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2.
Front Immunol ; 11: 596761, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33329586

RESUMO

The disease course of COVID-19 in patients with immunodeficiencies is unclear, as well as the optimal therapeutic strategy. We report a case of a 37-year old male with common variable immunodeficiency disorder and a severe SARS-CoV-2 infection. After administration of convalescent plasma, the patient's condition improved rapidly. Despite clinical recovery, viral RNA remained detectable up to 60 days after onset of symptoms. We propose that convalescent plasma might be considered as a treatment option in patients with CVID and severe COVID-19. In addition, in patients with immunodeficiencies, a different clinical course is possible, with prolonged viral shedding.


Assuntos
Anticorpos Antivirais/administração & dosagem , Imunodeficiência de Variável Comum , RNA Viral , Eliminação de Partículas Virais , Adulto , /imunologia , Imunodeficiência de Variável Comum/sangue , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/terapia , Humanos , Imunização Passiva , Masculino , RNA Viral/sangue , RNA Viral/imunologia , /metabolismo , Eliminação de Partículas Virais/efeitos dos fármacos , Eliminação de Partículas Virais/imunologia
4.
Am J Surg Pathol ; 44(8): 1073-1081, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32235152

RESUMO

Common variable immunodeficiency (CVID) and selective immunoglobulin A deficiency (IgAD) often cause chronic lung disease, but the pulmonary pathologic features of these systemic diseases are poorly recognized by pathologists. It has been claimed that CVID cases show a characteristic combination of noncaseating granulomas-lymphoid proliferations termed granulomatous-lymphocytic interstitial lung disease (GLILD). We present 34 surgical lung biopsy cases of CVID and 4 of IgAD. Noncaseating granulomas were seen in 23/34 (68%) CVID and 2/4 (50%) IgAD cases. A statistically identical pattern of benign lymphoid proliferation was found in CVID and IgAD whether or not granulomas were present. Organizing pneumonia, sometimes considered a part of GLILD, was seen in 25/34 (74%) CVID and 2/4 (50%) IgAD cases and did not correlate with the presence of granulomas. On follow-up, 3 CVID patients died (only 1 of pulmonary disease), while 21 others are alive at 1 to 300 months with no difference by presence or absence of granulomas. Three IgAD patients with follow-up are alive. We conclude that CVID and IgAD are indistinguishable in surgical lung biopsies and a subset of both show patterns that would qualify as GLILD, while other cases lack granulomas but have identical patterns of lymphoid infiltration and organizing pneumonia. We suggest that GLILD is neither a specific nor a useful entity, and biopsies from CVID and IgAD patients should be diagnosed simply by microscopic pattern(s) observed. The prognosis of CVID with lymphoid infiltrates with or without granulomas in this series was good, contrary to claims in the literature about GLILD.


Assuntos
Imunodeficiência de Variável Comum/patologia , Granuloma do Sistema Respiratório/patologia , Deficiência de IgA/patologia , Doenças Pulmonares Intersticiais/patologia , Pulmão/patologia , Linfócitos/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Proliferação de Células , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/mortalidade , Imunodeficiência de Variável Comum/terapia , Feminino , Granuloma do Sistema Respiratório/imunologia , Granuloma do Sistema Respiratório/mortalidade , Granuloma do Sistema Respiratório/terapia , Humanos , Deficiência de IgA/imunologia , Deficiência de IgA/mortalidade , Deficiência de IgA/terapia , Pulmão/imunologia , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/mortalidade , Doenças Pulmonares Intersticiais/terapia , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , América do Norte , Valor Preditivo dos Testes , Prognóstico , Adulto Jovem
6.
Am J Surg Pathol ; 44(5): 617-625, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32187043

