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1.
Mol Genet Genomic Med ; : e1574, 2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33443819

RESUMO

BACKGROUND: Variants in the GJB2 gene encoding the gap junction protein connexin-26 (Cx26) can cause autosomal recessive nonsyndromic hearing loss or a variety of phenotypically variable autosomal dominant disorders that effect skin and hearing, such as palmoplantar keratoderma (PPK) with deafness and keratitis-ichthyosis-deafness (KID) syndrome. Here, we report a patient with chronic mucocutaneous candidiasis, hyperkeratosis with resorption of the finger tips, profound bilateral sensorineural hearing loss, and normal hair and ocular examination. Exome analysis identified a novel missense variant in GJB2 (NM_004004.5:c.101T>A, p.Met34Lys) that was inherited from a mosaic unaffected parent in the setting of a well-reported GJB2 loss of function variant (NM_004004.5:c.35delG, p.Gly12Valfs*2) on the other allele. METHOD: Rat epidermal keratinocytes were transfected with cDNA encoding wildtype Cx26 and/or the Met34Lys mutant of Cx26. Fixed cells were immunolabeled in order to assess the subcellular location of the Cx26 mutant and cell images were captured. RESULTS: Expression in rat epidermal keratinocytes revealed that the Met34Lys mutant was retained in the endoplasmic reticulum, unlike wildtype Cx26, and failed to reach the plasma membrane to form gap junctions. Additionally, the Met34Lys mutant acted dominantly to wildtype Cx26, restricting its delivery to the cell surface. CONCLUSION: Overall, we show the p.Met34Lys variant is a novel dominant acting variant causing PPK with deafness. The presence of a loss a function variant on the other allele creates a more severe clinical phenotype, with some features reminiscent of KID syndrome.

2.
Blood Adv ; 4(23): 6051-6063, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33290544

RESUMO

Most children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have mild or minimal disease, with a small proportion developing severe disease or multisystem inflammatory syndrome in children (MIS-C). Complement-mediated thrombotic microangiopathy (TMA) has been associated with SARS-CoV-2 infection in adults but has not been studied in the pediatric population. We hypothesized that complement activation plays an important role in SARS-CoV-2 infection in children and sought to understand if TMA was present in these patients. We enrolled 50 hospitalized pediatric patients with acute SARS-CoV-2 infection (n = 21, minimal coronavirus disease 2019 [COVID-19]; n = 11, severe COVID-19) or MIS-C (n = 18). As a biomarker of complement activation and TMA, soluble C5b9 (sC5b9, normal 247 ng/mL) was measured in plasma, and elevations were found in patients with minimal disease (median, 392 ng/mL; interquartile range [IQR], 244-622 ng/mL), severe disease (median, 646 ng/mL; IQR, 203-728 ng/mL), and MIS-C (median, 630 ng/mL; IQR, 359-932 ng/mL) compared with 26 healthy control subjects (median, 57 ng/mL; IQR, 9-163 ng/mL; P < .001). Higher sC5b9 levels were associated with higher serum creatinine (P = .01) but not age. Of the 19 patients for whom complete clinical criteria were available, 17 (89%) met criteria for TMA. A high proportion of tested children with SARS-CoV-2 infection had evidence of complement activation and met clinical and diagnostic criteria for TMA. Future studies are needed to determine if hospitalized children with SARS-CoV-2 should be screened for TMA, if TMA-directed management is helpful, and if there are any short- or long-term clinical consequences of complement activation and endothelial damage in children with COVID-19 or MIS-C.


Assuntos
/diagnóstico , Microangiopatias Trombóticas/diagnóstico , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/patologia , Adolescente , Anticorpos Antivirais/sangue , Biomarcadores/metabolismo , /virologia , Criança , Pré-Escolar , Análise por Conglomerados , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Creatinina/sangue , Feminino , Humanos , Masculino , RNA Viral/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , /isolamento & purificação , Índice de Gravidade de Doença , Microangiopatias Trombóticas/complicações
3.
Public Health Genomics ; : 1-6, 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33291115

RESUMO

AIMS: This study was undertaken to examine how a layperson is likely to interpret genetic information delivered in a clinical setting. METHODS: A novel survey was designed to engage the reader in a simulated discussion of heritability as it might relate to human disease. The survey took approximately 5 min to administer. 307 individuals of different backgrounds completed the survey in the outpatient waiting room on their cell phone. RESULTS: Overall, basic knowledge of inheritance and the concepts of heredity scored very well in the study cohort. Both knowledge and interpretation questions were answered correctly more often than not. There was generally no association between the scores on survey and gender or age. CONCLUSIONS: People recognize the basic concepts of heritability but struggle with real-life interpretations and more nuanced concepts of heredity.

