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1.
Clin Infect Dis ; 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429907

RESUMO

BACKGROUND: While clinical manifestations of anti-interferon-γ (IFN-γ) autoantibody-associated immunodeficiency syndrome have been reported, its natural history is not well understood. METHODS: Clinical data of 74 patients with anti-IFN-γ autoantibodies at Srinagarind Hospital in Thailand were collected at annual follow-up visits (median follow-up duration: 7.5 years). Clinical data at annual follow-up visits for 19 patients and at the initial visit for 4 patients with anti-IFN-γ autoantibodies at the National Institutes of Health in the US were collected by chart review (median follow-up duration: 4.5 years). Anti-IFN-γ autoantibody levels were measured in serial plasma samples. RESULTS: Ninety-one percent of US patients were of Southeast Asian descent and there was a stronger female predominance (91%) in the US than Thailand (64%). M. abscessus (34%) and M. avium complex (83%) were the most commonly isolated nontuberculous mycobacteria in Thailand and the US, respectively. Skin infections were more common in Thailand (P=0.001) whereas bone (P<0.0001), lung (P=0.002), and central nervous system (P=0.03) infections were more common in the US. Twenty-four percent of Thai patients died, mostly from infections. None of the 19 US patients with follow-up data died. Overall, anti-IFN-γ autoantibody levels decreased over time in Thailand (P<0.001) and the US (P=0.017), as well as with cyclophosphamide (P=0.01) and rituximab therapy (P=0.001). CONCLUSIONS: Patients with anti-IFN-γ autoantibodies in Thailand and US had distinct demographic and clinical features. While titers generally decreased with time, anti-IFN-γ autoantibody disease has a chronic clinical course with persistent infections and death. Close long-term surveillance for new infections is recommended.

2.
Front Immunol ; 10: 1433, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354696

RESUMO

Signal transducer and activator of transcription (STAT1)1 gain of function (GOF) pathogenic variants have been associated with increased levels of phosphorylated STAT1 and STAT1-dependent cellular responses. Delayed dephosphorylation was proposed as the underlying mechanism leading to the characteristically raised pSTAT1 levels. We examined the levels of STAT1 protein and message as well as rates of STAT1 phosphorylation, dephosphorylation, and degradation associated with STAT1 GOF pathogenic variants. Fresh peripheral blood mononuclear cells (PBMC) from 14 STAT1 GOF patients carrying 10 different pathogenic variants in the coiled-coil, DNA binding, and SH2 domains and healthy donors were used to study STAT1 levels and phosphorylation (pSTAT1) following IFNγ and IFNα stimulation. STAT1 protein levels were measured by flow cytometry and immunoblot. STAT1 mRNA levels were measured using quantitative reverse transcription PCR. STAT1 protein degradation was studied using cycloheximide. Patient IFNγ and IFNα induced peak pSTAT1 was higher than in healthy controls. The velocity of pSTAT1 dephosphorylation after treatment of IFNγ stimulated CD14+ monocytes with the Janus Kinase (JAK)-inhibitor ruxolitinib was significantly faster in patient cells. STAT1 protein levels in patient CD14+ monocytes and CD3+ T cells were higher than in healthy donors. There was a strong and positive correlation between CD14+ STAT1 protein levels and peak pSTAT1 levels. Patient fresh PBMC STAT1 mRNA levels were increased at rest and after 16 h of incubation. STAT1 protein degradation was similar in patient and healthy volunteer cells. Patient IFNγ receptors 1 and 2 and JAK2 levels were normal. One patient in our cohort was treated with the oral JAK inhibitor ruxolitinib. Treatment was associated with normalization of both STAT1 protein and peak pSTAT1 levels. After JAK inhibitor treatment was stopped the patient's CD14+ monocyte STAT1 protein and peak phosphorylation levels increased proportionally. These findings suggest that patients with STAT1 GOF mutations have higher levels of total STAT1 protein, leading to high levels of pSTAT1 after stimulation, despite rapid STAT1 dephosphorylation and normal degradation.