RESUMO

Common variable immunodeficiency (CVID) has a heterogenous clinical presentation and can be challenging to diagnose. Distinct histologic changes have been linked with CVID in several organ systems, which can help identify the correct diagnosis. In this study we review a cohort of hepatic CVID biopsies, to better define the spectrum of histologic and biochemical alterations. We reviewed 26 liver biopsies from 24 patients with CVID, obtained at 4 institutions between 2010 and 2019. Histologic slides were examined, and pathologic, biochemical, and clinical features were recorded. A control cohort of 21 patients with nodular regenerative hyperplasia (NRH) but lacking CVID was also examined. Liver function tests were frequently abnormal, especially alkaline phosphatase (median: 193 IU/L) and aspartate transaminase (median: 56 U/L), elevated in 23 and 17 of 25 biopsies, respectively. Fifteen patients had CVID involvement of other organs. Histologic features of primary biliary cholangitis were present in 2 patients, with florid duct lesions and prominent bile duct injury, in association with positive antimitochondrial antibodies. Among the other 24 biopsies, mild to moderate portal and lobular inflammation were present in 18 and 17 of 24 biopsies, respectively. Overall, 22 of 24 biopsies showed NRH-like changes. Plasma cell were absent. A distinct pattern of pericellular fibrosis was present in 23 of 26 biopsies overall. Involvement ranged from focal centrizonal fibrosis to bridging fibrosis and was accompanied by increased intrasinusoidal lymphocytes in 13 of 24 biopsies. Pericellular fibrosis was identified in 1 of 21 biopsies in the control cohort. Additional findings included granulomatous inflammation or nonhepatocellular foreign body-type multinucleate giant cells, identified in 4 biopsies. Three of 6 examined biopsies also demonstrated focal hepatocellular copper deposition. Hepatic disease in CVID is often associated with elevated alkaline phosphatase and aspartate transaminase and is characterized histologically by the mild nonspecific portal and lobular hepatitis, absence of plasma cells, NRH-like changes, and less commonly, typical histologic features of primary biliary cholangitis. We have also identified a distinctive pattern of delicate pericellular fibrosis that is a helpful clue to the diagnosis of hepatic disease in CVID, especially when accompanied by NRH-like changes.


Assuntos
Imunodeficiência de Variável Comum/complicações , Hepatite/etiologia , Hipertensão Portal/etiologia , Cirrose Hepática/etiologia , Fígado/patologia , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Biópsia , Estudos de Casos e Controles , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/imunologia , Feminino , Hepatite/imunologia , Hepatite/patologia , Humanos , Hipertensão Portal/imunologia , Hipertensão Portal/patologia , Fígado/imunologia , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Plasmócitos/imunologia , Plasmócitos/patologia , Valor Preditivo dos Testes , Turquia , Estados Unidos , Adulto Jovem
7.
Clin Immunol ; 212: 108362, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32058070

RESUMO

A number of gastrointestinal complications occur in common variable immunodeficiency (CVID). Infections are one cause, but various forms of severe non-infectious enteropathy also lead to substantial morbidity. The presence of T cell lymphocytic infiltrates in the mucosa have suggested that vedolizumab, a humanized monoclonal antibody which binds to alpha4 beta7 integrin and inhibits the migration of effector T-lymphocytes into gastrointestinal tissues, would be an effective treatment. A previous report of 3 CVID cases suggested benefit in 2 subjects. In this study 7 CVID patients with severe enteropathy were treated with vedolizumab. Four of the 7 completed vedolizumab induction therapy but 3 subjects had acute decompensation during induction and treatment was stopped. While one subject showed improvement, 6 of the 7 patients were withdrawn from therapy. While vedolizumab may be of use in some CVID subjects, it was not ultimately found helpful in most of these patients.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Imunodeficiência de Variável Comum/imunologia , Fármacos Gastrointestinais/uso terapêutico , Enteropatias/tratamento farmacológico , Adulto , Idoso , Imunodeficiência de Variável Comum/complicações , Feminino , Humanos , Inflamação , Enteropatias/etiologia , Enteropatias/imunologia , Enteropatias/patologia , Síndromes de Malabsorção/etiologia , Síndromes de Malabsorção/terapia , Masculino , Desnutrição/etiologia , Desnutrição/terapia , Pessoa de Meia-Idade , Nutrição Parenteral , Falha de Tratamento
8.
Int Arch Allergy Immunol ; 181(3): 228-237, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31901904