4.
Pediatr Rheumatol Online J ; 18(1): 89, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33198759

RESUMO

BACKGROUND: To examine critical interactions between juvenile idiopathic arthritis synovial fibroblasts (JFLS) and chondrocytes (Ch), and their role in bony overgrowth seen in patients with juvenile idiopathic arthritis (JIA). METHODS: Control (CFLS) and JFLS were cultured in synoviocyte media containing recombinant BMP4. Ch were cultured in either CFLS or JFLS conditioned-media without stimulation. Media supernatants were analyzed by ELISA. RNA from conditioned media experiment was analyzed by ClariomS microarray. RESULTS: As expected, genes expressed in untreated JFLS and CFLS cultured in synoviocyte media were similar to each other and this expression differed from untreated Ch cultured in chondrocyte media. JFLS favor BMP ligand gene expression while downregulating TGFß receptors' expression. Noggin and chordin, antagonists with high affinity for BMP4, are JFLS- but not Ch-preferred regulators of BMP signaling. Compared to Ch, JFLS overexpress collagen X (COLX), a marker of chondrocyte hypertrophy. Exogenous BMP4 causes JFLS to significantly decrease expression of noggin and collagen II (COL2), a marker of chondrocyte proliferation, and causes overexpression of COLX and alkaline-phosphatase (ALP). Chondrocytes cultured in JFLS-conditioned media (Ch-JFLS) express BMP genes and favor chordin protein expression over other antagonists. Ch-JFLS have significantly increased expression of COL2 and significantly decreased expression of COLX. CONCLUSIONS: These data suggest JFLS, in the presence of BMP4, undergo hypertrophy and that JFLS-conditioned media influence chondrocytes to become highly proliferative. To the authors' knowledge, no prior study has shown that JFLS and chondrocytes play a direct role in the bony overgrowth in joints of patients with JIA and that BMPs or regulation of these growth factors influence the interaction between two prominent synovial cell types.

5.
J Particip Med ; 12(4): e22297, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-33252341

RESUMO

BACKGROUND: Although fever is considered a sign of infection, many individuals with primary immunodeficiency (PI) anecdotally report a lower-than-normal average body temperature on online forums sponsored by the Immune Deficiency Foundation (IDF). There is limited knowledge about the average body temperature and fever response in PI. OBJECTIVE: This study aims to compare median body temperatures between adults with and without PI diagnoses living in the same household and to engage individuals living with PI throughout the research process. METHODS: Patients with PI designed and launched a prospective cohort comparison study as citizen scientists. A multidisciplinary team designed and implemented a patient-informed study with continuous patient-driven input. Median body temperatures were compared between the 2 cohorts using the Mann-Whitney test with Bonferroni correction. The IDF conducted a post-study patient experience survey. RESULTS: Data from 254 households were analyzed (254/350, 72.6% participation rate). The PI population was predominantly female (218/254, 85.8%), White (248/254, 97.6%), and with a median age of 49 years. The non-PI population was largely male (170/254, 66.9%), White (236/254, 92.9%), and with a median age of 53 years. Common variable immunodeficiency was the most common PI diagnosis (190/254, 74.8%). Of the 254 individuals with PI, 123 (48.4%) reported a lower-than-normal nonsick body temperature, whereas 108 (42.5%) reported a normal (between 97°F and 99°F) nonsick body temperature. Among individuals with PI, when infected, 67.7% (172/254) reported the absence of fever, whereas 19.7% (50/254) reported a normal fever response. The recorded median body temperature was minimally but statistically significantly higher for patients with PI in the morning. Although 22.4% (57/254) of patients with PI self-reported illness, a fever of 100.4°F or higher was uncommon; 77.2% (196/254) had a normal temperature (between 97°F and 99°F), and 16.2% (41/254) had a lower-than-normal temperature (between 95.0°F and 96.9°F) when sick. For these sick patients with PI, the median body temperature was minimally but statistically significantly higher for patients in the morning and early evening. Overall, 90.9% (231/254) of participants would be very likely to participate in future IDF studies, although 94.1% (239/254) participants had never taken part in previous studies. CONCLUSIONS: To our knowledge, this is the first study to evaluate average body temperature in individuals with PI. Although there were small statistically significant differences in body temperatures between PI and non-PI subjects, the clinical significance is unclear and should be interpreted with caution, given the methodological issues associated with our small convenience sample and study design. As PIs are heterogeneous, more research is needed about how the fever response differs among diverse PIs compared with healthy controls. This study highlights that individuals with PI are knowledgeable about their health and can offer unique insights and direction to researchers and clinicians.

