Do HLA class II genes protect against pulmonary tuberculosis? A systematic review and meta-analysis.

Pulmonary tuberculosis (PTB) develops by a complex combination of environmental, immunological and socioeconomic factors and genetic susceptibility. The human leukocyte antigen (HLA) is the most polymorphic biological system and plays an essential role in the immune response against PTB. The aim of this study was to carry out a systematic review and meta-analysis evaluating the relationship between HLA-DRB1, HLA-DQB1 and HLA-DQA1 gene polymorphisms as possible risk or protective factors for PTB. A systematic search of the PubMed and Scopus databases was conducted following the guidelines described in the PRISMA statement. Fifty-six alleles were included in the meta-analysis. In the total pooled results, HLA-DRB1*08:03 (OR 1.95, CI 1.29-2.96), HLA-DQB1*06:01 (OR 1.78, CI 1.39-2.28), HLA-DQB1*06:09 (OR 2.27, 95 % CI 1.04-4.96) and HLA-DQA1*01:01 (OR 2.12, CI 1.11-4.03) genes were related to higher susceptibility to PTB. Conversely, the presence of the genes HLA-DRB1*07:01 (OR 0.74, CI 0.56-0.97), HLA-DQB1*03:01 (OR 0.77, CI 0.61-0.97), HLA-DQB1*04:02 (OR 0.57, CI 0.39-0.83), HLA-DQA1*04:01 (OR 0.50, CI 0.26-0.95) and HLA-DQA1*05:01 (OR 0.66, CI 0.48-0.92) demonstrated protection against PTB. In an analysis by ethnic subgroups, we found more genetic associations in Caucasians than in Asians. These findings suggest that HLAs may be used as markers for acquisition and development of PTB. To strengthen PTB susceptibility/resistance, we recommend further multicentric studies in different geographic regions, with certainty of controls' exposure to M. tuberculosis by use of marker of latent or active PTB, with analysis stratified by ethnic groups, with descriptions of specific alleles and carrying out immunological functionality tests.

Tuberculosis in an autosomal recessive case of chronic granulomatous disease due to mutation of the NCF1 gene

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Interferon-gamma reduces the proliferation of M-tuberculosis within macrophages from a patient with a novel hypomorphic NEMO mutation

X-linked ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is caused by mutations in the nuclear factor-kappa B essential modulator (NEMO) gene. Here, we report the clinical and genetic features of a XL-EDA-ID patient who developed bacillus Calmette-Guerin infection. Patient lymphocytes failed to degrade IB-, and sequencing of NEMO identified the novel mutation c.1238A>C/p.H413P. Furthermore, patient monocyte-derived macrophages ingested Mycobacterium tuberculosis normally, but failed to control the intracellular proliferation of bacilli, a defect which was improved in the presence of interferon-gamma (IFN-). This work expands the genetic spectrum of XL-EDA-ID and demonstrates improvement in macrophage function in a NEMO-deficient patient by IFN-

Peripheral blood mononuclear cells from severe asthmatic children release lower amounts of IL-12 and IL-4 after LPS stimulation

INTRODUCTION: Asthma is an inflammatory disorder of the airways associated with bronchial hyperresponsiveness, airway obstruction, and increased mucus production, with a predominance of type 2 immune response (Th2). According to the hygiene hypothesis, exposure to environmental bacterial lipopolysaccharide (LPS) may induce a type 1 immune response (Th1), modulating the development of asthma. OBJECTIVE: In this study we investigated cytokine production by peripheral blood mononuclear cells (PBMC) from children and adolescents with severe asthma, in response to LPS stimulation in vitro. MATERIALS AND METHODS: 26 children were selected: 13 severe asthmatics and 13 healthy controls, aged between 5 and 18 years. They were evaluated through routine medical history, physical examination and lung function test to diagnose severe asthma. Allergy status was confirmed by skin prick test and specific IgE assay. We collected blood samples to analyse in vitro LPS-induced cytokines release by PBMC. RESULTS: PBMC from severe asthmatic children produced lower levels of IL-12p70 in basal conditions and after 12 and 24 h stimulation with LPS compared to healthy controls. PBMC from severe asthmatic children produced lower levels of IL-4 after 24 h LPS stimulation compared to healthy controls. PBMC from severe asthmatic children produced more levels IL-17 and IL-10 after stimulus with LPS compared to healthy controls. The release of IFN-γ, IL-5 and TNF-α by PBMC from severe asthmatic children was similar to healthy controls. CONCLUSION: Our results demonstrate that LPS directly influence the cytokine profile of PBMC in children with severe asthma. These observations may be potentially helpful in developing new treatment strategies