RESUMO

INTRODUCTION: Common variable immunodeficiency (CVID) is characterized by recurrent infections, autoimmunity, lymphoproliferation, hypogammaglobulinemia, and defective antibody production. In CVID, B-cell abnormalities were described to predict end organ involvement and prognosis. Pediatric-onset CVID is much rarer than adult CVID, and lymphocyte subset abnormalities have not been thoroughly evaluated. OBJECTIVE: We sought to determine lymphocyte subset abnormalities and their association with end organ involvement in pediatric-onset CVID patients. METHODS: The clinical manifestations and laboratory findings including absolute numbers and percentages of B-, T-, and NK cell populations were assessed in pediatric-onset CVID patients and compared to age-matched healthy controls. The patients were divided into 2 groups according to age at assessment (pediatric CVID patients: 10-16 years, n = 9; and adult CVID patients: >16 years, n = 13). The comparisons between lymphocyte subsets and organ involvement were also evaluated. RESULTS: Mean age at symptom onset was 18 (3-204) months. All CVID patients with pediatric onset had decreased levels of total and memory B cells, CD4+ T cells, CD4+CD45RA+ naive T cells, and recent thymic emigrant (RTE) cells. On the other hand, they had increases in CD8+CD45RO+ memory T cells. Interestingly, adult CVID patients demonstrated high frequencies of activated and double-negative T cells, which were unique only for this group of patients. Specific cellular abnormalities associated with the reduction in B and NK cells and increase in CD8+ T cells were found in patients with bronchiectasis. Moreover, in pediatric CVID patients, low serum IgA levels and decreased numbers of naive T and RTE cells were determined as risk factors for chronic diarrhea. CONCLUSIONS: Specific abnormalities in B- and T-lymphocyte compartments were identified in pediatric-onset CVID patients and appear to be associated with end organ manifestations.


Assuntos
Linfócitos B/imunologia , Imunodeficiência de Variável Comum/imunologia , Subpopulações de Linfócitos/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Autoimunidade , Criança , Feminino , Humanos , Memória Imunológica , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Adulto Jovem
9.
Clin Immunol ; 210: 108309, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31751612

RESUMO

Mutations affecting the non-canonical pathway of NF-κB were recently identified to underlie a form of common variable immunodeficiency strongly associated with autoimmunity. Although intrinsic B-cell abnormalities explain most of the humoral defects of this disease, detailed data on the impact of NFKB2 on follicular helper (Tfh) and regulatory (Tregs) T cells are scarce. Here, we show that Tfh, CXCR5+, and CXCR5- Treg cell subsets were significantly reduced in patients heterozygous for a truncating mutation of NFKB2. Plasma CXCL13 levels were reduced, underlining an important role for NFKB2 in regulating the germinal center (GC) response. Proinflammatory IFNγ, IL-17 and IL-10 cytokine production by CD4 T cells was lower in the mutated patients, but the production of IL-4 and IL-21 was not altered. Taken together, our findings show that NFKB2 influences the quality and efficiency of human GC reaction, by affecting not only the B cells but also GC-relevant T cell subsets.


Assuntos
Imunodeficiência de Variável Comum/imunologia , Centro Germinativo/imunologia , Subunidade p52 de NF-kappa B/genética , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Autoimunidade , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Criança , Imunodeficiência de Variável Comum/genética , Citocinas/metabolismo , Feminino , Humanos , Masculino , NF-kappa B/genética , NF-kappa B/metabolismo , Deleção de Sequência/genética , Transdução de Sinais , Adulto Jovem
10.
Rev Paul Pediatr ; 38: e2018146, 2020.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31778409

