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1.
Pediatr Infect Dis J ; 39(2): e25-e27, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31929435

RESUMO

We present a case of herpes zoster ophthalmicus in an otherwise healthy 14-month-old male associated with vaccine-strain varicella-zoster virus 11 weeks after monovalent varicella vaccine administration. Herpes zoster ophthalmicus, especially in the setting of familial immunoglobulin A deficiency, prompted further immunologic workup. A high index of suspicion is necessary for timely diagnosis and treatment of vaccine-strain herpes zoster.

2.
Public Health Rep ; 134(2_suppl): 58S-63S, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31682555

RESUMO

The Plain community is the fastest-growing religious minority in Wisconsin. This community has a high incidence of genetic disorders, many of which are identifiable through newborn screening. We describe efforts by the Wisconsin Newborn Screening Program (WNSP) to improve health care in the Plain community by targeting early identification of, and intervention for, patients with inherited metabolic disorders. WNSP formed partnerships with families and health care providers to increase awareness of screening procedures and the intended benefits of screening, modify testing algorithms to enhance detection, and establish medical homes for patients with confirmed disorders. The estimated number of Plain newborns screened increased by 25.5% during the study period, from 547 in 2011 to 736 in 2017; 122 persons underwent carrier testing, and 143 newborns received second-tier testing. From 2014 to 2017, affected patients received 71 metabolic evaluations in their community medical home without travel to major health centers. This article demonstrates how a comprehensive public health program can help increase screening rates, enhance detection, and establish follow-up care in a hard-to-reach religious community. A key lesson learned was the importance of communication among all stakeholders to develop an effective public health program.

3.
J Clin Invest ; 129(11): 4724-4738, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31566583

RESUMO

We report on 2 patients with compound heterozygous mutations in forkhead box N1 (FOXN1), a transcription factor essential for thymic epithelial cell (TEC) differentiation. TECs are critical for T cell development. Both patients had a presentation consistent with T-/loB+NK+ SCID, with normal hair and nails, distinct from the classic nude/SCID phenotype in individuals with autosomal-recessive FOXN1 mutations. To understand the basis of this phenotype and the effects of the mutations on FOXN1, we generated mice using CRISPR-Cas9 technology to genocopy mutations in 1 of the patients. The mice with the Foxn1 compound heterozygous mutations had thymic hypoplasia, causing a T-B+NK+ SCID phenotype, whereas the hair and nails of these mice were normal. Characterization of the functional changes due to the Foxn1 mutations revealed a 5-amino acid segment at the end of the DNA-binding domain essential for the development of TECs but not keratinocytes. The transcriptional activity of this Foxn1 mutant was partly retained, indicating a region that specifies TEC functions. Analysis of an additional 9 FOXN1 mutations identified in multiple unrelated patients revealed distinct functional consequences contingent on the impact of the mutation on the DNA-binding and transactivation domains of FOXN1.

4.
Am J Hum Genet ; 105(3): 549-561, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31447097

RESUMO

FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of T cell receptor excision circles (TRECs) and T cell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent T cell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4+ but lower than normal CD8+ cell counts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1nu/+ (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3 weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of T cell lymphopenia at birth.

5.
BMC Res Notes ; 12(1): 423, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311588

RESUMO

Epidemiologic and cross-sectional studies suggest that early life farming and animal exposures are associated with major health benefits, influencing immune development and modifying the subsequent risk of allergic diseases, including asthma. The Wisconsin Infant Study Cohort (WISC) study was established in central Wisconsin to test the hypothesis that early life animal farm exposures are associated with distinct innate immune cell maturation trajectories, decreased allergen sensitization and reduced respiratory viral illness burden during the first 2 years of life. Beginning in 2013, a total of 240 families have been enrolled, 16,522 biospecimens have been collected, and 4098 questionnaires have been administered and entered into a secure database. Study endpoints include nasal respiratory virus identification and respiratory illness burden score, allergic sensitization, expression of allergic disease, and anti-viral immune response maturation and profiles. The WISC study prospective design, broad biospecimen collections, and unique US rural community will provide insights into the role of environmental exposures on early life immune maturation profiles associated with protection from allergic sensitization and significant respiratory viral disease burden. The WISC study findings will ultimately inform development of new strategies to promote resistance to severe respiratory viral illnesses and design primary prevention approaches for allergic diseases for all infants.