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Current state and future perspectives of the Latin American Society for Immunodeficiencies (LASID)

Primary immunodeficiencies (PID) are genetic diseases that affect the immune system and for the last 20 years, the Latin American Society for Immunodeficiencies (LASID) has been promoting initiatives in awareness, research, diagnosis, and treatment for the affected patients in Latin America. These initiatives have resulted in the development of programmes such as the LASID Registry (with 4900 patients registered as of January 2014), fellowships in basic and clinical research, PID summer schools, biannual meetings, and scientific reports, amongst others. These achievements highlight the critical role that LASID plays as a scientific organisation in promoting science, research and education in this field in Latin America. However, challenges remain in some of these areas and the Society must envision additional strategies to tackle them for the benefit of the patients. In June 2013, a group of experts in the field met to discuss the contributions of LASID to the initiatives of PID in Latin America, and this article summarises the current state and future perspectives of this society and its role in the advance of PIDs in Latin America

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Doctors’ awareness concerning primary immunodeficiencies in Brazil

BACKGROUND: PIDs are a heterogeneous group of genetic illnesses, and delay in their diagnosis is thought to be caused by a lack of awareness among physicians concerning PIDs. The latter is what we aimed to evaluate in Brazil. METHODS: Physicians working at general hospitals all over the country were asked to complete a 14-item questionnaire. One of the questions described 25 clinical situations that could be associated with PIDs and a score was created based on percentages of appropriate answers. RESULTS: A total of 4026 physicians participated in the study: 1628 paediatricians (40.4%), 1436 clinicians (35.7%), and 962 surgeons (23.9%). About 67% of the physicians had learned about PIDs in medical school or residency training, 84.6% evaluated patients who frequently took antibiotics, but only 40.3% of them participated in the immunological evaluation of these patients. Seventy-seven percent of the participating physicians were not familiar with the warning signs for PIDs. The mean score of correct answers for the 25 clinical situations was 48.08% (±16.06). Only 18.3% of the paediatricians, 7.4% of the clinicians, and 5.8% of the surgeons answered at least 2/3 of these situations appropriately. CONCLUSIONS: There is a lack of medical awareness concerning PIDs, even among paediatricians, who have been targeted with PID educational programmes in recent years in Brazil. An increase in awareness with regard to these disorders within the medical community is an important step towards improving recognition and treatment of PIDs

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Peripheral blood mononuclear cells from severe asthmatic children release lower amounts of IL-12 and IL-4 after LPS stimulation.

INTRODUCTION: Asthma is an inflammatory disorder of the airways associated with bronchial hyperresponsiveness, airway obstruction, and increased mucus production, with a predominance of type 2 immune response (Th2). According to the hygiene hypothesis, exposure to environmental bacterial lipopolysaccharide (LPS) may induce a type 1 immune response (Th1), modulating the development of asthma. OBJECTIVE: In this study we investigated cytokine production by peripheral blood mononuclear cells (PBMC) from children and adolescents with severe asthma, in response to LPS stimulation in vitro. MATERIALS AND METHODS: 26 children were selected: 13 severe asthmatics and 13 healthy controls, aged between 5 and 18 years. They were evaluated through routine medical history, physical examination and lung function test to diagnose severe asthma. Allergy status was confirmed by skin prick test and specific IgE assay. We collected blood samples to analyse in vitro LPS-induced cytokines release by PBMC. RESULTS: PBMC from severe asthmatic children produced lower levels of IL-12p70 in basal conditions and after 12 and 24h stimulation with LPS compared to healthy controls. PBMC from severe asthmatic children produced lower levels of IL-4 after 24h LPS stimulation compared to healthy controls. PBMC from severe asthmatic children produced more levels IL-17 and IL-10 after stimulus with LPS compared to healthy controls. The release of IFN-γ, IL-5 and TNF-α by PBMC from severe asthmatic children was similar to healthy controls. CONCLUSION: Our results demonstrate that LPS directly influence the cytokine profile of PBMC in children with severe asthma. These observations may be potentially helpful in developing new treatment strategies.

Doctors' awareness concerning primary immunodeficiencies in Brazil.