RESUMO

OBJECTIVE: To report a case of a child with primary immunodeficiency who at eight years developed digestive symptoms, culminating with the diagnosis of a neuroendocrine tumor at ten years of age. CASE DESCRIPTION: One-year-old boy began to present recurrent pneumonias in different pulmonary lobes. At four years of age, an immunological investigation showed a decrease in IgG and IgA serum levels. After the exclusion of other causes of hypogammaglobinemia, he was diagnosed with a Common Variable Immunodeficiency and started to receive monthly replacement of human immunoglobulin. The patient evolved well, but at 8 years of age began with epigastrium pain and, at 10 years, chronic persistent diarrhea and weight loss. After investigation, a neuroendocrine tumor was diagnosed, which had a rapid progressive evolution to death. COMMENTS: Medical literature has highlighted the presence of gastric tumors in adults with Common Variable Immunodeficiency, emphasizing the importance of early diagnosis and the investigation of digestive neoplasms. Up to now there is no description of neuroendocrine tumor in pediatric patients with Common Variable Immunodeficiency. We believe that the hypothesis of digestive neoplasm is important in children with Common Variable Immunodeficiency and with clinical manifestations similar to the case described here in the attempt to improve the prognosis for pediatric patients.


Assuntos
Imunodeficiência de Variável Comum/complicações , Tumores Neuroendócrinos/diagnóstico , Pneumonia/diagnóstico , Dor Abdominal/diagnóstico , Dor Abdominal/etiologia , Antineoplásicos/uso terapêutico , Criança , Imunodeficiência de Variável Comum/imunologia , Diarreia/diagnóstico , Diarreia/etiologia , Evolução Fatal , Humanos , Neoplasias Intestinais/diagnóstico por imagem , Neoplasias Intestinais/patologia , Neoplasias Intestinais/cirurgia , Masculino , Metástase Neoplásica/patologia , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/terapia , Pneumonia/etiologia , Recidiva , Perda de Peso
11.
Front Immunol ; 11: 607918, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33424856

RESUMO

The inability of patients with CVID to mount specific antibody responses to pathogens has raised concerns on the risk and severity of SARS-CoV-2 infection, but there might be a role for protective T cells in these patients. SARS-CoV-2 reactive T cells have been reported for SARS-CoV-2 unexposed healthy individuals. Until now, there is no data on T cell immunity to SARS-CoV-2 infection in CVID. This study aimed to evaluate reactive T cells to human endemic corona viruses (HCoV) and to study pre-existing SARS-CoV-2 reactive T cells in unexposed CVID patients. We evaluated SARS-CoV-2- and HCoV-229E and -OC43 reactive T cells in response to seven peptide pools, including spike and nucleocapsid (NCAP) proteins, in 11 unexposed CVID, 12 unexposed and 11 post COVID-19 healthy controls (HC). We further characterized reactive T cells by IFNγ, TNFα and IL-2 profiles. SARS-CoV-2 spike-reactive CD4+ T cells were detected in 7 of 11 unexposed CVID patients, albeit with fewer multifunctional (IFNγ/TNFα/IL-2) cells than unexposed HC. CVID patients had no SARS-CoV-2 NCAP reactive CD4+ T cells and less reactive CD8+ cells compared to unexposed HC. We observed a correlation between T cell reactivity against spike of SARS-CoV-2 and HCoVs in unexposed, but not post COVID-19 HC, suggesting cross-reactivity. T cell responses in post COVID-19 HC could be distinguished from unexposed HC by higher frequencies of triple-positive NCAP reactive CD4+ T cells. Taken together, SARS-CoV-2 reactive T cells are detectable in unexposed CVID patients albeit with lower recognition frequencies and polyfunctional potential. Frequencies of triple-functional reactive CD4+ cells might provide a marker to distinguish HCoV cross-reactive from SARS-CoV-2 specific T cell responses. Our data provides evidence, that anti-viral T cell immunity is not relevantly impaired in most CVID patients.


