO

Non-canonical NF-κB-pathway signaling is integral in immunoregulation. Heterozygous mutations in NFKB2 have recently been established as a molecular cause of common variable immunodeficiency (CVID) and DAVID-syndrome, a rare condition combining deficiency of anterior pituitary hormone with CVID. Here, we investigate 15 previously unreported patients with primary immunodeficiency (PID) from eleven unrelated families with heterozygous NFKB2-mutations including eight patients with the common p.Arg853* nonsense mutation and five patients harboring unique novel C-terminal truncating mutations. In addition, we describe the clinical phenotype of two patients with proximal truncating mutations. Cohort analysis extended to all 35 previously published NFKB2-cases revealed occurrence of early-onset PID in 46/50 patients (mean age of onset 5.9 years, median 4.0 years). ACTH-deficiency occurred in 44%. Three mutation carriers have deceased, four developed malignancies. Only two mutation carriers were clinically asymptomatic. In contrast to typical CVID, most patients suffered from early-onset and severe disease manifestations, including clinical signs of T cell dysfunction e.g., chronic-viral or opportunistic infections. In addition, 80% of patients suffered from (predominately T cell mediated) autoimmune (AI) phenomena (alopecia > various lymphocytic organ-infiltration > diarrhea > arthritis > AI-cytopenia). Unlike in other forms of CVID, auto-antibodies or lymphoproliferation were not common hallmarks of disease. Immunophenotyping showed largely normal or even increased quantities of naïve and memory CD4+ or CD8+ T-cells and normal T-cell proliferation. NK-cell number and function were also normal. In contrast, impaired B-cell differentiation and hypogammaglobinemia were consistent features of NFKB2-associated disease. In addition, an array of lymphocyte subpopulations, such as regulatory T cell, Th17-, cTFH-, NKT-, and MAIT-cell numbers were decreased. We conclude that heterozygous damaging mutations in NFKB2 represent a distinct PID entity exceeding the usual clinical spectrum of CVID. Impairment of the non-canonical NF-κB pathways affects function and differentiation of numerous lymphocyte-subpopulations and thus causes a heterogeneous, more severe form of PID phenotype with early-onset. Further characteristic features are multifaceted, primarily T cell-mediated autoimmunity, such as alopecia, lymphocytic organ infiltration, and in addition frequently ACTH-deficiency.

3.
Pediatr Blood Cancer ; 65(11): e27344, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30070073

RESUMO

In this report, we evaluate the hypothesis that hemophagocytic lymphohistiocytosis in patients with defects of lymphocyte cytotoxicity is usually triggered by infections. We show that in the majority of patients, extensive virus PCR panels performed in addition to routine microbiological investigations remain negative and summarize 25 patients with onset of hemophagocytic lymphohistiocytosis in utero or within the first 10 days of life, in none of which an associated bacterial or viral infection was reported. These observations, even though preliminary, invite to consider a key role of lymphocyte cytotoxicity in controlling T-cell homeostasis also in the absence of apparent infectious stimuli.

4.
Immunol Cell Biol ; 96(10): 1060-1071, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29790605

RESUMO

Premature T-cell immunosenescence with CD57+ CD8+ T-cell accumulation has been linked to immunodeficiency and autoimmunity in primary immunodeficiencies including activated PI3 kinase delta syndrome (APDS). To address whether CD57 marks the typical senescent T-cell population seen in adult individuals or identifies a distinct population in APDS, we compared CD57+ CD8+ T cells from mostly pediatric APDS patients to those of healthy adults with similarly prominent senescent T cells. CD57+ CD8+ T cells from APDS patients were less differentiated with more CD27+ CD28+ effector memory T cells showing increased PD1 and Eomesodermin expression. In addition, transition of naïve to CD57+ CD8+ T cells was not associated with the characteristic telomere shortening. Nevertheless, they showed the increased interferon-gamma secretion, enhanced degranulation and reduced in vitro proliferation typical of senescent CD57+ CD8+ T cells. Thus, hyperactive PI3 kinase signaling favors premature accumulation of a CD57+ CD8+ T-cell population, which shows most functional features of typical senescent T cells, but is different in terms of differentiation and relative telomere shortening. Initial observations indicate that this specific differentiation state may offer the opportunity to revert premature T-cell immunosenescence and its potential contribution to inflammation and immunodeficiency in APDS.