BACKGROUND: PIDs are a heterogeneous group of genetic illnesses, and delay in their diagnosis is thought to be caused by a lack of awareness among physicians concerning PIDs. The latter is what we aimed to evaluate in Brazil. METHODS: Physicians working at general hospitals all over the country were asked to complete a 14-item questionnaire. One of the questions described 25 clinical situations that could be associated with PIDs and a score was created based on percentages of appropriate answers. RESULTS: A total of 4026 physicians participated in the study: 1628 paediatricians (40.4%), 1436 clinicians (35.7%), and 962 surgeons (23.9%). About 67% of the physicians had learned about PIDs in medical school or residency training, 84.6% evaluated patients who frequently took antibiotics, but only 40.3% of them participated in the immunological evaluation of these patients. Seventy-seven percent of the participating physicians were not familiar with the warning signs for PIDs. The mean score of correct answers for the 25 clinical situations was 48.08% (±16.06). Only 18.3% of the paediatricians, 7.4% of the clinicians, and 5.8% of the surgeons answered at least 2/3 of these situations appropriately. CONCLUSIONS: There is a lack of medical awareness concerning PIDs, even among paediatricians, who have been targeted with PID educational programmes in recent years in Brazil. An increase in awareness with regard to these disorders within the medical community is an important step towards improving recognition and treatment of PIDs.

Current state and future perspectives of the Latin American Society for Immunodeficiencies (LASID).

Primary immunodeficiencies (PID) are genetic diseases that affect the immune system and for the last 20 years, the Latin American Society for Immunodeficiencies (LASID) has been promoting initiatives in awareness, research, diagnosis, and treatment for the affected patients in Latin America. These initiatives have resulted in the development of programmes such as the LASID Registry (with 4900 patients registered as of January 2014), fellowships in basic and clinical research, PID summer schools, biannual meetings, and scientific reports, amongst others. These achievements highlight the critical role that LASID plays as a scientific organisation in promoting science, research and education in this field in Latin America. However, challenges remain in some of these areas and the Society must envision additional strategies to tackle them for the benefit of the patients. In June 2013, a group of experts in the field met to discuss the contributions of LASID to the initiatives of PID in Latin America, and this article summarises the current state and future perspectives of this society and its role in the advance of PIDs in Latin America.

Severe combined immunodeficiency in Brazil: management, prognosis, and BCG-associated complications.

BACKGROUND: Severe combined immunodeficiency (SCID) is one of the most severe forms of primary immunodeficiency. The objectives of this study were to analyze the diagnosis, treatment, and prognosis of SCID in Brazil and to document the impact of BCG vaccine. METHODS: We actively searched for cases by contacting all Brazilian referral centers. RESULTS: We contacted 23 centers and 70 patients from 65 families. Patients were born between 1996 and 2011, and 49 (70%) were male. More than half (39) of the diagnoses were made after 2006. Mean age at diagnosis declined from 9.7 to 6.1 months (P = .058) before and after 2000, respectively, and mean delay in diagnosis decreased from 7.9 to 4.2 months (P = .009). Most patients (60/70) were vaccinated with BCG before the diagnosis, 39 of 60 (65%) had complications related to BCG vaccine, and the complication was disseminated in 29 of 39 (74.3%). Less than half of the patients (30, 42.9%) underwent hematopoietic stem cell transplantation (HSCT). Half of the patients died (35, 50%), and 23 of these patients had not undergone HSCT. Disseminated BCG was the cause of death, either alone or in association with other causes, in 9 of 31 cases (29%, no data for 4 cases). CONCLUSIONS: In Brazil, diagnosis of SCID has improved over the last decade, both in terms of the number of cases and age at diagnosis, although a much higher number of cases had been expected. Mortality is higher than in developed countries. Complications of BCG vaccine are an important warning sign for the presence of SCID and account for significant morbidity during disease progression.

Guidelines for the use of human immunoglobulin therapy in patients with primary immunodeficiencies in Latin America

Antibodies are an essential component of the adaptative immune response and hold long-term memory of the immunological experiences throughout life. Antibody defects represent approximately half of the well-known primary immunodeficiencies requiring immunoglobulin replacement therapy. In this article, the authors review the current indications and therapeutic protocols in the Latin American environment. Immunoglobulin replacement therapy has been a safe procedure that induces dramatic positive changes in the clinical outcome of patients who carry antibody defects

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Severe combined immunodeficiency in Brazil: management, prognosis, and BCG-associated complications