3.
Elife ; 82019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31244471

RESUMO

The AIRE gene plays a key role in the development of central immune tolerance by promoting thymic presentation of tissue-specific molecules. Patients with AIRE-deficiency develop multiple autoimmune manifestations and display autoantibodies against the affected tissues. In 2016 it was reported that: i) the spectrum of autoantibodies in patients with AIRE-deficiency is much broader than previously appreciated; ii) neutralizing autoantibodies to type I interferons (IFNs) could provide protection against type 1 diabetes in these patients (Meyer et al., 2016). We attempted to replicate these new findings using a similar experimental approach in an independent patient cohort, and found no evidence for either conclusion.


Assuntos
Diabetes Mellitus Tipo 1 , Interferon Tipo I , Poliendocrinopatias Autoimunes , Autoanticorpos , Humanos , Fatores de Transcrição
5.
J Allergy Clin Immunol ; 141(5): 1844-1853.e2, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28859974

RESUMO

BACKGROUND: Sumoylation is a posttranslational reversible modification of cellular proteins through the conjugation of small ubiquitin-related modifier (SUMO) and comprises an important regulator of protein function. OBJECTIVE: We sought to characterize the molecular mechanism of a novel mutation at the SUMO motif on signal transducer and activator of transcription 1 (STAT1). METHODS: STAT1 sequencing and functional characterization were performed in transfection experiments by using immunoblotting and immunoprecipitation in STAT1-deficient cell lines. Transcriptional response and target gene activation were also investigated in PBMCs. RESULTS: We identified a novel STAT1 mutation (c.2114A>T, p.E705V) within the SUMO motif (702IKTE705) in a patient with disseminated Rhodococcus species infection, Norwegian scabies, chronic mucocutaneous candidiasis, hypothyroidism, and esophageal squamous cell carcinoma. The mutation is located in the tail segment and is predicted to disrupt STAT1 sumoylation. Immunoprecipitation experiments performed in transfected cells confirmed absent STAT1 sumoylation for E705V, whereas it was present in wild-type (WT) STAT1 cells, as well as the loss-of-function mutants L706S and Y701C. Furthermore, stimulation with IFN-γ led to enhanced STAT1 phosphorylation, enhanced transcriptional activity, and target gene expression in the E705V-transfected compared with WT-transfected cells. Computer modeling of WT and mutant STAT1 molecules showed variations in the accessibility of the phosphorylation site Y701, which corresponded to the loss-of-function and gain-of-function variants. CONCLUSION: This is the first report of a mutation in the STAT1 sumoylation motif associated with clinical disease. These data reinforce sumoylation as a key posttranslational regulatory modification of STAT1 and identify a novel mechanism for gain-of-function STAT1 disease in human subjects.

6.
Open Forum Infect Dis ; 4(4): ofx202, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29226168

RESUMO

Heterozygous STAT1 gain-of-function (GOF) mutations are associated with chronic mucocutaneous candidiasis and a broad spectrum of infectious, inflammatory, and vascular manifestations. We describe therapeutic failures with the Janus Kinase (JAK) inhibitor ruxolitinib in 2 STAT1 GOF patients with severe invasive or cutaneous fungal infections.

7.
Open Forum Infect Dis ; 4(4): ofx211, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29181420

RESUMO

Cryptococcus gattii infections, especially including those with severe clinical manifestations, may be related to underlying host immunologic factors. We present 2 cases with autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF), a key cytokine in macrophage function. Immunologic evaluation for anti-GM-CSF antibodies may be important to inform management and counseling.

