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1.
Sci Immunol ; 3(24)2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29907691

RESUMO

Heterozygosity for human signal transducer and activator of transcription 3 (STAT3) dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the STAT3 promoter. The patients' cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack T helper 17 (TH17) cells, have an excess of TH2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent autoinduction and sustained activity of STAT3.

2.
Nat Commun ; 8(1): 2176, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29259162

RESUMO

Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both families we identify biallelic mutations in DNASE2, associated with a loss of DNase II endonuclease activity. We record increased interferon alpha protein levels using digital ELISA, enhanced interferon signaling by RNA-Seq analysis and constitutive upregulation of phosphorylated STAT1 and STAT3 in patient lymphocytes and monocytes. A hematological disease transcriptomic signature and increased numbers of erythroblasts are recorded in patient peripheral blood, suggesting that interferon might have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans.


Assuntos
Desoxirribonucleases/deficiência , Endodesoxirribonucleases/deficiência , Doenças Hereditárias Autoinflamatórias/enzimologia , Interferon-alfa/imunologia , Transdução de Sinais/imunologia , Adolescente , Antivirais/farmacologia , Criança , Desoxirribonucleases/genética , Desoxirribonucleases/imunologia , Endodesoxirribonucleases/genética , Endodesoxirribonucleases/imunologia , Eritroblastos/imunologia , Feminino , Perfilação da Expressão Gênica , Hematopoese/imunologia , Doenças Hereditárias Autoinflamatórias/sangue , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/imunologia , Humanos , Interferon-alfa/sangue , Interferon-alfa/metabolismo , Masculino , Mutação , Fosforilação , RNA Mensageiro/análise , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Análise de Sequência de RNA , Regulação para Cima/efeitos dos fármacos
3.
J Exp Med ; 214(5): 1547-1555, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28420733

RESUMO

Type I interferons (IFNs) are essential mediators of antiviral responses. These cytokines have been implicated in the pathogenesis of autoimmunity, most notably systemic lupus erythematosus (SLE), diabetes mellitus, and dermatomyositis, as well as monogenic type I interferonopathies. Despite a fundamental role in health and disease, the direct quantification of type I IFNs has been challenging. Using single-molecule array (Simoa) digital ELISA technology, we recorded attomolar concentrations of IFNα in healthy donors, viral infection, and complex and monogenic interferonopathies. IFNα protein correlated well with functional activity and IFN-stimulated gene expression. High circulating IFNα levels were associated with increased clinical severity in SLE patients, and a study of the cellular source of IFNα protein indicated disease-specific mechanisms. Measurement of IFNα attomolar concentrations by digital ELISA will enhance our understanding of IFN biology and potentially improve the diagnosis and stratification of pathologies associated with IFN dysregulation.


Assuntos
Ensaio de Imunoadsorção Enzimática/métodos , Interferon-alfa/sangue , Humanos , Fatores Reguladores de Interferon/sangue , Fatores Reguladores de Interferon/líquido cefalorraquidiano , Interferon-alfa/líquido cefalorraquidiano , Lúpus Eritematoso Sistêmico/sangue , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Linfócitos T/metabolismo , Estomatite Vesicular/imunologia
4.
Genes Chromosomes Cancer ; 56(3): 221-230, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27750397

RESUMO

Plasma-cell post-transplantation lymphoproliferative disorder (PC-PTLD) is a rare monomorphic PTLD entity divided into plasma cell myeloma (PCM) and plasmacytoma-like lesion (PLL) PTLD. To date, there are no exhaustive published cytogenetic data on PC-PTLD. We report array-based comparative genomic hybridization (aCGH) of 10 cases of PCM and PLL-PTLD. Patients had received kidney (n = 6), heart (n = 2), lung (n = 1) or bone marrow (n = 1) transplantation. There were six men and median age at time of PTLD was 56.5 years (3-74). We identified two different cytological features, plasmacytic and plasmablastic, among six PLL and three PCM PTLD. Eight cases were associated with EBV. First line treatment was heterogeneous: rituximab alone (n = 5), CHOP-like (n = 3) and multiple myeloma-like (n = 1). One patient died before any treatment. After a median follow-up of 19.5 months (0-150), five patients died (four from PTLD) and five were alive without evidence of disease. By aCGH, 5/10 demonstrated a complex profile. The most frequent abnormalities were +7q (5/10), +16q (5/10), +17q (5/10), +17p (4/10), +5q (4/10), t7 (4/10), t9 (3/10), del1p (3/10). No del17p13 (TP53) were observed. Del1p32.3 (CDKN2C) was observed in 2 cases. On univariate prognostic analysis, a complex aCGH was associated with a shorter OS. Thus, cytogenetic abnormalities seem to be closely related to those reported in multiple myeloma or diffuse large B cell lymphoma. Complex aCGH constitutes an unfavorable prognostic marker and aCGH should be integrated in the evaluation of patients with PLL/PCM-PTLD. © 2016 Wiley Periodicals, Inc.