6.
Immunol Res ; 68(6): 379-388, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33161558

RESUMO

Health-related quality of life (HRQOL) is an emerging topic of interest in patients with immunodeficiency. Information about HRQOL in common variable immunodeficiency (CVID) is limited. The primary objective was to compare primary immunodeficiency disease (PIDD) patients with and without common variable immunodeficiency (CVID) on HRQOL domains using Patient-Reported Outcomes Measurement Information System (PROMIS-29) survey data from the United States Immunodeficiency Network (USIDNET) registry. The primary endpoint variables were scores on 7 HRQOL domains. The USIDNET registry was used to select patients with baseline PROMIS-29 data collected between 2015 and 2018. Descriptive statistics, Fisher's exact test, and Student's two-sample t test were used to compare patients with CVID versus patients with non-CVID on demographic and clinical characteristics. The single-sample t test was used to compare sample means to the normed population mean of 50. A general linear model approach to multiple regression with backward selection was used to remove factors that did not contribute significant information to the multivariable models, while controlling for multiple testing. Potential explanatory variables included group (CVID/non-CVID), sex, age, and BMI. Among 184 PIDD patients, 146 (79%) were diagnosed with CVID. Patients had a mean (SD) age of 53 (13.8), were predominantly female (83%), and were Caucasian (98%). PROMIS-29 results revealed a significant effect of group (CVID/non-CVID) on the anxiety, fatigue, and social participation domains, with fatigue being the most statistically significant. Fatigue, anxiety, and social participation may be key factors influencing HRQOL among patients with CVID. Future prospective longitudinal studies using PROMIS-29 will be needed to confirm these findings and to determine the mechanisms through which these factors develop in CVID, and how they can be improved.

7.
J Clin Immunol ; 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33205244

RESUMO

PURPOSE: Primary immunodeficiency disorders (PIDs) affect immune system development and/or function, increase infection susceptibility, and cause dysregulation or both. Recognition of PID requires assessment about the normal state of infection frequency and microbiology. To help clarify infection characteristics, we use data mined from the US Immunodeficiency Network (USIDNET) registry among primary antibody deficiency (PAD) patients before diagnosis. METHODS: We analyzed PAD patient data from the USIDNET registry prior to ultimate diagnosis. Our analysis included basic descriptive statistics for 8 major infection subtypes and significance testing for comparing infection rate by specific organisms across 7 distinct PAD subtypes. RESULTS: Of 2038 patients reviewed, 1259 (61.8%) had infections reported prior to diagnosis. Most (77.4%) had four or less reported infections prior to diagnosis; however, some suffered up to 16 infections. Infection patterns differed across the PAD subtypes. Patients with agammaglobulinemia differed significantly from patients with all other forms of PAD studied in at least one infection category, whereas patients with CVID differed from 3 other PAD categories in at least one infection category. Patterns of infections in patients with hypogammaglobulinemia, specific antibody deficiency, and transient hypogammaglobulinemia were less unique. For each of the infection types, bacteria were the most prevalent cause of disease. CONCLUSIONS: Our data shows that distinct subtypes of PAD display unique infection patterns. We also show that patients with agammaglobulinemia suffer more invasive infections and differ most significantly from all other forms of PAD studied. Our analysis has broad implications about infection surveillance, progression, and vulnerability by PAD subtype.

8.
Curr Opin Allergy Clin Immunol ; 20(6): 574-581, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33044342

RESUMO

PURPOSE OF THE REVIEW: The aim of this article is to summarize recent data on rubella virus (RuV) vaccine in chronic inflammation focusing on granulomas in individuals with primary immunodeficiencies (PIDs). RECENT FINDINGS: The live attenuated RuV vaccine has been recently associated with cutaneous and visceral granulomas in children with various PIDs. RuV vaccine strain can persist for decades subclinically in currently unknown body site(s) before emerging in granulomas. Histologically, RuV is predominately localized in M2 macrophages in the granuloma centers. Multiple mutations accumulate during persistence resulting in emergence of immunodeficiency-related vaccine-derived rubella viruses (iVDRVs) with altered immunological, replication, and persistence properties. Viral RNA was detected in granuloma biopsies and nasopharyngeal secretions and infectious virus were isolated from the granuloma lesions. The risk of iVDRV transmissibility to contacts needs to be evaluated. Several broad-spectrum antiviral drugs have been tested recently but did not provide significant clinical improvement. Hematopoietic stem cell transplantation remains the only reliable option for curing chronic RuV-associated granulomas in PIDs. SUMMARY: Persistence of vaccine-derived RuVs appears to be a crucial factor in a significant proportion of granulomatous disease in PIDs. RuV testing of granulomas in PID individuals might help with case management.

