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1.
J Clin Immunol ; 38(2): 204-213, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29423883

RESUMO

BACKGROUND: Immunologists are increasingly being asked to assess patients with non-classical and secondary antibody deficiency to determine their potential need for immunoglobulin replacement therapy (IGRT). Immunoglobulin is a limited, expensive resource and no clear guidance exists for this broad patient group. The purpose of this survey is to establish what factors influence the decision to commence IGRT in adult patients, when diagnostic criteria for primary antibody deficiency are not fulfilled. METHODS: Under the auspices of the United Kingdom Primary Immunodeficiency Network (UKPIN), a study group was established which circulated an online questionnaire to the consultant body across the UK and Ireland. Results provided a snapshot of the current clinical practice of 71% of consultant immunologists, from 30 centers. RESULTS: In order of importance, factors which influence the decision to commence IGRT include number of hospital admissions with infection, serum IgG level, bronchiectasis, radiologically proven pneumonia, number of positive sputum cultures, number of antibiotic courses, and results of immunization studies. The commonest test vaccine used was Pneumovax 23 with measurement of serotype-specific responses at 4 weeks, with a threshold of 0.35 µg/ml in 2/3 of serotypes measured. Eighty-six percent of patients are treated with a trial of prophylactic antibiotics prior to consideration of IGRT. Efficacy of IGRT trial is assessed at between 6 and 12 months. CONCLUSIONS: There was consistency in clinical practice using a combination of clinical history, evidence of infections, and vaccination testing for diagnosis. However, there was some variation in the implementation of this practice, particularly in vaccine choice and assessment of response to vaccination.

2.
J Allergy Clin Immunol Pract ; 5(4): 938-945, 2017 Jul - Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28351785

RESUMO

A proportion of people living with common variable immunodeficiency disorders develop granulomatous-lymphocytic interstitial lung disease (GLILD). We aimed to develop a consensus statement on the definition, diagnosis, and management of GLILD. All UK specialist centers were contacted and relevant physicians were invited to take part in a 3-round online Delphi process. Responses were graded as Strongly Agree, Tend to Agree, Neither Agree nor Disagree, Tend to Disagree, and Strongly Disagree, scored +1, +0.5, 0, -0.5, and -1, respectively. Agreement was defined as greater than or equal to 80% consensus. Scores are reported as mean ± SD. There was 100% agreement (score, 0.92 ± 0.19) for the following definition: "GLILD is a distinct clinico-radio-pathological ILD occurring in patients with [common variable immunodeficiency disorders], associated with a lymphocytic infiltrate and/or granuloma in the lung, and in whom other conditions have been considered and where possible excluded." There was consensus that the workup of suspected GLILD requires chest computed tomography (CT) (0.98 ± 0.01), lung function tests (eg, gas transfer, 0.94 ± 0.17), bronchoscopy to exclude infection (0.63 ± 0.50), and lung biopsy (0.58 ± 0.40). There was no consensus on whether expectant management following optimization of immunoglobulin therapy was acceptable: 67% agreed, 25% disagreed, score 0.38 ± 0.59; 90% agreed that when treatment was required, first-line treatment should be with corticosteroids alone (score, 0.55 ± 0.51).


Assuntos
Imunodeficiência de Variável Comum , Granuloma , Doenças Pulmonares Intersticiais , Instituições de Caridade , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/diagnóstico por imagem , Imunodeficiência de Variável Comum/tratamento farmacológico , Imunodeficiência de Variável Comum/patologia , Consenso , Granuloma/diagnóstico , Granuloma/diagnóstico por imagem , Granuloma/tratamento farmacológico , Granuloma/patologia , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/patologia , Sociedades Médicas , Reino Unido
3.
AIDS ; 30(12): 1867-76, 2016 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-27124901

RESUMO

OBJECTIVES: Many children with HIV infection now survive into adulthood. This study explored the impact of vertically acquired HIV in the era of antiretroviral therapy on the development of humoral immunity. DESIGN: Natural and vaccine-related immunity to pneumococcus and B-cell phenotype was characterized and compared in three groups of young adults: those with vertically-acquired infection, those with horizontally acquired infection and healthy controls. METHODS: Serotype-specific pneumococcal (Pnc) immunoglobulin M and G concentrations before and up to 1 year post-Pnc polysaccharide (Pneumovax) immunization were determined, and opsonophagocytic activity was analysed. B-cell subpopulations and dynamic markers of B-cell signalling, turnover and susceptibility to apoptosis were evaluated by flow cytometry. RESULTS: HIV-infected patients showed impaired natural Pnc immunity and reduced humoral responses to immunization with Pneumovax; this was greatest in those viraemic at time of the study. Early-life viral control before the age of 10 years diminished these changes. Expanded populations of abnormally activated and immature B-cells were seen in both HIV-infected cohorts. Vertically infected patients were particularly vulnerable to reductions in marginal zone and switched memory populations. These aberrations were reduced in patients with early-life viral control. CONCLUSION: In children with HIV, damage to B-cell memory populations and impaired natural and vaccine immunity to pneumococcus is evident in early adult life. Sustained viral control from early childhood may help to limit this effect and optimize humoral immunity in adult life.