8.
Front Immunol ; 8: 820, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28769929

RESUMO

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by biallelic autoimmune regulator (AIRE) mutations that manifests with chronic mucocutaneous candidiasis (CMC) and autoimmunity. Patients with STAT1 gain-of-function (GOF) mutations also develop CMC and autoimmunity; they exhibit increased STAT1 protein levels at baseline and STAT1 phosphorylation (pSTAT1) upon interferon (IFN)-γ stimulation relative to healthy controls. AIRE interacts functionally with a protein that directly regulates STAT1, namely protein inhibitor of activated STAT1, which inhibits STAT1 activation. Given the common clinical features between patients with AIRE and STAT1 GOF mutations, we sought to determine whether APECED patients also exhibit increased levels of STAT1 protein and phosphorylation in CD14+ monocytes. We obtained peripheral blood mononuclear cells from 8 APECED patients and 13 healthy controls and assessed the levels of STAT1 protein and STAT1 tyrosine phosphorylation at rest and following IFN-γ stimulation, as well as the levels of STAT1 mRNA. The mean STAT1 protein levels in CD14+ monocytes exhibited a ~20% significant decrease in APECED patients both at rest and after IFN-γ stimulation relative to that of healthy donors. Similarly, the mean peak value of IFN-γ-induced pSTAT1 level was ~20% significantly lower in APECED patients compared to that in healthy controls. The decrease in STAT1 and peak pSTAT1 in APECED patients was not accompanied by decreased STAT1 mRNA or anti-IFN-γ autoantibodies; instead, it correlated with the presence of autoantibodies to type I IFN and decreased AIRE-/- monocyte surface expression of IFN-γ receptor 2. Our data show that, in contrast to patients with STAT1 GOF mutations, APECED patients show a moderate but consistent and significant decrease in total STAT1 protein levels, associated with lower peak levels of pSTAT1 molecules after IFN-γ stimulation.

9.
Open Forum Infect Dis ; 4(2): ofx082, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28638843

RESUMO

Idiopathic CD4+ lymphopenia (ICL) predisposes to opportunistic infections (OIs) but can often remain asymptomatic and does not have a strong association with monogenic mutations. Likewise, cryptococcal meningoencephalitis, the most common OI in ICL, is not strongly associated with monogenic mutations. In this study, we describe 2 patients with ICL plus an additional immune defect: one from an E57K genetic mutation in the nuclear factor-κß essential modulator, and the other with acquired autoantibodies to granulocyte-macrophage colony-stimulating factor. Thus, these cases may exemplify a "multi-hit model" in patients with ICL who acquire OIs.

10.
Clin Infect Dis ; 64(3): 275-283, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-28011613

RESUMO

BACKGROUND: Cryptococcus can cause meningoencephalitis (CM) among previously healthy non-HIV adults. Spinal arachnoiditis is under-recognized, since diagnosis is difficult with concomitant central nervous system (CNS) pathology. METHODS: We describe 6 cases of spinal arachnoiditis among 26 consecutively recruited CM patients with normal CD4 counts who achieved microbiologic control. We performed detailed neurological exams, cerebrospinal fluid (CSF) immunophenotyping and biomarker analysis before and after adjunctive immunomodulatory intervention with high dose pulse corticosteroids, affording causal inference into pathophysiology. RESULTS: All 6 exhibited severe lower motor neuron involvement in addition to cognitive changes and gait disturbances from meningoencephalitis. Spinal involvement was associated with asymmetric weakness and urinary retention. Diagnostic specificity was improved by MRI imaging which demonstrated lumbar spinal nerve root enhancement and clumping or lesions. Despite negative fungal cultures, CSF inflammatory biomarkers, sCD27 and sCD21, as well as the neuronal damage biomarker, neurofilament light chain (NFL), were elevated compared to healthy donor (HD) controls. Elevations in these biomarkers were associated with clinical symptoms and showed improvement with adjunctive high dose pulse corticosteroids. CONCLUSIONS: These data suggest that a post-infectious spinal arachnoiditis is an important complication of CM in previously healthy individuals, requiring heightened clinician awareness. Despite microbiological control, this syndrome causes significant pathology likely due to increased inflammation and may be amenable to suppressive therapeutics.