9.
Clin Infect Dis ; 2020 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-32866230

RESUMO

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition of immune dysregulation. Children often suffer from primary genetic forms of HLH, which can be triggered by infection. Others suffer from secondary HLH as a complication of infection, malignancy, or rheumatologic disease. Identifying the exact cause of HLH is crucial, as definitive treatment for primary disease is hematopoietic stem cell transplant. Adenoviruses have been associated with HLH but molecular epidemiology data are lacking. METHODS: We describe the clinical and virologic characteristics of 5 children admitted with adenovirus infection during 2018-2019 who developed HLH or HLH-like illness. Detailed virologic studies, including virus isolation and comprehensive molecular typing were performed. RESULTS: All patients recovered; clinical management varied but included immunomodulating and antiviral therapies. A genetic predisposition for HLH was not identified in any patient. Adenovirus isolates were recovered from 4/5 cases; all were identified as genomic variant 7d. Adenovirus type 7 DNA was detected in the fifth case. Phylogenetic analysis of genome sequences identified two clusters - one related to strains implicated in 2016-2017 outbreaks in Pennsylvania and New Jersey, the other related to a 2009 Chinese strain. CONCLUSIONS: It can be challenging to determine whether HLH is the result of an infectious pathogen alone or genetic predisposition triggered by an infection. We describe 5 children from the same center presenting with an HLH-like illness after onset of adenovirus type 7 infection. None of the patients were found to have a genetic predisposition to HLH. These findings suggest that adenovirus 7 infection alone can result in HLH.

10.
J Clin Immunol ; 2020 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-32949294

RESUMO

PURPOSE: DiGeorge syndrome has substantial heterogeneity with variable immune deficiency and dysregulation. Implicated immunopathology includes reduced thymic output and increased peripheral homeostatic proliferation with Th2 skewing and expansion of self-reactive cells. We hypothesized that T cell lymphopenia severity will be associated with higher odds of autoimmunity and/or asthma. METHODS: Using the US Immunodeficiency Network registry, we identified patients with 22q11.2 deletion (and/or TBX1). Initial absolute CD3+ T cell values were stratified: normal, 50-99% and below 50% of the lower limit of age-adjusted normal values. Patients with and without reported autoimmunity and asthma were compared using chi-square tests and multivariate logistic regression. RESULTS: Among 415 patients, autoimmunity was reported in 17 (4.1%), and asthma was reported in 28 (6.7%). Compared with those with no reported autoimmunity, patients with reported autoimmunity more frequently had low CD19+ B cells [3.3% (12/364) vs 28.6% (4/14); p = 0.002] and low IgG [6.2% (20/321) vs 29.4% (5/17); p = 0.005] levels. There were no statistically significant differences in other immune characteristics among those with and without reported asthma. Patients with absolute CD3 levels below 50% of age-adjusted normal values had higher odds of reported autoimmunity (n = 319, OR = 7.56, 95% CI = 1.58-36.17, p = 0.01) and reported asthma (n = 319, OR = 4.5, 95% CI = 1.06-18.93, p = 0.04) as compared with those with normal CD3 values, adjusted for age and low IgG. CONCLUSIONS: Absolute CD3+ T cell counts below 50% of age-adjusted normal values may be associated with higher odds of autoimmunity and/or asthma in patients with DiGeorge syndrome and be potentially useful to identify higher-risk patients.