Assuntos
Subpopulações de Linfócitos B/imunologia , Infecções por HIV/imunologia , Infecções por HIV/transmissão , Imunidade Humoral , Transmissão Vertical de Doença Infecciosa , Streptococcus pneumoniae/imunologia , Adolescente , Adulto , Anticorpos Antibacterianos/sangue , Criança , Transmissão de Doença Infecciosa , Feminino , Citometria de Fluxo , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Proteínas Opsonizantes/sangue , Fagocitose , Infecções Pneumocócicas/imunologia , Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/imunologia , Adulto Jovem
4.
Vaccine ; 31(19): 2328-32, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23523406

RESUMO

Prior exposure to intact Streptococcus pneumoniae can induce a protective antibody response to proteins antigens, which prevents subsequent invasive disease. This may be achieved either by colonisation with live bacteria or by immunisation with killed cells. Such approaches could provide novel vaccine strategies that overcome the serotype restriction of conjugate vaccines, and would aim to prevent disease caused by all strains of S. pneumoniae. Serum antibody is required to prevent invasive disease, but which in vitro measure of antibody response correlates best with protective immunity has not been established for protein antigens. Using a model of homologous protection induced through D39 colonisation of CD1 mice, we investigate the potential for heterologous protection against two distinct serotype strains and its serological correlates. Serum IgG from colonised mice bound to heterologous strains in whole cell ELISA at titres similar to the homologous D39. However, no cross-protection was observed, correlating with lack of surface binding of IgG to whole bacteria as measured by flow cytometry. Serum antibody binding to pre-lysed and untreated bacteria in the whole cell ELISA was similar suggesting that ELISA does not discriminate between surface and subcapsular antigens, unlike the flow cytometric approach. Thus, flow cytometric binding to whole bacteria maybe a more reliable correlate of cross-protection for novel species-wide vaccines than whole cell ELISA.


Assuntos
Ensaio de Imunoadsorção Enzimática , Imunoglobulina G/sangue , Infecções Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Animais , Anticorpos/imunologia , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Reações Cruzadas/imunologia , Citometria de Fluxo , Imunoglobulina G/imunologia , Camundongos , Nasofaringe/microbiologia , Infecções Pneumocócicas/microbiologia , Infecções Pneumocócicas/prevenção & controle , Pneumonia/imunologia , Vacinação , Vacinas/imunologia
5.
Vaccine ; 30(30): 4453-9, 2012 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-22561489

RESUMO

Live attenuated vaccines have been proposed as a strategy to induce protective immunity against infectious diseases. Recent data have demonstrated that nasopharyngeal colonisation with Streptococcus pneumoniae induces protective immunity against subsequent invasive infection, suggesting nasal vaccination with live attenuated bacteria could be a preventative strategy. However the bacterial factors affecting the strength of this adaptive immune response remain unclear. In a direct comparison with the parent wild-type strain, we found that colonisation with bacteria lacking either capsule or surface lipoproteins led to significantly diminished protection. Immunity after colonisation was not dependent on serum IgG to capsular antigens. Colonisation density and duration was reduced for all the non-protective strains, suggesting that protective immunity maybe related to the extent of nasopharyngeal bacterial exposure. To investigate this hypothesis, we utilised an auxotrophic bacterial Δpab strain where duration of colonisation could be controlled by supply and removal of para-amino-benzoic acid (PABA) to mouse drinking water. Supporting colonisation with the Δpab strain for 5 days with PABA led to a faster serum antibody response compared to colonisation for less than 48 h. This enhanced immunogenicity was associated with a trend towards protection. The data presented here aid our understanding of why only certain live attenuated strains are able to function as effective vaccines, and may be valuable in informing the constituents of future live attenuated vaccines.