5.
Eur J Paediatr Neurol ; 22(5): 870-877, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29843966

RESUMO

CD59 is involved in lymphocyte signal transduction and regulates complement-mediated cell lysis by inhibiting the membrane attack complex. In the cases reported so far, congenital isolated CD59 deficiency was associated with recurrent episodes of hemolytic anemia, peripheral neuropathy, and strokes. Here, we report on a patient from a consanguineous Turkish family, who had a first episode of hemolytic anemia at one month of age and presented at 14 months with acute Guillain-Barré syndrome (GBS). The child suffered repeated infection-triggered relapses leading to the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Although partly steroid-responsive, the polyneuropathy failed to be stabilized by a number of immunosuppressive agents. At the age of 6 years, he developed acute hemiparesis and showed progressive stenosis of proximal cerebral arteries, evolving into Moyamoya syndrome (MMS) with recurrent infarctions leading to death at 8 years of age. Post-mortem genetic analysis revealed a pathogenic p.(Asp49Valfs*31) mutation in CD59. Re-analysis of brain biopsy specimens showed absent CD59 expression and severe endothelial damage. Whereas strokes are a known feature of CD59 deficiency, MMS has not previously been described in this condition. Therefore, we conclude that in MMS combined with hemolysis or neuropathy CD59 deficiency should be considered. Establishing the diagnosis and targeted therapy with eculizumab might have prevented the lethal course in our patient.

6.
Blood ; 131(13): 1442-1455, 2018 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-29326099

RESUMO

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.

7.
J Clin Immunol ; 37(8): 770-780, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28936583

RESUMO

We report our experience in using flow cytometry-based immunological screening prospectively as a decision tool for the use of genetic studies in the diagnostic approach to patients with hemophagocytic lymphohistiocytosis (HLH). We restricted genetic analysis largely to patients with abnormal immunological screening, but included whole exome sequencing (WES) for those with normal findings upon Sanger sequencing. Among 290 children with suspected HLH analyzed between 2010 and 2014 (including 17 affected, but asymptomatic siblings), 87/162 patients with "full" HLH and 79/111 patients with "incomplete/atypical" HLH had normal immunological screening results. In 10 patients, degranulation could not be tested. Among the 166 patients with normal screening, genetic analysis was not performed in 107 (all with uneventful follow-up), while 154 single gene tests by Sanger sequencing in the remaining 59 patients only identified a single atypical CHS patient. Flow cytometry correctly predicted all 29 patients with FHL-2, XLP1 or 2. Among 85 patients with defective NK degranulation (including 13 asymptomatic siblings), 70 were Sanger sequenced resulting in a genetic diagnosis in 55 (79%). Eight patients underwent WES, revealing mutations in two known and one unknown cytotoxicity genes and one metabolic disease. FHL3 was the most frequent genetic diagnosis. Immunological screening provided an excellent decision tool for the need and depth of genetic analysis of HLH patients and provided functionally relevant information for rapid patient classification, contributing to a significant reduction in the time from diagnosis to transplantation in recent years.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Células Matadoras Naturais/imunologia , Proteínas com Domínio LIM/genética , Proteínas com Homeodomínio LIM/genética , Linfo-Histiocitose Hemofagocítica/diagnóstico , Proteínas Musculares/genética , Fatores de Transcrição/genética , Doenças Assintomáticas , Degranulação Celular , Criança , Citometria de Fluxo , Testes Genéticos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas com Domínio LIM/metabolismo , Proteínas com Homeodomínio LIM/metabolismo , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/imunologia , Proteínas Musculares/metabolismo , Mutação/genética , Transplante de Órgãos , Guias de Prática Clínica como Assunto , Prognóstico , Estudos Prospectivos , Irmãos , Fatores de Transcrição/metabolismo , Sequenciamento Completo do Exoma
9.
Front Immunol ; 8: 426, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28458669