Assuntos
Asma/diagnóstico , Exposição Ambiental/análise , Fazendas , Hipersensibilidade/diagnóstico , Adulto , Animais , Asma/epidemiologia , Asma/etiologia , Estudos Transversais , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Hipersensibilidade/epidemiologia , Hipersensibilidade/etiologia , Lactente , Masculino , Idade Materna , Gravidez , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Estudos Prospectivos , Projetos de Pesquisa , Wisconsin/epidemiologia
6.
Respir Res ; 20(1): 115, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182091

RESUMO

BACKGROUND: Single birth cohort studies have been the basis for many discoveries about early life risk factors for childhood asthma but are limited in scope by sample size and characteristics of the local environment and population. The Children's Respiratory and Environmental Workgroup (CREW) was established to integrate multiple established asthma birth cohorts and to investigate asthma phenotypes and associated causal pathways (endotypes), focusing on how they are influenced by interactions between genetics, lifestyle, and environmental exposures during the prenatal period and early childhood. METHODS AND RESULTS: CREW is funded by the NIH Environmental influences on Child Health Outcomes (ECHO) program, and consists of 12 individual cohorts and three additional scientific centers. The CREW study population is diverse in terms of race, ethnicity, geographical distribution, and year of recruitment. We hypothesize that there are phenotypes in childhood asthma that differ based on clinical characteristics and underlying molecular mechanisms. Furthermore, we propose that asthma endotypes and their defining biomarkers can be identified based on personal and early life environmental risk factors. CREW has three phases: 1) to pool and harmonize existing data from each cohort, 2) to collect new data using standardized procedures, and 3) to enroll new families during the prenatal period to supplement and enrich extant data and enable unified systems approaches for identifying asthma phenotypes and endotypes. CONCLUSIONS: The overall goal of CREW program is to develop a better understanding of how early life environmental exposures and host factors interact to promote the development of specific asthma endotypes.


Assuntos
Asma/diagnóstico , Asma/epidemiologia , Exposição Ambiental/análise , Estilo de Vida , Vigilância da População/métodos , Adolescente , Asma/genética , Criança , Pré-Escolar , Estudos de Coortes , Exposição Ambiental/prevenção & controle , Feminino , Humanos , Lactente , Masculino , Adulto Jovem
7.
Blood ; 132(17): 1737-1749, 2018 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-30154114

RESUMO

The Primary Immune Deficiency Treatment Consortium (PIDTC) performed a retrospective analysis of 662 patients with severe combined immunodeficiency (SCID) who received a hematopoietic cell transplantation (HCT) as first-line treatment between 1982 and 2012 in 33 North American institutions. Overall survival was higher after HCT from matched-sibling donors (MSDs). Among recipients of non-MSD HCT, multivariate analysis showed that the SCID genotype strongly influenced survival and immune reconstitution. Overall survival was similar for patients with RAG, IL2RG, or JAK3 defects and was significantly better compared with patients with ADA or DCLRE1C mutations. Patients with RAG or DCLRE1C mutations had poorer immune reconstitution than other genotypes. Although survival did not correlate with the type of conditioning regimen, recipients of reduced-intensity or myeloablative conditioning had a lower incidence of treatment failure and better T- and B-cell reconstitution, but a higher risk for graft-versus-host disease, compared with those receiving no conditioning or immunosuppression only. Infection-free status and younger age at HCT were associated with improved survival. Typical SCID, leaky SCID, and Omenn syndrome had similar outcomes. Landmark analysis identified CD4+ and CD4+CD45RA+ cell counts at 6 and 12 months post-HCT as biomarkers predictive of overall survival and long-term T-cell reconstitution. Our data emphasize the need for patient-tailored treatment strategies depending upon the underlying SCID genotype. The prognostic significance of CD4+ cell counts as early as 6 months after HCT emphasizes the importance of close follow-up of immune reconstitution to identify patients who may need additional intervention to prevent poor long-term outcome.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Transplante de Células-Tronco Hematopoéticas , Reconstituição Imune/imunologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/mortalidade , Imunodeficiência Combinada Severa/terapia , Genótipo , Humanos , Contagem de Linfócitos , Estudos Retrospectivos
9.
PLoS One ; 12(10): e0180664, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29045416