11.
J Clin Immunol ; 40(8): 1124-1131, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32880085

RESUMO

Clinical data from ADA-SCID patients registered in the U.S. Immunodeficiency Network (USIDNet) Repository were analyzed. Sixty-four ADA-SCID patients born between 1981 and 2017 had clinical data entered by their local (or home) enrolling institution. Median age at diagnosis was 1 month for those with a positive family history and 3 months for those without a prior family history, with some diagnosed at birth and one as late as 9 years of age. Overall survival was 79.7%, which increased to 94.1% since 2010. These patients had multiple infections and pulmonary, gastrointestinal, and neurological complications. The majority received enzyme replacement therapy (ERT) at some time, including 88% of those born since 2010. Twenty-six patients underwent allogeneic hematopoietic stem cell transplant (HSCT). HSCT successfully supported survival (17/26, 65%) using a variety of cell sources (bone marrow, mobilized peripheral blood, and cord blood) from sibling, family and unrelated donors. Nineteen patients underwent autologous HSCT with gene therapy (GT) using retroviral and lentiviral vectors and all are surviving. The prognosis for patients with ADA-SCID has continued to improve but these patients do have multiple early and potentially long-term conditions that require medical monitoring and management.

12.
Pediatr Blood Cancer ; 67(11): e28693, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32885904

RESUMO

There are no proven safe and effective therapies for children who develop life-threatening complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Convalescent plasma (CP) has demonstrated potential benefit in adults with SARS-CoV-2, but has theoretical risks.We present the first report of CP in children with life-threatening coronavirus disease 2019 (COVID-19), providing data on four pediatric patients with acute respiratory distress syndrome. We measured donor antibody levels and recipient antibody response prior to and following CP infusion. Infusion of CP was not associated with antibody-dependent enhancement (ADE) and did not suppress endogenous antibody response. We found CP was safe and possibly efficacious. Randomized pediatric trials are needed.


Assuntos
/terapia , /terapia , Adolescente , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/sangue , Anticorpos Antivirais/uso terapêutico , Humanos , Imunização Passiva/métodos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , /imunologia , Índice de Gravidade de Doença
14.
J Clin Invest ; 130(11): 5967-5975, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-32730233

RESUMO

BACKGROUNDInitial reports from the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic described children as being less susceptible to coronavirus disease 2019 (COVID-19) than adults. Subsequently, a severe and novel pediatric disorder termed multisystem inflammatory syndrome in children (MIS-C) emerged. We report on unique hematologic and immunologic parameters that distinguish between COVID-19 and MIS-C and provide insight into pathophysiology.METHODSWe prospectively enrolled hospitalized patients with evidence of SARS-CoV-2 infection and classified them as having MIS-C or COVID-19. Patients with COVID-19 were classified as having either minimal or severe disease. Cytokine profiles, viral cycle thresholds (Cts), blood smears, and soluble C5b-9 values were analyzed with clinical data.RESULTSTwenty patients were enrolled (9 severe COVID-19, 5 minimal COVID-19, and 6 MIS-C). Five cytokines (IFN-γ, IL-10, IL-6, IL-8, and TNF-α) contributed to the analysis. TNF-α and IL-10 discriminated between patients with MIS-C and severe COVID-19. The presence of burr cells on blood smears, as well as Cts, differentiated between patients with severe COVID-19 and those with MIS-C.CONCLUSIONPediatric patients with SARS-CoV-2 are at risk for critical illness with severe COVID-19 and MIS-C. Cytokine profiling and examination of peripheral blood smears may distinguish between patients with MIS-C and those with severe COVID-19.FUNDINGFinancial support for this project was provided by CHOP Frontiers Program Immune Dysregulation Team; National Institute of Allergy and Infectious Diseases; National Cancer Institute; the Leukemia and Lymphoma Society; Cookies for Kids Cancer; Alex's Lemonade Stand Foundation for Childhood Cancer; Children's Oncology Group; Stand UP 2 Cancer; Team Connor; the Kate Amato Foundations; Burroughs Wellcome Fund CAMS; the Clinical Immunology Society; the American Academy of Allergy, Asthma, and Immunology; and the Institute for Translational Medicine and Therapeutics.


Assuntos
Betacoronavirus/metabolismo , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Infecções por Coronavirus , Citocinas/sangue , Pandemias , Pneumonia Viral , Síndrome de Resposta Inflamatória Sistêmica , Adolescente , Criança , Pré-Escolar , Infecções por Coronavirus/sangue , Infecções por Coronavirus/epidemiologia , Feminino , Humanos , Masculino , Pneumonia Viral/sangue , Pneumonia Viral/epidemiologia , Estudos Prospectivos , Índice de Gravidade de Doença , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/epidemiologia
15.
Expert Rev Clin Immunol ; 16(7): 717-732, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32720819

