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1.
Proc (Bayl Univ Med Cent) ; 31(3): 324-325, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29904299

RESUMO

Acute pancreatitis is an inflammatory condition of the pancreas manifesting with abdominal pain and elevated serum levels of pancreatic enzymes. Gallstones and chronic alcohol use are the most commonly described causes. A less studied cause is cholesterolosis, gallbladder polyps that cause mechanical obstruction of the sphincter of Oddi. Here, we present the case of a 55-year-old woman who presented with acute pancreatitis and was found to have cholesterol polyps in her gallbladder with no evidence of gallstones. The patient underwent cholecystectomy with complete resolution of her symptoms.

2.
Front Immunol ; 9: 544, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29651287

RESUMO

Anti-cytokine autoantibodies (ACAAs) have been described in a growing number of primary immunodeficiencies with autoimmune features, including autoimmune polyendocrine syndrome type I (APS-1), a prototypical disease of defective T cell-mediated central tolerance. Whether defects in peripheral tolerance lead to similar ACAAs is unknown. Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) is caused by mutations in FOXP3, a master regulator of T regulatory cells (Treg), and consequently results in defective T cell-mediated peripheral tolerance. Unique autoantibodies have previously been described in IPEX. To test the hypothesis that ACAAs are present in IPEX, we designed and fabricated antigen microarrays. We discovered elevated levels of IgG ACAAs against interferon-α (IFN-α) in a cohort of IPEX patients. Serum from IPEX patients blocked IFN-α signaling in vitro and blocking activity was tightly correlated with ACAA titer. To show that blocking activity was mediated by IgG and not other serum factors, we purified IgG and showed that blocking activity was contained entirely in the immunoglobulin fraction. We also screened for ACAAs against IFN-α in a second geographically distinct cohort. In these samples, ACAAs against IFN-α were elevated in a post hoc analysis. In summary, we report the discovery of ACAAs against IFN-α in IPEX, an experiment of nature demonstrating the important role of peripheral T cell tolerance.

4.
J Allergy Clin Immunol Pract ; 5(5): 1344-1350.e3, 2017 Sep - Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28286158

RESUMO

BACKGROUND: Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder associated with recurrent otitis. Most SMS cases result from heterozygous interstitial chromosome 17p11.2 deletions that encompass not only the intellectual disability gene retinoic acid-induced 1 but also other genes associated with immunodeficiency, autoimmunity, and/or malignancy. OBJECTIVES: The goals of this study were to describe the immunological consequence of 17p11.2 deletions by determining the prevalence of immunological diseases in subjects with SMS and by assessing their immune systems via laboratory methods. METHODS: We assessed clinical histories of 76 subjects with SMS with heterozygous 17p11.2 deletions and performed in-depth immunological testing on 25 representative cohort members. Laboratory testing included determination of serum antibody concentrations, vaccine titers, and lymphocyte subset frequencies. Detailed reactivity profiles of SMS serum antibodies were performed using custom-made antigen microarrays. RESULTS: Of 76 subjects with SMS, 74 reported recurrent infections including otitis (88%), pneumonia (47%), sinusitis (42%), and gastroenteritis (34%). Infections were associated with worsening SMS-related neurobehavioral symptoms. The prevalence of autoimmune and atopic diseases was not increased. Malignancy was not reported. Laboratory evaluation revealed most subjects with SMS to be deficient of isotype-switched memory B cells and many to lack protective antipneumococcal antibodies. SMS antibodies were not more reactive than control antibodies to self-antigens. CONCLUSIONS: Patients with SMS with heterozygous 17p.11.2 deletions display an increased susceptibility to sinopulmonary infections, but not to autoimmune, allergic, or malignant diseases. SMS sera display an antibody reactivity profile favoring neither recognition of pathogen-associated antigens nor self-antigens. Prophylactic strategies to prevent infections may also provide neurobehavioral benefits to selected patients with SMS.


Assuntos
Linfócitos B/imunologia , Síndromes de Imunodeficiência/epidemiologia , Síndrome de Smith-Magenis/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Proteína DEAD-box 58/genética , Feminino , Humanos , Switching de Imunoglobulina , Memória Imunológica , Lactente , Deficiência Intelectual , Masculino , Mutação/genética , Otite , Pneumonia , Prevalência , Sinusite , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/imunologia , Adulto Jovem
6.
J Allergy Clin Immunol ; 137(1): 204-213.e3, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26365387

