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1.
Medicine (Baltimore) ; 98(43): e17609, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651871

RESUMO

RATIONALE: Bacillus cereus (B cereus) is an aerobic or facultative anaerobic gram-positive, spore-forming bacterium. It can cause fatal disease and generally manifests as 3 distinct syndromes: food intoxication, localized infection, and systemic infection. It is a rare infection that can occur in immunocompetent persons with osteolytic and high-titer anti-IFN-γ autoantibodies. PATIENT CONCERNS: We reported a case of an HIV-negative 24-year old man with an interrupted fever and a 20-day history of progressive ache in the right thigh and high-titer anti-IFN-γ autoantibodies. Magnetic resonance imaging, X-radiography, high-resolution computed tomography, and 3-dimensional reconstruction of the bone showed multiple lucent defects with moth-eaten destruction of the bone and cortical substance of bone in the right femur. Emission CT showed significantly increased uptake in the femur. DIAGNOSIS AND INTERVENTIONS: The patient was originally misdiagnosed with osteosarcoma; acute osteomyelitis was also considered. He received intravenous piperacillin, sulbactam, and levofloxacin during hospitalization; however, he did not respond to the 3-week antibiotic course and his condition worsened. After cultures from incisional biopsy specimens were obtained from the femoral cavity, B cereus-induced osteomyelitis was diagnosed. He received intravenous injections of moxifloxacin 400 mg qd for 4 weeks and oral moxifloxacin 400 mg qd for 8 weeks. OUTCOMES: The patient's symptoms and signs improved. His X-radiography, HRCT, MRI, and 3-dimensional reconstruction of the bone showed absolute absorption in the right femur. However, the anti-IFN-γ autoantibody titer was still high. No recurrence was observed after 24 months of follow-up. He is still undergoing follow-up at this time. LESSONS: This is the first case involving a patient with B cereus infection showing a high titer of anti-IFN-γ autoantibodies. B cereus infection can involve the bone, leading to osteolysis in HIV-negative individuals. Although this patient was HIV-negative and had no other comorbidities, the presence of high titer anti-IFN-γ autoantibodies may be the primary reason for B cereus infection. Clinicians should pay more attention to the identification of osteolytic destruction caused by tumor and infection.


Assuntos
Anticorpos Antibacterianos/sangue , Autoanticorpos/sangue , Bacillus cereus/isolamento & purificação , Interferon gama/imunologia , Osteólise/sangue , Antibacterianos/administração & dosagem , Bacillus cereus/imunologia , Osso e Ossos/imunologia , Humanos , Masculino , Moxifloxacina/administração & dosagem , Osteólise/tratamento farmacológico , Osteólise/microbiologia , Adulto Jovem
2.
Mater Sci Eng C Mater Biol Appl ; 104: 109927, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31500038

RESUMO

Tissue engineering with scaffolds provides novel prospects for bone/cartilage damage healing. Previous studies mainly focus on the development of physical/chemical property of scaffold and their efficiency on tissue regeneration. The biocompatibility and biodegradation of scaffold have been questioned with their rapidly increased application, since the ultimate clinical application requires biological safety and efficiency of biomaterials. After scaffolds are implanted in living organisms, excessive inflammatory response and foreign body reaction may compromise tissue healing outcomes, or eventually lead to the failure of regeneration. Further, scaffolds degradation and degraded derivatives may elicit immunogenic reaction, cause environmental change, influence encapsulated drug/growth factor release and cellular activity. Hence, the understanding of the degradation characteristics of various biomaterials is required as well. Non-invasive monitoring the fate of scaffolds inside the body needs to be explored for temporally and longitudinally optical observation. The review mainly aims to provide a retrospective summary and discussion of the biocompatibility, immune response and fate of scaffold in cartilage/bone tissue engineering. The continuing development of sophisticated biocompatible and biomimetic scaffolds will eventually lead to clinical application which can improve the quality of patients' care and life.