RESUMO

BACKGROUND: Rhinovirus infections during infancy account for the majority of respiratory illness health care utilization and are an associated risk factor for subsequent development of allergic asthma. Neonatal type I interferon production is diminished compared to adults after stimulation with TLR agonists. However, broad profiling of immune cell responses to infectious rhinovirus has not been undertaken and we hypothesized that additional immune differences can be identified in neonates. In this study, we undertook a comparative analysis of neonatal and adult blood immune cell responses after in vitro incubation with infectious RV-A16 for 6 and 24 hours. METHODS: Intracellular proinflammatory and type I interferon cytokines along with expression of surface co-stimulatory and maturation markers were measured using multi-parameter flow cytometry. RESULTS: Both circulating myeloid dendritic cell (mDC) and plasmacytoid dendritic cell (pDC) frequency were lower in cord blood. Qualitative and quantitative plasmacytoid dendritic cell IFN-alpha + TNF- alpha responses to rhinovirus were significantly lower in cord pDCs. In cord blood samples, the majority of responsive pDCs were single-positive TNF-alpha producing cells, whereas in adult samples rhinovirus increased double-positive TNF-alpha+IFN-alpha+ pDCs. Rhinovirus upregulated activation and maturation markers on monocytes, mDCs, pDCs, and B cells, but CD40+CD86+ monocytes, mDCs, and pDCs cells were significantly higher in adult samples compared to cord samples. Surprisingly, rhinovirus increased CD40+CD86+ B cells to a significantly greater extent in cord samples compared to adults. CONCLUSIONS: These findings define a number of cell-specific differences in neonatal responses to rhinovirus. This differential age-related immune response to RV may have implications for the immune correlates of protection to viral respiratory illness burden and determination of potential biomarkers for asthma risk.


Assuntos
Linfócitos B/imunologia , Células Dendríticas/imunologia , Imunidade , Ativação Linfocitária/imunologia , Rhinovirus/imunologia , Adulto , Biomarcadores/metabolismo , Diferenciação Celular/imunologia , Citocinas/metabolismo , Antígenos HLA-DR/metabolismo , Células HeLa , Humanos , Recém-Nascido , Cordão Umbilical/citologia
11.
J Clin Invest ; 127(7): 2842-2854, 2017 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-28581443

RESUMO

The quantity and activation state of adipose tissue macrophages (ATMs) impact the development of obesity-induced metabolic diseases. Appetite-controlling hormones play key roles in obesity; however, our understanding of their effects on ATMs is limited. Here, we have shown that human and mouse ATMs express NPFFR2, a receptor for the appetite-reducing neuropeptide FF (NPFF), and that NPFFR2 expression is upregulated by IL-4, an M2-polarizing cytokine. Plasma levels of NPFF decreased in obese patients and high-fat diet-fed mice and increased following caloric restriction. NPFF promoted M2 activation and increased the proliferation of murine and human ATMs. Both M2 activation and increased ATM proliferation were abolished in NPFFR2-deficient ATMs. Mechanistically, the effects of NPFF involved the suppression of E3 ubiquitin ligase RNF128 expression, resulting in enhanced stability of phosphorylated STAT6 and increased transcription of the M2 macrophage-associated genes IL-4 receptor α (Il4ra), arginase 1 (Arg1), IL-10 (Il10), and alkylglycerol monooxygenase (Agmo). NPFF induced ATM proliferation concomitantly with the increase in N-Myc downstream-regulated gene 2 (Ndrg2) expression and suppressed the transcription of Ifi200 cell-cycle inhibitor family members and MAF bZIP transcription factor B (Mafb), a negative regulator of macrophage proliferation. NPFF thus plays an important role in supporting healthy adipose tissue via the maintenance of metabolically beneficial ATMs.


Assuntos
Tecido Adiposo/imunologia , Proliferação de Células , Ativação de Macrófagos , Macrófagos/imunologia , Oligopeptídeos/imunologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Arginase/genética , Arginase/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Fator de Transcrição MafB/genética , Fator de Transcrição MafB/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Oligopeptídeos/genética , Proteínas/genética , Proteínas/imunologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia
12.
Genet Med ; 19(3): 352-356, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27513192

