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1.
Blood ; 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31942606

RESUMO

Using whole exome sequencing to examine the genetic causes of immune deficiency in 235 CVID patients seen in New York, 128 patients from Sweden, and 208 from Iran, revealed 73 known disease-causing genes associated with this heterogeneous immune defect. The patients at the time of study ranged from age 4 to age 90. Overall, for 31%, 36% and 54% of the patients in United States, Swedish or Iranian cohorts, mutations were identified. The multiplicity of genes identified reflects the complex requirements of B cell antigen signaling, activation, survival, migration, maturation and maintenance of antibody-secreting memory B cell populations to the plasma cell stage. For the United States and Swedish cohorts, CVID subjects with non-infectious complications, lymphoid infiltrations, inflammatory, or autoimmunity, were more likely to have an identifiable gene, but in both cohorts, numerous subjects with these medical conditions had no potential gene that could be assigned. Specific clinical patterns of illnesses were also not linked to any given gene defect as there was considerable overlap in clinical presentations. These observations provide a broad perspective on the complexity of the genetic and immunologic phenotypes found in 571 CVID subjects of different ages and backgrounds.

2.
Front Immunol ; 10: 2503, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824477

RESUMO

Monozygotic twins provide a unique opportunity to better understand complex genetic diseases and the relative contribution of heritable factors in shaping the immune system throughout life. Common Variable Immunodeficiency Disorders (CVID) are primary antibody defects displaying wide phenotypic and genetic heterogeneity, with monogenic transmission accounting for only a minority of the cases. Here, we report a pair of monozygotic twins concordant for CVID without a family history of primary immunodeficiency. They featured a remarkably similar profile of clinical manifestations and immunological alterations at diagnosis (established at age 37) and along the subsequent 15 years of follow-up. Interestingly, whole-exome sequencing failed to identify a monogenic cause for CVID, but unraveled a combination of heterozygous variants, with a predicted deleterious impact. These variants were found in genes involved in relevant immunological pathways, such as JUN, PTPRC, TLR1, ICAM1, and JAK3. The potential for combinatorial effects translating into the observed disease phenotype is inferred from their roles in immune pathways, namely in T and B cell activation. The combination of these genetic variants is also likely to impose a significant constraint on environmental influences, resulting in a similar immunological phenotype in both twins, despite exposure to different living conditions. Overall, these cases stress the importance of integrating NGS data with clinical and immunological phenotypes at the single-cell level, as provided by multi-dimensional flow-cytometry, in order to understand the complex genetic landscape underlying the vast majority of patients with CVID, as well as those with other immunodeficiencies.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31887391

RESUMO

BACKGROUND: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentations of lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data for non-transplanted patients beyond previous patient reports or meta-reviews are scarce. OBJECTIVE: This international, retrospective study was conducted to elucidate the longitudinal clinical course of transplanted and non-transplanted LRBA-deficient patients. METHODS: We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity (IDDA) score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices. RESULTS: Twenty-four of 76 LRBA-deficient patients from 29 centers (10 years median follow-up, range: 1-52) underwent HSCT from 2005 to 2019. Overall survival after HSCT (median follow-up 20 months) was 70.8% (17/24 patients); all deaths were due to non-specific, early, transplant-related mortality. Currently, 82.7% (43/52) of non-transplanted patients (aged 3-69 years) are alive. Of 17 HSCT survivors, seven are in complete and five in good partial remission without treatment (12/17, 70.6%). Only five of 43 non-transplanted patients (11.6%) are without immunosuppression. IDDA scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P=0.005) or in patients who received abatacept or sirolimus as compared to other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome. CONCLUSIONS: The life-long disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT.

