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1.
Int Arch Allergy Immunol ; 181(1): 1-10, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31593946

RESUMO

In recent decades, the worldwide prevalence of allergic disease has increased considerably. The atopic march is a model aimed at explaining the apparent progression of allergic diseases from atopic dermatitis (AD) to allergic asthma (AA) and to allergic rhinitis (AR). It hypothesizes that allergic disease begins, typically in children, with the development of AD, then AA, and finally progresses to AR. This theory has been widely studied in cross-sectional and long-term longitudinal studies and it has been found that as prevalence of AD declines, prevalence of AA increases. A similar relationship is reported between AA and AR. The legitimacy of the atopic march model is, however, currently debated. Epidemiological evidence and criticism of longitudinal studies point to an overstatement of the atopic march's prevalence and incorrect mechanisms, opening a discussion for alternative models to better explain the pathophysiological and epidemiological processes that promote this progression of allergic diseases. Albeit, risk factors for the development and progression of allergic disease, particularly AD, are critical in identifying disease progression. Investigating the role of age, severity, family history, phenotype, and genetic traits may give a better indication into the progression of allergic diseases. In addition, studies following patients from infancy into adulthood and a general increase in longitudinal studies would help broaden the knowledge of allergic disease progression and the atopic march.


Assuntos
Alergia e Imunologia/tendências , Asma/epidemiologia , Dermatite Atópica/epidemiologia , Rinite Alérgica/epidemiologia , Adulto , Animais , Criança , Progressão da Doença , Medicina Baseada em Evidências , Humanos , Modelos Imunológicos , Prevalência
2.
IEEE Trans Cybern ; 50(1): 164-177, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30235158

RESUMO

The intelligent devices in Internet of Things (IoT) not only provide services but also consider how to allocate heterogeneous resources and reduce resource consumption and service time as far as possible. This issue becomes crucial in the case of large-scale IoT environments. In order for the IoT service system to respond to multiple requests simultaneously and provide Pareto optimal decisions, we propose an immune-endocrine system inspired hierarchical coevolutionary multiobjective optimization algorithm (IE-HCMOA) in this paper. In IE-HCMOA, a multiobjective immune algorithm based on global ranking with vaccine is designed to choose superior antibodies. Meanwhile, we adopt clustering in top population to make the operations more directional and purposeful and realize self-adaptive searching. And we use the human forgetting memory mechanism to design two-level memory storage for the choice problem of solutions to achieve promising performance. In order to validate the practicability and effectiveness of IE-HCMOA, we apply it to the field of agricultural IoT service. The simulation results demonstrate that the proposed algorithm can obtain the best Pareto, the strongest exploration ability, and excellent performance than nondominated neighbor immune algorithms and NSGA-II.


Assuntos
Algoritmos , Técnicas de Apoio para a Decisão , Modelos Imunológicos , Análise por Conglomerados , Sistema Endócrino , Humanos , Sistema Imunitário , Vacinas/imunologia
3.
BMC Bioinformatics ; 20(Suppl 6): 579, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31823716

RESUMO

BACKGROUND: In recent years, the study of immune response behaviour using bottom up approach, Agent Based Modeling (ABM), has attracted considerable efforts. The ABM approach is a very common technique in the biological domain due to high demand for a large scale analysis tools for the collection and interpretation of information to solve biological problems. Simulating massive multi-agent systems (i.e. simulations containing a large number of agents/entities) requires major computational effort which is only achievable through the use of parallel computing approaches. RESULTS: This paper explores different approaches to parallelising the key component of biological and immune system models within an ABM model: pairwise interactions. The focus of this paper is on the performance and algorithmic design choices of cell interactions in continuous and discrete space where agents/entities are competing to interact with one another within a parallel environment. CONCLUSIONS: Our performance results demonstrate the applicability of these methods to a broader class of biological systems exhibiting typical cell to cell interactions. The advantage and disadvantage of each implementation is discussed showing each can be used as the basis for developing complete immune system models on parallel hardware.