RESUMO

PURPOSE: This community project is an initiative through the University of Wisconsin Biochemical Genetics Clinic and the Wisconsin Newborn Screening Program to identify members of the Plain population who are at risk for having children with maple syrup urine disease (MSUD) or propionic acidemia (PA) or who have PA. METHODS: Because of the high prevalence of metabolic conditions in the Plain population and the importance of early intervention, a statewide outreach project was developed to provide targeted variant analysis of the common MSUD and PA pathogenic variants in this population through health-care provider distribution of blood spot testing kits. Awareness was achieved through outreach efforts with the state midwives guild and Plain population meetings. RESULTS: Eighty individuals were tested; diagnosis was confirmed for three adults with PA and one couple was identified as being at risk for having a child with PA. Genetic counseling was provided to those identified. Follow-up diagnostic testing was completed for the at-risk couple's children; none were found to be affected. CONCLUSION: This initiative successfully provided accessible clinical testing for MSUD and PA for a high-risk population. Early identification of at-risk couples sets the foundation for early care of at-risk neonates, thereby improving future clinical outcomes.Genet Med 19 3, 352-356.


Assuntos
Amish/genética , Testes Genéticos/métodos , Doença da Urina de Xarope de Bordo/genética , Acidemia Propiônica/genética , Adolescente , Adulto , Idoso , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/genética , Criança , Pré-Escolar , Feminino , Aconselhamento Genético/métodos , Humanos , Recém-Nascido , Masculino , Doença da Urina de Xarope de Bordo/diagnóstico , Doença da Urina de Xarope de Bordo/prevenção & controle , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Pessoa de Meia-Idade , Triagem Neonatal/métodos , Acidemia Propiônica/diagnóstico , Acidemia Propiônica/prevenção & controle , Wisconsin
13.
Laryngoscope ; 127(4): 882-887, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27653511

RESUMO

OBJECTIVES/HYPOTHESIS: The larynx is a mucosal organ rich in lymphatic tissue that is regularly exposed to a multitude of inhaled, ingested, and refluxed microorganisms and irritants. The first line of mucosal immune defense is the barrier, including resident immune cells. T regulatory (Treg) cells are a specialized subset of CD4+ T cells that suppress or dampen immune responses to prevent damaging immunopathology. As Treg cells have been shown to preferentially accumulate at sites of infection, and Treg responses may contribute to persistence of infection by impairing antibacterial immunity, we sought to quantify these cells in laryngeal tissue exposed to smoking and reflux. STUDY DESIGN: Cross-sectional study. METHODS: Using an epigenetic assay, we quantified Treg and T cells and calculated the ratio of Treg to T cells (i.e., cellular ratio of immune tolerance [ImmunoCRIT]) in disease-free laryngeal biopsies representing four inflammatory states: 1) tobacco-exposed tissue, 2) refluxate and tobacco-exposed tissue, 3) refluxate-exposed tissue, and 4) unexposed tissue. RESULTS: There was epigenetic evidence of Treg cells in all tissues, and we found no differences in Treg cell frequency relative to smoking and reflux in laryngeal tissue collected from 42 non-treatment-seeking participants. There was a decrease in total T cell frequency and an increase in ImmunoCRIT values in smokers regardless of reflux status. CONCLUSIONS: In this study, laryngeal tissue from smokers show decreased overall T cells and increased ImmunoCRIT values. Our findings indicate that laryngeal inflammation is not directly mediated by loss of Treg cells in response to smoking and reflux in local tissue and increased ImmunoCRIT values in smokers implicate a role for this environmental exposure in modulating laryngeal immune homeostasis. More studies are indicated to explore Treg cell dysfunction in the pathophysiology of laryngeal disease. LEVEL OF EVIDENCE: NA Laryngoscope, 127:882-887, 2017.


Assuntos
Refluxo Gastroesofágico/imunologia , Imunidade nas Mucosas/fisiologia , Mucosa Laríngea/imunologia , Refluxo Laringofaríngeo/imunologia , Fumar/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Fatores Etários , Idoso , Estudos Transversais , Feminino , Refluxo Gastroesofágico/fisiopatologia , Homeostase/imunologia , Humanos , Tolerância Imunológica/fisiologia , Refluxo Laringofaríngeo/fisiopatologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores Sexuais , Fumar/efeitos adversos , Adulto Jovem
14.
J Community Health ; 41(2): 282-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26433724