4.
J Clin Immunol ; 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31858365

RESUMO

BACKGROUND: Inducible T cell co-stimulator (ICOS) deficiency has been categorized as a combined immunodeficiency often complicated by enteropathies, autoimmunity, lymphoproliferation, and malignancy. We report seven new patients and four novel ICOS mutations resulting in a common variable immunodeficiency (CVID)-like phenotype and show that dysregulated IL-12 release, reduced cytotoxic T lymphocyte-associated protein 4 (CTLA4) expression, and skewing towards a Th1-dominant phenotype are all associated with inflammatory complications in this condition. METHODS: A combination of whole exome and Sanger sequencing was used to identify novel mutations. Standard clinical and immunological evaluation was performed. FACS and ELISA-based assays were used to study cytokine responses and ICOS/ICOSL/CTLA4 expression following stimulation of whole blood and PBMCs with multiple TLR ligands, anti-CD3, and PHA. RESULTS: Four novel ICOS mutations included homozygous c.323_332del, homozygous c.451C>G, and compound heterozygous c.58+1G>A/c.356T>C. The predominant clinical phenotype was that of antibody deficiency associated with inflammatory complications in 4/7 patients. Six out of seven patients were treated with immunoglobulin replacement and one patient died from salmonella sepsis. All patients who were tested showed reduced IL-10 and IL-17 cytokine responses, normal IL-1ß, IL6, and TNF release following LPS stimulation and highly elevated IL-12 production in response to combined LPS/IFNγ stimulation. This was associated with skewing of CD4+ T cells towards Th1 phenotype and increased expression of ICOSL on monocytes. Lastly, reduced CTLA4 expression was found in 2 patients. One patient treated with ustekinumab for pancytopenia due to granulomatous bone marrow infiltration failed to respond to this targeted therapy. CONCLUSIONS: ICOS deficiency is associated with defective T cell activation, with simultaneously enhanced stimulation of monocytes. The latter is likely to result from a lack of ICOS/ICOSL interaction which might be necessary to provide negative feedback which limits monocytes activation.

5.
Annu Rev Anim Biosci ; 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31846352

RESUMO

Immunoglobulins (Igs), as one of the hallmarks of adaptive immunity, first arose approximately 500 million years ago with the emergence of jawed vertebrates. Two events stand out in the evolutionary history of Igs from cartilaginous fish to mammals: (a) the diversification of Ig heavy chain (IgH) genes, resulting in Ig isotypes or subclasses associated with novel functions, and (b) the diversification of genetic and structural strategies, leading to the creation of the antibody repertoire we know today. This review first gives an overview of the IgH isotypes identified in jawed vertebrates to date and then highlights the implications or applications of five new recent discoveries arising from comparative studies of Igs derived from different vertebrate species. Expected final online publication date for the Annual Review of Animal Biosciences, Volume 8 is February 15, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

6.
Stem Cell Res ; 41: 101613, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31689593

RESUMO

Selective immunoglobulin-A deficiency (IgAD) is the most common primary immunodeficiency (PID) in the Western world and results in higher susceptibility to infections, autoimmune disorders and malignancies. We generated human induced pluripotent stem cell lines from two patients with selective IgAD, PHAi001 and PHAi002. Patient samples were reprogrammed using non-integrative based methods. Pluripotency of the PHAi001 and PHAi002 cell lines was confirmed by their expression of stem cell markers and capacity to differentiate into cells of the three germ layers. The PHAi001 and PHAi002 lines are a unique resource for experimental modeling of selective IgAD and associated disorders.

7.
ACS Synth Biol ; 8(8): 1723-1729, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31277549

RESUMO

Genome engineering is essential for application of synthetic biology in probiotics including lactobacilli and bifidobacteria. Several homologous recombination system-based mutagenesis tools have been developed for these bacteria, but still have many limitations in different species or strains. Here we developed a genome engineering method based on an inducible self-destruction plasmid delivering homologous DNA into bacteria. Excision of the replicon by induced recombinase facilitates selection of homologous recombination events. This new genome editing tool called inducible plasmid self-destruction (IPSD) was successfully used to perform gene knockout and knock-in in lactobacilli and bifidobacteria. Due to its simplicity and universality, the IPSD strategy may provide a general approach for genetic engineering of various bacterial species.

9.
Artigo em Inglês | MEDLINE | ID: mdl-30622570

RESUMO

Background: Atypical X-linked severe combined immunodeficiency (X-SCID) is a variant of cellular immunodeficiency due to hypomorphic mutations in the interleukin 2 receptor gamma (IL2RG) gene. Due to a leaky clinical phenotype, diagnosis and appropriate treatment are challenging in these patients. Case presentation: We report a 16-year-old patient with a Tlow B+ NK+ cellular immunodeficiency due to a novel nonsense mutation in exon 8 (p.R328X) of the IL2RG gene. Functional impairment of the IL2RG was confirmed by IL2-Janus kinase 3-signal transducer and activator of transcription signaling pathway investigation. In addition, the characteristics of the mutations previously described in 39 patients with an atypical phenotype were reviewed and analyzed from the literature. Conclusion: This is the first report of an atypical X-SCID phenotype due to an exon 8 mutation in the IL2RG gene. The variability in the phenotypic spectrum of classic X-SCID associated gene highlights the necessity of multi-disciplinary cooperation vigilance for a more accurate diagnostic workup.