Assuntos
Simulação por Computador , Sistema Imunitário , Modelos Imunológicos , Algoritmos , Humanos , Biologia de Sistemas
4.
BMC Complement Altern Med ; 19(1): 369, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842843

RESUMO

BACKGROUND: Bletilla striata is a traditional Chinese medicine used to treat hemorrhage, scald, gastric ulcer, pulmonary diseases and inflammations. In this study, we investigated bioactivity of the effective fraction of B. striata (EFB) in reducing the inflammatory cytokine production induced by water or organic extracts of PM2.5. METHODS: PM2.5 extracts were collected and analyzed by chromatographic system and inductively coupled plasma mass spectrometer. Cell viability was measured using MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay, and cell supernatant was analyzed by flow cytometry, ELISA, and qRT-PCR in cultured mouse macrophage cell line RAW264.7 treated with EFB and PM2.5 extracts. Expressions of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathway were measured by Western blot. RESULTS: PM2.5 composition is complex and the toxicity of PM2.5 extracts were not noticeable. The treatment of EFB at a wide dose-range of 0-40 µg/mL did not cause significant change of RAW264.7 cell proliferation. EFB pretreatment decreased the inflammatory cytokines in the macrophage. Further analysis showed that EFB significantly attenuated PM2.5-induced proinflammatory protein expression and downregulated the levels of phosphorylated NF-κBp65, inhibitor of kappa B (IκB)-α, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38. CONCLUSIONS: Our study demonstrated the potential effectiveness of B. striata extracts for treating PM2.5-triggered pulmonary inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Orchidaceae , Material Particulado/toxicidade , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/química , Sobrevivência Celular/efeitos dos fármacos , Citocinas/análise , Citocinas/genética , Inflamação/metabolismo , Camundongos , Modelos Imunológicos , Extratos Vegetais/química , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia
5.
Mol Biol (Mosk) ; 53(5): 815-829, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31661480

RESUMO

The modern era of research in immunology is characterized by an unprecedented level of detail about structural characteristics of the immune system and the regulation of activities of its numerous components, which function together as a whole distributed-parameter system. Mathematical modeling provides an analytical tool to describe, analyze, and predict the dynamics of immune responses by applying a reductionist approach. In modern systems immunology and mathematical immunology as a new interdisciplinary field, a great challenge is to formulate the mathematical models of the human immune system that reflect the level achieved in understanding its structure and describe the processes that sustain its function. To this end, a systematic development of multiscale mathematical models has to be advanced. An appropriate methodology should consider (1) the intracellular processes of immune cell fate regulation, (2) the population dynamics of immune cells in various organs, and (3) systemic immunophysiological processes in the whole host organism. Main studies aimed at modeling the intracellular regulatory networks are reviewed in the context of multiscale mathematical modelling. The processes considered determine the regulation of the immune cell fate, including activation, division, differentiation, apoptosis, and migration. Because of the complexity and high dimensionality of the regulatory networks, identifying the parsimonious descriptions of signaling pathways and regulatory loops is a pressing problem of modern mathematical immunology.


Assuntos
Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Modelos Imunológicos , Apoptose , Diferenciação Celular , Movimento Celular , Humanos , Transdução de Sinais
6.
PLoS Comput Biol ; 15(9): e1007344, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31504033

RESUMO

Prostate cancer (PCa) is the most commonly diagnosed malignancy and the second leading cause of cancer-related death in American men. Androgen deprivation therapy (ADT) has become a standard treatment strategy for advanced PCa. Although a majority of patients initially respond to ADT well, most of them will eventually develop castration-resistant PCa (CRPC). Previous studies suggest that ADT-induced changes in the immune microenvironment (mE) in PCa might be responsible for the failures of various therapies. However, the role of the immune system in CRPC development remains unclear. To systematically understand the immunity leading to CRPC progression and predict the optimal treatment strategy in silico, we developed a 3D Hybrid Multi-scale Model (HMSM), consisting of an ODE system and an agent-based model (ABM), to manipulate the tumor growth in a defined immune system. Based on our analysis, we revealed that the key factors (e.g. WNT5A, TRAIL, CSF1, etc.) mediated the activation of PC-Treg and PC-TAM interaction pathways, which induced the immunosuppression during CRPC progression. Our HMSM model also provided an optimal therapeutic strategy for improving the outcomes of PCa treatment.