Assuntos
Osso e Ossos/imunologia , Cartilagem/imunologia , Engenharia Tecidual/métodos , Tecidos Suporte/química , Animais , Materiais Biocompatíveis/farmacologia , Osso e Ossos/efeitos dos fármacos , Cartilagem/efeitos dos fármacos , Humanos , Sistema Imunitário/fisiologia
3.
J Immunol Res ; 2019: 4260987, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31211147

RESUMO

Bone metastases are prevalent in many common cancers such as breast, prostate, and lung cancers, and novel therapies for treating bone metastases are needed. Human immune system-engrafted models are used in immuno-oncology (IO) studies for subcutaneous cancer cell or patient-derived xenograft implantations that mimic primary tumor growth. Novel efficacy models for IO compounds on bone metastases need to be established. The study was performed using CIEA NOG (NOG) mice engrafted with human CD34+ hematopoietic stem cells (huNOG) and age-matched immunodeficient NOG mice. Bone phenotyping was performed to evaluate baseline differences. BT-474 human breast cancer cells were inoculated into the tibia bone marrow, and cancer-induced bone changes were monitored by X-ray imaging. Bone content and volume were analyzed by dual X-ray absorptiometry and microcomputed tomography. Tumor-infiltrating lymphocytes (TILs) and the expression of immune checkpoint markers were analyzed by immunohistochemistry. Bone phenotyping showed no differences in bone architecture or volume of the healthy bones in huNOG and NOG mice, but the bone marrow fat was absent in huNOG mice. Fibrotic areas were observed in the bone marrow of some huNOG mice. BT-474 tumors induced osteoblastic bone growth. Bone lesions appeared earlier and were larger, and bone mineral density was higher in huNOG mice. huNOG mice had a high number of human CD3-, CD4-, and CD8-positive T cells and CD20-positive B cells in immune-related organs. A low number of TILs and PD-1-positive cells and low PD-L1 expression were observed in the BT-474 tumors at the endpoint. This study reports characterization of the first breast cancer bone growth model in huNOG mice. BT-474 tumors represent a "cold" tumor with a low number of TILs. This model can be used for evaluating the efficacy of combination treatments of IO therapies with immune-stimulatory compounds or therapeutic approaches on bone metastatic breast cancer.


Assuntos
Desenvolvimento Ósseo , Osso e Ossos/imunologia , Osso e Ossos/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Osteoblastos/metabolismo , Animais , Biomarcadores , Desenvolvimento Ósseo/imunologia , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Linfócitos/imunologia , Linfócitos/metabolismo , Camundongos , Células Mieloides/imunologia , Células Mieloides/metabolismo , Microtomografia por Raio-X
4.
J Immunol ; 202(4): 1021-1030, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30718290

RESUMO

Calcium (Ca2+) is an important second messenger in lymphocytes and is essential in regulating various intracellular pathways that control critical cell functions. Ca2+ channels are located in the plasma membrane and intracellular membranes, facilitating Ca2+ entry into the cytoplasm. Upon Ag receptor stimulation, Ca2+ can enter the lymphocyte via the Ca2+ release-activated Ca2+ channel found in the plasma membrane. The increase of cytosolic Ca2+ modulates signaling pathways, resulting in the transcription of target genes implicated in differentiation, activation, proliferation, survival, and apoptosis of lymphocytes. Along with Ca2+ release-activated Ca2+ channels, several other channels have been found in the membranes of T and B lymphocytes contributing to key cellular events. Among them are the transient receptor potential channels, the P2X receptors, voltage-dependent Ca2+ channels, and the inositol 1,4,5-trisphosphate receptor as well as the N-methyl-d-aspartate receptors. In this article, we review the contributions of these channels to mediating Ca2+ currents that drive specific lymphocyte functions.