10.
Genet Med ; 21(1): 243-251, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29921932

RESUMO

PURPOSE: The etiology of 80% of patients with primary antibody deficiency (PAD), the second most common type of human immune system disorder after human immunodeficiency virus infection, is yet unknown. METHODS: Clinical/immunological phenotyping and exome sequencing of a cohort of 126 PAD patients (55.5% male, 95.2% childhood onset) born to predominantly consanguineous parents (82.5%) with unknown genetic defects were performed. The American College of Medical Genetics and Genomics criteria were used for validation of pathogenicity of the variants. RESULTS: This genetic approach and subsequent immunological investigations identified potential disease-causing variants in 86 patients (68.2%); however, 27 of these patients (31.4%) carried autosomal dominant (24.4%) and X-linked (7%) gene defects. This genetic approach led to the identification of new phenotypes in 19 known genes (38 patients) and the discovery of a new genetic defect (CD70 pathogenic variants in 2 patients). Medical implications of a definite genetic diagnosis were reported in ~50% of the patients. CONCLUSION: Due to misclassification of the conventional approach for targeted sequencing, employing next-generation sequencing as a preliminary step of molecular diagnostic approach to patients with PAD is crucial for management and treatment of the patients and their family members.


Assuntos
Predisposição Genética para Doença , Testes Genéticos , Genômica , Doenças do Sistema Imunitário/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Exoma/genética , Exoma/imunologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Masculino , Mutação , Fenótipo , Análise de Sequência de DNA , Sequenciamento Completo do Exoma , Adulto Jovem
11.
Artigo em Inglês | MEDLINE | ID: mdl-30544260

RESUMO

Background: Single-nucleotide polymorphisms (SNPs) in the fucosyltransferase genes FUT2 and FUT3 have been associated with susceptibility to various infectious and inflammatory disorders. FUT variations influence the expression of human histo-blood group antigens (HBGAs) (H-type 1 and Lewis), which are highly expressed in the gut and play an important role in microbial attachment, metabolism, colonization, and shaping of the microbiome. In particular, FUT polymorphisms confer susceptibility to specific rotavirus and norovirus genotypes, which has important global health implications. Methods: We designed a genotyping method using a nested polymerase chain reaction approach to determine the frequency of SNPs in FUT2 and FUT3, thereby inferring the prevalence of Lewisb-positive, Lewisb-negative, secretor, and nonsecretor phenotypes in 520 Swedish newborns. Results: There was an increased frequency of homozygotes for the minor allele for 1 SNP in FUT2 and 4 SNPs in FUT3. Overall, 37.3% of newborns were found to have Lewis b negative phenotypes (Le (a+b-) or Le (a-b-). Using our new, sensitive genotyping method, we were able to genetically define the Le (a-b-) individuals based on their secretor status and found that the frequency of Lewis b negative newborns in our cohort was 28%. Conclusions: Given the high frequency of fucosyltransferase polymorphisms observed in our newborn cohort and the implications for disease susceptibility, FUT genotyping might play a future role in personalized health care, including recommendations for disease screening, therapy, and vaccination.

