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1.
Artigo em Inglês | MEDLINE | ID: mdl-32006723

RESUMO

BACKGROUND: Bacillus Calmette-Guérin (BCG) vaccine is a live attenuated bacterial vaccine derived from Mycobacterium bovis, which is mostly administered to neonates in regions where tuberculosis is endemic. Adverse reactions after BCG vaccination are rare; however, immunocompromised individuals and in particular patients with primary immunodeficiencies (PIDs) are prone to develop vaccine-derived complications. OBJECTIVE: To systematically review demographic, clinical, immunologic, and genetic data of PIDs that present with BCG vaccine complications. Moreover, we performed a meta-analysis aiming to determine the BCG-vaccine complications rate for patients with PID. METHODS: We conducted electronic searches on Embase, Web of Science, PubMed, and Scopus (1966 to September 2018) introducing terms related to PIDs, BCG vaccination, and BCG vaccine complications. Studies with human subjects with confirmed PID, BCG vaccination history, and vaccine-associated complications (VACs) were included. RESULTS: A total of 46 PIDs associated with BCG-VAC were identified. Severe combined immunodeficiency was the most common (466 cases) and also showed the highest BCG-related mortality. Most BCG infection cases in patients with PID were reported from Iran (n = 219 [18.8%]). The overall frequency of BCG-VAC in the included 1691 PID cases was 41.5% (95% CI, 29.9-53.2; I2 = 98.3%), based on the results of the random-effect method used in this meta-analysis. Patients with Mendelian susceptibility to mycobacterial diseases had the highest frequency of BCG-VACs with a pooled frequency of 90.6% (95% CI, 79.7-1.0; I2 = 81.1%). CONCLUSIONS: Several PID entities are susceptible to BCG-VACs. Systemic neonatal PID screening programs may help to prevent a substantial amount of BCG vaccination complications.

3.
Front Immunol ; 10: 2742, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31849949

RESUMO

Almost 70 years after establishing the concept of primary immunodeficiency disorders (PIDs), more than 320 monogenic inborn errors of immunity have been identified thanks to the remarkable contribution of high-throughput genetic screening in the last decade. Approximately 40 of these PIDs present with autoimmune or auto-inflammatory symptoms as the primary clinical manifestation instead of infections. These PIDs are now recognized as diseases of immune dysregulation. Loss-of function mutations in genes such as FOXP3, CD25, LRBA, IL-10, IL10RA, and IL10RB, as well as heterozygous gain-of-function mutations in JAK1 and STAT3 have been reported as causative of these disorders. Identifying these syndromes has considerably contributed to expanding our knowledge on the mechanisms of immune regulation and tolerance. Although whole exome and whole genome sequencing have been extremely useful in identifying novel causative genes underlying new phenotypes, these approaches are time-consuming and expensive. Patients with monogenic syndromes associated with autoimmunity require faster diagnostic tools to delineate therapeutic strategies and avoid organ damage. Since these PIDs present with severe life-threatening phenotypes, the need for a precise diagnosis in order to initiate appropriate patient management is necessary. More traditional approaches such as flow cytometry are therefore a valid option. Here, we review the application of flow cytometry and discuss the relevance of this powerful technique in diagnosing patients with PIDs presenting with immune dysregulation. In addition, flow cytometry represents a fast, robust, and sensitive approach that efficiently uncovers new immunopathological mechanisms underlying monogenic PIDs.

4.
J Clin Immunol ; 39(8): 860, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31676980

RESUMO

The original version of this article contained an error in Fig. 1. The incomplete heredogram mistakenly appeared in panel d.

5.
Curr Opin Pediatr ; 31(6): 869-873, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31693599

RESUMO

PURPOSE OF REVIEW: We briefly address the advances in genetics, pathophysiology, and phenotypes of chronic granulomatous disease (CGD). This is one of the most studied primary immunodeficiencies, which comprise mutations in genes encoding the different subunits of the NADPH oxidase system. Those mutations lead to defective reactive oxygen species production, and consequently a failure to eliminate pathogens. RECENT FINDINGS: Patients with CGD are susceptible to fungal, bacterial, and parasitic infections. Other symptoms, as systemic adverse effects to BCG vaccine and hyperinflammation, are also important clinical conditions in this disease. This wide-ranging clinical spectrum of CGD comes from heterogeneity of mutations, X-linked-CGD or autosomal recessive inheritance, and diverse environmental pressure factors. Early accurate diagnosis and prompt treatment are necessary to diminish the consequences of the disease. The most used diagnostic tests are dihydrorhodamine, cytochrome c reduction, and luminol-enhanced chemiluminescence assay. SUMMARY: The determination of mutations is essential for diagnosis confirmation and genetic counseling. CGD treatment usually includes prophylactic antibiotics and antifungals. Prophylactic recombinant human interferon-γ, immunosuppressors or immune modulators may be, respectively, indicated for preventing infections or inflammatory manifestations. Hematopoietic stem cell transplantation and gene therapy are currently the available options for curative treatment of CGD.