Assuntos
Biomarcadores Tumorais/genética , Hibridização Genômica Comparativa/métodos , Transtornos Linfoproliferativos/diagnóstico , Transplante de Órgãos/efeitos adversos , Plasmócitos/patologia , Transplante de Células-Tronco/efeitos adversos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
5.
Ann Biol Clin (Paris) ; 74(5): 597-605, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27707674

RESUMO

The diagnostics and follow-up of monoclonal gammopathies such as multiple myeloma require precise analysis of the monoclonal component as well as the other immunoglobulins isotypes, which might be limited by the sensitivity of standard laboratory methods. New serum biomarkers were developed for routine practice in the last decades, such as the free light chain assays and more recently the heavy/light chain assays. Studies have shown that serum free light chain measurement was useful in the identification and follow-up of pauci or nonsecretory myeloma, free light-chain multiple myeloma and AL amyloidosis. It is also an important prognostic marker for monoclonal gammopathy of undetermined significance and AL amyloidosis progression. Hevylite method enables quantitative analysis of heavy/light chain pairs of IgG, IgA and IgM immunoglobulins. This technique has a promising potential to enrich the standard analytic tools as it enables to assess the concentration and ratio of the levels of both tumor and physiological immunoglobulins (heavy/light chain pair suppression), which is not possible with serum protein electrophoresis or global quantitative analysis of immunoglobulin isotypes. This review includes the latest International myeloma working group recommendations and key data presented at the Euromedlab convention in June 2015 Paris regarding serum free light chain and heavy/light chain assays in the biological monitoring of dysglobulinemia.


Assuntos
Biomarcadores/sangue , Imunoglobulinas/sangue , Monitorização Fisiológica/métodos , Paraproteinemias/diagnóstico , Amiloidose/sangue , Amiloidose/diagnóstico , Seguimentos , Humanos , Cadeias Leves de Imunoglobulina/sangue , Amiloidose de Cadeia Leve de Imunoglobulina , Mieloma Múltiplo/sangue , Mieloma Múltiplo/diagnóstico , Paraproteinemias/sangue , Guias de Prática Clínica como Assunto , Prognóstico
6.
J Exp Med ; 213(11): 2413-2435, 2016 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-27647349

RESUMO

Combined immunodeficiency (CID) refers to inborn errors of human T cells that also affect B cells because of the T cell deficit or an additional B cell-intrinsic deficit. In this study, we report six patients from three unrelated families with biallelic loss-of-function mutations in RLTPR, the mouse orthologue of which is essential for CD28 signaling. The patients have cutaneous and pulmonary allergy, as well as a variety of bacterial and fungal infectious diseases, including invasive tuberculosis and mucocutaneous candidiasis. Proportions of circulating regulatory T cells and memory CD4+ T cells are reduced. Their CD4+ T cells do not respond to CD28 stimulation. Their CD4+ T cells exhibit a "Th2" cell bias ex vivo and when cultured in vitro, contrasting with the paucity of "Th1," "Th17," and T follicular helper cells. The patients also display few memory B cells and poor antibody responses. This B cell phenotype does not result solely from the T cell deficiency, as the patients' B cells fail to activate NF-κB upon B cell receptor (BCR) stimulation. Human RLTPR deficiency is a CID affecting at least the CD28-responsive pathway in T cells and the BCR-responsive pathway in B cells.