12.
PLoS Med ; 15(12): e1002717, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30562348

RESUMO

BACKGROUND: Small for gestational age (SGA) has been associated with increased risks of stillbirth and neonatal mortality, but data on long-term childhood mortality are scarce. Maternal antenatal care, including globally reducing the risk of SGA birth, may be key to achieving the Millennium Development Goal of reducing under-5 mortality. We therefore aimed to examine the association between SGA and mortality from 28 days to <18 years using a population-based and a sibling control design. METHODS AND FINDINGS: In a Swedish population study, we identified 3,795,603 non-malformed singleton live births and 2,781,464 full siblings born from January 1, 1973, to December 31, 2012. We examined the associations of severe (<3rd percentile) and moderate (3rd to <10th percentile) SGA with risks of death from 28 days to <18 years after birth. Children born SGA were first compared to non-SGA children from the population, and then to non-SGA siblings. The sibling-based analysis, by design, features a better control for unmeasured factors that are shared between siblings (e.g., socioeconomic status, lifestyle, and genetic factors). Hazard ratios (HRs) were calculated using Cox proportional hazards and flexible parametric survival models. During follow-up (1973-2013), there were 10,838 deaths in the population-based analysis and 1,572 deaths in sibling pairs with discordant SGA and mortality status. The crude mortality rate per 10,000 person-years was 5.32 in children born with severe SGA, 2.76 in children born with moderate SGA, and 1.93 in non-SGA children. Compared with non-SGA children, children born with severe SGA had an increased risk of death in both the population-based (HR = 2.58, 95% CI = 2.38-2.80) and sibling-based (HR = 2.61, 95% CI = 2.19-3.10) analyses. Similar but weaker associations were found for moderate SGA in the population-based (HR = 1.37, 95% CI = 1.28-1.47) and sibling-based (HR = 1.38, 95% CI = 1.22-1.56) analyses. The excess risk was most pronounced between 28 days and <1 year of age but remained throughout childhood. The greatest risk increase associated with severe SGA was noted for deaths due to infection and neurologic disease. Although we have, to our knowledge, the largest study sample so far addressing the research question, some subgroup analyses, especially the analysis of cause-specific mortality, had limited statistical power using the sibling-based approach. CONCLUSIONS: We found that SGA, especially severe SGA, was associated with an increased risk of childhood death beyond the neonatal period, with the highest risk estimates for death from infection and neurologic disease. The similar results obtained between the population- and sibling-based analyses argue against strong confounding by factors shared within families.


Assuntos
Mortalidade da Criança/tendências , Mortalidade Infantil/tendências , Recém-Nascido Pequeno para a Idade Gestacional , Nascimento Vivo/epidemiologia , Vigilância da População , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional/fisiologia , Masculino , Vigilância da População/métodos , Fatores de Risco , Suécia/epidemiologia
13.
Clin Immunol ; 197: 40-44, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30145329

RESUMO

B cell activation by Toll-like receptor 9 (TLR9) ligands is dependent on STAT3 and is important for optimal antibody responses to microbial antigens. B cells from patients with common variable immune deficiency (CVID) have impaired proliferation and differentiation in response to the TLR9 ligand CpG, despite normal levels of TLR9 expression. We demonstrate that CpG-driven STAT3 phosphorylation, but not activation of NFκB and p38, is selectively impaired in B cells from CVID patients. These results suggest that defective STAT3 activation contributes to the defective TLR9 and antibody response of B cells in CVID.


Assuntos
Linfócitos B/imunologia , Imunodeficiência de Variável Comum/imunologia , Ativação Linfocitária/imunologia , Fator de Transcrição STAT3/imunologia , Receptor Toll-Like 9/imunologia , Subpopulações de Linfócitos B/imunologia , Linfócitos B/metabolismo , Estudos de Casos e Controles , Proliferação de Células , DNA Bacteriano , Humanos , Imunoglobulina G/metabolismo , Leucócitos Mononucleares , NF-kappa B , Oligodesoxirribonucleotídeos , Fosforilação , Fator de Transcrição STAT3/metabolismo , Receptor Toll-Like 9/metabolismo
14.
Pediatr Allergy Immunol ; 29(8): 863-872, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30152884

RESUMO

BACKGROUND: Primary immunodeficiency disorders (PID) is a group of heterogeneous diseases mainly characterized by severe and recurrent infections and an increased susceptibility to lymphoproliferative, atopic, and autoimmune conditions. The clinical diagnosis should preferably be complemented by a genetic diagnosis. To date, PID-related reports from China seldom attempt to make a genetic test for their patients. METHODS: Our study aimed to evaluate demographic data, clinical manifestations, and molecular diagnosis of PID patients from southern China. Moreover, by comparison with previous reports, we provide a picture of the current status of PID in mainland China. A total number of 160 pediatric PID patients (106 males and 54 females) were enrolled, and targeted next-generation sequencing was conducted using 269 PID-related genes and subsequently confirmed by Sanger sequencing and familial segregation analysis. RESULT: The autoinflammatory disease group was the most common subcategory of PID (20%), followed by immune dysregulation (17.5%) and combined immunodeficiencies (16.2%). Antibody deficiency disorders were identified in only 11.9% of the cohort. The putative causative gene was identified in 70 patients (43.8%), and an X-linked pattern was found in 45.7% of the genetically diagnosed patients. CONCLUSION: The current study provides the first collective study of PID phenotypes and genotypes in south China and provides a strong argument for the diagnostic application of targeted next-generation sequencing panels in patients with suspected PID.