RESUMO

Old Order Amish and Mennonites, or Plain populations, are a growing minority in North America with unique health care delivery and access challenges coupled with higher frequencies of genetic disorders. The objective of this study was to determine newborn screening use and attitudes from western Wisconsin Plain communities. A cross-sectional survey, with an overall response rate of 25 %, provided data representing 2010 children. In households with children (n = 297), the rate of newborn screening was 74 % and all children were screened in 40 % of these households. Lack of access to testing was the most common reason for not screening all children and parental age was inversely associated with testing. The majority of respondents reported some or more knowledge of screening, viewed screening as important, and had access to screening in their communities. Households with children who had never received newborn screening (26 %) reported lower frequencies of favorable responses in all categories compared to households that had at least one child screened. The difference in access to newborn screening was less marked between the groups compared to differences on knowledge and consideration of its importance. Moreover, 55 % of households who had never screened any of their children reported being unlikely or unsure of screening any future children. A focus on improving access to newborn screening alongside establishing approaches to change parental perceptions on the importance of newborn screening is necessary for increasing newborn screening in these Plain communities.


Assuntos
Amish , Doenças Genéticas Inatas/diagnóstico , Testes Genéticos , Estudos Transversais , Humanos , Recém-Nascido , Medicina Preventiva , Inquéritos e Questionários , Wisconsin
15.
Science ; 345(6204): 1623-1627, 2014 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-25213377

RESUMO

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory receptor found on immune cells. The consequences of mutations in CTLA4 in humans are unknown. We identified germline heterozygous mutations in CTLA4 in subjects with severe immune dysregulation from four unrelated families. Whereas Ctla4 heterozygous mice have no obvious phenotype, human CTLA4 haploinsufficiency caused dysregulation of FoxP3(+) regulatory T (Treg) cells, hyperactivation of effector T cells, and lymphocytic infiltration of target organs. Patients also exhibited progressive loss of circulating B cells, associated with an increase of predominantly autoreactive CD21(lo) B cells and accumulation of B cells in nonlymphoid organs. Inherited human CTLA4 haploinsufficiency demonstrates a critical quantitative role for CTLA-4 in governing T and B lymphocyte homeostasis.


Assuntos
Antígeno CTLA-4/genética , Mutação em Linhagem Germinativa , Haploinsuficiência , Doenças do Sistema Imunitário/genética , Imunidade/genética , Adulto , Animais , Linfócitos B/imunologia , Feminino , Fatores de Transcrição Forkhead/imunologia , Humanos , Masculino , Camundongos , Camundongos Mutantes , Linhagem , Linfócitos T Reguladores/imunologia , Adulto Jovem
17.
N Engl J Med ; 370(25): 2408-17, 2014 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-24896819

RESUMO

A 14-year-old boy with severe combined immunodeficiency presented three times to a medical facility over a period of 4 months with fever and headache that progressed to hydrocephalus and status epilepticus necessitating a medically induced coma. Diagnostic workup including brain biopsy was unrevealing. Unbiased next-generation sequencing of the cerebrospinal fluid identified 475 of 3,063,784 sequence reads (0.016%) corresponding to leptospira infection. Clinical assays for leptospirosis were negative. Targeted antimicrobial agents were administered, and the patient was discharged home 32 days later with a status close to his premorbid condition. Polymerase-chain-reaction (PCR) and serologic testing at the Centers for Disease Control and Prevention (CDC) subsequently confirmed evidence of Leptospira santarosai infection.


Assuntos
Encéfalo/patologia , Líquido Cefalorraquidiano/microbiologia , DNA Bacteriano/análise , Leptospira/genética , Leptospirose/diagnóstico , Meningoencefalite/diagnóstico , Análise de Sequência de DNA/métodos , Adenosina Desaminase/deficiência , Adolescente , Agamaglobulinemia/complicações , Biópsia , Febre/etiologia , Cefaleia/etiologia , Humanos , Leptospira/isolamento & purificação , Leptospirose/complicações , Leptospirose/microbiologia , Masculino , Meningoencefalite/complicações , Meningoencefalite/microbiologia , Imunodeficiência Combinada Severa/complicações
18.
Blood ; 123(17): 2703-14, 2014 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-24421327