Assuntos
Aracnoidite/congênito , Cryptococcus , Encefalite Infecciosa/complicações , Meningite Criptocócica/complicações , Meningoencefalite/complicações , Adulto , Anti-Inflamatórios/uso terapêutico , Aracnoidite/diagnóstico por imagem , Aracnoidite/tratamento farmacológico , Aracnoidite/imunologia , Aracnoidite/microbiologia , Biomarcadores/líquido cefalorraquidiano , Relação CD4-CD8 , Feminino , Humanos , Imunossupressores/uso terapêutico , Encefalite Infecciosa/líquido cefalorraquidiano , Encefalite Infecciosa/tratamento farmacológico , Encefalite Infecciosa/imunologia , Angiografia por Ressonância Magnética , Masculino , Meningite Criptocócica/tratamento farmacológico , Meningite Criptocócica/imunologia , Meningoencefalite/líquido cefalorraquidiano , Meningoencefalite/tratamento farmacológico , Meningoencefalite/imunologia , Metotrexato/uso terapêutico , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Exame Neurológico , Pulsoterapia , Tacrolimo/uso terapêutico , Adulto Jovem
12.
JCI Insight ; 1(13)2016 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-27588307

RESUMO

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by homozygous AIRE mutations. It classically presents with chronic mucocutaneous candidiasis and autoimmunity that primarily targets endocrine tissues; hypoparathyroidism and adrenal insufficiency are most common. Developing any two of these classic triad manifestations establishes the diagnosis. Although widely recognized in Europe, where nonendocrine autoimmune manifestations are uncommon, APECED is less defined in patients from the Western Hemisphere. We enrolled 35 consecutive American APECED patients (33 from the US) in a prospective observational natural history study and systematically examined their genetic, clinical, autoantibody, and immunological characteristics. Most patients were compound heterozygous; the most common AIRE mutation was c.967_979del13. All but one patient had anti-IFN-ω autoantibodies, including 4 of 5 patients without biallelic AIRE mutations. Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjögren's-like syndrome, uncommon entities in European APECED cohorts, affected 40%-80% of American cases. Development of a classic diagnostic dyad was delayed at mean 7.38 years. Eighty percent of patients developed a median of 3 non-triad manifestations before a diagnostic dyad. Only 20% of patients had their first two manifestations among the classic triad. Urticarial eruption, intestinal dysfunction, and enamel hypoplasia were prominent among early manifestations. Patients exhibited expanded peripheral CD4+ T cells and CD21loCD38lo B lymphocytes. In summary, American APECED patients develop a diverse syndrome, with dramatic enrichment in organ-specific nonendocrine manifestations starting early in life, compared with European patients. Incorporation of these new manifestations into American diagnostic criteria would accelerate diagnosis by approximately 4 years and potentially prevent life-threatening endocrine complications.

