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1.
Curr Opin Infect Dis ; 32(4): 330-336, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31116133

RESUMO

PURPOSE OF REVIEW: The current review gives a concise and updated overview of the relative new field of anticytokine autoantibodies (ACAA) and associated infections with a focus on recent findings regarding clinical manifestions, diagnostic and treatments. RECENT FINDINGS: Several recent case reports of unusual presentations of patients with neutralizing autoantibodies to IFN-γ and granulocyt macrophage colony-stimulating factor and expand the spectrum of clinical manifestations and suggest that anticytokine-mediated acquired immunodeficiency causing susceptibility to infection may be underdiagnosed. There is an expanding geographical distribution of antigranulocyt macrophage colony-stimulating factor associated Cryptococcus gattii infection. The spectrum of identified infections in patients with neutralizing antibodies to IFN-γ has a strong endemic component. Rituximab or cyclophophamide in addition to antimycobacterials could be a treatment options in refractory cases. NF-κB2 deficiency may be associated with a complex pattern of high titre neutralizing ACAA similar to autoimmune polyglandular syndrome type I and Thymoma. New technique for the detection of anticytokine antibodies are presented. Quantiferon testing, which is widely available for TB-diagnostic, may be repurposed to detect anti-IFN-γ autoantibodies. We propose that this test could be as well used to show if they are neutralizing. SUMMARY: ACAA are an emerging cause of acquired immunodeficiency which is likely underdiagnosed. Recent case reports document expanding spectra of clinical manifestations. NF-κB2 deficiency may be associated with a complex anti cytokine autoantibody pattern.

3.
RMD Open ; 3(2): e000550, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29177082

RESUMO

At the population level, rheumatoid arthritis (RA) is generally viewed as autoimmune in nature with a small subgroup of cases having a palindromic form or systemic autoinflammatory disorder (SAID) phenotype. Herein, we describe resistant cases of classical autoantibody associated RA that had clinical, genetic and therapeutic responses indicative of coexistent autoinflammatory disease. Five patients with clinically overlapping features between RA and SAID including polysynovitis and autoantibody/shared epitope positivity, and who had abrupt severe self-limiting attacks including fevers and serositis, are described. Mutations or single nucleotide polymorphisms in recognised autoinflammatory pathways were evident. Generally, these cases responded poorly to conventional Disease-modifying anti-rheumatic drugs (DMARD) treatment with some excellent responses to colchicine or interleukin 1 pathway blockade. A subgroup of RA cases have a mixed autoimmune-autoinflammatory phenotype and genotype with therapeutic implications.

4.
Front Immunol ; 8: 1485, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29163546

RESUMO

G6PC3 deficiency typically causes severe congenital neutropenia, associated with susceptibility to infections, cardiac and urogenital abnormalities. However, here we describe two boys of Pakistani origin who were found to have G6PC3 deficiency due to c.130 C>T mutation, but who have clinical phenotypes that are typical for a systemic autoinflammatory syndrome. The index case presented with combination of unexplained fevers, severe mucosal ulcers, abdominal symptoms, and inflammatory arthritis. He eventually fully responded to anti-TNF therapy. In this study, we show that compared with healthy controls, neutrophils and monocytes from patients have reduced glycolytic reserve. Considering that healthy myeloid cells have been shown to switch their metabolic pathways to glycolysis in response to inflammatory cues, we studied what impact this might have on production of the inflammatory cytokines. We have demonstrated that patients' monocytes, in response to lipopolysaccharide, show significantly increased production of IL-1ß and IL-18, which is NLRP3 inflammasome dependent. Furthermore, additional whole blood assays have also shown an enhanced production of IL-6 and TNF from the patients' cells. These cases provide further proof that autoinflammatory complications are also seen within the spectrum of primary immune deficiencies, and resulting from a wider dysregulation of the immune responses.