RESUMO

INTRODUCTION: During the last 4 decades, registration of patients with primary immunodeficiencies (PID) has played an essential role in different aspects of these diseases worldwide including epidemiological indexes, policymaking, quality controls of care/life, facilitation of genetic studies and clinical trials as well as improving our understanding about the natural history of the disease and the immune system function. However, due to the limitation of sustainable resources supporting these registries, inconsistency in diagnostic criteria and lack of molecular diagnosis as well as difficulties in the documentation and designing any universal platform, the global perspective of these diseases remains unclear. AREAS COVERED: Published and unpublished studies from January 1981 to June 2020 were systematically reviewed on PubMed, Web of Science and Scopus. Additionally, the reference list of all studies was hand-searched for additional studies. This effort identified a total of 104614 registered patients and suggests identification of at least 10590 additional PID patients, mainly from countries located in Asia and Africa. Molecular defects in genes known to cause PID were identified and reported in 13852 (13.2% of all registered) patients. EXPERT OPINION: Although these data suggest some progress in the identification and documentation of PID patients worldwide, achieving the basic requirement for the global PID burden estimation and registration of undiagnosed patients will require more reinforcement of the progress, involving both improved diagnostic facilities and neonatal screening.

18.
Inflamm Bowel Dis ; 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32556182

RESUMO

BACKGROUND: Defining epithelial cell contributions to inflammatory bowel disease (IBD) is essential for the development of much needed therapies for barrier repair. Children with very early onset (VEO)-IBD have more extensive, severe, and refractory disease than older children and adults with IBD and, in some cases, have defective barrier function. We therefore evaluated functional and transcriptomic differences between pediatric IBD (VEO and older onset) and non-IBD epithelium using 3-dimensional, biopsy-derived organoids. METHODS: We measured growth efficiency relative to histopathological and clinical parameters in patient enteroid (ileum) and colonoid (colon) lines. We performed RNA-sequencing on patient colonoids and subsequent flow cytometry after multiple passages to evaluate changes that persisted in culture. RESULTS: Enteroids and colonoids from pediatric patients with IBD exhibited decreased growth associated with histological inflammation compared with non-IBD controls. We observed increased LYZ expression in colonoids from pediatric IBD patients, which has been reported previously in adult patients with IBD. We also observed upregulation of antigen presentation genes HLA-DRB1 and HLA-DRA, which persisted after prolonged passaging in patients with pediatric IBD. CONCLUSIONS: We present the first functional evaluation of enteroids and colonoids from patients with VEO-IBD and older onset pediatric IBD, a subset of which exhibits poor growth. Enhanced, persistent epithelial antigen presentation gene expression in patient colonoids supports the notion that epithelial cell-intrinsic differences may contribute to IBD pathogenesis.

19.
Blood ; 135(23): 2094-2105, 2020 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-32268350

RESUMO

Wiskott-Aldrich syndrome (WAS) is an X-linked disease caused by mutations in the WAS gene, leading to thrombocytopenia, eczema, recurrent infections, autoimmune disease, and malignancy. Hematopoietic cell transplantation (HCT) is the primary curative approach, with the goal of correcting the underlying immunodeficiency and thrombocytopenia. HCT outcomes have improved over time, particularly for patients with HLA-matched sibling and unrelated donors. We report the outcomes of 129 patients with WAS who underwent HCT at 29 Primary Immune Deficiency Treatment Consortium centers from 2005 through 2015. Median age at HCT was 1.2 years. Most patients (65%) received myeloablative busulfan-based conditioning. With a median follow-up of 4.5 years, the 5-year overall survival (OS) was 91%. Superior 5-year OS was observed in patients <5 vs ≥5 years of age at the time of HCT (94% vs 66%; overall P = .0008). OS was excellent regardless of donor type, even in cord blood recipients (90%). Conditioning intensity did not affect OS, but was associated with donor T-cell and myeloid engraftment after HCT. Specifically, patients who received fludarabine/melphalan-based reduced-intensity regimens were more likely to have donor myeloid chimerism <50% early after HCT. In addition, higher platelet counts were observed among recipients who achieved full (>95%) vs low-level (5%-49%) donor myeloid engraftment. In summary, HCT outcomes for WAS have improved since 2005, compared with prior reports. HCT at a younger age continues to be associated with superior outcomes supporting the recommendation for early HCT. High-level donor myeloid engraftment is important for platelet reconstitution after either myeloablative or busulfan-containing reduced intensity conditioning. (This trial was registered at www.clinicaltrials.gov as #NCT02064933.).

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