Assuntos
Cápsulas Bacterianas/imunologia , Lipoproteínas/imunologia , Nasofaringe/microbiologia , Pneumonia Pneumocócica/imunologia , Animais , Anticorpos Antibacterianos/sangue , Proteínas de Bactérias/imunologia , Imunoglobulina G/sangue , Camundongos , Nasofaringe/imunologia , Vacinas Pneumocócicas/imunologia , Pneumonia Pneumocócica/prevenção & controle , Vacinas Atenuadas/imunologia
6.
PLoS One ; 6(10): e25558, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22003400

RESUMO

The nasopharyngeal commensal bacteria Streptococcus pneumoniae is also a frequent cause of serious infections. Nasopharyngeal colonisation with S. pneumoniae inhibits subsequent re-colonisation by inducing Th17-cell adaptive responses, whereas vaccination prevents invasive infections by inducing antibodies to S. pneumoniae capsular polysaccharides. In contrast, protection against invasive infection after nasopharyngeal colonisation with mutant S. pneumoniae strains was associated with antibody responses to protein antigens. The role of colonisation-induced Th17-cell responses during subsequent invasive infections is unknown. Using mouse models, we show that previous colonisation with S. pneumoniae protects against subsequent lethal pneumonia mainly by preventing bacteraemia with a more modest effect on local control of infection within the lung. Previous colonisation resulted in CD4-dependent increased levels of Th17-cell cytokines during subsequent infectious challenge. However, mice depleted of CD4 cells prior to challenge remained protected against bacteraemia, whereas no protection was seen in antibody deficient mice and similar protection could be achieved through passive transfer of serum. Serum from colonised mice but not antibody deficient mice promoted phagocytosis of S. pneumoniae, and previously colonised mice were able to rapidly clear S. pneumoniae from the blood after intravenous inoculation. Thus, despite priming for a Th17-cell response during subsequent infection, the protective effects of prior colonisation in this model was not dependent on CD4 cells but on rapid clearance of bacteria from the blood by antibody-mediated phagocytosis. These data suggest that whilst nasopharyngeal colonisation induces a range of immune responses, the effective protective responses depend upon the site of subsequent infection.


Assuntos
Anticorpos Antibacterianos/imunologia , Nasofaringe/imunologia , Pneumonia Pneumocócica/imunologia , Pneumonia Pneumocócica/prevenção & controle , Streptococcus pneumoniae/imunologia , Streptococcus pneumoniae/patogenicidade , Células Th17/imunologia , Animais , Bacteriemia/imunologia , Bacteriemia/prevenção & controle , Camundongos , Membrana Mucosa/imunologia , Fagocitose/imunologia , Pneumonia Pneumocócica/sangue
7.
Vaccine ; 28(42): 6915-22, 2010 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-20708698

RESUMO

BACKGROUND: Polysaccharide conjugate vaccines prime for lasting memory responses in children and young adults. The potential value of these vaccines in the elderly is unclear. METHODS: We compared the frequency of circulating pneumococcal capsular polysaccharide (PPS) specific IgG, IgA and IgM plasma and memory cells by cultured ELISpot and supernatant screening two years after vaccination with the 7-valent pneumococcal conjugate vaccine (7vCRM) and/or the 23-valent pneumococcal polysaccharide vaccine (PPV) in 252 adults aged 50-80 years. Some individuals received a six-month boost with 7vCRM or PPV. PPS specific IgG memory detected two years post-primary vaccination was correlated with published matched serum IgG concentration pre- and up to one year post-primary vaccination. RESULTS: There was no difference by vaccine schedule in the quantity of plasma or memory cells detected. The concentration of in vitro PPS IgG produced by memory B cells isolated two years post-vaccination correlated with pre-vaccination serum IgG concentration and not with D28 post-vaccination responses regardless of vaccination schedule. CONCLUSIONS: This study shows that circulating memory B cells numbers two years following immunisation with 7vCRM or PPV are best predicted by pre-vaccination serotype specific serum antibody concentration and not early post-vaccination serum antibody responses.


Assuntos
Anticorpos Antibacterianos/sangue , Linfócitos B/imunologia , Memória Imunológica , Vacinas Pneumocócicas/imunologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , ELISPOT , Feminino , Vacina Pneumocócica Conjugada Heptavalente , Humanos , Esquemas de Imunização , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Conjugadas/imunologia
8.
Vaccine ; 28(30): 4763-70, 2010 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-20471437

RESUMO

In young children, polyvalent pneumococcal polysaccharide conjugate vaccines (PCVs) have been shown to offer advantage over plain polysaccharide vaccines (PPVs) in both immunogenicity and priming for memory responses. In the elderly, the potential benefit of conjugate vaccines is unclear. Here, we explore the early kinetics of serum antibody and circulating plasma and memory B cell responses to pneumococcal capsular polysaccharide (PPS) in older adults (n=37) immunised a PPV vaccine, Pneumovax or a PCV: Prevenar. All individuals had serum evidence of pre-existing serotype-specific immunity. Following immunisation, a day 7 rise in circulating PPS-specific plasma and memory antibody secreting cells (AbSCs) was detected in both vaccine groups and this was sustained to day 28 in some PCV recipients. There was no difference between vaccine groups in serum antibody responses or the kinetics of the early PBMC-derived B cell responses. Although our sample cohort was small, these data are different from profiles in younger individuals at early time points post-immunisation and suggest that pneumococcal conjugate vaccines may not quantitatively enhance the generation of memory responses in the elderly.