Assuntos
Anticorpos Antivirais/sangue , Imunodeficiência de Variável Comum/imunologia , Coronaviridae/imunologia , Imunoglobulina G/sangue , Linfócitos T/imunologia , Adulto , Idoso , Imunodeficiência de Variável Comum/sangue , Reações Cruzadas , Citocinas/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
Artigo em Inglês | LILACS | ID: biblio-1057212

RESUMO

ABSTRACT Objective: To report a case of a child with primary immunodeficiency who at eight years developed digestive symptoms, culminating with the diagnosis of a neuroendocrine tumor at ten years of age. Case description: One-year-old boy began to present recurrent pneumonias in different pulmonary lobes. At four years of age, an immunological investigation showed a decrease in IgG and IgA serum levels. After the exclusion of other causes of hypogammaglobinemia, he was diagnosed with a Common Variable Immunodeficiency and started to receive monthly replacement of human immunoglobulin. The patient evolved well, but at 8 years of age began with epigastrium pain and, at 10 years, chronic persistent diarrhea and weight loss. After investigation, a neuroendocrine tumor was diagnosed, which had a rapid progressive evolution to death. Comments: Medical literature has highlighted the presence of gastric tumors in adults with Common Variable Immunodeficiency, emphasizing the importance of early diagnosis and the investigation of digestive neoplasms. Up to now there is no description of neuroendocrine tumor in pediatric patients with Common Variable Immunodeficiency. We believe that the hypothesis of digestive neoplasm is important in children with Common Variable Immunodeficiency and with clinical manifestations similar to the case described here in the attempt to improve the prognosis for pediatric patients.


RESUMO Objetivo: Relatar um caso de criança portadora de imunodeficiência primária que, aos oito anos, desenvolveu sintomas digestivos, culminando com o diagnóstico de tumor neuroendócrino aos dez anos de idade. Descrição do caso: Menino, com um ano de idade, começou a apresentar pneumonias de repetição em diferentes lobos pulmonares. Aos quatro anos, a investigação imunológica mostrou diminuição dos níveis séricos de IgG e IgA. Após exclusão de outras causas de hipogamaglobulinemia, teve diagnóstico de imunodeficiência comum variável, passando a receber reposição mensal de imunoglobulina humana. Evoluiu bem, porém, aos oito anos, começou com epigastralgia e, aos dez anos, diarreia crônica persistente e perda de peso. O quadro culminou com o diagnóstico de tumor neuroendócrino intestinal, de rápida progressão, com óbito do paciente. Comentários: A literatura tem chamado a atenção para tumores gástricos em adultos com imunodeficiência comum variável, alertando para a importância do diagnóstico precoce e da pesquisa de neoplasias digestivas. Até o momento, não há descrição de tumor neuroendócrino em pacientes pediátricos portadores de imunodeficiência comum variável. Acredita-se ser importante a hipótese de neoplasia digestiva diante de crianças com imunodeficiência comum variável e com manifestações clínicas semelhantes ao caso descrito, na tentativa de melhorar o prognóstico para pacientes pediátricos.


Assuntos
Humanos , Masculino , Criança , Pneumonia/diagnóstico , Imunodeficiência de Variável Comum/complicações , Tumores Neuroendócrinos/diagnóstico , Pneumonia/etiologia , Recidiva , Perda de Peso , Dor Abdominal/diagnóstico , Dor Abdominal/etiologia , Imunodeficiência de Variável Comum/imunologia , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/terapia , Evolução Fatal , Diarreia/diagnóstico , Diarreia/etiologia , Neoplasias Intestinais/cirurgia , Neoplasias Intestinais/patologia , Neoplasias Intestinais/diagnóstico por imagem , Metástase Neoplásica/patologia , Antineoplásicos/uso terapêutico
13.
Hematology Am Soc Hematol Educ Program ; 2019(1): 449-456, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31808912

RESUMO

Common variable immune deficiency (CVID) is one of the most common congenital immune defects encountered in clinical practice. The condition occurs equally in males and females, and most commonly in the 20- to 40-year-old age group. The diagnosis is made by documenting reduced serum concentrations of immunoglobulin G (IgG), IgA, and usually IgM, together with loss of protective antibodies. The genetics of this syndrome are complex and are still being unraveled, but the hallmarks for most patients, as with other immune defects, include acute and chronic infections of the sinopulmonary tract. However, other noninfectious autoimmune or inflammatory conditions may also occur in CVID, and indeed these may be the first and only sign that a significant immune defect is present. These manifestations include episodes of immune thrombocytopenia, autoimmune hemolytic anemia, or neutropenia, in addition to splenomegaly, generalized or worrisome lymphadenopathy, and malignancy, especially lymphoma. These issues commonly bring the patient to the attention of hematologists for both evaluation and treatment. This article discusses 3 cases in which patients with CVID had some of these presenting issues and what hematology input was required.