RESUMO

BACKGROUND: Anti-cytokine autoantibodies (ACAAs) are pathogenic in a handful of rare immunodeficiencies. However, the prevalence and significance of other ACAAs across immunodeficiencies have not yet been described. OBJECTIVE: We profiled ACAAs in a diverse cohort of serum samples from patients with immunodeficiency and assessed the sensitivity and specificity of protein microarrays for ACAA identification and discovery. METHODS: Highly multiplexed protein microarrays were designed and fabricated. Blinded serum samples from a cohort of 58 immunodeficiency patients and healthy control subjects were used to probe microarrays. Unsupervised hierarchical clustering was used to identify clusters of reactivity, and after unblinding, significance analysis of microarrays was used to identify disease-specific autoantibodies. A bead-based assay was used to validate protein microarray results. Blocking activity of serum containing ACAAs was measured in vitro. RESULTS: Protein microarrays were highly sensitive and specific for the detection of ACAAs in patients with autoimmune polyendocrine syndrome type I and pulmonary alveolar proteinosis, detecting ACAA levels consistent with those reported in the published literature. Protein microarray results were validated by using an independent bead-based assay. To confirm the functional significance of these ACAAs, we tested and confirmed the blocking activity of select ACAAs in vitro. CONCLUSION: Protein microarrays are a powerful tool for ACAA detection and discovery, and they hold promise as a diagnostic for the evaluation and monitoring of clinical immunodeficiency.


Assuntos
Autoanticorpos/sangue , Citocinas/imunologia , Síndromes de Imunodeficiência/imunologia , Humanos , Síndromes de Imunodeficiência/sangue , Análise Serial de Proteínas
7.
J Clin Invest ; 125(11): 4135-48, 2015 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-26457731

RESUMO

Patients with mutations of the recombination-activating genes (RAG) present with diverse clinical phenotypes, including severe combined immune deficiency (SCID), autoimmunity, and inflammation. However, the incidence and extent of immune dysregulation in RAG-dependent immunodeficiency have not been studied in detail. Here, we have demonstrated that patients with hypomorphic RAG mutations, especially those with delayed-onset combined immune deficiency and granulomatous/autoimmune manifestations (CID-G/AI), produce a broad spectrum of autoantibodies. Neutralizing anti-IFN-α or anti-IFN-ω antibodies were present at detectable levels in patients with CID-G/AI who had a history of severe viral infections. As this autoantibody profile is not observed in a wide range of other primary immunodeficiencies, we hypothesized that recurrent or chronic viral infections may precipitate or aggravate immune dysregulation in RAG-deficient hosts. We repeatedly challenged Rag1S723C/S723C mice, which serve as a model of leaky SCID, with agonists of the virus-recognizing receptors TLR3/MDA5, TLR7/-8, and TLR9 and found that this treatment elicits autoantibody production. Altogether, our data demonstrate that immune dysregulation is an integral aspect of RAG-associated immunodeficiency and indicate that environmental triggers may modulate the phenotypic expression of autoimmune manifestations.


Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Citocinas/imunologia , Proteínas de Ligação a DNA/deficiência , Doença Granulomatosa Crônica/imunologia , Proteínas de Homeodomínio/imunologia , Proteínas Nucleares/deficiência , Imunodeficiência Combinada Severa/imunologia , Adolescente , Adulto , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Especificidade de Anticorpos , Autoanticorpos/sangue , Doenças Autoimunes/genética , Criança , Pré-Escolar , RNA Helicases DEAD-box/imunologia , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Feminino , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/terapia , Proteínas de Homeodomínio/genética , Humanos , Lactente , Helicase IFIH1 Induzida por Interferon , Masculino , Camundongos , Camundongos Endogâmicos , Proteínas Nucleares/genética , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/terapia , Receptores Toll-Like/agonistas , Receptores Toll-Like/imunologia , Viroses/imunologia , Adulto Jovem
8.
Front Immunol ; 6: 138, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25904912

RESUMO

Autoimmunity is highly coincident with immunodeficiency. In a small but growing number of primary immunodeficiencies, autoantibodies are diagnostic of a given disease and implicated in disease pathogenesis. In order to improve our understanding of the role of autoantibodies in immunodeficiencies and to discover novel autoantibodies, new proteomic tools are needed. Protein microarrays have the ability to screen for reactivity to hundreds to many thousands of unique autoantigens simultaneously on a single chip using minimal serum input. Here, we review different types of protein microarrays and how they can be useful in framing the study of primary and secondary immunodeficiencies.