Assuntos
Modelos Imunológicos , Neoplasias de Próstata Resistentes à Castração/imunologia , Antagonistas de Androgênios/uso terapêutico , Biologia Computacional , Simulação por Computador , Citocinas/imunologia , Humanos , Linfonodos/imunologia , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Linfócitos T Reguladores/imunologia
7.
PLoS Pathog ; 15(9): e1007999, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31539404

RESUMO

The cellular DNA sensor cGMP-AMP synthase (cGAS) detects cytosolic viral DNA via the stimulator of interferon genes (STING) to initiate innate antiviral response. Herpesviruses are known to target key immune signaling pathways to persist in an immune-competent host. Marek's disease virus (MDV), a highly pathogenic and oncogenic herpesvirus of chickens, can antagonize host innate immune responses to achieve persistent infection. With a functional screen, we identified five MDV proteins that blocked beta interferon (IFN-ß) induction downstream of the cGAS-STING pathway. Specifically, the MDV major oncoprotein Meq impeded the recruitment of TANK-binding kinase 1 and IFN regulatory factor 7 (IRF7) to the STING complex, thereby inhibiting IRF7 activation and IFN-ß induction. Meq overexpression markedly reduced antiviral responses stimulated by cytosolic DNA, whereas knockdown of Meq heightened MDV-triggered induction of IFN-ß and downstream antiviral genes. Moreover, Meq-deficient MDV induced more IFN-ß production than wild-type MDV. Meq-deficient MDV also triggered a more robust CD8+ T cell response than wild-type MDV. As such, the Meq-deficient MDV was highly attenuated in replication and lymphoma induction compared to wild-type MDV. Taken together, these results revealed that MDV evades the cGAS-STING DNA sensing pathway, which underpins the efficient replication and oncogenesis. These findings improve our understanding of the virus-host interaction in MDV-induced lymphoma and may contribute to the development of novel vaccines against MDV infection.


Assuntos
Herpesvirus Galináceo 2/imunologia , Herpesvirus Galináceo 2/patogenicidade , Evasão da Resposta Imune , Doença de Marek/imunologia , Doença de Marek/virologia , Animais , Proteínas Aviárias/metabolismo , Carcinogênese , Galinhas , DNA Viral/imunologia , Patos , Herpesvirus Galináceo 2/fisiologia , Interações entre Hospedeiro e Microrganismos/imunologia , Imunidade Inata , Fator Regulador 7 de Interferon/metabolismo , Interferon beta/metabolismo , Doença de Marek/metabolismo , Modelos Imunológicos , Nucleotidiltransferases/metabolismo , Proteínas Oncogênicas Virais/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Proteínas Virais/imunologia , Replicação Viral
8.
PLoS Pathog ; 15(9): e1008040, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31527904

RESUMO

To escape CD8+ T-cell immunity, human cytomegalovirus (HCMV) US11 redirects MHC-I for rapid ER-associated proteolytic degradation (ERAD). In humans, classical MHC-I molecules are encoded by the highly polymorphic HLA-A, -B and -C gene loci. While HLA-C resists US11 degradation, the specificity for HLA-A and HLA-B products has not been systematically studied. In this study we analyzed the MHC-I peptide ligands in HCMV-infected cells. A US11-dependent loss of HLA-A ligands was observed, but not of HLA-B. We revealed a general ability of HLA-B to assemble with ß2m and exit from the ER in the presence of US11. Surprisingly, a low-complexity region between the signal peptide sequence and the Ig-like domain of US11, was necessary to form a stable interaction with assembled MHC-I and, moreover, this region was also responsible for changing the pool of HLA-B ligands. Our data suggest a two-pronged strategy by US11 to escape CD8+ T-cell immunity, firstly, by degrading HLA-A molecules, and secondly, by manipulating the HLA-B ligandome.


Assuntos
Citomegalovirus/imunologia , Citomegalovirus/metabolismo , Antígenos HLA-B/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Virais/metabolismo , Apresentação do Antígeno , Linhagem Celular , Citomegalovirus/genética , Degradação Associada com o Retículo Endoplasmático/imunologia , Antígenos HLA-A/metabolismo , Antígenos HLA-B/química , Células HeLa , Humanos , Evasão da Resposta Imune , Ligantes , Modelos Imunológicos , Modelos Moleculares , Domínios e Motivos de Interação entre Proteínas , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Proteínas Virais/química , Proteínas Virais/genética
9.
Chaos ; 29(8): 083127, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31472488

RESUMO

In this paper, we present a new fractional-order mathematical model for a tumor-immune surveillance mechanism. We analyze the interactions between various tumor cell populations and immune system via a system of fractional differential equations (FDEs). An efficient numerical procedure is suggested to solve these FDEs by considering singular and nonsingular derivative operators. An optimal control strategy for investigating the effect of chemotherapy treatment on the proposed fractional model is also provided. Simulation results show that the new presented model based on the fractional operator with Mittag-Leffler kernel represents various asymptomatic behaviors that tracks the real data more accurately than the other fractional- and integer-order models. Numerical simulations also verify the efficiency of the proposed optimal control strategy and show that the growth of the naive tumor cell population is successfully declined.