Assuntos
Alelos , Linfócitos B/imunologia , Proteínas dos Microfilamentos/genética , Mutação/genética , Linfócitos T/imunologia , Adolescente , Adulto , Sequência de Bases , Antígenos CD28/metabolismo , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Criança , Pré-Escolar , Dimerização , Feminino , Células HEK293 , Humanos , Memória Imunológica , Imunofenotipagem , Leucócitos/patologia , Masculino , NF-kappa B/metabolismo , Linhagem , Fenótipo , Receptores de Antígenos de Linfócitos B , Transdução de Sinais , Células Th17/imunologia , Células Th2/imunologia , Adulto Jovem
7.
Nephrol Ther ; 12 Suppl 1: S71-81, 2016 Apr.
Artigo em Francês | MEDLINE | ID: mdl-26972092

RESUMO

Cryoglobulins are circulating immunoglobulins that precipitate with cold temperature and dissolve with rewarming. Type 1 cryoglobulinemia is composed of a single monoclonal immunoglobulin and is associated with renal involvement in up to 40% of cases. Type 1 cryoglobulinemia is related to an underlying B-cell haematological malignancy in 60% of patients. In the remaining cases, in the absence of criteria for malignancy, the diagnosis of monoclonal gammopathy of renal significance should be established. The clinical and biological setting and histological features of type 1 cryoglobulinemia are globally similar to those of mixed cryoglobulinemia. In case of haematological malignancy, the treatment is guided by the nature of the underlying disease, and aims at inducing haematological remission, which is necessary for the renal response. The management of monoclonal gammopathy of renal significance has been clarified by an international consensus group and is based on the nature of the underlying clone. In case of monoclonal cryoglobulinemia associated with a plasma-cell clone (IgG or IgA), the treatment is based on the combination of bortezomib, cyclophosphamide and dexamethasone. In case of IgM monoclonal cryoglobulinemia, the treatment is similar to that of Waldenström macroglobulinemia, and is based on rituximab. The clinical course of renal monoclonal cryoglobulinemia is intimately associated with the haematological response, and is usually favourable.


Assuntos
Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Crioglobulinemia/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Dexametasona/uso terapêutico , Glomerulonefrite Membranoproliferativa/tratamento farmacológico , Glucocorticoides/uso terapêutico , Crioglobulinemia/classificação , Crioglobulinemia/complicações , Crioglobulinemia/diagnóstico , Quimioterapia Combinada , Glomerulonefrite Membranoproliferativa/diagnóstico , Glomerulonefrite Membranoproliferativa/etiologia , Humanos , Resultado do Tratamento
8.
Clin Kidney J ; 8(2): 237-9, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25815184

RESUMO

Light and heavy chain deposition disease (LHCDD) is a rare complication of monoclonal gammopathy. In all documented cases, LHCDD is the association of deposits of a monoclonal light chain with a normal heavy chain, especially in the kidneys. We describe here a 78-year-old woman whose renal biopsy showed nodular glomerulosclerosis, initially diagnosed as diabetic nephropathy. Detailed kidney biopsy immunofluorescence study corrected the diagnosis to γ1-κ-LHCDD. Advanced immunoblot analysis showed deletion of CH1 in the both blood and kidney heavy chain. We report here, to our knowledge, the first case of γ1 LHCDD associated with a deletion of CH1.

9.
Transplantation ; 99(5): 965-72, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25340597

RESUMO

BACKGROUND: Local inflammation is a potential cause of humoral alloimmune responses in renal transplantation, and de novo donor-specific anti-human leucocyte antigen antibodies (dnDSAs) have been associated with a history of acute rejection. METHODS: We investigated the frequencies and consequences of dnDSAs after a first episode of acute T-cell-mediated rejection (index TCMR) in previously unsensitized kidney transplant recipients. RESULTS: Of the 1,054 patients who underwent kidney transplantation between September 2004 and December 2010 at our center, we identified 75 unsensitized patients with at least one TCMR. Index TCMRs were diagnosed 4.4 ± 6.8 months after transplantation. The dnDSAs were assessed using the highly sensitive single-antigen human leukocyte antigen bead assay 5.1 ± 3.9 months after the index TCMR and were detected in 16 patients (21%). Patients who developed dnDSAs were more likely to have experienced pre-transplant sensitizing events and were indistinguishable in their clinical, biologic, and histologic variables at the time of index TCMR, although the tubulitis scores tended to be higher (P = 0.079). These patients experienced a significantly higher incidence of subsequent antibody-mediated rejection episodes (P < 0.001), but reduced death-censored graft survival was not observed after a median follow-up of 5.5 years post-transplantation. Follow-up biopsies revealed increased antibody-mediated changes with significantly higher glomerulitis scores and numerically higher C4d staining scores. CONCLUSION: Monitoring anti-human leukocyte antigen antibodies after cellular rejection may be useful, especially among patients with a history of pretransplant exposure to alloantigens, to predict subsequent humoral events and their consequences.