10.
Mol Ther ; 22(7): 1375-1387, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24682172

RESUMO

Effective therapeutic vaccines often require activation of T cell-mediated immunity. Robust T cell activation, including CD8 T cell responses, can be achieved using antibodies or antibody fragments to direct antigens of interest to professional antigen presenting cells. This approach represents an important advance in enhancing vaccine efficacy. Nucleic acid aptamers present a promising alternative to protein-based targeting approaches. We have selected aptamers that specifically bind the murine receptor, DEC205, a C-type lectin expressed predominantly on the surface of CD8α(+) dendritic cells (DCs) that has been shown to be efficient at facilitating antigen crosspresentation and subsequent CD8(+) T cell activation. Using a minimized aptamer conjugated to the model antigen ovalbumin (OVA), DEC205-targeted antigen crosspresentation was verified in vitro and in vivo by proliferation and cytokine production by primary murine CD8(+) T cells expressing a T cell receptor specific for the major histocompatibility complex (MHC) I-restricted OVA257-264 peptide SIINFEKL. Compared with a nonspecific ribonucleic acid (RNA) of similar length, DEC205 aptamer-OVA-mediated antigen delivery stimulated strong proliferation and production of interferon (IFN)-γ and interleukin (IL)-2. The immune responses elicited by aptamer-OVA conjugates were sufficient to inhibit the growth of established OVA-expressing B16 tumor cells. Our results demonstrate a new application of aptamer technology for the development of effective T cell-mediated vaccines.


Assuntos
Apresentação do Antígeno/imunologia , Antígenos/imunologia , Aptâmeros de Nucleotídeos/administração & dosagem , Aptâmeros de Nucleotídeos/genética , Animais , Antígenos/administração & dosagem , Linfócitos T CD8-Positivos/imunologia , Células CHO , Cricetinae , Cricetulus , Células Dendríticas/metabolismo , Imunidade Celular , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
12.
Arthritis Res Ther ; 14(1): R25, 2012 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-22300536

RESUMO

INTRODUCTION: Autoreactivity to histones is a pervasive feature of several human autoimmune disorders, including systemic lupus erythematosus (SLE). Specific post-translational modifications (PTMs) of histones within neutrophil extracellular traps (NETs) may potentially drive the process by which tolerance to these chromatin-associated proteins is broken. We hypothesized that NETs and their unique histone PTMs might be capable of inducing autoantibodies that target histones. METHODS: We developed a novel and efficient method for the in vitro production, visualization, and broad profiling of histone-PTMs of human and murine NETs. We also immunized Balb/c mice with murine NETs and profiled their sera on autoantigen and histone peptide microarrays for evidence of autoantibody production to their immunogen. RESULTS: We confirmed specificity toward acetyl-modified histone H2B as well as to other histone PTMs in sera from patients with SLE known to have autoreactivity against histones. We observed enrichment for distinctive histone marks of transcriptionally silent DNA during NETosis triggered by diverse stimuli. However, NETs derived from human and murine sources did not harbor many of the PTMs toward which autoreactivity was observed in patients with SLE or in MRL/lpr mice. Further, while murine NETs were weak autoantigens in vivo, there was only partial overlap in the immunoglobulin G (IgG) and IgM autoantibody profiles induced by vaccination of mice with NETs and those seen in patients with SLE. CONCLUSIONS: Isolated in vivo exposure to NETs is insufficient to break tolerance and may involve additional factors that have yet to be identified.


Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Histonas/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Neutrófilos/imunologia , Animais , Apoptose/imunologia , Linhagem Celular , Células Cultivadas , Cromatina/metabolismo , Grânulos Citoplasmáticos/metabolismo , Epigenômica/métodos , Células HL-60 , Histonas/genética , Histonas/metabolismo , Humanos , Immunoblotting , Imunoglobulina G/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos MRL lpr , Neutrófilos/citologia , Neutrófilos/metabolismo , Processamento de Proteína Pós-Traducional , Proteômica/métodos
13.
JSLS ; 16(4): 639-43, 2012 Oct-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23484577

RESUMO

INTRODUCTION: Portal vein thrombosis has been documented after laparoscopic general surgery and has been uncommonly observed after laparoscopic bariatric surgery. Among bariatric operations, the sleeve gastrectomy is being performed with ever-increasing frequency. Here we report the case of a man who presented with portal vein thrombosis after laparoscopic sleeve gastrectomy. CASE DESCRIPTION: A 41-y-old man underwent an uneventful laparoscopic sleeve gastrectomy for the treatment of morbid obesity, and presented on postoperative day 10 with nonfocal abdominal pain, nausea, vomiting, and leukocytosis. Computed tomography revealed portal vein thrombosis, which was found in the setting of Clostridium difficile colitis. DISCUSSION: Portal vein thrombosis may be identified with increasing frequency as the number of laparoscopic bariatric operations continues to increase. A high index of suspicion is necessary to diagnose this rare, but potentially lethal, complication.


Assuntos
Gastrectomia/efeitos adversos , Laparoscopia/efeitos adversos , Obesidade Mórbida/cirurgia , Veia Porta , Trombose Venosa/etiologia , Adulto , Fibrinolíticos/uso terapêutico , Seguimentos , Gastrectomia/métodos , Humanos , Masculino , Complicações Pós-Operatórias , Tomografia Computadorizada por Raios X , Ultrassonografia Doppler , Trombose Venosa/diagnóstico , Trombose Venosa/tratamento farmacológico
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