13.
Arthritis Rheumatol ; 68(7): 1677-87, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26815287

RESUMO

OBJECTIVE: Anticytokine autoantibodies occur across a range of hematologic, pulmonary, and infectious diseases. However, systematic investigation of their presence and significance in autoimmune diseases is lacking. This study was undertaken to examine the distinct functions of anticytokine autoantibodies in patients with systemic lupus erythematosus (SLE) compared to patients with other rheumatic diseases and healthy controls. METHODS: Serum samples from patients with SLE (n = 199), patients with primary Sjögren's syndrome (SS) (n = 150), patients with rheumatoid arthritis (RA) (n = 149), and healthy controls (n = 200) were screened for 24 anticytokine autoantibodies using a multiplex bead-based assay. To evaluate the biologic activity of anticytokine autoantibodies, their ability to block cytokine-induced signal transduction or protein expression was measured. RNA sequencing was performed on whole blood in a subset of healthy controls and patients with SLE. RESULTS: Patients with SLE and those with SS had a striking excess of autoantibodies against interferons and the interferon-responsive chemokine interferon-inducible protein 10 (IP-10). Only autoantibodies against type I interferon, interleukin-12 (IL-12), and IL-22 exhibited neutralizing activity. In SLE, the presence of anti-interferon-γ autoantibodies was correlated with more severe disease activity, higher levels of anti-double-stranded DNA antibodies, and elevated expression of interferon-α/ß-inducible genes. Conversely, in SLE patients with blocking anti-interferon-α autoantibodies, the type I interferon gene expression signature was normalized. Anti-type III interferon autoantibodies (λ2, λ3) and anti-IP-10 autoantibodies were newly recognized in SLE patient serum, and autoantibodies against macrophage-colony stimulating factor, IL-4, IL-7, IL-17, and IL-22, none of which have been previously identified in rheumatic conditions, were discovered. CONCLUSION: Anticytokine autoantibodies are associated with distinct patterns of disease in SLE, SS, and RA. Anti-interferon autoantibodies are overrepresented in patients with SLE and those with SS, and fall into distinct functional classes, with only a subset of anti-type I interferon antibodies exhibiting neutralizing activity. Anti-interferon-γ autoantibodies are correlated with increased disease activity and interferon-related gene expression, suggesting that such autoantibodies may contribute to the pathogenesis of SLE.


Assuntos
Artrite Reumatoide/imunologia , Autoanticorpos/fisiologia , Citocinas/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Síndrome de Sjogren/imunologia , Artrite Reumatoide/sangue , Autoanticorpos/sangue , Humanos , Interferons/imunologia , Lúpus Eritematoso Sistêmico/sangue , Síndrome de Sjogren/sangue
14.
Clin Infect Dis ; 62(6): 770-773, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26646678

RESUMO

Interferon-gamma (IFNγ) neutralizing autoantibodies are associated with disseminated nontuberculous mycobacterial infections. We report a previously healthy Thai woman with disseminated tuberculosis and high-titer IFNγ-neutralizing autoantibodies, who developed a severe inflammatory reaction during anti-tuberculosis treatment. IFNγ contributes to host control of tuberculosis but appears inessential for tuberculosis paradoxical reactions.


Assuntos
Antibacterianos/efeitos adversos , Anticorpos Neutralizantes/biossíntese , Autoanticorpos/sangue , Interferon gama/imunologia , Tuberculose Miliar/imunologia , Antibacterianos/administração & dosagem , Autoanticorpos/imunologia , Feminino , Humanos , Imunoglobulina G/imunologia , Inflamação/imunologia , Inflamação/microbiologia , Interferon gama/sangue , Pessoa de Meia-Idade , Tuberculose Miliar/tratamento farmacológico , Tuberculose Miliar/etnologia , Estados Unidos
15.
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
16.
PLoS Pathog ; 11(5): e1004884, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26020932