Assuntos
Rejeição de Enxerto/imunologia , Antígenos HLA/imunologia , Isoanticorpos/sangue , Transplante de Rim , Linfócitos T/imunologia , Doadores de Tecidos , Adulto , Idoso , Biópsia , Creatinina/sangue , Feminino , Humanos , Rim/patologia , Masculino , Pessoa de Meia-Idade
10.
Ann Biol Clin (Paris) ; 71(3): 325-32, 2013 May-Jun.
Artigo em Francês | MEDLINE | ID: mdl-23747670

RESUMO

French medical laboratories must be accredited before November 2016 according to NF/EN/ISO 15189 standard. However, technical accreditation guidelines cannot be applied literally for the determination of specific IgE for several reasons: more than 600 allergen tests, lack of international gold standard, limited external quality controls. Furthermore, the technique for determination of specific IgE is CE DM-IVD marked, common to all specificities, automatised, standardized according to a single calibration curve. Thus, we propose an efficient but reasonable solution conform to the idea of the accreditation by validating the process. We recommend: a flexible extend type A; choice of only one representative allergen (Dermatophagoides pteronyssinus) for repeatability and precision (20 tests, 2 levels 0.5-1 and 8-12 kUA/L) performed on patients sera, reproducibility (30 consecutive determinations using an Internal Quality Control/IQC), accuracy (IQC and rare External Quality Controls) compared with peers. Sensitivity, specificity, dynamic range, detection threshold are determinated by the provider. Linearity may be checked if the laboratory practices sample dilution for values higher than the upper limit guaranteed by the provider. In the absence of international gold standard, the uncertainty is not measurable. In case of change of instrument, the results obtained by the systems must be compared through 35 tests of different specificities distributed across the range of calibration and including 5 values close to the detection limit. This methodology allows a scientifically effective verification, technically and financially reasonable, to ensure the excellence of the performance of the laboratory with regard to peers and users (allergologists and patients).


Assuntos
Acreditação/normas , Alérgenos/imunologia , Técnicas de Laboratório Clínico/normas , Imunoglobulina E/análise , Laboratórios/legislação & jurisprudência , Técnicas de Laboratório Clínico/economia , Técnicas de Laboratório Clínico/métodos , Análise Custo-Benefício , Humanos , Hipersensibilidade/sangue , Hipersensibilidade/diagnóstico , Hipersensibilidade/imunologia , Imunoglobulina E/imunologia , Laboratórios/economia , Laboratórios/normas , Guias de Prática Clínica como Assunto , Controle de Qualidade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Incerteza , Estudos de Validação como Assunto
11.
Leuk Lymphoma ; 54(4): 767-77, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22385269

RESUMO

The type I cryoglobulins (CGs) account for 10-15% of all cryoglobulins and are found in patients with hematological disorders. We here describe the largest series of seven cases of type I cryoglobulinemia associated with multiple myeloma (MM) and provide a detailed review of the literature associated with this disorder, with the aim of improving the future diagnosis and therapeutic management of this rare disease. Six of the cases in our series were men aged 28-69 years, and most of the subject patients had an immunoglobulin G (IgG) monoclonal component and stage I indolent MM that manifested as cryoglobulin-related symptoms. The patients were all karyotypically normal. Clinical manifestations in this group were: skin lesions (five cases, 71.4%), rheumatologic failure (four cases, 57.1%), neurological abnormalities (two cases, 28.6%), mixed cutaneous/rheumatologic/renal defects (one case, 14.3%) and one case in which the cryoglobulinemia was asymptomatic. Two patients experienced acute renal failure but underwent a full recovery following treatment for MM. We conclude from our analysis that treatment approaches for severe type I cryoglobulinemia should involve plasmapheresis at the onset to achieve a rapid control of the CG-related symptoms, and that specific MM treatments should be introduced also at an early stage to avoid cryoglobulinemia relapse. In this context, bortezomib and lenalidomide are potentially the most effective therapeutic agents.