RESUMO

PSTPIP1 is a cytoskeletal adaptor and F-BAR protein that has been implicated in autoinflammatory disease, most notably in the PAPA syndrome: pyogenic sterile arthritis, pyoderma gangrenosum, and acne. However, the mechanism by which PSTPIP1 regulates the actin cytoskeleton and contributes to disease pathogenesis remains elusive. Here, we show that endogenous PSTPIP1 negatively regulates macrophage podosome organization and matrix degradation. We identify a novel PSTPIP1-R405C mutation in a patient presenting with aggressive pyoderma gangrenosum. Identification of this mutation reveals that PSTPIP1 regulates the balance of podosomes and filopodia in macrophages. The PSTPIP1-R405C mutation is in the SRC homology 3 (SH3) domain and impairs Wiskott-Aldrich syndrome protein (WASP) binding, but it does not affect interaction with protein-tyrosine phosphatase (PTP)-PEST. Accordingly, WASP inhibition reverses the elevated F-actin content, filopodia formation, and matrix degradation induced by PSTPIP1-R405C. Our results uncover a novel role for PSTPIP1 and WASP in orchestrating different types of actin-based protrusions. Our findings implicate the cytoskeletal regulatory functions of PSTPIP1 in the pathogenesis of pyoderma gangrenosum and suggest that the cytoskeleton is a rational target for therapeutic intervention in autoinflammatory disease.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas do Citoesqueleto/metabolismo , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Macrófagos/metabolismo , Acne Vulgar/metabolismo , Actinas/metabolismo , Algoritmos , Artrite Infecciosa/metabolismo , Quimiotaxia , Citoesqueleto/metabolismo , DNA/metabolismo , Glutationa Transferase/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Humanos , Inflamação/metabolismo , Microscopia de Fluorescência , Mutação , Fenótipo , Estrutura Terciária de Proteína , Pseudópodes/metabolismo , Pioderma Gangrenoso/metabolismo , RNA Interferente Pequeno/metabolismo , Proteína da Síndrome de Wiskott-Aldrich/metabolismo
19.
Am J Med Genet A ; 161A(6): 1432-5, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23613309

RESUMO

A male child with clinical features consistent with EEC/EECUT plus syndrome (ectrodactyly, ectodermal dysplasia, clefting, urinary tract abnormalities, and thymic abnormalities) including mild ectodermal abnormalities, ectrodactyly of hands and feet, cleft palate, bilateral hydronephrosis, and T cell lymphopenia is reported. He was noted to have T cell receptor excision circle (TREC) analysis below the cutoff for normal on newborn screening and T cell lymphopenia on further immunologic evaluation. A novel, presumably pathogenic de novo 3 bp deletion in exon 7 of TP63 (c.970_972delATT; NCBI Reference Sequence NM_003722.4) was identified. This observation provides supporting evidence for the association between TP63 mutations and EECUT plus syndrome. Clinicians caring for infants presenting with EEC spectrum disorders in the newborn period should also consider the possibility of T cell lymphopenia.


Assuntos
Fissura Palatina/genética , Displasia Ectodérmica/genética , Deformidades Congênitas dos Membros/genética , Linfopenia/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Sequência de Bases , Criança , Fenda Labial/diagnóstico , Fenda Labial/genética , Fissura Palatina/diagnóstico , Displasia Ectodérmica/diagnóstico , Éxons/genética , Genótipo , Humanos , Hidronefrose/diagnóstico , Hidronefrose/genética , Hibridização in Situ Fluorescente , Deformidades Congênitas dos Membros/diagnóstico , Linfopenia/diagnóstico , Masculino , Fenótipo , Deleção de Sequência , Linfócitos T/patologia
20.
Clin Mol Allergy ; 11(1): 1, 2013 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-23347774

RESUMO

BACKGROUND: T regulatory (Treg) cells are important in balancing immune responses and dysregulation of Treg cells has been implicated in the pathogenesis of multiple disease states including asthma. In this study, our primary aim was to determine Treg cell frequency in the peripheral blood of children with and without asthma. The secondary aim was to explore the association between Treg cell frequency with allergen sensitization, disease severity and medication use. METHODS: Peripheral blood mononuclear cells from healthy control subjects (N = 93) and asthmatic children of varying disease severity (N = 66) were characterized by multi-parameter flow cytometry. RESULTS: Our findings demonstrate that children with asthma had a significantly increased frequency of Treg cells compared to children without asthma. Using a multivariate model, increased Treg cell frequency in children with asthma was most directly associated with inhaled corticosteroid use, and not asthma severity, allergic sensitization, or atopic status of the asthma. CONCLUSION: We conclude that low dose, local airway administration of corticosteroids is sufficient to impact the frequency of Treg cells in the peripheral blood. These data highlight the importance of considering medication exposure when studying Treg cells and suggest inhaled corticosteroid use in asthmatics may improve disease control through increased Treg cell frequency.

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