RESUMO

The fungus Cryptococcus is a major cause of meningoencephalitis in HIV-infected as well as HIV-uninfected individuals with mortalities in developed countries of 20% and 30%, respectively. In HIV-related disease, defects in T-cell immunity are paramount, whereas there is little understanding of mechanisms of susceptibility in non-HIV related disease, especially that occurring in previously healthy adults. The present description is the first detailed immunological study of non-HIV-infected patients including those with severe central nervous system (s-CNS) disease to 1) identify mechanisms of susceptibility as well as 2) understand mechanisms underlying severe disease. Despite the expectation that, as in HIV, T-cell immunity would be deficient in such patients, cerebrospinal fluid (CSF) immunophenotyping, T-cell activation studies, soluble cytokine mapping and tissue cellular phenotyping demonstrated that patients with s-CNS disease had effective microbiological control, but displayed strong intrathecal expansion and activation of cells of both the innate and adaptive immunity including HLA-DR+ CD4+ and CD8+ cells and NK cells. These expanded CSF T cells were enriched for cryptococcal-antigen specific CD4+ cells and expressed high levels of IFN-γ as well as a lack of elevated CSF levels of typical T-cell specific Th2 cytokines -- IL-4 and IL-13. This inflammatory response was accompanied by elevated levels of CSF NFL, a marker of axonal damage, consistent with ongoing neurological damage. However, while tissue macrophage recruitment to the site of infection was intact, polarization studies of brain biopsy and autopsy specimens demonstrated an M2 macrophage polarization and poor phagocytosis of fungal cells. These studies thus expand the paradigm for cryptococcal disease susceptibility to include a prominent role for macrophage activation defects and suggest a spectrum of disease whereby severe neurological disease is characterized by immune-mediated host cell damage.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Cryptococcus neoformans/imunologia , Células Matadoras Naturais/imunologia , Meningite Criptocócica/imunologia , Células Th1/imunologia , Adulto , Autopsia , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Linfócitos T CD4-Positivos/microbiologia , Linfócitos T CD8-Positivos/microbiologia , Estudos de Coortes , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Células Matadoras Naturais/microbiologia , Ativação Linfocitária , Masculino , Meningite Criptocócica/líquido cefalorraquidiano , Meningite Criptocócica/microbiologia , Pessoa de Meia-Idade , Adulto Jovem
17.
Clin Infect Dis ; 60(7): 1017-25, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25472947

RESUMO

BACKGROUND: Nocardia species cause infections in both immunocompromised and otherwise immunocompetent patients, although the mechanisms defining susceptibility in the latter group are elusive. Anticytokine autoantibodies are an emerging cause of pathogen-specific susceptibility in previously healthy human immunodeficiency virus-uninfected adults, including anti-granulocyte macrophage colony-stimulating factor (GM-CSF) autoantibodies with cryptococcal meningitis. METHODS: Plasma from patients with disseminated/extrapulmonary nocardiosis and healthy controls was screened for anticytokine autoantibodies using a particle-based approach. Autoantibody function was assessed by intranuclear staining for GM-CSF-induced STAT5 phosphorylation in normal cells incubated with either patient or normal plasma. GM-CSF-mediated cellular activation by Nocardia was assessed by staining for intracellular cytokine production and intranuclear STAT5 phosphorylation. RESULTS: We identified neutralizing anti-GM-CSF autoantibodies in 5 of 7 patients studied with central nervous system nocardiosis and in no healthy controls (n = 14). GM-CSF production was induced by Nocardia in vitro, suggesting a causative role for anti-GM-CSF autoantibodies in Nocardia susceptibility and dissemination. CONCLUSIONS: In previously healthy adults with otherwise unexplained disseminated/extrapulmonary Nocardia infections, anti-GM-CSF autoantibodies should be considered. Their presence may suggest that these patients may be at risk for later development of pulmonary alveolar proteinosis or other opportunistic infections, and that patients may benefit from therapeutic GM-CSF administration.


Assuntos
Anticorpos Neutralizantes/sangue , Autoanticorpos/sangue , Fator Estimulador de Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Nocardiose/imunologia , Nocardia/imunologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
MAbs ; 6(6): 1608-20, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25484038

RESUMO

Anti-cytokine autoantibodies have been widely reported to be present in human plasma, both in healthy subjects and in patients with underlying autoimmune conditions, such as autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) or thymic epithelial neoplasms. While often asymptomatic, they can cause or facilitate a wide range of diseases including opportunistic infections. The potential therapeutic value of specific neutralizing anti-cytokine autoantibodies has not been thoroughly investigated. Here we used mammalian cell display to isolate IL17A-specific antibodies from a thymoma patient with proven high-titer autoantibodies against the same. We identified 3 distinct clonotypes that efficiently neutralized IL17A in a cell-based in vitro assay. Their potencies were comparable to those of known neutralizing antibodies, including 2, AIN457 (secukinumab) and ixekizumab that are currently in clinical development for the treatment of various inflammatory disorders. These data clearly demonstrate that the human autoantibody repertoire can be mined for antibodies with high therapeutic potential for clinical development.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Autoanticorpos/imunologia , Interleucina-17/imunologia , Timoma/imunologia , Sequência de Aminoácidos , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Monoclonais Humanizados/genética , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/isolamento & purificação , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/isolamento & purificação , Afinidade de Anticorpos/imunologia , Autoanticorpos/genética , Autoanticorpos/isolamento & purificação , Linhagem Celular , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Células HEK293 , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/imunologia , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Interleucina-17/genética , Dados de Sequência Molecular , Testes de Neutralização , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes/imunologia , Homologia de Sequência de Aminoácidos , Anticorpos de Cadeia Única/genética , Anticorpos de Cadeia Única/imunologia , Timoma/sangue
19.
Allergy Asthma Proc ; 35(5): 415-22, 2014 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25295810