Assuntos
Crioglobulinemia/diagnóstico , Crioglobulinemia/etiologia , Mieloma Múltiplo/complicações , Mieloma Múltiplo/diagnóstico , Adulto , Crioglobulinemia/terapia , Evolução Fatal , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/terapia , Necrose , Estadiamento de Neoplasias , Pele/patologia , Resultado do Tratamento
12.
Medicine (Baltimore) ; 91(4): e1-19, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22751495

RESUMO

Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) is the main genetic etiology of hyper-immunoglobulin (Ig) E syndrome. We documented the molecular, cellular, and clinical features of 60 patients with heterozygous STAT3 mutations from 47 kindreds followed in France. We identified 11 known and 13 new mutations of STAT3. Low levels of interleukin (IL)-6-dependent phosphorylation and nuclear translocation (or accumulation) of STAT3 were observed in Epstein-Barr virus-transformed B lymphocytes (EBV-B cells) from all STAT3-deficient patients tested. The immunologic phenotype was characterized by high serum IgE levels (96% of the patients), memory B-cell lymphopenia (94.5%), and hypereosinophilia (80%). A low proportion of IL-17A-producing circulating T cells was found in 14 of the 15 patients tested. Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%). Up to 90% of the patients had pneumonia, mostly caused by Staph. aureus (31%) or Streptococcus pneumoniae (30%). Recurrent pneumonia was associated with secondary bronchiectasis and pneumatocele (67%), as well as secondary aspergillosis (22%). Up to 92% of the patients had dermatitis and connective tissue abnormalities, with facial dysmorphism (95%), retention of decidual teeth (65%), osteopenia (50%), and hyperextensibility (50%). Four patients developed non-Hodgkin lymphoma. The clinical outcome was favorable, with 56 patients, including 43 adults, still alive at the end of study (mean age, 21 yr; range, 1 mo to 46 yr). Only 4 patients died, 3 from severe bacterial infection (aged 1, 15, and 29 yr, respectively). Antibiotic prophylaxis (90% of patients), antifungal prophylaxis (50%), and IgG infusions (53%) improved patient health, as demonstrated by the large decrease in pneumonia recurrence. Overall, the prognosis of STAT3 deficiency may be considered good, provided that multiple prophylactic measures, including IgG infusions, are implemented.


Assuntos
Hospedeiro Imunocomprometido/genética , Síndrome de Job/epidemiologia , Síndrome de Job/genética , Fator de Transcrição STAT3/deficiência , Fator de Transcrição STAT3/genética , Adolescente , Adulto , Distribuição por Idade , Criança , Pré-Escolar , Estudos Transversais , Análise Mutacional de DNA , Bases de Dados Factuais , Eczema/epidemiologia , Eczema/etiologia , Feminino , França/epidemiologia , Predisposição Genética para Doença/epidemiologia , Heterozigoto , Humanos , Incidência , Lactente , Recém-Nascido , Síndrome de Job/complicações , Síndrome de Job/imunologia , Masculino , Pessoa de Meia-Idade , Fosforilação , Pneumonia Bacteriana/epidemiologia , Pneumonia Bacteriana/etiologia , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/etiologia , Medição de Risco , Índice de Gravidade de Doença , Distribuição por Sexo , Transdução de Sinais , Dermatopatias Bacterianas/epidemiologia , Dermatopatias Bacterianas/etiologia , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/etiologia , Análise de Sobrevida , Adulto Jovem
13.
J Immunol ; 188(4): 2023-9, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22250089

RESUMO

Ig class-switch recombination (Ig-CSR) deficiencies are rare primary immunodeficiencies characterized by defective switched isotype (IgG/IgA/IgE) production. Depending on the molecular defect, defective Ig-CSR may also be associated with impaired somatic hypermutation (SHM) of the Ig V regions. Although the mechanisms underlying Ig-CSR and SHM in humans have been revealed (at least in part) by studying natural mutants, the role of mismatch repair in this process has not been fully elucidated. We studied in vivo and in vitro Ab maturation in eight MSH6-deficient patients. The skewed SHM pattern strongly suggests that MSH6 is involved in the human SHM process. Ig-CSR was found to be partially defective in vivo and markedly impaired in vitro. The resolution of γH2AX foci following irradiation of MSH6-deficient B cell lines was also found to be impaired. These data suggest that in human CSR, MSH6 is involved in both the induction and repair of DNA double-strand breaks in switch regions.