RESUMO

Chediak-Higashi syndrome (CHS) is caused by autosomal recessive mutations in LYST, resulting in enlarged lysosomal compartments in multiple cell types. CHS patients display oculocutaneous albinism and may develop life-threatening hemophagocytic lymphohistiocytosis (HLH). While NK cell-mediated cytotoxicity has been reported to be uniformly defective, variable defects in T cell-mediated cytotoxicity has been observed. The latter has been linked to the degree of HLH susceptibility. Since the discrepancies in NK cell- and T cell-mediated cellular cytotoxicity might result from differences in regulation of cytotoxic granule release, we here evaluated perforin-containing secretory lysosome size and number in freshly isolated lymphocytes from CHS patients and furthermore compared their exocytic capacities. Whereas NK cells from CHS patients generally contained a single, gigantic perforin-containing granule, cytotoxic T cells predominantly contained several smaller granules. Nonetheless, in a cohort of 21 CHS patients, cytotoxic T cell and NK cell granule exocytosis were similarly impaired upon activating receptor stimulation. Mechanistically, polarization of cytotoxic granules was defective in cytotoxic lymphocytes from CHS patients, with EEA1, a marker of early endosomes, mislocalizing to lysosomal structures. The results leads to the conclusion that lysosome enlargement corresponds to loss of distinct organelle identity in the endocytic pathway, which on a subcellular level more adversely affects NK cells than T cells. Hence, vesicular size or numbers do not per se dictate the impairment of lysosomal exocytosis in the two cell types studied.

10.
Eur J Immunol ; 47(2): 364-373, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27925643

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome characterized by hyperactivation of lymphocytes and histiocytes. T cells play a key role in HLH pathogenesis, but their differentiation pattern is not well characterized in patients with active HLH. We compared T-cell activation patterns between patients with familial HLH (1°HLH), 2°HLH without apparent infectious trigger (2°HLH) and 2°HLH induced by a viral infection (2°V-HLH). Polyclonal CD8+ T cells are highly activated in 1°HLH and 2°V-HLH, but less in 2°HLH as assessed by HLA-DR expression and marker combination with CD45RA, CCR7, CD127, PD-1 and CD57. Absence of increased HLA-DR expression on T cells excluded active 1° HLH with high sensitivity and specificity. A high proportion of polyclonal CD127- CD4+ T cells expressing HLA-DR, CD57, and perforin is a signature of infants with 1°HLH, much less prominent in virus-associated 2°HLH. The similar pattern and extent of CD8+ T-cell activation compared to 2° V-HLH is compatible with a viral trigger of 1°HLH. However, in most 1°HLH patients no triggering infection was documented and the unique activation of cytotoxic CD4+ T cells indicates that the overall T-cell response in 1°HLH is different. This may reflect different pathways of pathogenesis of these two HLH variants.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfo-Histiocitose Hemofagocítica/imunologia , Viroses/imunologia , Antígenos CD57/metabolismo , Diferenciação Celular , Células Cultivadas , Feminino , Antígenos HLA-DR/metabolismo , Humanos , Lactente , Recém-Nascido , Ativação Linfocitária , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/etiologia , Masculino , Perforina/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Viroses/complicações , Viroses/diagnóstico
11.
Eur J Immunol ; 46(11): 2639-2649, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27615517

RESUMO

Tyrosine kinase 2 (TYK2) associates with interferon (IFN) alpha receptor, IL-10 receptor (IL-10R) beta and other cytokine receptor subunits for signal transduction, in response to various cytokines, including type-I and type-III IFNs, IL-6, IL-10, IL-12 and IL-23. Data on TYK2 dependence on cytokine responses and in vivo consequences of TYK2 deficiency are inconsistent. We investigated a TYK2 deficient patient, presenting with eczema, skin abscesses, respiratory infections and IgE levels >1000 U/mL, without viral or mycobacterial infections and a corresponding cellular model to analyze the role of TYK2 in type-III IFN mediated responses and NK-cell function. We established a novel simple diagnostic monocyte assay to show that the mutation completely abolishes the IFN-α mediated antiviral response. It also partly reduces IL-10 but not IL-6 mediated signaling associated with reduced IL-10Rß expression. However, we found almost normal type-III IFN signaling associated with minimal impairment of virus control in a TYK2 deficient human cell line. Contrary to observations in TYK2 deficient mice, NK-cell phenotype and function, including IL-12/IL-18 mediated responses, were normal in the patient. Thus, preserved type-III IFN responses and normal NK-cell function may contribute to antiviral protection in TYK2 deficiency leading to a surprisingly mild human phenotype.