RESUMO

As immunologists, we are frequently asked to evaluate patients with recurrent infections. These infections can provide us with clues regarding what pathways might be aberrant in a given patient, e.g., specific pyogenic bacteria with Toll-like receptor problems, atypical mycobacteria with interferon gamma receptor autoantibodies, and Candida/staphylococcal infections with cellular immune abnormalities. We present a 55-year-old man who presented to our immunology clinic with onychodystrophy of the toenails and fingernails and recurrent oral-esophageal candidiasis. The differential diagnosis for recurrent yeast infections is complex and includes usual suspects as well as some that are not as straightforward.


Assuntos
Candidíase/diagnóstico , Candidíase/microbiologia , Candida , Candidíase/complicações , Candidíase Mucocutânea Crônica/complicações , Candidíase Mucocutânea Crônica/diagnóstico , Candidíase Mucocutânea Crônica/microbiologia , Diagnóstico Diferencial , Humanos , Masculino , Pessoa de Meia-Idade , Timoma/complicações , Timoma/diagnóstico , Timoma/cirurgia , Tomografia Computadorizada por Raios X , Resultado do Tratamento
20.
J Clin Immunol ; 34(8): 928-32, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25149293

RESUMO

INTRODUCTION: Anti-interferon-γ (IFNγ) autoantibodies have been associated with disseminated mycobacterial infections, mostly in patients from Southeast Asia. PURPOSE: We studied an American-born, Caucasian female with M. avium complex infection of the subglottic mucosa and brain for underlying etiologies of infection. METHODS: Plasma was screened for anticytokine autoantibodies using a Luminex-based approach. The ability of patient plasma to block IFNγ-induced STAT1 phosphorylation in normal blood cells was evaluated by flow cytometry with intracellular staining. Plasma inhibition of IFNγ production and IFNγ-induced cytokines in normal and patient blood cells washed of autologous plasma was also evaluated. RESULTS: Patient plasma contained high-titer IgG anti-IFNγ autoantibodies, primarily of the IgG1 subclass. Patient but not control plasma prevented IFNγ-induced STAT1 phosphorylation and expression of the IFNγ-inducible cytokines tumor necrosis factor (TNF) α and interleukin (IL)-12 in normal blood cells. Patient blood cells washed free of autologous plasma demonstrated normal IFNγ production and response. CONCLUSIONS: Disseminated nontuberculous mycobacterial infections should always prompt immune evaluation. This first case of disseminated nontuberculous mycobacterial infection and anti-IFNγ autoantibodies in an American-born Caucasian suggests that anti-cytokine autoantibodies are not racially or regionally restricted.


Assuntos
Autoanticorpos/sangue , Interferon gama/imunologia , Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare/imunologia , Adulto , Asma/complicações , Encéfalo/patologia , Dispneia/complicações , Grupo com Ancestrais do Continente Europeu , Feminino , Citometria de Fluxo , Humanos , Imagem por Ressonância Magnética , Infecção por Mycobacterium avium-intracellulare/complicações , Infecção por Mycobacterium avium-intracellulare/diagnóstico , Fumar , Estados Unidos
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