Assuntos
Proteínas de Ligação a DNA/deficiência , Switching de Imunoglobulina , Síndromes de Imunodeficiência/genética , Adolescente , Linfócitos B , Sequência de Bases , Proliferação de Células , Células Cultivadas , Criança , Pré-Escolar , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Feminino , Histonas/genética , Humanos , Deficiência de IgG/genética , Imunoglobulina G/sangue , Região Variável de Imunoglobulina/genética , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA , Hipermutação Somática de Imunoglobulina , Adulto Jovem
14.
J Allergy Clin Immunol ; 129(3): 770-7, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22153772

RESUMO

BACKGROUND: Primary immunoglobulin deficiencies lead to recurrent bacterial infections of the respiratory tract and bronchiectasis, even with adequate immunoglobulin replacement therapy. It is not known whether patients able to secrete IgM (eg, those with hyper-IgM [HIgM] syndrome) are as susceptible to these infections as patients who lack IgM production (eg, those with panhypogammaglobulinemia [PHG]). OBJECTIVE: This study is aimed at identifying specific microbiological and clinical (infections) characteristics that distinguish immunoglobulin-substituted patients with PHG from patients with HIgM syndrome. METHODS: A cohort of patients with HIgM syndrome (n = 25) and a cohort of patients with PHG (n = 86) were monitored prospectively for 2 years while receiving similar polyvalent immunoglobulin replacement therapies. Regular bacterial analyses of nasal swabs and sputum were performed, and clinical events were recorded. In parallel, serum and saliva IgM antibody concentrations were measured. RESULTS: When compared with patients with PHG, patients with HIgM syndrome were found to have a significantly lower risk of nontypeable Haemophilus influenzae carriage in particular (relative risk, 0.39; 95% CI, 0.21-0.63). Moreover, patients with HIgM syndrome (including those unable to generate somatic hypermutations of immunoglobulin genes) displayed anti-nontypeable H influenzae IgM antibodies in their serum and saliva. Also, patients with HIgM syndrome had a lower incidence of acute respiratory tract infections. CONCLUSIONS: IgM antibodies appear to be microbiologically and clinically protective and might thus attenuate the infectious consequences of a lack of production of other immunoglobulin isotypes in patients with HIgM syndrome. Polyvalent IgG replacement therapy might not fully compensate for IgM deficiency. It might thus be worth adapting long-term antimicrobial prophylactic regimens according to the underlying B-cell immunodeficiency phenotype.


Assuntos
Agamaglobulinemia/imunologia , Anticorpos Antivirais/metabolismo , Infecções por Haemophilus/imunologia , Haemophilus influenzae/imunologia , Síndrome de Imunodeficiência com Hiper-IgM/imunologia , Imunoglobulina M/metabolismo , Adolescente , Agamaglobulinemia/complicações , Agamaglobulinemia/epidemiologia , Anticorpos Antivirais/imunologia , Criança , Feminino , Infecções por Haemophilus/complicações , Infecções por Haemophilus/epidemiologia , Haemophilus influenzae/patogenicidade , Humanos , Síndrome de Imunodeficiência com Hiper-IgM/complicações , Síndrome de Imunodeficiência com Hiper-IgM/epidemiologia , Imunoglobulina M/imunologia , Incidência , Masculino , Estudos Prospectivos , Sistema Respiratório/imunologia , Sistema Respiratório/patologia , Sistema Respiratório/virologia , Risco
15.
Nat Med ; 17(11): 1456-65, 2011 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-22019886