Assuntos
Vigilância Imunológica , Modelos Imunológicos , Neoplasias/imunologia , Animais , Humanos
10.
Int J Mol Sci ; 20(18)2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31514450

RESUMO

An imbalanced T-cell homeostasis plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Co-stimulatory and co-inhibitory molecules regulate T-cell differentiation, survival, and cytokine production. B- and T-lymphocyte attenuator (BTLA) is a co-inhibitory molecule which negatively regulates T-cell activation. The aim of this study was to investigate BTLA expression on regulatory and effector CD4+ T-cells in SLE patients with and without lupus nephritis (LN) during active and inactive disease. Therefore, peripheral blood of forty-one SLE patients and twenty-one healthy controls (HC) was phenotypically analyzed. Next, ex vivo stimulated T-cells were analyzed for the expression of BTLA on Th1-, Th2-, and Th17-effector cells by flow cytometry. Renal involvement was defined as biopsy-proven LN. Disease activity was assessed by SLE disease activity index (SLEDAI). Percentages of peripheral unstimulated BTLA+ CD4+ T-cells were significantly decreased in SLE patients with active disease. However, ex vivo stimulated Th1, Th2, and Th17 effector T-cells, expressed increased percentages of BTLA expression in active disease. In contrast, the BTLA expression on CD4+CD25++CD127- regulatory T-cells was not significantly different. BTLA seems to be an important co-inhibitory molecule in the T-cell homeostasis of patients with systemic lupus erythematosus and crucial for disease activity.


Assuntos
Lúpus Eritematoso Sistêmico/imunologia , Receptores Imunológicos/metabolismo , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Adulto , Feminino , Humanos , Nefrite Lúpica/imunologia , Ativação Linfocitária/imunologia , Masculino , Modelos Imunológicos , Linfócitos T Reguladores/imunologia
11.
Med Hypotheses ; 131: 109319, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31443751

RESUMO

We hypothesize that exogenous intrapleural injection of interleukin-27 may improve outcome and prognosis in patients with tuberculous pleural effusion (TPE). Studies have found that the balance of Th1/Th2 determines the development trend of TPE. High concentrations of IFN-γ and TNF-α in pleural effusion are associated with pleural adhesion in patients with TPE. Interleukin-27 is a member of the IL-12 family, and IL-27 has a dual regulatory effect on Th1 immunity. On one hand, IL-27 can promote the initial CD4+ T cell proliferation by inducing the expression of T-bet, IL-12Rß2 and ICAM-1 in the initial CD4+ T cells, and also promote its differentiation into Th1 cells and IFN-γ production in the early infection. On the other hand, in the case of high Th1 polarization, IL-27 induced STAT3 phosphorylation and inhibited TNF and IL-12 production in activated peritoneal macrophages, indicating a novel feedback mechanism by which IL-27 can modulate excessive inflammation, thereby preventing damage to the body caused by excessive immune response. Studies haves confirmed that after stimulation of antigen by mononuclear cells in TPE, the Th1 and Th2 cell subsets and Th1/Th2 ratio markedly increase, and the increase of Th1 is more obvious than that of Th2. Therefore, compared to patients with TPE in the high-level IL-27 group, we hypothesized that pleural effusion is absorbed more slowly, pleural thickening is more obvious, pleural adhesions are more extensive, and the incidence of thoracic collapse is higher in the low-level IL-27 group under the same conditions of anti-tuberculosis treatment. However, exogenous intrapleural injection of IL-27 may induce Stat3 phosphorylation and inhibit TNF and IL-12 production, finally reduces the secretion of IFN-γ and TNF-α. This negative regulation inhibits the excessive inflammatory reaction caused by tuberculosis infection, reduces pleural adhesion, pleural thickening and local pleural tissue damage, thereby improving the prognosis of patients.