5.
Curr Opin Allergy Clin Immunol ; 16(6): 523-529, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27755185

RESUMO

PURPOSE OF REVIEW: Concise overview of the field of anticytokine autoantibodies with a focus on recent developments. RECENT FINDINGS: Advances in particular in the analysis of autoantibodies to IFNγ, granulocyte-macrophage colony-stimulating factor (GM-CSF) and type I IFN are presented. The target epitope for anti-IFNγ autoantibodies has been found to have high homology to a protein from Aspergillus suggesting molecular mimicry as a mechanism of breaking self-tolerance. A treatment strategy using a recombinant, epitope-depleted version of IFNγ is suggested. Autoantibodies to GM-CSF are associated with disseminated Crytococcus and Nocardia infections thus expanding the spectrum of associated diseases beyond pulmonary alveolar proteinosis. Detailed analysis of anti-GM-CSF autoantibody clones derived from pulmonary alveolar proteinosis patients show evidence of high somatic mutation suggesting T cell-dependent affinity maturation; full GM-CSF neutralization is achieved by synergistic binding of antibodies targeting various distinct noncross-reactive epitopes and leading to antigen sequestration and Fc-mediated clearance. Single mAbs in contrast may lead to higher GM-CSF bioavailability. Anti type I IFN-specific autoantibodies derived from autoimmune polyglandular syndrome type I patients are of extreme high affinity and negatively correlate with the incidence of type I diabetes and may be thus considered to be protective. Hypomorphic severe combined immune deficiency may be associated with complex anticytokine patterns and the emergence of anti type I IFN autoantibodies correlates with severe viral infection histories. SUMMARY: Anticytokine autoantibodies may cause susceptibility to infections. In autoimmune/autoinflammatory conditions, anticytokine autoantibodies may be protective or promote disease.


Assuntos
Autoanticorpos/metabolismo , Infecção/imunologia , Inflamação/imunologia , Proteinose Alveolar Pulmonar/imunologia , Tolerância a Antígenos Próprios , Animais , Autoanticorpos/imunologia , Autoimunidade , Reações Cruzadas , Epitopos/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Interferons/imunologia
6.
PLoS One ; 11(5): e0155059, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27167980

RESUMO

The recently described Mucosal Associated Invariant T (MAIT) cells mediate specific recognition of bacterial and fungal vitamin B2 metabolites. As innate T cells, they possess broad effector responses, including IFN- including Iproduction, that are comparable to conventional T cell responses. Immunodeficiencies associated with systemic Th17 deficiency may also be compounded by defects in MAIT immunity. We evaluated Th17 immunity in this innate T cell compartment in primary (AD-HIES) and secondary immunodeficiency (thymoma) patients with conventional Th17 deficiency and susceptibility to fungal and bacterial disease. Our results suggest that MAIT cells are both reduced and functional deficient in STAT3 deficiency and thymoma patients with IL-12/23 autoantibodies. In contrast, thymoma patients without autoantibodies preserved the normal number and functional MAIT cells.


Assuntos
Síndromes de Imunodeficiência/imunologia , Células T Invariáveis Associadas à Mucosa/imunologia , Células Th17/imunologia , Adulto , Idoso , Estudos de Casos e Controles , Citocinas/biossíntese , Feminino , Humanos , Espaço Intracelular/metabolismo , Masculino , Pessoa de Meia-Idade
7.
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
8.
Paediatr Int Child Health ; 35(1): 69-71, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24863105

RESUMO

Although neonatal vaccination with bacille Calmette-Guérin (BCG) is considered to be safe, complications with disseminated disease are associated with underlying immuno-deficiency disorders. A BCG-vaccinated 4-month-old girl of Sri Lankan parentage developed progressive left axillary lymphadenopathy and severe bronchopneumonia. Lymph node biopsy demonstrated epithelioid granulomata and acid-fast bacilli. An older sibling had had a similar clinical presentation and the outcome had been fatal. Investigation for immuno-deficiency detected complete IL12RB1 deficiency. Full recovery followed a prolonged course of anti-tuberculous chemotherapy. She was put on lifelong isoniazid prophylaxis. In HIV-negative infants with unusual complications related to BCG vaccination, a primary immuno-deficiency disorder should be considered.


Assuntos
Vacina BCG/efeitos adversos , Síndromes de Imunodeficiência/complicações , Mycobacterium bovis/isolamento & purificação , Receptores de Interleucina-12/deficiência , Tuberculose/diagnóstico , Tuberculose/microbiologia , Antituberculosos/uso terapêutico , Vacina BCG/administração & dosagem , Biópsia , Feminino , Histocitoquímica , Humanos , Lactente , Pulmão/patologia , Linfonodos/patologia , Sri Lanka , Resultado do Tratamento
9.
J Cyst Fibros ; 13(6): 632-8, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24636807