Assuntos
Interferons/imunologia , Síndrome de Job/imunologia , Células Matadoras Naturais/imunologia , TYK2 Quinase/deficiência , TYK2 Quinase/metabolismo , Animais , Linhagem Celular , Criança , Suscetibilidade a Doenças/imunologia , Suscetibilidade a Doenças/virologia , Eczema/etiologia , Eczema/imunologia , Humanos , Imunoglobulina E/sangue , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Camundongos , Mutação , Receptores de Citocinas/imunologia , Receptores de Interleucina-10/genética , Receptores de Interleucina-10/imunologia , Transdução de Sinais/imunologia , Pele/patologia , TYK2 Quinase/genética , TYK2 Quinase/imunologia
12.
BMJ Case Rep ; 20162016 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-27681353

RESUMO

A 16-year-old boy of Caucasian ethnicity was evaluated for recurrent febrile episodes occurring during most of his life without establishment of any microbial aetiology. During febrile episodes he developed extensive splenomegaly, lymphadenopathy, anaemia, severe abdominal pain and general malaise. Lymph node biopsies demonstrated inflammation and sinus histiocytosis but no malignancy or granuloma. The patient underwent seroconversion for Epstein-Barr virus (EBV) infection during the hospitalisation. Genetic testing identified a hemizygous frameshift mutation in the X linked inhibitor of apoptosis (XIAP)-gene as well as variants in the MEFV gene indicating Familial Mediterranean Fever (FMF). XIAP expression was markedly reduced in the patient, while a functional assay assessing tumour necrosis factor (TNF)α production of monocytes in response to NOD2 stimulation displayed reduced activity. We suggest that the heterozygous MEFV variants and the hemizygous XIAP variant in combination triggered the prolonged and pathological inflammatory response to EBV infection.

13.
J Clin Immunol ; 36(7): 733-8, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27492372

RESUMO

The X-linked inhibitor of apoptosis (XIAP) deficiency is a primary immunodeficiency characterized by Epstein-Barr virus (EBV)-driven hemophagocytic lymphohistiocytosis (HLH), splenomegaly, and colitis. Here, we present, for the first time, granulomatous hepatitis and granulomatous and lymphocytic interstitial lung disease (GLILD) as manifestations of XIAP deficiency. We report successful treatment of GLILD in XIAP deficiency with rituximab and azathioprine and discuss the role of XIAP deficiency in immune dysregulation.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/complicações , Hepatite/complicações , Doenças Pulmonares Intersticiais/complicações , Linfo-Histiocitose Hemofagocítica/complicações , Transtornos Linfoproliferativos/complicações , Azatioprina/uso terapêutico , Biomarcadores , Biópsia , Medula Óssea/patologia , Pré-Escolar , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Hepatite/diagnóstico , Hepatite/terapia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imunofenotipagem , Fígado/patologia , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Linfonodos/patologia , Linfócitos/imunologia , Linfócitos/metabolismo , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/terapia , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/terapia , Masculino , Mutação , Linhagem , Fenótipo , Testes de Função Respiratória , Rituximab/uso terapêutico , Tomografia Computadorizada por Raios X , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética
14.
Blood ; 127(25): 3281-90, 2016 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-27099148