Background: Severe combined immunodeficiency (SCID) is one of the most severe forms of primary immunodeficiency. The objectives of this study were to analyze the diagnosis, treatment, and prognosis of SCID in Brazil and to document the impact of BCG vaccine. Methods: We actively searched for cases by contacting all Brazilian referral centers. Results: We contacted 23 centers and 70 patients from 65 families. Patients were born between 1996 and 2011, and 49 (70%) were male. More than half (39) of the diagnoses were made after 2006. Mean age at diagnosis declined from 9.7 to 6.1 months ( P= .058) before and after 2000, respectively, and mean delay in diagnosis decreased from 7.9 to 4.2 months ( P= .009). Most patients (60/70) were vaccinated with BCG before the diagnosis, 39 of 60 (65%) had complications related to BCG vaccine, and the complication was disseminated in 29 of 39 (74.3%). Less than half of the patients (30, 42.9%) underwent hematopoietic stem cell transplantation (HSCT). Half of the patients died (35, 50%), and 23 of these patients had not undergone HSCT. Disseminated BCG was the cause of death, either alone or in association with other causes, in 9 of 31 cases (29%, no data for 4 cases). Conclusions: In Brazil, diagnosis of SCID has improved over the last decade, both in terms of the number of cases and age at diagnosis, although a much higher number of cases had been expected. Mortality is higher than in developed countries. Complications of BCG vaccine are an important warning sign for the presence of SCID and account for significant morbidity during disease progression (AU)

Antecedentes: La inmunodeficiencia severa combinada (IDSC) es una de las formas más graves de la inmunodeficiencia primaria. El objetivo de este estudio fue analizar el estado del diagnóstico, tratamiento y pronóstico de esta enfermedad en Brasil y documentar el impacto de la vacunación con BCG (bacillus Calmette-Guérin). Métodos: Los casos fueron seleccionados tras contactar con los centros de referencia de Brasil. Resultados: Se contactaron 23 centros en total, que permitieron recopilar a 70 pacientes entre los años 1996 y 2011 procedentes de 65 familias, 49 de ellos (70%) varones. En más de la mitad de ellos (39), el diagnóstico fue realizado con posteriridad al año 2006. La edad media en el diagnóstico varió entre los 9,7 a los 6,1 meses (p=0.058), antes y después del año 2000, respectivamente, y el tiempo en que se realizó el diagnóstico disminuyó de los 7,9 a los 4,2 meses (p=0.009). La mayoría de ellos (60/70) se habían vacunado con BCG antes del diagnóstico, 39/60 (65%) tuvieron complicaciones con la BCG y en 29/39 (74.3%) la enfermedad se diseminó. En menos de la mitad de los pacientes (30/70, 42,9%) se realizó un trasplate de células madre (HSCT). La mitad de los pacientes (35/70, 50%) murieron; 23/35 de ellos sin HSCT. La diseminación del BCG fue la causa de la muerte, sola o asociada con otras causas, en 9/31 casos (29%, en 4 casos sin datos). Conclusiones: En conclusión, el diagnóstico de IDSC en Brasil ha mejorado en la última década, tanto en términos numéricos, cómo respecto a la edad de detección de la enfermedad. La mortalidad es alta en comparación con los países desarrollados. La vacuna con BCG provoca complicaciones importantes en estos pacientes, lo cual alerta sobre el posible diagnóstico y progresión de esta enfermedad (AU)

Respiratory allergen from house dust mite is present in human milk and primes for allergic sensitization in a mouse model of asthma.

There is an urgent need to identify environmental risk and protective factors in early life for the prevention of allergy. Our study demonstrates the presence of respiratory allergen from house dust mite, Der p 1, in human breast milk. Der p 1 in milk is immunoreactive, present in similar amounts as dietary egg antigen, and can be found in breast milk from diverse regions of the world. In a mouse model of asthma, oral exposure to Der p through breast milk strongly promotes sensitization rather than protect the progeny as we reported with egg antigen. These data highlight that antigen administration to the neonate through the oral route may contribute to child allergic sensitization and have important implications for the design of studies assessing early oral antigen exposure for allergic disease prevention. The up-to-now unknown worldwide presence of respiratory allergen in maternal milk allows new interpretation and design of environmental control epidemiological studies for allergic disease prevention.

Guidelines for the use of human immunoglobulin therapy in patients with primary immunodeficiencies in Latin America.

Antibodies are an essential component of the adaptative immune response and hold long-term memory of the immunological experiences throughout life. Antibody defects represent approximately half of the well-known primary immunodeficiencies requiring immunoglobulin replacement therapy. In this article, the authors review the current indications and therapeutic protocols in the Latin American environment. Immunoglobulin replacement therapy has been a safe procedure that induces dramatic positive changes in the clinical outcome of patients who carry antibody defects.