RESUMO

Anemia because of insufficient production of and/or response to erythropoietin (Epo) is a major complication of chronic kidney disease and cancer. The mechanisms modulating the sensitivity of erythroblasts to Epo remain poorly understood. We show that, when cultured with Epo at suboptimal concentrations, the growth and clonogenic potential of erythroblasts was rescued by transferrin receptor 1 (TfR1)-bound polymeric IgA1 (pIgA1). Under homeostatic conditions, erythroblast numbers were increased in mice expressing human IgA1 compared to control mice. Hypoxic stress of these mice led to increased amounts of pIgA1 and erythroblast expansion. Expression of human IgA1 or treatment of wild-type mice with the TfR1 ligands pIgA1 or iron-loaded transferrin (Fe-Tf) accelerated recovery from acute anemia. TfR1 engagement by either pIgA1 or Fe-Tf increased cell sensitivity to Epo by inducing activation of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways. These cellular responses were mediated through the TfR1-internalization motif, YXXΦ. Our results show that pIgA1 and TfR1 are positive regulators of erythropoiesis in both physiological and pathological situations. Targeting this pathway may provide alternate approaches to the treatment of ineffective erythropoiesis and anemia.


Assuntos
Anemia/fisiopatologia , Proliferação de Células , Eritroblastos/fisiologia , Eritropoese/fisiologia , Imunoglobulina A/metabolismo , Animais , Células Cultivadas , Eritroblastos/citologia , Eritroblastos/efeitos dos fármacos , Eritropoetina/farmacologia , Humanos , Hipóxia/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Receptores da Transferrina/metabolismo , Transdução de Sinais/fisiologia , Transferrina/farmacologia
17.
Am J Kidney Dis ; 56(1): 117-21, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20471736

RESUMO

A 62-year-old woman presented with nephrotic syndrome, monoclonal gammopathy, and membranous-like nephropathy with nonorganized deposits composed of monoisotypic immunoglobulin G1 lambda protein. Nephrotic syndrome remitted after a brief course of treatment with melphalan despite ongoing production of the monoclonal protein. The circulating monoclonal immunoglobulin G1 lambda showed unusual in vitro aggregation properties, including dependence on low ionic strength and neutral pH, suggesting that electrostatic interactions had a role in the precipitation process. This case illustrates the importance of looking for monoclonal immunoglobulin deposits when kidney biopsy findings are suggestive of membranous nephropathy. In addition, our in vitro demonstrations of the role of physicochemical factors in immunoglobulin precipitation help elucidate the pathogenesis of immunoglobulin deposition disorders. Although binding to podocyte antigens is a well-recognized determinant of subepithelial immunoglobulin deposition, proneness to aggregation as described in this case also might be nephritogenic.


Assuntos
Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/diagnóstico , Imunoglobulina G/sangue , Gamopatia Monoclonal de Significância Indeterminada/sangue , Gamopatia Monoclonal de Significância Indeterminada/diagnóstico , Feminino , Humanos , Pessoa de Meia-Idade , Paraproteinemias/sangue , Paraproteinemias/diagnóstico
18.
Am J Kidney Dis ; 53(6): 1063-7, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19084310

RESUMO

Pauci-immune renal vasculitis is associated strongly with antineutrophil cytoplasmic antibodies (ANCAs) of the immunoglobulin G (IgG) class, which are detected in 80% to 90% of affected patients. IgA ANCAs have been reported in association with various conditions, but never in the setting of pauci-immune vasculitis. A 28-year-old man with unexplained polyclonal hyper-IgA1 diagnosed in childhood presented with decreased kidney function, nephrotic syndrome, and microscopic hematuria. Kidney biopsy showed pauci-immune crescentic glomerulonephritis. Serum test results were negative for IgG ANCA by means of both indirect immunofluorescence and enzyme-linked immunosorbent assay techniques. Conversely, indirect immunofluorescence performed using anti-IgA antibody was strongly positive with a cytoplasmic ANCA pattern, and an enzyme-linked immunosorbent assay test had positive results for both antimyeloperoxidase and anti-proteinase 3 IgA. IgA ANCAs were not detected in 2 control serum samples from 1 patient with polyclonal hyper-IgA and 1 patient with monoclonal hyper-IgA. The patient received corticosteroids and 4 weekly perfusions of rituximab (375 mg/m2). After a 6-month follow-up, decreased kidney function and nephrotic syndrome persisted and IgA ANCA titers were unchanged. However, a control kidney biopsy showed a decrease in vasculitis activity. This first case of pauci-immune vasculitis associated with ANCA of the IgA class suggests the potential pathogenetic role of these peculiar antibodies. Additional studies are needed to determine whether IgA ANCAs, which are not routinely screened for, can be detected in patients with pauci-immune vasculitis either alone or in association with IgG ANCA.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/sangue , Glomerulonefrite por IGA/imunologia , Imunoglobulina A/sangue , Adulto , Anticorpos Anticitoplasma de Neutrófilos/biossíntese , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/patologia , Humanos , Imunoglobulina A/biossíntese , Masculino , Vasculite/diagnóstico , Vasculite/imunologia , Vasculite/patologia
19.
J Exp Med ; 205(11): 2465-72, 2008 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-18824584