Assuntos
Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/genética , Imunodeficiência de Variável Comum/imunologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
14.
Molecules ; 24(24)2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31817348

RESUMO

The aim of this study was to explore the immunomodulatory effects of the Meretrix meretrix oligopeptide (MMO, QLNWD) in cyclophosphamide (CTX)-induced immune-deficient mice. Compared to untreated, CTX-induced immune-deficient mice, the spleen and thymus indexes of mice given moderate (100 mg/kg) and high (200 mg/kg) doses of MMO were significantly higher (p < 0.05), and body weight loss was alleviated. Hematoxylin-eosin (H&E) staining revealed that MMO reduced spleen injury, thymus injury, and liver injury induced by CTX in mice. Furthermore, MMO boosted the production of immunoglobulin G (IgG) and hemolysin in the serum and promoted the proliferation and differentiation of spleen T-lymphocytes. Taken together, our findings suggest that MMO plays a vital role in protection against immunosuppression in CTX-induced immune-deficient mice and could be a potential immunomodulatory candidate for use in functional foods or immunologic adjuvants.


Assuntos
Bivalves/química , Imunodeficiência de Variável Comum , Fatores Imunológicos , Oligopeptídeos , Linfócitos T , Animais , Imunodeficiência de Variável Comum/tratamento farmacológico , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/patologia , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Especificidade de Órgãos/efeitos dos fármacos , Especificidade de Órgãos/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia
15.
Front Immunol ; 10: 2812, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827477

RESUMO

Adiponectin exerts beneficial pleiotropic effects through three receptors, AdipoR1, AdipoR2, and T-cadherin; it also exerts immunomodulatory effects. We previously demonstrated that adiponectin levels are altered in common variable immunodeficiency disease (CVID). The purpose of the present study was to investigate further the specific involvement of adiponectin in CVID by characterizing (i) the expression profile of adiponectin receptors on peripheral blood mononuclear cells; (ii) the levels of another relevant adipokine, namely leptin; (iii) the levels of five other cytokines (IL-2, IL-6, IL-10, TNFα, and IFNγ) in 24 patients on maintenance therapy, in 18 treatment-naïve patients (before and 24 h after the first Ig infusion) and in 28 healthy controls. We found that (i) adiponectin was down-expressed in patients on maintenance therapy and in treatment-naïve patients, and that it increased in treatment-naïve patients 24 h after the first Ig infusion; (ii) leptin expression did not differ between maintenance patients and controls either before or after the first Ig infusion; (iii) AdipoR1 expression was significantly higher on B lymphocytes, monocytes and NK cells of CVID patients than in controls; (iv) the expression of AdipoR1 and AdipoR2 on B lymphocytes, monocytes and NK cells was higher after the first Ig infusion than in treatment-naïve patients; (v) T-cadherin expression did not differ between treatment- naïve CVID patients and controls, and was not affected by Ig infusion; and (vi) IL-6, IL-8, IL-10, and TNFα levels were differently expressed in CVID patients on therapy maintenance and were not affected by the first Ig replacement therapy. This is the first study to demonstrate that the expression of AdipoRs in peripheral blood mononuclear cells from CVID patients differs from that of controls, and changes after the first Ig infusion. The specificity of adiponectin involvement in CVID is supported by the absence of changes in leptin levels and in the levels of the cytokines investigated. Taken together, these results suggest that the adiponectin system plays an important and specific role in CVID. A better understanding of adiponectin as a link in the cross-talk between the immune system and adipose tissue may provide additional benefits for the management of CVID patients.