Assuntos
Interleucinas/uso terapêutico , Modelos Imunológicos , Derrame Pleural/etiologia , Tuberculose Pleural/tratamento farmacológico , Animais , Retroalimentação Fisiológica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Injeções , Interferon gama/metabolismo , Interleucina-12/biossíntese , Interleucina-12/genética , Interleucinas/administração & dosagem , Interleucinas/fisiologia , Modelos Animais , Fosforilação , Pleura , Prognóstico , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ratos , Proteínas Recombinantes/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Resultado do Tratamento , Tuberculose Pleural/complicações , Tuberculose Pleural/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética
12.
Med Hypotheses ; 131: 109313, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31443758

RESUMO

Fibrodysplasia ossificans progressiva (FOP) is a rare hereditary disease caused by a mutation in the intracellular domain of the activin A receptor type I and is characterized by episodes (flare-ups) of progressive heterotopic endochondral ossification (HO) in the soft tissues. The mutation alone is not sufficient for the occurrence of HO since flare-ups are triggered by inflammation and activation of the innate immune system. A number of cellular and humoral mediators have been implicated in animal and in vitro models. Observations in humans support the inflammatory nature of the condition, but data on the involved mediators are variable. We hypothesize that for induction of flare-ups in patients with FOP increase in at least one of the pro-inflammatory cytokines is both essential and sufficient to trigger the entire process of the inflammatory cells influx resulting in the novel ectopic bone formation and we suggest that C-C motif ligand 5 (CCL5), a pro-inflammatory chemokine also known as Regulated on activation, normal T-cell expressed and secreted (RANTES), might be the key candidate. CCL5 is a chemoattractant for all cellular types implicated in HO and is produced by the cells of the tissue microenvironment at the sites of HO as well as by the pro-inflammatory cellular mediators. CCL5 induces ossification in cultured human pluripotent mesenchymal cells (hMSCs) and in the primary culture of monocytes from FOP patients (but not from their healthy relatives), stimulation with lipopolysaccharide induces CCL5 expression. Finally, in a pilot study we used a panel of 23 cytokines and chemokines to screen the plasma samples of three subjects: a female patient with FOP during a flare-up; a female patient with hyperostosis corticalis generalisata (van Buchem disease), another rare disease characterized by excessive bone formation at the sites where it regularly occurs that does not include inflammatory events; and a healthy woman without bone disorders. There appeared a rather clear-cut signal of a 2-fold higher level of CCL5 in the FOP patient vs. the healthy subject and the van Buchem patient. Evaluation of the hypothesis would require an international prospective study, with main motivation being the lack of a conclusive treatment as the major unmet need in FOP. A treatment targeting CCL5 receptor already exists and is used in HIV-infected patients.


Assuntos
Quimiocina CCL5/sangue , Terapia de Alvo Molecular , Miosite Ossificante/sangue , Ossificação Heterotópica/sangue , Quimiocina CCL5/antagonistas & inibidores , Citocinas/fisiologia , Feminino , Humanos , Inflamação , Lipopolissacarídeos/farmacologia , Células-Tronco Mesenquimais/metabolismo , Modelos Imunológicos , Monócitos/metabolismo , Miosite Ossificante/tratamento farmacológico , Miosite Ossificante/imunologia , Ossificação Heterotópica/imunologia , Osteocondrodisplasias/sangue , Células-Tronco Pluripotentes/metabolismo
13.
Med Hypotheses ; 131: 109294, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31443760

RESUMO

Narcolepsy type 1 is a lifelong sleep disorder characterized by the loss of hypocretin-producing neurons in the brain. Environmental agents, including influenza, neurotoxic metals, and combustion smoke, have been implicated in the pathogenesis, especially in carriers of the human leukocyte antigen class II DQB1*06:02 allele. Sensitive experimental approaches have recently revealed hypocretin-autoreactive CD4+ and CD8+ T cells in the blood of narcoleptic patients. However, such potentially harmful cells are also detectable, to a lesser degree, in control DQB1*06:02 carriers, suggesting that the integrity of the blood-brain barrier (BBB) provides a neuroprotective effect. Here, we present the hypothesis that external toxic agents induce neuroinflammation in the olfactory bulb and concomitant overproduction of proinflammatory cytokines (e.g., tumor necrosis factor-α and interferon-γ); this, in turn, compromises the BBB, allowing autoimmune cells to access and kill hypocretinergic neurons. Such sequential pathological alterations could occur insidiously, passing unnoticed and consequently being underestimated. The elevated number of autoreactive T cells in narcoleptics relative to controls might reflect externally induced immunomodulation rather than a direct disease trigger.