RESUMO

Reduced-intensity conditioning has improved survival after hematopoietic stem cell transplantation (HSCT) for hemophagocytic lymphohistiocytosis (HLH) at the cost of more frequent mixed chimerism. The minimum level of donor chimerism (DC) required to prevent HLH reactivation in humans remains to be determined. In a multicenter retrospective study, 103 patients transplanted for hereditary HLH (2000-2013) and DC permanently or transiently <75% (overall, CD3(+), CD56(+)) were analyzed regarding DC, specific immunologic function, occurrence of systemic reactivations (≥5/8 HLH criteria), partial systemic flares (<5 criteria and HLH-directed treatment), isolated central nervous system reactivations, and management. Recurrence was reported in 18 patients (systemic reactivation n = 11, partial flare n = 3, isolated central nervous system reactivation n = 4). Ten events occurred during profound immune suppression before day 180 (median DC, 10%; range, 1-100%; CD3(+) if available, otherwise overall DC), which renders a differentiation between secondary post-HSCT HLH and HLH related to the genetic defect difficult. Eight events occurred between 0.5 and 6.7 years post-HSCT (median DC, 13%; range, 0-30%). In 5 patients, overall and lineage-specific DC were ≤10% for >6 months (median, 5.1; range, 1.1-10 years) without reactivation. A second HSCT was performed in 18 patients (median, DC 4%; range, 0-19%). Death from reactivation occurred in 4 patients (22% of recurrences). Six patients died of transplant complications following a second HSCT (33% of second HSCT). We conclude that a DC >20%-30% is protective against late reactivation. Lower levels do not, however, inescapably result in recurrences. The decision for or against second HSCT must be based on a thorough risk assessment.


Assuntos
Quimerismo , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/terapia , Doadores de Tecidos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Recém-Nascido , Masculino , Recidiva , Estudos Retrospectivos , Condicionamento Pré-Transplante/métodos , Imunologia de Transplantes , Transplante Homólogo/efeitos adversos , Resultado do Tratamento , Adulto Jovem
15.
Blood ; 127(8): 997-1006, 2016 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-26744459

RESUMO

Genetic disorders affecting biogenesis and transport of lysosome-related organelles are heterogeneous diseases frequently associated with albinism. We studied a patient with albinism, neutropenia, immunodeficiency, neurodevelopmental delay, generalized seizures, and impaired hearing but with no mutation in genes so far associated with albinism and immunodeficiency. Whole exome sequencing identified a homozygous mutation in AP3D1 that leads to destabilization of the adaptor protein 3 (AP3) complex. AP3 complex formation and the degranulation defect in patient T cells were restored by retroviral reconstitution. A previously described hypopigmented mouse mutant with an Ap3d1 null mutation (mocha strain) shares the neurologic phenotype with our patient and shows a platelet storage pool deficiency characteristic of Hermansky-Pudlak syndrome (HPS) that was not studied in our patient because of a lack of bleeding. HPS2 caused by mutations in AP3B1A leads to a highly overlapping phenotype without the neurologic symptoms. The AP3 complex exists in a ubiquitous and a neuronal form. AP3D1 codes for the AP3δ subunit of the complex, which is essential for both forms. In contrast, the AP3ß3A subunit, affected in HPS2 patients, is substituted by AP3ß3B in the neuron-specific heterotetramer. AP3δ deficiency thus causes a severe neurologic disorder with immunodeficiency and albinism that we propose to classify as HPS10.


Assuntos
Complexo 3 de Proteínas Adaptadoras/genética , Subunidades delta do Complexo de Proteínas Adaptadoras/genética , Síndrome de Hermanski-Pudlak/classificação , Síndrome de Hermanski-Pudlak/genética , Síndromes de Imunodeficiência/genética , Convulsões/genética , Eletroforese em Gel de Poliacrilamida , Imunofluorescência , Humanos , Mutação , Transfecção
16.
Haematologica ; 100(7): 978-88, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26022711