6.
Int Immunopharmacol ; 77: 105976, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31732450

RESUMO

BAY 41-2272 increases guanosine 3', 5'-cyclic monophosphate (cGMP) levels by stimulating soluble guanylate cyclase (sGC). In this study, we evaluated the effect of BAY 41-2272 on human T lymphocyte functions. Pretreating T cells for 24 h with BAY 41-2272 at 3 µM and 30 µM, followed by activation with 90 nM phorbol myristate acetate (PMA), inhibited interferon-gamma (IFN-γ) production, with 3 µM and 30 µM BAY causing 16.5-fold and 12.1-fold inhibition, respectively, compared to PMA alone (p < 0.05, one-way ANOVA followed by Tukey's test). We also observed suppressive effects on the expression of CD69, with 30 µM BAY causing 3.55-fold lower expression than PMA/ionomycin (p < 0.001 one-way ANOVA followed by Tukey's test), and T-bet, with 30 µM BAY causing 1.47-fold lower expression than PMA/ionomycin (p < 0.05, one-way ANOVA test followed by Tukey's test). Additionally, T lymphocyte proliferation was reduced 2.13-fold and 4.3-fold, respectively, by 3 µM BAY and 30 µM BAY compared to PMA/ionomycin (p < 0.01, p < 0.001, one-way ANOVA followed by Tukey's test). BAY 41-2272 inhibits human T lymphocyte function and may be explored as an immunomodulatory drug in patients with autoimmune/inflammatory diseases and lymphoproliferative syndromes.

7.
Front Pediatr ; 7: 391, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31612120

RESUMO

Chronic granulomatous disease (CGD) is an inherited, genetically heterogeneous disease characterized by defective phagocytic cell microbicidal function, leading to increased susceptibility to bacterial and fungal infections. CGD is caused by mutations in components of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, which is responsible for reactive oxygen species production during phagocytosis. Mutations in the neutrophil cytosolic factor 2 (NCF2) gene account for <5% of all cases. Here, we report a case of a 2-year-old female with persistent recurrent pneumopathy, even under trimethoprim-sulfamethoxazole (TMP-SMX) and itraconazole prophylaxis combined with IFNγ treatment. Genetic analysis revealed a novel homozygous mutation in NCF2, sequence depletion in a splicing region (c.256_257+2delAAGT NM_000433), leading to a K86Ifs*2 residue change in the p67-phox protein.

9.
J Allergy Clin Immunol ; 144(4): 897-905, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31419546

RESUMO

Severe combined immunodeficiency (SCID) represents the most lethal form of primary immunodeficiency, with mortality rates of greater than 90% within the first year of life without treatment. Hematopoietic stem cell transplantation and gene therapy are the only curative treatments available, and the best-known prognostic factors for success are age at diagnosis, age at hematopoietic stem cell transplantation, and the comorbidities that develop in between. There are no evidence-based guidelines for standardized clinical care for patients with SCID during the time between diagnosis and definitive treatment, and we aim to generate a consensus management strategy on the supportive care of patients with SCID. First, we gathered available information about SCID diagnostic and therapeutic guidelines, then we developed a document including diagnostic and therapeutic interventions, and finally we submitted the interventions for expert consensus through a modified Delphi technique. Interventions are grouped in 10 topic domains, including 123 "agreed" and 38 "nonagreed" statements. This document intends to standardize supportive clinical care of patients with SCID from diagnosis to definitive treatment, reduce disease burden, and ultimately improve prognosis, particularly in countries where newborn screening for SCID is not universally available and delayed diagnosis is the rule. Our work intends to provide a tool not only for immunologists but also for primary care physicians and other specialists involved in the care of patients with SCID.

10.
Int Immunopharmacol ; 75: 105767, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31376626

RESUMO

BAY 41-2272 is a guanylyl cyclase (GC) stimulator derived from YC-1 (3-[(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole]). Previous studies by our group showed that BAY 41-2272 activates human monocytes via soluble guanylyl cyclase (sGC) and cGMP. In this study, we investigated the effect of BAY 41-2272 on human neutrophil function and found that 30 µM BAY 41-2272 inhibits neutrophil migration (1.82-fold lower than FMLP, P < 0.05 by one-way ANOVA followed by Tukey's test), oxidative burst (1.70-fold lower than PMA, P < 0.05 by one-way ANOVA followed by Tukey's test), and IL-8 cytokine production (1.80-fold lower than PMA, P < 0.05 by one-way ANOVA followed by Tukey's test). Our results suggest that these effects are independent of the sGC pathway but dependent instead on cGMP production, as the response induced by 30 µM BAY 41-2272 was 6.40-fold greater than that observed in our negative control (P < 0.05 by parametric t-test). 1H-[1, 2, 4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ), which is an irreversible inhibitor of sGC, was unable to reverse the effects of BAY 41-2272 on human neutrophils, indicating that this drug acts independently of sGC. Our results confirm the immunomodulatory effect of BAY 41-2272 on human neutrophils.

11.
J Clin Immunol ; 39(6): 529, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31214926
12.
World Allergy Organ J ; 12(3): 100018, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30937141

RESUMO

Background: X-linked agammaglobulinemia is an inherited immunodeficiency recognized since 1952. In spite of seven decades of experience, there is still a limited understanding of regional differences in presentation and complications. This study was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to better understand regional needs, challenges and unique patient features. Methods: A survey instrument was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to collect both structured and semi-structured data on X-linked agammaglobulinemia. The survey was sent to 54 centers around the world chosen on the basis of World Allergy Organization participation and/or registration in the European Society for Immunodeficiencies. There were 40 centers that responded, comprising 32 countries. Results: This study reports on 783 patients from 40 centers around the world. Problems with diagnosis are highlighted by the reported delays in diagnosis>24 months in 34% of patients and the lack of genetic studies in 39% of centers Two infections exhibited regional variation. Vaccine-associated paralytic poliomyelitis was seen only in countries with live polio vaccination and two centers reported mycobacteria. High rates of morbidity were reported. Acute and chronic lung diseases accounted for 41% of the deaths. Unusual complications such as inflammatory bowel disease and large granular lymphocyte disease, among others were specifically enumerated, and while individually uncommon, they were collectively seen in 20.3% of patients. These data suggest that a broad range of both inflammatory, infectious, and autoimmune conditions can occur in patients. The breadth of complications and lack of data on management subsequently appeared as a significant challenge reported by centers. Survival above 20 years of age was lowest in Africa (22%) and reached above 70% in Australia, Europe and the Americas. Centers were asked to report their challenges and responses (n = 116) emphasized the difficulties in access to immunoglobulin products (16%) and reflected the ongoing need for education of both patients and referring physicians. Conclusions: This is the largest study of patients with X-linked agammaglobulinemia and emphasizes the continued morbidity and mortality of XLA despite progress in diagnosis and treatment. It presents a world view of the successes and challenges for patients and physicians alike. A pivotal finding is the need for education of physicians regarding typical symptoms suggesting a possible diagnosis of X-linked agammaglobulinemia and sharing of best practices for the less common complications.

13.
Expert Rev Clin Immunol ; 15(5): 529-540, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30681380

RESUMO

INTRODUCTION: CD40 ligand (CD40L) deficiency or X-linked Hyper-IgM syndrome is a severe primary immunodeficiency caused by mutations in the CD40L gene. Despite currently available treatments, CD40L-deficient patients remain susceptible to life-threatening infections and have poor long term survival. Areas covered: Here, we discuss clinical and immunological characteristics of CD40L deficiency as well as current therapeutic strategies used for patient management. This review highlights that beyond B cell defects, patients' susceptibility to opportunistic pathogens might be due to impaired T cell and innate immune responses. In this context, we discuss how better knowledge of CD40L function and regulation may result in the development of new treatments. Expert opinion: Despite the introduction of hematopoietic stem-cell transplantation, immunoglobulin replacement, granulocyte colony-stimulating factor (G-CSF) administration, and prophylactic antibiotic therapies, life-threatening infections still cause high morbidity and mortality among CD40L-deficient patients. The reasons for this inadequate response to current therapies remains poorly understood, but recent reports suggest the involvement of CD40L-CD40 interaction in early stages of the innate immune system ontogeny. The development of novel gene therapeutic approaches and the use of redirected immunotherapies represent alternative treatment methods that could offer reduced morbidity and mortality rates for patients with CD40L deficiency.

14.
J Periodontol ; 90(7): 747-755, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30644104

RESUMO

BACKGROUND: Mesenchymal stem cells differentiate into distinct mesenchymal cell lineages and regulate the immune response. The aim of this study was to determine whether periodontal ligament-derived mesenchymal stem cells (PDLSCs) have the ability to modulate neutrophil responses via paracrine mechanisms. METHODS: CD105-enriched PDLSCs were seeded for 24 h and challenged with Porphyromonas gingivalis total protein extract (PgPE) (0 or 2 ug/mL) for 3 h. Cells were then washed and further cultured for 18 h and the supernatants were collected and stored. Next, neutrophil-differentiated human promyelocytic leukemia HL-60 cells (HL60D) were treated with PDLSCs supernatants and HL-60D activation and functional responses were determined. RESULTS: PgPE treatment induced higher secretion of inflammatory markers and chemokines by PDLSCs, including RANTES, eotaxin, interferon (IFN)-γ- inducible protein 10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), IFN-γ, interleukin (IL)-6, IL-8 and IL-1ra (P < 0.05). HL-60D recruitment rate was increased by 4.7 ± 1.09-fold when exposed to PgPE-treated PDLSCs supernatants. PgPE-treated PDLSCs supernatants promoted a 1.78 ± 1.04-fold increase in the production of intracellular reactive oxygen species (ROS) by PMA-stimulated HL-60D, whereas PgPE-untreated PDLSCs supernatants led to a 16% reduction in intracellular ROS. In sharp contrast, neither PgPE-untreated nor PgPE-treated PDLSCs supernatants altered tumor necrosis factor (TNF)-α and IL-1ß secretion by HL-60D cells. CONCLUSION: Together, these findings suggest an important role of PDLSCs in the recognition of P. gingivalis, paracrine recruitment and activation of antimicrobial mechanisms in innate immune cells, without interfering in cytokine responses.


Assuntos
Células-Tronco Mesenquimais , Ligamento Periodontal , Diferenciação Celular , Células Cultivadas , Humanos , Neutrófilos , Osteogênese
15.
J Cell Biochem ; 120(3): 4321-4332, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30260027

RESUMO

Interferon-γ (IFN-γ) plays an important role in innate and adaptive immunity against intracellular infections and is used clinically for the prevention and control of infections in chronic granulomatous disease (CGD) and inborn defects in the IFN-γ/interleukin (IL)-12 axis. Using transcriptome profiling (RNA-seq), we sought to identify differentially expressed genes, transcripts and exons in Epstein-Barr virus-transformed B lymphocytes (B-EBV) cells from CGD patients, IFN-γ receptor deficiency patients, and normal controls, treated in vitro with IFN-γ for 48 hours. Our results show that IFN-γ increased the expression of a diverse array of genes related to different cellular programs. In cells from normal controls and CGD patients, IFN-γ-induced expression of genes relevant to oxidative killing, nitric oxide synthase pathway, proteasome-mediated degradation, antigen presentation, chemoattraction, and cell adhesion. IFN-γ also upregulated genes involved in diverse stages of messenger RNA (mRNA) processing including pre-mRNA splicing, as well as others implicated in the folding, transport, and assembly of proteins. In particular, differential exon expression of WARS (encoding tryptophanyl-transfer RNA synthetase, which has an essential function in protein synthesis) induced by IFN-γ in normal and CGD cells suggests that this gene may have an important contribution to the benefits of IFN-γ treatment for CGD. Upregulation of mRNA and protein processing related genes in CGD and IFNRD cells could mediate some of the effects of IFN-γ treatment. These data support the concept that IFN-γ treatment may contribute to increased immune responses against pathogens through regulation of genes important for mRNA and protein processing.

20.
J Clin Immunol ; 38(8): 917-926, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30470982

RESUMO

The results of hematopoietic stem cell transplant (HSCT) for primary immunodeficiency diseases (PID) have been improving over time. Unfortunately, developing countries do not experience the same results. This first report of Brazilian experience of HSCT for PID describes the development and results in the field. We included data from transplants in 221 patients, performed at 11 centers which participated in the Brazilian collaborative group, from July 1990 to December 2015. The majority of transplants were concentrated in one center (n = 123). The median age at HSCT was 22 months, and the most common diseases were severe combined immunodeficiency (SCID) (n = 67) and Wiskott-Aldrich syndrome (WAS) (n = 67). Only 15 patients received unconditioned transplants. Cumulative incidence of GVHD grades II to IV was 23%, and GVHD grades III to IV was 10%. The 5-year overall survival was 71.6%. WAS patients had better survival compared to other diseases. Most deaths (n = 53) occurred in the first year after transplantation mainly due to infection (55%) and GVHD (13%). Although transplant for PID patients in Brazil has evolved since its beginning, we still face some challenges like delayed diagnosis and referral, severe infections before transplant, a limited number of transplant centers with expertise, and resources for more advanced techniques. Measures like newborn screening for SCID may hasten the diagnosis and ameliorate patients' conditions at the moment of transplant.


Assuntos
Doença Enxerto-Hospedeiro/epidemiologia , Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência/terapia , Doenças Raras/terapia , Brasil/epidemiologia , Diagnóstico Tardio , Países em Desenvolvimento , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/mortalidade , Lactente , Recém-Nascido , Masculino , Triagem Neonatal , Doenças Raras/epidemiologia , Doenças Raras/mortalidade , Análise de Sobrevida
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