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3.
J Clin Immunol ; 39(1): 45-54, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30547383

RESUMO

Studies of chest computed tomography (CT) in patients with primary antibody deficiency syndromes (ADS) suggest a broad range of bronchial pathology. However, there are as yet no multicentre studies to assess the variety of bronchial pathology in this patient group. One of the underlying reasons is the lack of a consensus methodology, a prerequisite to jointly document chest CT findings. We aimed to establish an international platform for the evaluation of bronchial pathology as assessed by chest CT and to describe the range of bronchial pathologies in patients with antibody deficiency. Ffteen immunodeficiency centres from 9 countries evaluated chest CT scans of patients with ADS using a predefined list of potential findings including an extent score for bronchiectasis. Data of 282 patients with ADS were collected. Patients with common variable immunodeficiency disorders (CVID) comprised the largest subgroup (232 patients, 82.3%). Eighty percent of CVID patients had radiological evidence of bronchial pathology including bronchiectasis in 61%, bronchial wall thickening in 44% and mucus plugging in 29%. Bronchiectasis was detected in 44% of CVID patients aged less than 20 years. Cough was a better predictor for bronchiectasis than spirometry values. Delay of diagnosis as well as duration of disease correlated positively with presence of bronchiectasis. The use of consensus diagnostic criteria and a pre-defined list of bronchial pathologies allows for comparison of chest CT data in multicentre studies. Our data suggest a high prevalence of bronchial pathology in CVID due to late diagnosis or duration of disease.


Assuntos
Brônquios/patologia , Síndromes de Imunodeficiência/patologia , Parede Torácica/patologia , Adolescente , Adulto , Idoso , Bronquiectasia/patologia , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/patologia , Feminino , Humanos , Lactente , Masculino , Espirometria/métodos , Tomografia Computadorizada por Raios X/métodos , Adulto Jovem
4.
J Clin Immunol ; 38(4): 539, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29713933

RESUMO

The article Assessment of Local Adverse Reactions to Subcutaneous Immunoglobulin (SCIG) in Clinical Trials, written by Mark Ballow, Richard L. Wasserman, Stephen Jolles, Helen Chapel, Mel Berger, Siraj A. Misbah, was originally published Online First without open access.

7.
Gut ; 66(6): 1060-1073, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-26953272

RESUMO

OBJECTIVE: Patients with Niemann-Pick disease type C1 (NPC1), a lysosomal lipid storage disorder that causes neurodegeneration and liver damage, can present with IBD, but neither the significance nor the functional mechanism of this association is clear. We studied bacterial handling and antibacterial autophagy in patients with NPC1. DESIGN: We characterised intestinal inflammation in 14 patients with NPC1 who developed IBD. We investigated bacterial handling and cytokine production of NPC1 monocytes or macrophages in vitro and compared NPC1-associated functional defects to those caused by IBD-associated nucleotide-binding oligomerization domain-containing protein 2 (NOD2) variants or mutations in X-linked inhibitor of apoptosis (XIAP). RESULTS: Patients with the lysosomal lipid storage disorder NPC1 have increased susceptibility to early-onset fistulising colitis with granuloma formation, reminiscent of Crohn's disease (CD). Mutations in NPC1 cause impaired autophagy due to defective autophagosome function that abolishes NOD2-mediated bacterial handling in vitro similar to variants in NOD2 or XIAP deficiency. In contrast to genetic NOD2 and XIAP variants, NPC1 mutations do not impair NOD2-receptor-interacting kinase 2 (RIPK2)-XIAP-dependent cytokine production. Pharmacological activation of autophagy can rescue bacterial clearance in macrophages in vitro by increasing the autophagic flux and bypassing defects in NPC1. CONCLUSIONS: NPC1 confers increased risk of early-onset severe CD. Our data support the concept that genetic defects at different checkpoints of selective autophagy cause a shared outcome of CD-like immunopathology linking monogenic and polygenic forms of IBD. Muramyl dipeptide-driven cytokine responses and antibacterial autophagy induction are parallel and independent signalling cascades downstream of the NOD2-RIPK2-XIAP complex.