Assuntos
Linfócitos B/imunologia , Vacinas Pneumocócicas/uso terapêutico , Fatores Etários , Idoso , Anticorpos Antibacterianos/análise , Especificidade de Anticorpos , Feminino , Vacina Pneumocócica Conjugada Heptavalente , Humanos , Imunoglobulina A/análise , Imunoglobulina A/biossíntese , Imunoglobulina G/análise , Imunoglobulina G/biossíntese , Imunoglobulina M/análise , Imunoglobulina M/biossíntese , Imunoglobulinas/análise , Memória Imunológica , Cinética , Masculino , Pessoa de Meia-Idade , Plasmócitos/imunologia , Vacinas Pneumocócicas/imunologia , Polissacarídeos Bacterianos/imunologia , Fatores Sexuais , Vacinação , Vacinas Conjugadas
9.
J Infect Dis ; 198(4): 481-5, 2008 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-18582200

RESUMO

Levels of circulating naive and memory B cells were measured in human immunodeficiency virus (HIV)-infected children and control subjects to determine whether the irreversible depletion of memory B cells described in HIV-infected adults occurs in children with HIV infection. Depletion of circulating IgD+ memory B cells was seen in HIV-infected children despite control of the HIV load with highly active antiretroviral therapy (HAART) (P =. 04). IgD+ memory B cell percentages did not correlate with CD4+ cell percentages (P =. 027) or disease duration (P =. 026). Naive/transitional and IgD- memory B cell numbers were not affected. Pediatric HIV infection is associated with selective depletion of circulating IgD+ memory B cells despite control of the HIV load with HAART.


Assuntos
Terapia Antirretroviral de Alta Atividade , Linfócitos B , Infecções por HIV/imunologia , HIV-1/imunologia , Imunoglobulina D/sangue , Memória Imunológica , Adolescente , Criança , Pré-Escolar , Feminino , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Masculino , Pediatria , Carga Viral/estatística & dados numéricos
10.
Infect Immun ; 76(8): 3761-70, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18541650

RESUMO

Results from studies using mice deficient in specific complement factors and clinical data on patients with an inherited deficiency of the classical complement pathway component C2 suggest that the classical pathway is vital for immunity to Streptococcus pneumoniae. However, the consequences of defects in classical pathway activity for opsonization with C3b and the phagocytosis of different S. pneumoniae serotypes in human serum are not known, and there has not been a systematic analysis of the abilities of sera from subjects with a C2 deficiency to opsonize S. pneumoniae. Hence, to investigate the role of the classical pathway in immunity to S. pneumoniae in more detail, flow cytometry assays of opsonization with C3b and the phagocytosis of three capsular serotypes of S. pneumoniae were performed using human sera depleted of the complement factor C1q or B or sera obtained from C2-deficient subjects. The results demonstrate that, in human serum, the classical pathway is vital for C3b-iC3b deposition onto cells of all three serotypes of S. pneumoniae and seems to be more important than the alternative pathway for phagocytosis. Compared to the results for sera from normal subjects, C3b-iC3b deposition and total anti-S. pneumoniae antibody activity levels in sera obtained from C2(-/-) subjects were reduced and the efficiency of phagocytosis of all three S. pneumoniae strains was impaired. Anticapsular antibody levels did not correlate with phagocytosis or C3b-iC3b deposition. These data confirm that the classical pathway is vital for complement-mediated phagocytosis of S. pneumoniae and demonstrate why subjects with a C2 deficiency have a marked increase in susceptibility to S. pneumoniae infections.


Assuntos
Atividade Bactericida do Sangue/imunologia , Complemento C3b/metabolismo , Via Clássica do Complemento/imunologia , Fagocitose/imunologia , Streptococcus pneumoniae/imunologia , Anticorpos Antibacterianos/imunologia , Anticorpos Antibacterianos/metabolismo , Complemento C2/deficiência , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Imunoglobulina M/imunologia , Imunoglobulina M/metabolismo
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