RESUMO

BACKGROUND: Pneumococcal immunization is recommended in children with cystic fibrosis (CF). To date, however, there are no published studies on the efficacy of pneumococcal vaccination in this group of patients. METHODS: We carried out a retrospective study of serotype-specific pneumococcal antibody responses to immunization with Prevenar 7 and Pneumovax II in a cohort of children with CF. RESULTS: Nine children had been immunized with Prevenar 7, and all had serotype-specific pneumococcal antibody levels in the protective range (>0.35mg/L) to all 7 immunizing serotypes. In contrast, only 7 of 33 patients (21%) immunized with Pneumovax II made protective antibody responses to all 7 serotypes, and 3 failed to make protective antibodies to any of the serotypes. Controlling for age as a confounder in the analysis, children with impaired antibody responses to pneumococcal polysaccharide (Pneumovax II) immunization had lower Shwachman-Kulczycki scores than children with normal polysaccharide antibody responses. All isolates of Pseudomonas aeruginosa occurred in patients with impaired anti-pneumococcal antibody responses, and a broader range of respiratory pathogens was isolated from these children. CONCLUSIONS: Impaired antibody responses to immunization with Pneumovax II are common in children with CF and this may be associated with increased disease severity.


Assuntos
Anticorpos Antibacterianos/sangue , Fibrose Cística/imunologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas , Streptococcus pneumoniae/imunologia , Adolescente , Formação de Anticorpos , Criança , Pré-Escolar , Fibrose Cística/sangue , Feminino , Vacina Pneumocócica Conjugada Heptavalente , Humanos , Masculino , Infecções por Pseudomonas/epidemiologia , Pseudomonas aeruginosa , Estudos Retrospectivos
10.
Science ; 342(6160): 866-71, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-24136356

RESUMO

Genetic mutations cause primary immunodeficiencies (PIDs) that predispose to infections. Here, we describe activated PI3K-δ syndrome (APDS), a PID associated with a dominant gain-of-function mutation in which lysine replaced glutamic acid at residue 1021 (E1021K) in the p110δ protein, the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated families, but not among 3346 healthy subjects. APDS was characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased immunoglobulin M, and reduced immunoglobulin G2 levels in serum and impaired vaccine responses. The E1021K mutation enhanced membrane association and kinase activity of p110δ. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein and were prone to activation-induced cell death. Selective p110δ inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, which suggested a therapeutic approach for patients with APDS.


Assuntos
Predisposição Genética para Doença , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Fosfatidilinositol 3-Quinases/genética , Infecções Respiratórias/genética , Infecções Respiratórias/patologia , Classe I de Fosfatidilinositol 3-Quinases , Humanos , Síndromes de Imunodeficiência/imunologia , Linfócitos/imunologia , Mutação , Linhagem , Fosfatos de Fosfatidilinositol/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Infecções Respiratórias/imunologia
11.
J Exp Med ; 207(2): 291-7, 2010 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-20123958

RESUMO

Most patients with autoimmune polyendocrine syndrome type I (APS-I) display chronic mucocutaneous candidiasis (CMC). We hypothesized that this CMC might result from autoimmunity to interleukin (IL)-17 cytokines. We found high titers of autoantibodies (auto-Abs) against IL-17A, IL-17F, and/or IL-22 in the sera of all 33 patients tested, as detected by multiplex particle-based flow cytometry. The auto-Abs against IL-17A, IL-17F, and IL-22 were specific in the five patients tested, as shown by Western blotting. The auto-Abs against IL-17A were neutralizing in the only patient tested, as shown by bioassays of IL-17A activity. None of the 37 healthy controls and none of the 103 patients with other autoimmune disorders tested had such auto-Abs. None of the patients with APS-I had auto-Abs against cytokines previously shown to cause other well-defined clinical syndromes in other patients (IL-6, interferon [IFN]-gamma, or granulocyte/macrophage colony-stimulating factor) or against other cytokines (IL-1beta, IL-10, IL-12, IL-18, IL-21, IL-23, IL-26, IFN-beta, tumor necrosis factor [alpha], or transforming growth factor beta). These findings suggest that auto-Abs against IL-17A, IL-17F, and IL-22 may cause CMC in patients with APS-I.


Assuntos
Candidíase Mucocutânea Crônica/imunologia , Interleucina-17/imunologia , Interleucinas/imunologia , Poliendocrinopatias Autoimunes/imunologia , Adolescente , Adulto , Autoanticorpos/sangue , Autoanticorpos/imunologia , Autoimunidade , Western Blotting , Candidíase Mucocutânea Crônica/sangue , Candidíase Mucocutânea Crônica/etiologia , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Humanos , Interferon gama/imunologia , Masculino , Pessoa de Meia-Idade , Poliendocrinopatias Autoimunes/sangue , Poliendocrinopatias Autoimunes/complicações , Adulto Jovem
13.
Clin Chem ; 54(5): 883-90, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18356243