Assuntos
Acetilmuramil-Alanil-Isoglutamina/metabolismo , Autofagia/genética , Doença de Crohn/genética , Granuloma/genética , Macrófagos/efeitos dos fármacos , Doença de Niemann-Pick Tipo C/genética , Doença de Niemann-Pick Tipo C/fisiopatologia , Proteína Adaptadora de Sinalização NOD2/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Acetilmuramil-Alanil-Isoglutamina/farmacologia , Adolescente , Adulto , Antibacterianos/farmacologia , Autofagia/efeitos dos fármacos , Bactérias , Células Cultivadas , Criança , Pré-Escolar , Clorpromazina/farmacologia , Doença de Crohn/complicações , Doença de Crohn/patologia , Antagonistas de Dopamina/farmacologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Gentamicinas/farmacologia , Granuloma/patologia , Humanos , Imidazóis/farmacologia , Leucócitos Mononucleares , Lisossomos , Macrófagos/fisiologia , Masculino , Mutação , Doença de Niemann-Pick Tipo C/complicações , Proteína Adaptadora de Sinalização NOD2/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/farmacologia , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/antagonistas & inibidores , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/deficiência , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Adulto Jovem
9.
Front Immunol ; 7: 317, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27597852

RESUMO

Patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are prone to present with antibody production deficits associated with recurrent or severe bacterial infections that might benefit from human immunoglobulin (Ig) (IVIg/SCIg) replacement therapy. However, the original IVIg trial data were done before modern therapies were available, and the current indications do not take into account the shift in the immune situation of current treatment combinations and changes in the spectrum of infections. Besides, patients affected by other B cell malignancies present with similar immunodeficiency and manifestations while they are not covered by the current IVIg indications. A potential beneficial strategy could be to vaccinate patients at monoclonal B lymphocytosis and monoclonal gammopathy of undetermined significance stages (for CLL and MM, respectively) or at B-cell malignancy diagnosis, when better antibody responses are attained. We have to re-emphasize the need for assessing and monitoring specific antibody responses; these are warranted to select adequately those patients for whom early intervention with prophylactic anti-infective therapy and/or IVIg is preferred. This review provides an overview of the current scenario, with a focus on prevention of infection in patients with hematological malignancies and the role of Ig replacement therapy.

11.
Hematol Oncol ; 34(3): 121-32, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27402426

RESUMO

Secondary immunodeficiencies occur as a consequence of various diseases, including hematological malignancies, and the use of pharmacological therapies, such as immunosuppressive, anti-inflammatory, and biological drugs. Infections are the main cause of morbidity and mortality in multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients. Recent advances in treatment have prolonged the duration of remission and the time between relapse phases in MM and CLL patients. However, managing multiple relapses and the use of salvage therapies can lead to cumulative immunosuppression and a higher risk of infections. The pathogenesis of immune deficiency secondary to lymphoproliferative malignancy is multifactorial including disease- and treatment-related factors. Supportive treatment, including early vaccination, anti-infective prophylaxis, and replacement immunoglobulin, plays a key role in preventing infections in MM and CLL. This article provides an overview of the basic immunology necessary to understand the pathogenesis of secondary immunodeficiency and the infectious complications in MM and CLL. We also discuss the evidence supporting the role of prophylactic replacement immunoglobulin treatment in patients with antibody failure secondary to MM and CLL and the indications for its use. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Neoplasias Hematológicas/terapia , Síndromes de Imunodeficiência/etiologia , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/prevenção & controle , Leucemia Linfocítica Crônica de Células B/terapia , Mieloma Múltiplo/terapia , Feminino , Neoplasias Hematológicas/imunologia , Humanos , Leucemia Linfocítica Crônica de Células B/imunologia , Masculino , Mieloma Múltiplo/imunologia
13.
Clin Immunol ; 163: 17-21, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26680607