RESUMO

Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and laboratory criteria. Current criteria were created to identify patients with familial hemophagocytic lmyphohistiocytosis in immediate need of immunosuppressive therapy. However, these criteria also identify patients with infection-associated hemophagocytic inflammatory states lacking genetic defects typically predisposing to hemophagocytic lymphohistiocytosis. These patients include those with primary immunodeficiencies, in whom the pathogenesis of the inflammatory syndrome may be distinctive and aggressive immunosuppression is contraindicated. To better characterize hemophagocytic inflammation associated with immunodeficiencies, we combined an international survey with a literature search and identified 63 patients with primary immunodeficiencies other than cytotoxicity defects or X-linked lymphoproliferative disorders, presenting with conditions fulfilling current criteria for hemophagocytic lymphohistiocytosis. Twelve patients had severe combined immunodeficiency with <100/µL T cells, 18 had partial T-cell deficiencies; episodes of hemophagocytic lymphohistiocytosis were mostly associated with viral infections. Twenty-two patients had chronic granulomatous disease with hemophagocytic episodes mainly associated with bacterial infections. Compared to patients with cytotoxicity defects, patients with T-cell deficiencies had lower levels of soluble CD25 and higher ferritin concentrations. Other criteria for hemophagocytoc lymphohistiocytosis were not discriminative. Thus: (i) a hemophagocytic inflammatory syndrome fulfilling criteria for hemophagocytic lymphohistiocytosis can be the initial manifestation of primary immunodeficiencies; (ii) this syndrome can develop despite severe deficiency of T and NK cells, implying that the pathophysiology is distinct and not appropriately described as "lympho"-histiocytosis in these patients; and (iii) current criteria for hemophagocytoc lymphohistiocytosis are insufficient to differentiate hemophagocytic inflammatory syndromes with different pathogeneses. This is important because of implications for therapy, in particular for protocols targeting T cells.


Assuntos
Síndromes de Imunodeficiência/diagnóstico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Transtornos Linfoproliferativos/diagnóstico , Sistema de Registros , Adolescente , Adulto , Infecções Bacterianas/complicações , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/imunologia , Criança , Pré-Escolar , Diagnóstico Diferencial , Europa (Continente) , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/tratamento farmacológico , Síndromes de Imunodeficiência/imunologia , Fatores Imunológicos/uso terapêutico , Lactente , Recém-Nascido , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Leishmaniose/complicações , Leishmaniose/tratamento farmacológico , Leishmaniose/imunologia , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/patologia , Transtornos Linfoproliferativos/complicações , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/imunologia , Masculino , Micoses/complicações , Micoses/tratamento farmacológico , Micoses/imunologia , Infecções Oportunistas/complicações , Infecções Oportunistas/tratamento farmacológico , Infecções Oportunistas/imunologia , Esteroides/uso terapêutico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/patologia , Terminologia como Assunto , Viroses/complicações , Viroses/tratamento farmacológico , Viroses/imunologia
17.
J Clin Immunol ; 35(5): 439-44, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25943627

RESUMO

PURPOSE: X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was originally described in male patients with X-linked lymphoproliferative syndrome type 2 (XLP2). Recent observations have highlighted a critical role of XIAP for the regulation of NOD2 signaling and are probably the molecular basis for increasingly recognized further immune dysregulatory symptoms of XIAP deficient patients, such as inflammatory bowel disease (IBD). We describe a large Caucasian family in which IBD and erythema nodosum (EN) also manifested in female carriers of XIAP mutations. METHODS: Clinical data and laboratory findings including flow cytometric analysis of XIAP protein expression and sequencing of the BIRC4 gene. NOD2 signaling was investigated by determination of TNFα production in monocytes upon L18-MDP stimulation in vitro. RESULTS: The BIRC4 nonsense mutation p.P225SfsX226 was identified as the genetic cause of XIAP deficiency in our family. Surprisingly, clinical symptoms were not restricted to male patients, but also occurred in several female carriers. The most severely affected carrier demonstrated random X-inactivation, leading to a significant expression of mutated XIAP protein in monocytes, and consequently to impaired NOD2 responses in vitro. CONCLUSION: Our report provides further evidence that clinical symptoms of XIAP deficiency are not restricted to male patients. Random X-inactivation may be associated with EN and mild IBD also in female carriers of BIRC4 mutations. Analysis of the X-inactivation pattern reflected by XIAP protein expression can identify such carriers and the analysis of NOD2 signaling by flow cytometry can confirm the functional significance. XIAP expression patterns should be investigated in female patients with a family history of EN and/or IBD.