Assuntos
Imunodeficiência de Variável Comum/tratamento farmacológico , Citocinas/sangue , Imunoglobulinas/administração & dosagem , Receptores de Adiponectina/imunologia , Adiponectina/sangue , Adiponectina/genética , Adulto , Caderinas/genética , Caderinas/imunologia , Imunodeficiência de Variável Comum/sangue , Imunodeficiência de Variável Comum/imunologia , Citocinas/imunologia , Feminino , Humanos , Imunoglobulinas/sangue , Leptina/sangue , Leptina/genética , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Receptores de Adiponectina/genética , Fator de Necrose Tumoral alfa/sangue , Adulto Jovem
16.
Front Immunol ; 10: 2484, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31708923

RESUMO

Primary immunodeficiencies are heritable disorders of immune function. CD19 is a B cell co-receptor important for B cell development, and CD19 deficiency is a known genetic risk factor for a rare form of primary immunodeficiency known as "common variable immunodeficiency" (CVID); an antibody deficiency resulting in low levels of serum IgG and IgA. Enteropathies are commonly observed in CVID patients but the underlying reason for this is undefined. Here, we utilize CD19-/- mice as a model of CVID to test the hypothesis that antibody deficiency negatively impacts gut physiology under steady-state conditions. As anticipated, immune phenotyping experiments demonstrate that CD19-/- mice develop a severe B cell deficiency in gut-associated lymphoid tissues that result in significant reductions to antibody concentrations in the gut lumen. Antibody deficiency was associated with defective anti-commensal IgA responses and the outgrowth of anaerobic bacteria in the gut. Expansion of anaerobic bacteria coincides with the development of a chronic inflammatory condition in the gut of CD19-/- mice that results in an intestinal malabsorption characterized by defects in lipid metabolism and transport. Administration of the antibiotic metronidazole to target anaerobic members of the microbiota rescues mice from disease indicating that intestinal malabsorption is a microbiota-dependent phenomenon. Finally, intestinal malabsorption in CD19-/- mice is a gluten-sensitive enteropathy as exposure to a gluten-free diet also significantly reduces disease severity in CD19-/- mice. Collectively, these results support an effect of antibody deficiency on steady-state gut physiology that compliment emerging data from human studies linking IgA deficiency with non-infectious complications associated with CVID. They also demonstrate that CD19-/- mice are a useful model for studying the role of B cell deficiency and gut dysbiosis on gluten-sensitive enteropathies; a rapidly emerging group of diseases in humans with an unknown etiology.


Assuntos
Anticorpos/sangue , Doença Celíaca/imunologia , Imunodeficiência de Variável Comum/imunologia , Intestinos/imunologia , Animais , Antibacterianos/farmacologia , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Antígenos CD19/imunologia , Linfócitos B/imunologia , Modelos Animais de Doenças , Feminino , Microbioma Gastrointestinal/imunologia , Perfilação da Expressão Gênica , Glutens/imunologia , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Absorção Intestinal/efeitos dos fármacos , Contagem de Linfócitos , Masculino , Mastócitos/imunologia , Metronidazol/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/imunologia
17.
Expert Rev Clin Immunol ; 15(11): 1225-1233, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31592698

RESUMO

Objectives: Common variable immunodeficiency is a primary immunodeficiency disease characterized by hypogammaglobulinemia and heterogeneous clinical features. Neutropenia is a rare complication among CVID patients leading to a higher rate of infections and morbidity. Multiple factors (e.g. autoimmunity, infections, drugs and etc.) are found to underlie this complication.Methods: In the present study, demographic, clinical and laboratory data were compared between two groups of CVID patients with and without neutropenia.Results: Frequency of neutropenia was 8.1%. Infectious complications were the most prevalent clinical manifestations regardless of presence of neutropenia. However, candida infection and septicemia were significantly higher in neutropenic patients (p = 0.001 and p = 0.01, respectively). The most prominent clinical phenotypes of CVID patients with neutropenia were polyclonal lymphocytic infiltration and autoimmunity, both being considerably higher compared to the non-neutropenic group (p = 0.04 and p = 0.009, respectively). The mortality rate in neutropenic patients was higher than in patients without neutropenia (61.1 vs. 25.2%, p = 0.004).Conclusion: Although neutropenia is a rare complication among CVID patients, it is associated with frequent and severe clinical complications, including autoimmunity and lymphoproliferative conditions. Also, its accompaniment with higher mortality frequency in CVID patients indicates a need for more precise attention and consideration regarding specific treatment in neutropenic patients.