RESUMO

Loss-of-function mutations in DOCK8 are linked to hyper-IgE syndrome. Patients typically present with recurrent sinopulmonary infections, severe cutaneous viral infections, food allergies and elevated serum IgE. Although patients may present with a spectrum of disease-related symptoms, molecular mechanisms explaining phenotypic variability in patients are poorly defined. Here we characterized a novel compound heterozygous mutation in DOCK8 in a patient diagnosed with primary combined immunodeficiency which was not typical of classical DOCK8 deficiency. In contrast to previously identified mutations in DOCK8 which result in complete loss of function, the newly identified single nucleotide insertion results in expression of a truncated DOCK8 protein. Functional evaluation of the truncated DOCK8 protein revealed its hypomorphic function. In addition we found somatic reversion of DOCK8 predominantly in T cells. The combination of somatic reversion and hypomorphic DOCK8 function explains the milder and atypical phenotype of the patient and further broadens the spectrum of DOCK8-associated disease.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/genética , Imunoglobulina E/imunologia , Imunoglobulina M/imunologia , Síndromes de Imunodeficiência/imunologia , Bronquiectasia/etiologia , Bronquiectasia/imunologia , Criança , Feminino , Heterozigoto , Humanos , Imunoglobulina G/imunologia , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/genética , Mutação , Recidiva , Infecções Respiratórias/etiologia , Infecções Respiratórias/imunologia
14.
Nat Commun ; 6: 8442, 2015 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-26450413

RESUMO

Autoimmune diseases (AIDs) are polygenic diseases affecting 7-10% of the population in the Western Hemisphere with few effective therapies. Here, we quantify the heritability of paediatric AIDs (pAIDs), including JIA, SLE, CEL, T1D, UC, CD, PS, SPA and CVID, attributable to common genomic variations (SNP-h(2)). SNP-h(2) estimates are most significant for T1D (0.863±s.e. 0.07) and JIA (0.727±s.e. 0.037), more modest for UC (0.386±s.e. 0.04) and CD (0.454±0.025), largely consistent with population estimates and are generally greater than that previously reported by adult GWAS. On pairwise analysis, we observed that the diseases UC-CD (0.69±s.e. 0.07) and JIA-CVID (0.343±s.e. 0.13) are the most strongly correlated. Variations across the MHC strongly contribute to SNP-h(2) in T1D and JIA, but does not significantly contribute to the pairwise rG. Together, our results partition contributions of shared versus disease-specific genomic variations to pAID heritability, identifying pAIDs with unexpected risk sharing, while recapitulating known associations between autoimmune diseases previously reported in adult cohorts.


Assuntos
Doenças Autoimunes/congênito , Doenças Autoimunes/genética , Adolescente , Idade de Início , Estudos de Casos e Controles , Criança , Pré-Escolar , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
16.
Clin Immunol ; 160(2): 301-14, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26122175

RESUMO

Common Variable Immunodeficiency Disorders (CVIDs) are the most prevalent cause of primary antibody failure. CVIDs are highly variable and a genetic causes have been identified in <5% of patients. Here, we performed whole genome sequencing (WGS) of 34 CVID patients (94% sporadic) and combined them with transcriptomic profiling (RNA-sequencing of B cells) from three patients and three healthy controls. We identified variants in CVID disease genes TNFRSF13B, TNFRSF13C, LRBA and NLRP12 and enrichment of variants in known and novel disease pathways. The pathways identified include B-cell receptor signalling, non-homologous end-joining, regulation of apoptosis, T cell regulation and ICOS signalling. Our data confirm the polygenic nature of CVID and suggest individual-specific aetiologies in many cases. Together our data show that WGS in combination with RNA-sequencing allows for a better understanding of CVIDs and the identification of novel disease associated pathways.