Advancing the management of primary immunodeficiency diseases in Latin America: Latin American Society for Immunodeficiencies (LASID) Initiatives

Primary immunodeficiency diseases (PIDD) are associated with significant morbidity and mortality and result in a significant public health burden. This is in part due to the lack of appropriate diagnosis and treatment of these patients. It is critical that governments become aware of this problem and provide necessary resources to reduce this impact on health care systems. Leading physicians in their respective countries must be supported by their own governments in order to implement tools and provide education and thus improve the diagnosis and treatment of PIDD. The Latin American Society of Primary Immunodeficiencies (LASID) has initiated a large number of activities aimed at achieving these goals, including the establishment of a PIDD registry, development of educational programmes and guidelines, and the introduction of a PIDD fellowship programme. These initiatives are positively impacting the identification and appropriate treatment of patients with PIDD in Latin America. Nevertheless, much remains to be done to ensure that every person with PIDD receives proper therapy(AU)

High-performance liquid chromatography under partially denaturing conditions (dHPLC) is a fast and cost-effective method for screening molecular defects: four novel mutations found in X-linked chronic granulomatous disease.

Implementing precise techniques in routine diagnosis of chronic granulomatous disease (CGD), which expedite the screening of molecular defects, may be critical for a quick assumption of patient prognosis. This study compared the efficacy of single-strand conformation polymorphism analysis (SSCP) and high-performance liquid chromatography under partially denaturing conditions (dHPLC) for screening mutations in CGD patients. We selected 10 male CGD patients with a clinical history of severe recurrent infections and abnormal respiratory burst function. gDNA, mRNA and cDNA samples were prepared by standard methods. CYBB exons were amplified by PCR and screened by SSCP or dHPLC. Abnormal DNA fragments were sequenced to reveal the nature of the mutations. The SSCP and dHPLC methods showed DNA abnormalities, respectively, in 55% and 100% of the cases. Sequencing of the abnormal DNA samples confirmed mutations in all cases. Four novel mutations in CYBB were identified which were picked up only by the dHPLC screening (c.904 insC, c.141+5 g>t, c.553 T>C, and c.665 A>T). This work highlights the relevance of dHPLC, a sensitive, fast, reliable and cost-effective method for screening mutations in CGD, which in combination with functional assays assessing the phagocyte respiratory burst will contribute to expedite the definitive diagnosis of X-linked CGD, direct treatment, genetic counselling and to have a clear assumption of the prognosis. This strategy is especially suitable for developing countries.

Advancing the management of primary immunodeficiency diseases in Latin America: Latin American Society for Immunodeficiencies (LASID) Initiatives.

Primary immunodeficiency diseases (PIDD) are associated with significant morbidity and mortality and result in a significant public health burden. This is in part due to the lack of appropriate diagnosis and treatment of these patients. It is critical that governments become aware of this problem and provide necessary resources to reduce this impact on health care systems. Leading physicians in their respective countries must be supported by their own governments in order to implement tools and provide education and thus improve the diagnosis and treatment of PIDD. The Latin American Society of Primary Immunodeficiencies (LASID) has initiated a large number of activities aimed at achieving these goals, including the establishment of a PIDD registry, development of educational programmes and guidelines, and the introduction of a PIDD fellowship programme. These initiatives are positively impacting the identification and appropriate treatment of patients with PIDD in Latin America. Nevertheless, much remains to be done to ensure that every person with PIDD receives proper therapy.

Human leucocytes response to viable, extended freeze-drying or heat-killed Mycobacterium bovis bacillus Calmette-Guérin.

We investigated the effects of viable, extended freeze-drying (EFD) or heat-killed (HK) Mycobacterium bovis bacillus Calmette-Guérin (BCG) in respiratory burst activity, gene expression of CYBB and NCF1 encoding components of the human phagocyte nicotinamide adenine dinucleotide (NADPH) oxidase, TLR2 expression, and in IL-10 and TNF-α cytokine production by human peripheral blood mononuclear cells (PBMCs). Viable BCG significantly inhibited TLR2 and CYBB gene expression, as well as superoxide release by human PBMC. All BCG stimuli augmented IL-10 release, but only HK BCG or viable BCG increased TNF-α release by PBMCs. Our studies show that viable BCG can impair the NADPH oxidase system activation and the TLR2 route in human PBMCs. As well, different BCG preparations can distinctly influence cytokine production by human PBMCs.