Assuntos
Imunodeficiência de Variável Comum , Neutropenia , Adolescente , Adulto , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/epidemiologia , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/patologia , Feminino , Seguimentos , Humanos , Masculino , Neutropenia/epidemiologia , Neutropenia/imunologia , Neutropenia/patologia , Estudos Retrospectivos
18.
Curr Opin Allergy Clin Immunol ; 19(6): 578-585, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31573993

RESUMO

PURPOSE OF REVIEW: The landscape of common variable immunodeficiency disorder (CVID) is rapidly evolving as the availability of next-generation sequencing leads to the discovery of new monogenic causes with the clinical phenotype of CVID. Herein, the biology of cytotoxic T lymphocyte-associated protein four (CTLA-4), differentially expressed in FDCP6 homolog (DEF6), and lipopolysaccharide responsive beige-like anchor protein (LRBA), and their impact on the development of a dysregulated, rather than an isolated, infectious phenotype of CVID are explored. RECENT FINDINGS: The broad clinical phenotype associated with these monogenic forms of CVID is described, and common approaches to treatment are reviewed. SUMMARY: Knowledge of the biology, clinical manifestations, and treatment options trialed thus far in patients with CTLA-4 insufficiency, DEF6 deficiency, and LRBA deficiency are essential in the consideration and effective management of patients with CVID stemming from these monogenic causes.


Assuntos
Antígeno CTLA-4/metabolismo , Imunodeficiência de Variável Comum/imunologia , Linfócitos T/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antígeno CTLA-4/genética , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Predisposição Genética para Doença , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Mutação/genética , Fenótipo
20.
Allergol. immunopatol ; 47(5): 457-466, sept.-oct. 2019. tab, graf
Artigo em Inglês | IBECS | ID: ibc-186520

RESUMO

Background: Common variable immunodeficiency (CVID) is a heterogeneous group of primary antibody deficiencies defined by marked reductions in serum IgG, IgA and/or IgM levels and recurrent bacterial infections. Some patients are associated with defects in T cells and regulatory T cells (Tregs), resulting in recurrent viral infections and early-onset autoimmune disease. Methods: We analyzed whether there is an association between Tregs cells (CD4+CD25+CD127low and CD4+CD25+FoxP3+); memory T cells (CD4+CD45RO+); memory B cells (CD19+CD27-IgD-); and CD21low B cells (CD19+CD38lowCD21low); as well as autoimmune manifestations in 36 patients with CVID (25 women and 11 men, mean age 24 years), all by flow cytometry. Results: Fourteen patients presented with autoimmune diseases (AI) (39%), including 11 with autoimmune thrombocytopenia (ITP) (31%); two with vitiligo (6%); one with systemic lupus erythematosus (LES) (3%); and one with multiple sclerosis (MS) (3%). CVID patients with AI had a reduced proportion of Tregs (both CD4+CD25+CD127low and FoxP3+ cells) compared with healthy controls. CVID patients with AI had expanded CD21low B cell populations compared with patients who did not have AI. A correlation between increased CD4+CD45RO T cell populations and reduced Tregs was also observed. Conclusions: Our results showed that 39% of patients with CVID had AI and reduced Tregs populations. Research in this area might provide noteworthy data to better understand immune dysfunction and dysregulation related to CVID


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Assuntos
Humanos , Masculino , Feminino , Adulto Jovem , Doenças Autoimunes/metabolismo , Linfócitos B/imunologia , Imunodeficiência de Variável Comum/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T Reguladores/imunologia , Subpopulações de Linfócitos B/imunologia , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Receptores de Complemento 3d/metabolismo
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