Assuntos
Barreira Hematoencefálica/fisiologia , Cadeias beta de HLA-DQ/imunologia , Modelos Imunológicos , Narcolepsia/imunologia , Bulbo Olfatório/fisiopatologia , Animais , Autoantígenos/imunologia , Autoantígenos/metabolismo , Citocinas/fisiologia , Poluentes Ambientais/farmacocinética , Poluentes Ambientais/toxicidade , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Humanos , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Mimetismo Molecular , Narcolepsia/etiologia , Narcolepsia/fisiopatologia , Neurônios/metabolismo , Neurônios/patologia , Bulbo Olfatório/efeitos dos fármacos , Orexinas/imunologia , Orexinas/metabolismo , Especificidade do Receptor de Antígeno de Linfócitos T , Subpopulações de Linfócitos T/imunologia
14.
Med Hypotheses ; 131: 109281, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31443770

RESUMO

The data of literature are discordant about the role of mast cells in different types of neoplasms. In this paper the authors propose the hypothesis that tumor-associated mast cells may switch to different polarization states, conditioning the immunogenic capacities of the different neoplasms. Anti-inflammatory polarized mast cells should express cytokines such as interleukin-10 (IL-10) and then mast cells number should be inversely related to the intensity of inflammatory infiltrate. On the contrary, when mast cells do not express anti-inflammatory cytokines their number should be directly related to the intensity of the inflammatory infiltrate. In this paper we briefly argue around feasible approaches, based on the retrospective studies of tumor tissue samples from neoplasms considered "immunologically hot" and neoplasms considered "immunologically cold", through immunohistochemistry and immunofluorescence techniques (confocal microscopy). The establishment of the actual existence of a polarization interchange of mast cells, could lead to a new vision in prognostic terms, useful to contrive new approaches in immunotherapy of tumors.


Assuntos
Citocinas/biossíntese , Mastócitos/imunologia , Modelos Imunológicos , Neoplasias/imunologia , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Antígenos de Neoplasias/análise , Contagem de Células , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunoquímica , Inflamação , Linfócitos do Interstício Tumoral/química , Macrófagos/química , Mastócitos/metabolismo , Mastócitos/ultraestrutura , Microscopia Confocal , Neoplasias/química , Neoplasias/ultraestrutura , Inclusão em Parafina , Proteínas Proto-Oncogênicas c-kit/análise , Receptores de Superfície Celular/análise , Projetos de Pesquisa , Estudos Retrospectivos
15.
PLoS Comput Biol ; 15(7): e1007172, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31365522

RESUMO

In an inflammatory setting, macrophages can be polarized to an inflammatory M1 phenotype or to an anti-inflammatory M2 phenotype, as well as existing on a spectrum between these two extremes. Dysfunction of this phenotypic switch can result in a population imbalance that leads to chronic wounds or disease due to unresolved inflammation. Therapeutic interventions that target macrophages have therefore been proposed and implemented in diseases that feature chronic inflammation such as diabetes mellitus and atherosclerosis. We have developed a model for the sequential influx of immune cells in the peritoneal cavity in response to a bacterial stimulus that includes macrophage polarization, with the simplifying assumption that macrophages can be classified as M1 or M2. With this model, we were able to reproduce the expected timing of sequential influx of immune cells and mediators in a general inflammatory setting. We then fit this model to in vivo experimental data obtained from a mouse peritonitis model of inflammation, which is widely used to evaluate endogenous processes in response to an inflammatory stimulus. Model robustness is explored with local structural and practical identifiability of the proposed model a posteriori. Additionally, we perform sensitivity analysis that identifies the population of apoptotic neutrophils as a key driver of the inflammatory process. Finally, we simulate a selection of proposed therapies including points of intervention in the case of delayed neutrophil apoptosis, which our model predicts will result in a sustained inflammatory response. Our model can therefore provide hypothesis testing for therapeutic interventions that target macrophage phenotype and predict outcomes to be validated by subsequent experimentation.


Assuntos
Inflamação/imunologia , Macrófagos/imunologia , Modelos Imunológicos , Animais , Apoptose/imunologia , Biologia Computacional , Simulação por Computador , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/imunologia , Ativação de Macrófagos , Macrófagos/classificação , Macrófagos Peritoneais/classificação , Macrófagos Peritoneais/imunologia , Camundongos , Neutrófilos/citologia , Neutrófilos/imunologia , Fenótipo
16.
PLoS Comput Biol ; 15(8): e1007294, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31425503