RESUMO

Immunoglobulin (Ig) class switch recombination (CSR) deficiencies are rare primary immunodeficiencies characterized by the lack of switched isotype (IgG/IgA/IgE) production. In some cases, CSR deficiencies can be associated with abnormal somatic hypermutation. Analysis of CSR deficiencies has helped reveal the key functions of CSR-triggering molecules, i.e., CD40L, CD40, and effector molecules such as activation-induced cytidine deaminase and uracil N-glycosylase. We report a new form of B cell-intrinsic CSR deficiency found in three patients with deleterious, homozygous mutations in the gene encoding the PMS2 component of the mismatch repair machinery. CSR was found partially defective in vivo and markedly impaired in vitro. It is characterized by the defective occurrence of double-strand DNA breaks (DSBs) in switch regions and abnormal formation of switch junctions. This observation strongly suggests a role for PMS2 in CSR-induced DSB generation.


Assuntos
Adenosina Trifosfatases/deficiência , Linfócitos B/imunologia , Quebras de DNA de Cadeia Dupla , Enzimas Reparadoras do DNA/deficiência , Proteínas de Ligação a DNA/deficiência , Switching de Imunoglobulina/genética , Síndromes de Imunodeficiência/genética , Deleção de Sequência/genética , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Sequência de Bases , Western Blotting , Criança , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Citometria de Fluxo , Imunofluorescência , Mutação da Fase de Leitura/genética , Humanos , Endonuclease PMS2 de Reparo de Erro de Pareamento , Dados de Sequência Molecular , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA
20.
FEMS Immunol Med Microbiol ; 53(1): 107-13, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18422632

RESUMO

This pilot study investigated the immunomodulatory properties of seven probiotic strains. Eighty-three healthy volunteers aged 18-62 years consumed 2 x 10(10) CFU of bacteria or a placebo (maltodextrin) over 3 weeks (D0-D21). Subjects received an oral cholera vaccine at D7 and at D14; blood and saliva samples were collected at D0, D21 and D28. Serum samples were analyzed for specific IgA, IgG and IgM, and saliva samples were analyzed for specific IgA only, by ELISA. Statistical analyses were based on Wilcoxon's signed-rank test (intragroup analyses) and exact median t-test (intergroup analyses). Salivary analysis showed no difference in specific IgA concentrations between groups. Serum analysis indicated an effect of some of the tested strains on specific humoral responses. Between D0 and D21, IgG increased in two probiotic groups, for example, Bifidobacterium lactis Bl-04 and Lactobacillus acidophilus La-14, compared with controls (P=0.01). Trends toward significant changes in immunoglobulin serum concentrations compared with controls (P<0.1) were found for six out of the seven probiotic strains. In conclusion, some strains of probiotics demonstrated a faster immune response measured with serum immunoglobulin indicators, especially IgG, although overall vaccination was not influenced. Specific strains of probiotics may thus act as adjuvants to the humoral immune response following oral vaccination.


Assuntos
Isotipos de Imunoglobulinas/biossíntese , Probióticos/farmacologia , Adolescente , Adulto , Bifidobacterium , Vacinas contra Cólera/imunologia , Vacinas contra Cólera/farmacologia , Método Duplo-Cego , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Isotipos de Imunoglobulinas/sangue , Lactobacillus , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Saliva/imunologia , Tamanho da Amostra , Estatísticas não Paramétricas
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