Assuntos
Linfócitos B/metabolismo , Imunodeficiência de Variável Comum/genética , Genoma/genética , RNA Mensageiro/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Adulto , Receptor do Fator Ativador de Células B/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Análise de Sequência de DNA , Análise de Sequência de RNA , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Adulto Jovem
17.
Nat Genet ; 47(7): 717-726, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25985138

RESUMO

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Técnicas de Diagnóstico Molecular , Sequência de Bases , Análise Mutacional de DNA , Doenças Genéticas Inatas/genética , Genoma Humano , Humanos , Anotação de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Sensibilidade e Especificidade
18.
Nat Commun ; 6: 6804, 2015 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-25891430

RESUMO

Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B-cell abnormalities and inadequate antibody response. CVID patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10,999 controls across 123,127 single-nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P=2.0 × 10(-9)) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P=4.8 × 10(-16)). Clec16a knockdown (KD) mice showed reduced number of B cells and elevated IgM levels compared with controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition.


Assuntos
Linfócitos B/metabolismo , Imunodeficiência de Variável Comum/genética , Lectinas Tipo C/metabolismo , Proteínas de Transporte de Monossacarídeos/metabolismo , Animais , Estudos de Casos e Controles , Células Cultivadas , Imunodeficiência de Variável Comum/epidemiologia , Europa (Continente)/epidemiologia , Regulação da Expressão Gênica/fisiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Lectinas Tipo C/genética , Modelos Logísticos , Camundongos , Proteínas de Transporte de Monossacarídeos/genética , Razão de Chances , Polimorfismo de Nucleotídeo Único , Baço/citologia , Estados Unidos/epidemiologia
20.
J Allergy Clin Immunol ; 135(6): 1569-77, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25678086

RESUMO

BACKGROUND: Common variable immunodeficiency (CVID) is characterized clinically by inadequate quantity and quality of serum immunoglobulins with increased susceptibility to infections, resulting in significant morbidity and mortality. Only a few genes have been uncovered, and the genetic background of CVID remains elusive to date for the majority of patients. OBJECTIVE: We sought to seek novel associations of genes and genetic variants with CVID. METHODS: We performed association analyses in a discovery cohort of 164 patients with CVID and 19,542 healthy control subjects genotyped on the Immuno BeadChip from Illumina platform; replication of findings was examined in an independent cohort of 135 patients with CVID and 2,066 healthy control subjects, followed by meta-analysis. RESULTS: We identified 11 single nucleotide polymorphisms (SNPs) at the 16p11.2 locus associated with CVID at a genome-wide significant level in the discovery cohort. The most significant SNP, rs929867 (P = 6.21 × 10(-9)), is in the gene fused-in-sarcoma (FUS), with 4 other SNPs mapping to integrin CD11b (ITGAM). Results were confirmed in our replication cohort. Conditional association analysis suggests a single association signal at the 16p11.2 locus. A strong trend of association was also seen for 38 SNPs (P < 5 × 10(-5)) in the MHC region, supporting that this is a genuine CVID locus. Interestingly, we found that 80% of patients with the rare ITGAM variants have reduced switched memory B-cell counts. CONCLUSION: We report a novel association of CVID with rare variants at the FUS/ITGAM (CD11b) locus on 16p11.2. The association signal is enriched for promoter/enhancer markers in the ITGAM gene. ITGAM encodes the integrin CD11b, a part of complement receptor 3, a novel candidate gene implicated here for the first time in the pathogenesis of CVID.


Assuntos
Antígeno CD11b/genética , Cromossomos Humanos Par 16 , Imunodeficiência de Variável Comum/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Proteína FUS de Ligação a RNA/genética , Adulto , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Antígeno CD11b/imunologia , Estudos de Casos e Controles , Pré-Escolar , Estudos de Coortes , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/patologia , Elementos Facilitadores Genéticos , Feminino , Loci Gênicos , Humanos , Memória Imunológica , Desequilíbrio de Ligação , Masculino , Regiões Promotoras Genéticas , Proteína FUS de Ligação a RNA/imunologia
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