Assuntos
Eritema Nodoso/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Inflamatórias Intestinais/diagnóstico , Transtornos Linfoproliferativos/diagnóstico , Monócitos/metabolismo , Viroses/diagnóstico , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Acetilmuramil-Alanil-Isoglutamina/análogos & derivados , Acetilmuramil-Alanil-Isoglutamina/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Portador Sadio , Células Cultivadas , Criança , Pré-Escolar , Eritema Nodoso/etiologia , Eritema Nodoso/genética , Grupo com Ancestrais do Continente Europeu , Evolução Fatal , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/genética , Transtornos Linfoproliferativos/complicações , Transtornos Linfoproliferativos/genética , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Mutação/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo , Linhagem , Fatores Sexuais , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/metabolismo , Viroses/etiologia , Viroses/genética
18.
J Allergy Clin Immunol ; 136(2): 392-401, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25702838

RESUMO

BACKGROUND: Most patients with MHC class I (MHC-I) deficiency carry genetic defects in transporter associated with antigen processing 1 (TAP1) or TAP2. The clinical presentation can vary, and about half of the patients have severe skin disease. Previously, one report described ß2-microglobulin (ß2m) deficiency as another monogenetic cause of MHC-I deficiency, but no further immunologic evaluation was performed. OBJECTIVE: We sought to describe the molecular and immunologic features of ß2m deficiency in 2 Turkish siblings with new diagnoses. METHODS: Based on clinical and serologic findings, the genetic defect was detected by means of candidate gene analysis. The immunologic characterization comprises flow cytometry, ELISA, functional assays, and immunohistochemistry. RESULTS: Here we provide the first extensive clinical and immunologic description of ß2m deficiency in 2 siblings. The sister had recurrent respiratory tract infections and severe skin disease, whereas the brother was fairly asymptomatic but had bronchiectasis. Not only polymorphic MHC-I but also the related CD1a, CD1b, CD1c, and neonatal Fc receptor molecules were absent from the surfaces of ß2m-deficient cells. Absent neonatal Fc receptor surface expression led to low serum IgG and albumin levels in both siblings, whereas the heterozygous parents had normal results for all tested parameters except ß2m mRNA (B2M) expression. Similar to TAP deficiency in the absence of a regular CD8 T-cell compartment, CD8(+) γδ T cells were strongly expanded. Natural killer cells were normal in number but not "licensed to kill." CONCLUSION: The clinical presentation of patients with ß2m deficiency resembles that of patients with other forms of MHC-I deficiency, but because of the missing stabilizing effect of ß2m on other members of the MHC-I family, the immunologic defect is more extensive than in patients with TAP deficiency.


Assuntos
Bronquiectasia/imunologia , Síndromes de Imunodeficiência/imunologia , Infecções Respiratórias/imunologia , Úlcera Cutânea/imunologia , Microglobulina beta-2/imunologia , Imunidade Adaptativa , Adolescente , Adulto , Antígenos CD1/genética , Antígenos CD1/imunologia , Bronquiectasia/complicações , Bronquiectasia/genética , Bronquiectasia/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Consanguinidade , Feminino , Deleção de Genes , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunidade Inata , Imunoglobulina G/sangue , Imunoglobulina G/genética , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Masculino , Linhagem , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Receptores Fc/deficiência , Receptores Fc/genética , Receptores Fc/imunologia , Recidiva , Infecções Respiratórias/complicações , Infecções Respiratórias/genética , Infecções Respiratórias/patologia , Irmãos , Úlcera Cutânea/complicações , Úlcera Cutânea/genética , Úlcera Cutânea/patologia , Microglobulina beta-2/deficiência , Microglobulina beta-2/genética
20.
J Clin Immunol ; 35(1): 22-5, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25491289

RESUMO

Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically heterogeneous hyperinflammatory syndrome, caused by an uncontrolled and ineffective proliferation and activation of T-lymphocytes, NK-cells, and macrophages that infiltrate multiple organs. Herein, a patient is presented who suffered from hepatitis and atypical brain lesions. Genetic studies revealed a homozygous mutation in the STXP2 gene; and thus, the diagnosis of FHL5 was confirmed.


Assuntos
Linfo-Histiocitose Hemofagocítica/genética , Proteínas Munc18/genética , Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Idade de Início , Encéfalo/patologia , Criança , Evolução Fatal , Hepatite Autoimune/genética , Hepatite Autoimune/imunologia , Homozigoto , Humanos , Células Matadoras Naturais/imunologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/imunologia , Imagem por Ressonância Magnética , Masculino , Mutação , Linfócitos T/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA