RESUMO
Mendelian susceptibility to mycobacterial disease (MSMD) is a rare genetic disorder characterized by impaired immunity against intracellular pathogens, such as mycobacteria, attenuated Mycobacterium bovis-Bacillus Calmette-Guérin (BCG) vaccine strains, and environmental mycobacteria in otherwise healthy individuals. Retrospective study reviewed the clinical, immunological, and genetic characteristics of patients with MSMD in Mexico. Overall, 22 patients diagnosed with MSMD from 2006 to 2021 were enrolled: 14 males (64%) and eight females. After BCG vaccination, 12 patients (70%) developed BCG infection. Furthermore, 6 (22%) patients developed bacterial infections mainly caused by Salmonella, as what is described next in the text is fungal infections, particularly Histoplasma. Seven patients died of disseminated BCG disease. Thirteen different pathogenic variants were identified in IL12RB1 (n = 13), IFNGR1 (n = 3), and IFNGR2 (n = 1) genes. Interleukin-12Rß1 deficiency is the leading cause of MSMD in our cohort. Morbidity and mortality were primarily due to BCG infection.
Assuntos
Infecções por Mycobacterium , Mycobacterium bovis , Masculino , Feminino , Humanos , Estudos Retrospectivos , Vacina BCG , Predisposição Genética para Doença , México/epidemiologia , Receptores de Interleucina-12/genética , Infecções por Mycobacterium/epidemiologia , Infecções por Mycobacterium/genéticaRESUMO
Obesity is associated with an increased incidence and aggressiveness of breast cancer and is estimated to increment the development of this tumor by 50 to 86%. These associations are driven, in part, by changes in the serum molecules. Epidemiological studies have reported that Metformin reduces the incidence of obesity-associated cancer, probably by regulating the metabolic state. In this study, we evaluated in a breast cancer in-vitro model the activation of the IR-ß/Akt/p70S6K pathway by exposure to human sera with different metabolic and hormonal characteristics. Furthermore, we evaluated the effect of brief Metformin treatment on sera of obese postmenopausal women and its impact on Akt and NF-κB activation. We demonstrated that MCF-7 cells represent a robust cellular model to differentiate Akt pathway activation influenced by the stimulation with sera from obese women, resulting in increased cell viability rates compared to cells stimulated with sera from normal-weight women. In particular, stimulation with sera from postmenopausal obese women showed an increase in the phosphorylation of IR-ß and Akt proteins. These effects were reversed after exposure of MCF-7 cells to sera from postmenopausal obese women with insulin resistance with Metformin treatment. Whereas sera from women without insulin resistance affected NF-κB regulation. We further demonstrated that sera from post-Metformin obese women induced an increase in p38 phosphorylation, independent of insulin resistance. Our results suggest a possible mechanism in which obesity-mediated serum molecules could enhance the development of luminal A-breast cancer by increasing Akt activation. Further, we provided evidence that the phenomenon was reversed by Metformin treatment in a subgroup of women.
Assuntos
Neoplasias da Mama , Resistência à Insulina , Menopausa , Proteínas Proto-Oncogênicas c-akt , Neoplasias da Mama/patologia , Proliferação de Células , Sobrevivência Celular , Feminino , Humanos , Técnicas In Vitro , Metformina/farmacologia , NF-kappa B , Obesidade/complicações , Proteínas Proto-Oncogênicas c-akt/metabolismo , Soro/efeitos dos fármacos , Soro/metabolismoRESUMO
Antimicrobial resistance (AMR) is a global health problem that causes more than 1.27 million deaths annually; therefore, it is urgent to focus efforts on solving or reducing this problem. The major causes of AMR are the misuse of antibiotics and antimicrobials in agriculture, veterinary medicine, and human medicine, which favors the selection of drug-resistant microbes. One of the strategies proposed to overcome the problem of AMR is to use polyvalent human immunoglobulin or IVIG. The main advantage of this classic form of passive immunization is its capacity to enhance natural immunity mechanisms to eliminate bacteria, viruses, or fungi safely and physiologically. Experimental data suggest that, for some infections, local administration of IVIG may produce better results with a lower dose than intravenous application. This review presents evidence supporting the use of polyvalent human immunoglobulin in AMR, and the potential and challenges associated with its proposed usage.
Assuntos
Anti-Infecciosos , Doenças Transmissíveis , Humanos , Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Imunoglobulinas Intravenosas/farmacologia , Imunoglobulinas Intravenosas/uso terapêutico , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Doenças Transmissíveis/tratamento farmacológicoRESUMO
Latent tuberculosis infection (LTBI) is a subclinical mycobacterial infection defined on the basis of cellular immune response to mycobacterial antigens. The tuberculin skin test (TST) and the interferon gamma release assay (IGRA) are currently used to establish the diagnosis of LTB. However, neither TST nor IGRA is useful to discriminate between active and latent tuberculosis. Moreover, these tests cannot be used to predict whether an individual with LTBI will develop active tuberculosis (TB) or whether therapy for LTBI could be effective to decrease the risk of developing active TB. Therefore, in this article, we review current approaches and some efforts to identify an immunological marker that could be useful in distinguishing LTBI from TB and in evaluating the effectiveness of treatment of LTB on the risk of progression to active TB.
Assuntos
Tuberculose Latente/diagnóstico , Mycobacterium tuberculosis/fisiologia , Animais , Biomarcadores/metabolismo , Diagnóstico Diferencial , Progressão da Doença , Humanos , Interferon gama/metabolismo , Risco , Teste TuberculínicoRESUMO
The lipopolysaccharide (LPS) of Gram-negative bacteria is recognized on human monocytes and macrophages by TLR4 and MD2 and induces the production of inflammatory cytokines; the LPSâ¯+â¯IgG complexes co-stimulation increases the cytokine production, mediated by the Fc-γRIIa (CD32a). We stimulated human CD14â¯+â¯monocytes or THP-1 cells with LPS or LPSâ¯+â¯soluble human IgG (sIgG) and TNF-α transcription and production, assessed RT-qPCR, ELISA, or flow cytometry, was enhanced by 30% upon LPSâ¯+â¯sIgG compared to LPS stimulation. LPSâ¯+â¯sIgG co-stimulation affected the NF-κB pathway (p65 phosphorylation and nucleus translocation, and IkB- α degradation). The biochemical inhibition of IRAK 1/4 and Syk kinases suppressed the enhancer effect of LPSâ¯+â¯sIgG on TNF- α production, suggesting the involvement of both MyD88 dependent and independent pathways. Our results suggest that during LPS activation, sIgG may participate in a TLR4 - Fc-γR crosstalk.
Assuntos
Imunoglobulina G/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Receptores de IgG/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Células Cultivadas , Citocinas/metabolismo , Humanos , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Interleucina-2/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Antígeno 96 de Linfócito/imunologia , Antígeno 96 de Linfócito/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo , NF-kappa B/metabolismo , Receptor Cross-Talk/fisiologia , Receptores de IgG/imunologia , Transdução de Sinais/efeitos dos fármacos , Células THP-1 , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
PURPOSE: Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by an inability of phagocytes to produce reactive oxygen species, impairing their killing of various bacteria and fungi. We summarize here the 93 cases of CGD diagnosed in Mexico from 2011 to 2019. METHODS: Thirteen Mexican hospitals participated in this study. We describe the genetic, immunological, and clinical features of the 93 CGD patients from 78 unrelated kindreds. RESULTS: Eighty-two of the patients (88%) were male. All patients developed bacterial infections and 30% suffered from some kind of fungal infection. Fifty-four BCG-vaccinated patients (58%) presented infectious complications of BCG vaccine. Tuberculosis occurred in 29%. Granulomas were found in 56% of the patients. Autoimmune and inflammatory diseases were present in 15% of patients. A biological diagnosis of CGD was made in 89/93 patients, on the basis of NBT assay (n = 6), DHR (n = 27), and NBT plus DHR (n = 56). The deficiency was complete in all patients. The median age of biological diagnosis was 17 months (range, 0-186 months). A genetic diagnosis was made in 83/93 patients (when material was available), corresponding to CYBB (n = 64), NCF1 (n = 7), NCF2 (n = 7), and CYBA (n = 5) mutations. CONCLUSIONS: The clinical manifestations in these Mexican CGD patients were similar to those in patients elsewhere. This cohort is the largest in Latin America. Mycobacterial infections are an important cause of morbidity in Mexico, as in other countries in which tuberculosis is endemic and infants are vaccinated with BCG. X-linked CGD accounted for most of the cases in Mexico, as in other Latin American countries. However, a significant number of CYBA and NCF2 mutations were identified, expanding the spectrum of known causal mutations.
Assuntos
Doença Granulomatosa Crônica/imunologia , Mutação/genética , Infecções por Mycobacterium/epidemiologia , Mycobacterium/fisiologia , NADPH Oxidase 2/genética , NADPH Oxidases/genética , Adolescente , Autoimunidade , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Genes Ligados ao Cromossomo X , Doença Granulomatosa Crônica/epidemiologia , Doença Granulomatosa Crônica/genética , Humanos , Lactente , Recém-Nascido , Inflamação , Masculino , México/epidemiologiaRESUMO
Triple-negative breast cancer (TNBC) is one of the most aggressive tumors, with poor prognosis and high metastatic capacity. The aggressive behavior may involve inflammatory processes characterized by deregulation of molecules related to the immunological responses in which interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) are involved. It is known that calcitriol, the active vitamin D metabolite, modulates the synthesis of immunological mediators; however, its role in the regulation of IL-1ß and TNF-α in TNBC has been scarcely studied. In the present study, we showed that TNBC cell lines SUM-229PE and HCC1806 expressed vitamin D, IL-1ß, and TNF-α receptors. Moreover, calcitriol, its analogue EB1089, IL-1ß, and TNF-α inhibited cell proliferation. In addition, we showed that synthesis of both IL-1ß and TNF-α was stimulated by calcitriol and its analogue. Interestingly, the antiproliferative activity of calcitriol was significantly abrogated when the cells were treated with anti-IL-1ß receptor 1 (IL-1R1) and anti-TNF-α receptor type 1 (TNFR1) antibodies. Furthermore, the combination of calcitriol with TNF-α resulted in a greater antiproliferative effect than either agent alone, in the two TNBC cell lines and an estrogen receptor-positive cell line. In summary, this study demonstrated that calcitriol exerted its antiproliferative effects in part by inducing the synthesis of IL-1ß and TNF-α through IL-1R1 and TNFR1, respectively, in TNBC cells, highlighting immunomodulatory and antiproliferative functions of calcitriol in TNBC tumors.
Assuntos
Calcitriol/farmacologia , Proliferação de Células/efeitos dos fármacos , Interleucina-1beta/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Fator de Necrose Tumoral alfa/imunologia , Calcitriol/análogos & derivados , Linhagem Celular Tumoral , Feminino , Humanos , Fatores Imunológicos/farmacologia , Interleucina-1beta/genética , Receptores Tipo I de Interleucina-1/imunologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Candida albicans is a commensal fungus that can cause disease ranging in severity from moderate to severe mucosal infections to more serious life-threating disseminated infections in severely immunocompromised hosts. Chronic mucocutaneous candidiasis (CMC) occurs in patients with mutations in genes affecting IL-17-mediated immunity, such as STAT3, AIRE, RORC, CARD9, IL12B, and IL12RB1, or gain of function (GOF) mutations in STAT1. New strategies for the treatment of candidiasis are needed because of the increased burden of infections and the emergence of drug-resistant strains. In this study, we investigated an aspect of the role of antibodies in the control of C. albicans infection. We tested in vitro the effects of C. albicans opsonization with commercial human polyvalent intravenous IgG (IV IgG) on NADPH oxidase activity and killing of the fungi by blood leukocytes from 11 healthy donors and found a significant enhancement in both phenomena that was improved by IV IgG opsonization. Then, we hypothesized that the opsonization of Candida in vivo could help its elimination by mucosal phagocytes in human patients with mucocutaneous candidiasis. We tested a novel adjunctive treatment for oral candidiasis in humans based on topical treatment with IV IgG. For this purpose, we choose two pediatric patients with well-characterized primary immunodeficiencies who are susceptible to CMC. Two 8-year-old female patients with an autosomal recessive mutation in the IL12RB1 gene (P1, with oral candidiasis) and a GOF mutation in STAT1 (P2, with severe CMC persistent since the age of 8 months and resistant to pharmacological treatments) were treated with IV IgG administered daily three times a day as a mouthwash over the course of 2 weeks. The treatment with the IV IgG mouthwash reduced C. albicans mouth infection by 98 and 70% in P1 and P2, respectively, after 13 days, and complete fungal clearance was observed after complementary nystatin and caspofungin treatments, respectively. Therefore, treatment of oral candidiasis with human polyvalent IgG administered as a mouthwash helps eliminate mucosal infection in humans, circumventing drug resistance, and opening its potential use in patients with primary or transient immunodeficiency.
Assuntos
Antifúngicos/administração & dosagem , Candidíase Mucocutânea Crônica/tratamento farmacológico , Candidíase Bucal/tratamento farmacológico , Imunoglobulinas Intravenosas/administração & dosagem , Antissépticos Bucais/administração & dosagem , Administração Oral , Candida albicans/efeitos dos fármacos , Candida albicans/imunologia , Candida albicans/isolamento & purificação , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/imunologia , Candidíase Mucocutânea Crônica/microbiologia , Candidíase Bucal/genética , Candidíase Bucal/imunologia , Candidíase Bucal/microbiologia , Caspofungina/administração & dosagem , Criança , Farmacorresistência Fúngica/efeitos dos fármacos , Farmacorresistência Fúngica/imunologia , Quimioterapia Combinada , Feminino , Humanos , Mutação , Nistatina/administração & dosagem , Fagócitos/efeitos dos fármacos , Fagócitos/imunologia , Resultado do TratamentoRESUMO
The T cell immune response to viral infection includes the expansion of naïve T cells, effector cell differentiation and the induction of long-lived memory cells. We compared the differentiation of CD8+ T cells in patients with severe or mild pneumonia induced by influenza infection occurring during the 2009 influenza outbreak and compared their T cell subsets with those in blood samples obtained from healthy volunteers before the AH1N1 influenza outbreak in Mexico. Patients with severe influenza exhibited significantly lower numbers of effector memory CD8+CD26 high CD45RO+CCR7+ phenotype and lower numbers of central memory CD8+CD26high CD62L+CCR7+, CD26 high CD62L+CD127+ or CD26 high CD45RO+CD57 low phenotypes than patients with mild influenza or unexposed healthy subjects. Effector T cells with CD8+CD26CD62L low CD57+ phenotype were significantly diminished in severe influenza patients compared to those in patients with mild influenza or unexposed healthy subjects. These results suggest that low levels of circulating CD8+ T effector and central memory cells are associated with influenza severity.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/imunologia , Linfócitos T CD8-Positivos/virologia , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/fisiologia , Influenza Humana/virologia , México , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/virologiaRESUMO
Interferon (IFN)-γ displays a critical role in tuberculosis (TB), modulating the innate and adaptive immune responses. Previously, we reported that secretory leukocyte protease inhibitor (SLPI) is a pattern recognition receptor with anti-mycobacterial activity against Mycobacterium tuberculosis (Mtb). Herein, we determined whether IFN-γ modulated the levels of SLPI in TB patients. Plasma levels of SLPI and IFN-γ were studied in healthy donors (HDs) and TB patients. Peripheral blood mononuclear cells from HDs and patients with TB or defective IFN-γ receptor 1* were stimulated with Mtb antigen and SLPI, and IFN-γR expression levels were measured. Both SLPI and IFN-γ were significantly enhanced in plasma from those with TB compared with HDs. A direct association between SLPI levels and the severity of TB was detected. In addition, Mtb antigen stimulation decreased the SLPI produced by peripheral blood mononuclear cells from HDs, but not from TB or IFN-γR patients. Neutralization of IFN-γ reversed the inhibition of SLPI induced by Mtb antigen in HDs, but not in TB patients. Furthermore, recombinant IFN-γ was unable to modify the expression of SLPI in TB patients. Finally, IFN-γR expression was lower in TB compared with HD peripheral blood mononuclear cells. These results show that Mtb-induced IFN-γ down-modulated SLPI levels by signaling through the IFN-γR in HDs. This inhibitory mechanism was not observed in TB, probably because of the low expression of IFN-γR detected in these individuals.