Assuntos
Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Síndromes de Imunodeficiência/genética , Adolescente , Criança , Pré-Escolar , China , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/mortalidade , Lactente , Recém-Nascido , Masculino , Fenótipo
15.
Scand J Immunol ; : e12699, 2018 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-29943473

RESUMO

T-cell receptor excision circles (TRECs) and κ-deleting recombination excision circles (KRECs) are recently used for detection of T or B cell lymphopenia in neonates based on region-specific cutoff levels. Here, we report cutoffs for TREC and KREC copies useful for newborn screening and/or diagnosis of primary immunodeficiency diseases (PID) in Iran. DNA was extracted from a single 3.2 mm punch of dried blood spots collected from 2160 anonymized newborns referred to two major referral health centers between 2014 and 2016. For refinement of the cutoffs, 51 patients with a definite diagnosis of severe combined immunodeficiency, X-linked agammaglobulinaemia and combined immunodeficiency, including ataxia telangiectasia, human phosphoglucomutase 3 and Janus kinase-3 deficiency, as well as 47 healthy controls were included. Samples from patients with an X-linked hyper-IgM-syndrome, Wiskott-Aldrich syndrome and DNA ligase 4 deficiency were considered as disease controls. Triplex-quantitative real-time PCR was used. Cutoffs were calculated as TRECs < 11 and KRECs < 6 copies with an ACTB > 700 copies with sensitivity of 100% for TREC and 97% for KREC. Among thirty anonymized newborn samples (1.5%) with abnormal results for TREC and/or KREC, only twenty one available cases were retested and shown to be in the normal range except for three samples (0.15%). All of the patients with a definitive diagnosis were correctly identified based on our established TREC/KREC copy numbers. Determining cutoffs for TREC/KREC is essential for correctly identifying children with PID in newborn screening. Early diagnosis of PID patients enables appropriate measures and therapies like stem cell transplantation. This article is protected by copyright. All rights reserved.

16.
Front Immunol ; 9: 908, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29755475

RESUMO

The dietary pattern can influence the immune system directly, but may also modulate it indirectly by regulating the gut microbiota. Here, we investigated the effect of a 3-months lacto-ovo-vegetarian diet on the diversity of gut microbiota and the immune system in healthy omnivorous volunteers, using high-throughput sequencing technologies. The short-term vegetarian diet did not have any major effect on the diversity of the immune system and the overall composition of the metagenome. The prevalence of bacterial genera/species with known beneficial effects on the intestine, including butyrate-producers and probiotic species and the balance of autoimmune-related variable genes/families were, however, altered in the short-term vegetarians. A number of bacterial species that are associated with the expression level of IgA, a key immunoglobulin class that protects the gastrointestinal mucosal system, were also identified. Furthermore, a lower diversity of T-cell repertoire and expression level of IgE, as well as a reduced abundance of inflammation-related genes in the gut microbiota were potentially associated with a control group with long-term vegetarians. Thus, the composition and duration of the diet may have an impact on the balance of pro-/anti-inflammatory factors in the gut microbiota and immune system.


Assuntos
Bactérias/metabolismo , Dieta Vegetariana , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/imunologia , Metagenoma , Adulto , Bactérias/classificação , Butiratos/metabolismo , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunidade nas Mucosas , Imunoglobulina A , Inflamação , Masculino , Pessoa de Meia-Idade , Probióticos , Fatores de Tempo , Vegetarianos
17.
J Allergy Clin Immunol ; 142(6): 1922-1931.e2, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29678747