RESUMO

BACKGROUND: We developed a cost-efficient modular system for multiplex analysis of the multiple autoantibodies that characterize systemic rheumatoid diseases. METHODS: The nanodot array luminometric immunoassay (NALIA) system consists of conventional 96-well membrane-bottomed plates in which antigens or antibodies are adsorbed onto the underside of the membrane. Current arrays use a 5 x 5 format (25 dots/well), which allows 10 analytes to be measured in duplicate: double-stranded DNA (dsDNA), centromere protein B (CENP-B), PCNA, Sm, Sm ribonucleoprotein (Sm-RNP), U1-snRNP, Scl70, SSA/Ro, SSB/La, Jo-1, and controls. The test fluid, control sera, and subsequent reagents are drawn through the membrane. The captured analytes are quantified by monitoring chemiluminescence with a charge-coupled device (CCD) and analyzed with commercial array software. RESULTS: The assay can detect <20 x 10(3) IU/L of anti-dsDNA. The interwell CV was 10%-14%. There was an 83% concordance (kappa = 0.56) between the NALIA results obtained for anti-dsDNA assayed by beta-testing in a routine immunology diagnostic laboratory and the results obtained with a conventional ELISA reagent set. The concordance values for Ro, La, Sm, and RNP were 98% (kappa, 0.92), 93% (kappa, 0.41), 97% (kappa, 0.62), and 97% (kappa, 0.73), respectively. CONCLUSION: The NALIA approach promises to provide a highly economical platform for a wide range of applications that require assays of multiple analytes. The degree of concordance of our results with a conventional reagent set was no less than that occurring between different commercial products. A sample of serum from a finger stick provides a volume sufficient to perform the array assay.


Assuntos
Autoanticorpos/sangue , Doenças Reumáticas/imunologia , Humanos , Imunoensaio , Medições Luminescentes , Nanoestruturas , Análise Serial de Proteínas , Sensibilidade e Especificidade
14.
Clin Infect Dis ; 38(1): e10-4, 2004 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-14679469

RESUMO

We evaluated a patient with disseminated Mycobacterium tuberculosis and Mycobacterium chelonae infection, of which he died. He also developed autoimmune (type I) diabetes and primary hypothyroidism. His serum contained a high titer of immunoglobulin G autoantibody to interferon-gamma (IFN-gamma) capable of blocking in vitro responses to this cytokine by peripheral blood mononuclear cells from normal donors. These results suggest that autoantibodies to IFN-gamma can induce susceptibility to disseminated mycobacterial infection, which may be refractory to chemotherapy.


Assuntos
Autoanticorpos/sangue , Imunoglobulina G/sangue , Interferon gama/imunologia , Infecções por Micobactéria não Tuberculosa/imunologia , Tuberculose/imunologia , Autoimunidade , Diabetes Mellitus Tipo 1/etiologia , Suscetibilidade a Doenças , Humanos , Hipotireoidismo/etiologia , Masculino , Pessoa de Meia-Idade , Infecções por Micobactéria não Tuberculosa/complicações , Mycobacterium chelonae/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/complicações
16.
Vet. Méx ; 23(2): 125-30, abr.-jun. 1992. ilus, tab
Artigo em Espanhol | LILACS | ID: lil-118358

RESUMO

Se estudiaron extractos bacterianos solubilizados con Triton X-100 de los serotipos 1,2, 5 y 7 de Actinobacillus pleuropneumoniae. Los extractos se analizaron mediante electroforesis en geles de sodio-duodecil-sulfato (SDS) poliacrilamida e inmunotransferencia con sueros hiperinmunes de conejo y 9 sueros de cerdo A. pleuropneumoniae positivos. Los patrones electroforéticos mostraron las siguientes proteínas comunes a todos los serotipos: 26-29, 30-33, 43, 50, 66 y 81-83 Kd. En cuanto a los patrones antigénicos con sueros hiperinmunes de conejo, se observó un antígeno de 30-31 Kd de peso molecular reconocido por todos los antisueros con todos los serotipos (con excepción del serotipo 7, cuando reaccionó con el antisuero contra el serotipo 5).En relación con los antígenos reconocidos por sueros de cerdo, se onservó un grupo de antígenos cuyo peso molecular osciló entre 29 y 33 Kd, reconocido por todo los sueros con todos los serotipos, salvo la reacción de 3 sueros con el serotipo 2.


Assuntos
Actinobacillus/imunologia , Antígenos de Bactérias/isolamento & purificação , Eletroforese , Proteínas de Bactérias/isolamento & purificação
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