RESUMO

The strength and breadth of an individual's antibody repertoire is an important predictor of their response to influenza infection or vaccination. Although progress has been made in understanding qualitatively how repeated exposures shape the antibody mediated immune response, quantitative understanding remains limited. We developed a set of mathematical models describing short-term antibody kinetics following influenza infection or vaccination and fit them to haemagglutination inhibition (HI) titres from 5 groups of ferrets which were exposed to different combinations of trivalent inactivated influenza vaccine (TIV with or without adjuvant), A/H3N2 priming inoculation and post-vaccination A/H1N1 inoculation. We fit models with various immunological mechanisms that have been empirically observed but have not previously been included in mathematical models of antibody landscapes, including: titre ceiling effects, antigenic seniority and exposure-type specific cross reactivity. Based on the parameter estimates of the best supported models, we describe a number of key immunological features. We found quantifiable differences in the degree of homologous and cross-reactive antibody boosting elicited by different exposure types. Infection and adjuvanted vaccination generally resulted in strong, broadly reactive responses whereas unadjuvanted vaccination resulted in a weak, narrow response. We found that the order of exposure mattered: priming with A/H3N2 improved subsequent vaccine response, and the second dose of adjuvanted vaccination resulted in substantially greater antibody boosting than the first. Either antigenic seniority or a titre ceiling effect were included in the two best fitting models, suggesting a role for a mechanism describing diminishing antibody boosting with repeated exposures. Although there was considerable uncertainty in our estimates of antibody waning parameters, our results suggest that both short and long term waning were present and would be identifiable with a larger set of experiments. These results highlight the potential use of repeat exposure animal models in revealing short-term, strain-specific immune dynamics of influenza.


Assuntos
Anticorpos Antivirais/sangue , Furões/imunologia , Vacinas contra Influenza/administração & dosagem , Modelos Imunológicos , Infecções por Orthomyxoviridae/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Biologia Computacional , Reações Cruzadas , Modelos Animais de Doenças , Humanos , Imunização Secundária , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Cinética , Infecções por Orthomyxoviridae/virologia , Vacinas de Produtos Inativados/administração & dosagem
17.
PLoS Comput Biol ; 15(7): e1007133, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31329576

RESUMO

The collection of immunoglobulin genes in an individual's germline, which gives rise to B cell receptors via recombination, is known to vary significantly across individuals. In humans, for example, each individual has only a fraction of the several hundred known V alleles. Furthermore, the currently-accepted set of known V alleles is both incomplete (particularly for non-European samples), and contains a significant number of spurious alleles. The resulting uncertainty as to which immunoglobulin alleles are present in any given sample results in inaccurate B cell receptor sequence annotations, and in particular inaccurate inferred naive ancestors. In this paper we first show that the currently widespread practice of aligning each sequence to its closest match in the full set of IMGT alleles results in a very large number of spurious alleles that are not in the sample's true set of germline V alleles. We then describe a new method for inferring each individual's germline gene set from deep sequencing data, and show that it improves upon existing methods by making a detailed comparison on a variety of simulated and real data samples. This new method has been integrated into the partis annotation and clonal family inference package, available at https://github.com/psathyrella/partis, and is run by default without affecting overall run time.


Assuntos
Genes de Imunoglobulinas , Receptores de Antígenos de Linfócitos B/genética , Alelos , Biologia Computacional , Simulação por Computador , Bases de Dados Genéticas , Células Germinativas/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Modelos Genéticos , Modelos Imunológicos , Alinhamento de Sequência , Software
18.
PLoS Pathog ; 15(7): e1007900, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31269090

RESUMO

The Pseudomonas syringae acetyltransferase HopZ1a is delivered into host cells by the type III secretion system to promote bacterial growth. However, in the model plant host Arabidopsis thaliana, HopZ1a activity results in an effector-triggered immune response (ETI) that limits bacterial proliferation. HopZ1a-triggered immunity requires the nucleotide-binding, leucine-rich repeat domain (NLR) protein, ZAR1, and the pseudokinase, ZED1. Here we demonstrate that HopZ1a can acetylate members of a family of 'receptor-like cytoplasmic kinases' (RLCK family VII; also known as PBS1-like kinases, or PBLs) and promote their interaction with ZED1 and ZAR1 to form a ZAR1-ZED1-PBL ternary complex. Interactions between ZED1 and PBL kinases are determined by the pseudokinase features of ZED1, and mutants designed to restore ZED1 kinase motifs can (1) bind to PBLs, (2) recruit ZAR1, and (3) trigger ZAR1-dependent immunity in planta, all independently of HopZ1a. A ZED1 mutant that mimics acetylation by HopZ1a also triggers immunity in planta, providing evidence that effector-induced perturbations of ZED1 also activate ZAR1. Overall, our results suggest that interactions between these two RLCK families are promoted by perturbations of structural features that distinguish active from inactive kinase domain conformations. We propose that effector-induced interactions between ZED1/ZRK pseudokinases (RLCK family XII) and PBL kinases (RLCK family VII) provide a sensitive mechanism for detecting perturbations of either kinase family to activate ZAR1-mediated ETI.