RESUMO

BACKGROUND: A subgroup of patients with common variable immunodeficiencies (CVIDs) responds to vaccination. The aim of this study was to try to identify predictive markers for those with a humoral immune response after influenza vaccination. METHODS: Forty-eight patients with CVID (29 female and 19 male patients; mean age, 57.7 years) were vaccinated with the A(H1N1) influenza vaccine Pandemrix (GlaxoSmithKline, Wavre, Belgium) and boosted after 1 month. Blood samples were collected before each vaccination and 2 months later. Patients with a 4-fold titer increase in results on the hemagglutinin inhibition test (≥1:40) were considered responders and compared with nonresponders for clinical, immunologic, and genetic markers. RESULTS: Eight (16.7%) patients responded to the vaccination. A significantly higher proportion of the responders, who showed a EUROclass SmB-Trnorm21norm profile (P = .03) with a post-germinal center B-cell pattern (P = .04) in blood, experienced enteropathies (P = .04) compared with nonresponders. On the other hand, bronchiectasis was found exclusively among nonresponders (n = 7), as was autoimmune cytopenia (n = 5). Nonresponders with a EUROclass SmB-Trnorm21low profile (P = .02) had a significantly greater prevalence of progressive antibody deficiency (P = .048) and, at diagnosis, a higher mean serum IgM level (P = .03), lower mean serum IgG1 level (P = .007), expansion of absolute counts of cytotoxic CD8+ T cells (P = .033), and increased proportion of memory CD8+ T cells (P = .044) in blood. CVID-associated HLA markers were not detected in responders (P = .03). CONCLUSION: About one fifth of the patients with CVIDs achieved protective antibody levels after A(H1N1) vaccination and selected clinical, and immunologic markers were identified that might predict a positive outcome of influenza vaccination. Patients with CVID should be offered vaccination also against seasonal influenza because of the potential severity of the infection and risk for bacterial complications.


Assuntos
Imunodeficiência de Variável Comum/terapia , Vacinas contra Influenza/uso terapêutico , Influenza Humana/prevenção & controle , Adulto , Idoso , Anticorpos Antivirais/sangue , Biomarcadores , Linfócitos T CD8-Positivos/imunologia , Imunodeficiência de Variável Comum/sangue , Imunodeficiência de Variável Comum/imunologia , Citocinas/imunologia , Feminino , Hemaglutininas/imunologia , Humanos , Imunidade Humoral , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Vírus da Influenza A Subtipo H1N1 , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade
18.
Immunol Invest ; 47(5): 457-467, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29528757

RESUMO

BACKGROUND: Polyautoimmunity is defined as the presence of more than one autoimmune disorder in a single patient. Lipopolysaccharide (LPS)-responsive beige-like anchor (LRBA) deficiency is one of the monogenic causes of polyautoimmunity. The aim of this study was to report the characteristics of polyautoimmunity in patients with LRBA deficiency. METHODS: A total of 14 LRBA deficiency patients with confirmed autoimmunity were enrolled in this study. For those patients with polyautoimmunity, demographic information, clinical records, laboratory, and molecular data were collected. We also compared our results with the currently reported patients with LRBA deficiency associated with polyautoimmunity. RESULTS: In 64.2% (9 out of 14) of patients, autoimmunity presented as polyautoimmunity. In these patients, autoimmune cytopenias were the most frequent complication, observed in seven patients. Three patients presented with four different types of autoimmune conditions. The review of the literature showed that 41 of 72 reported LRBA deficient patients (74.5%) had also polyautoimmunity, with a wide spectrum of autoimmune diseases described. Hematopoietic stem cell transplantation is increasingly used as the treatment for patients with severe polyautoimmunity associated to LRBA deficiency. CONCLUSIONS: Mutation in LRBA gene is one of the causes of monogenic polyautoimmunity. Awareness of this association is important in order to make an early diagnosis and prompt treatment.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/deficiência , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Autoimunidade , Lipopolissacarídeos/imunologia , Adolescente , Adulto , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/terapia , Criança , Terapia Combinada , Biologia Computacional/métodos , Feminino , Humanos , Masculino , Mutação , Sistema de Registros , Avaliação de Sintomas , Adulto Jovem
20.
Front Immunol ; 9: 543, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29599784

RESUMO

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2-3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.


Assuntos
Síndromes de Imunodeficiência/tratamento farmacológico , Imunossupressores/uso terapêutico , Sistema de Registros , Sirolimo/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases , Europa (Continente) , Humanos , Pessoa de Meia-Idade , Sociedades Médicas , Adulto Jovem
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