Assuntos
Proteínas de Arabidopsis/imunologia , Proteínas de Arabidopsis/metabolismo , Arabidopsis/imunologia , Arabidopsis/metabolismo , Fosfotransferases/imunologia , Fosfotransferases/metabolismo , Imunidade Vegetal , Acetilação , Arabidopsis/genética , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/genética , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Proteínas de Transporte/química , Proteínas de Transporte/imunologia , Proteínas de Transporte/metabolismo , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Modelos Imunológicos , Mutação , Fosfotransferases/genética , Domínios e Motivos de Interação entre Proteínas , Proteínas Quinases/química , Proteínas Quinases/metabolismo , Pseudomonas syringae/imunologia , Pseudomonas syringae/metabolismo , Pseudomonas syringae/patogenicidade
19.
PLoS Comput Biol ; 15(7): e1007168, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31265463

RESUMO

Mathematical models have been used successfully at diverse scales of biological organization, ranging from ecology and population dynamics to stochastic reaction events occurring between individual molecules in single cells. Generally, many biological processes unfold across multiple scales, with mutations being the best studied example of how stochasticity at the molecular scale can influence outcomes at the population scale. In many other contexts, however, an analogous link between micro- and macro-scale remains elusive, primarily due to the challenges involved in setting up and analyzing multi-scale models. Here, we employ such a model to investigate how stochasticity propagates from individual biochemical reaction events in the bacterial innate immune system to the ecology of bacteria and bacterial viruses. We show analytically how the dynamics of bacterial populations are shaped by the activities of immunity-conferring enzymes in single cells and how the ecological consequences imply optimal bacterial defense strategies against viruses. Our results suggest that bacterial populations in the presence of viruses can either optimize their initial growth rate or their population size, with the first strategy favoring simple immunity featuring a single restriction modification system and the second strategy favoring complex bacterial innate immunity featuring several simultaneously active restriction modification systems.


Assuntos
Bactérias/imunologia , Bactérias/virologia , Bacteriófagos/imunologia , Biologia Computacional , Enzimas de Restrição-Modificação do DNA/imunologia , Ecossistema , Imunidade Inata , Consórcios Microbianos/imunologia , Modelos Biológicos , Modelos Imunológicos , Análise de Célula Única , Processos Estocásticos
20.
Int J Paleopathol ; 26: 37-47, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31185376

RESUMO

OBJECTIVE: Our primary objective is to re-visit the tuberculosis and leprosy cross-immunity. hypothesis through the careful integration of immunology and paleopathology. METHODS: Using an integrated theoretical analysis that evaluates clinical literature on human innate immunological responses, paleomicrobiology, bioarchaeology, and paleopathology, we develop a multifactorial model. RESULTS: Past populations do not represent homogeneous immunological landscapes, and therefore it is likely that leprosy in Medieval Europe did not uniformly decline due to cross-immunity. CONCLUSIONS: We recommend that bioarchaeological reconstructions of past disease experience take into consideration models that include variation in immune function based on past environments and social contexts. This provides a unique opportunity to conduct comprehensive analyses on complex immunological processes. SIGNIFICANCE: Extrapolating results from experimental immunology to larger populations elucidates complexities of disease cross-immunity and highlights the importance of synthesizing archaeological, social, paleopathological and biological data as a means of understanding disease in the past. LIMITATIONS: All extrapolations from data produced from in vitro studies to past populations, using living donors, pose significant limitations where, among other factors, the full reconstruction of past environmental and social contexts can frequently be sparse or incomplete. SUGGESTIONS FOR FUTURE RESEARCH: To reduce the limitations of integrating experimental immunology with bioarchaeological reconstructions (i.e. how to use skeletal samples to reconstruct inflammatory phenotypes), we propose that osteoimmunology, or the study of the interplay between immune cells and bone cells, should be considered a vital discipline and perhaps the foundation for the expansion of paleoimmunology.


Assuntos
Alergia e Imunologia , Hanseníase/imunologia , Modelos Imunológicos , Paleopatologia , Tuberculose/imunologia , Arqueologia , Reações Cruzadas , História Medieval , Humanos , Imunidade Inata/imunologia , Tuberculose/história
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