Assuntos
Osso e Ossos/metabolismo , Canais de Cálcio/metabolismo , Cálcio/metabolismo , Linfócitos/metabolismo , Animais , Osso e Ossos/imunologia , Canais de Cálcio/imunologia , Humanos , Linfócitos/imunologia , Receptores de Antígenos/imunologia
5.
Curr Stem Cell Res Ther ; 14(6): 474-481, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30767753

RESUMO

Aberrant or prolonged immune responses has been proved to be involved in bone homeostasis. As a component of the innate immune system, macrophages play a critical role in bone homeostasis. Conventionally, according to response to the various panel of stimuli, macrophages can be plastically classified into two major phenotypes: M1 and M2. M1 macrophages are generally proinflammatory, whereas M2 are anti-inflammatory. Although studies demonstrated that both M1 and M2 phenotypes have been implicated in various inflammatory bone diseases, their direct role in bone homeostasis remains unclear. Thus, in this review, we briefly discuss the term "osteoimmunology", which deals with the crosstalk and shared mechanisms of the bone and immune systems. In addition, we overview M1 and M2 macrophages for their role in osteoclastogenesis and osteogenesis as well as relevant signaling cascades involved.


Assuntos
Osso e Ossos/fisiologia , Homeostase , Macrófagos/fisiologia , Osteogênese , Animais , Osso e Ossos/imunologia , Osso e Ossos/metabolismo , Humanos , Transdução de Sinais
6.
Mol Immunol ; 110: 57-68, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-29191489

RESUMO

Bone metastasis is a fatal consequence of a subset of solid malignancies that fail to respond to conventional therapies. While a myriad of factors contribute to osteotropism and disseminated cell survival and outgrowth in bone, efforts to inhibit tumor cell growth in the bone-metastatic niche have largely relied on measures that disrupt the bi-directional interactions between bone resident and tumor cells. However, the targeting of isolated stromal interactions has proven ineffective to date in inhibiting bone-metastatic progression and patient mortality. Osteoimmune regulation is now emerging as a critical determinant of metastatic growth in the bone microenvironment. While this has highlighted the importance of innate immune populations in dictating the temporal development of overt bone metastases, the osteoimmunological processes that underpin tumor cell progression in bone remain severely underexplored. Along with tumor-intrinsic alterations that occur specifically within the bone microenvironment, innate osteoimmunological crosstalk poses an exciting area of future discovery and therapeutic development. Here we review current knowledge of the unique exchange that occurs between bone resident cells, innate immune populations and tumor cells that leads to the establishment of a tumor-permissive milieu.


Assuntos
Neoplasias Ósseas/secundário , Osso e Ossos/imunologia , Imunidade Inata/fisiologia , Mimetismo Molecular/fisiologia , Microambiente Tumoral/fisiologia , Animais , Neoplasias Ósseas/imunologia , Progressão da Doença , Humanos , Microambiente Tumoral/imunologia
7.
J Bone Miner Metab ; 37(1): 2-8, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30324535

RESUMO

The immune system and bone metabolism influence each other. An imbalance in the immune system, resulting in inflammatory stimuli may induce an imbalance in bone turnover via induction of osteoclast differentiation and inhibition of osteoblast differentiation, leading to various pathological conditions including osteoporosis. T-cell subsets, helper T (Th)1 and Th17, which activate the immune system, induce osteoclasts, whereas regulatory T (Treg) cells, responsible for immunosuppression, inhibit osteoclastic differentiation. In addition, inflammatory cytokines, such as the tumor necrosis factor (TNF), also cause an imbalance in bone turnover, induction of osteoclasts and inhibition of osteoblasts. Treatments targeting the immune system may regulate abnormalities in bone metabolism, while also controlling immune abnormalities. In rheumatoid arthritis (RA), a representative autoimmune disease, immune abnormality and accompanying prolongation of synovial inflammation cause bone and cartilage destruction, periarticular osteoporosis, and systemic osteoporosis. Joint damage and osteoporosis in RA occur through totally different mechanisms. Stimulation by inflammatory cytokines induces the expression of the receptor activator for nuclear factor-κB ligand (RANKL) in T cells and synovial cells, thereby inducing bone destruction due to osteoblast-independent osteoclast maturation. However, biological products targeting TNF or interleukin-6 not only control disease activity, but also inhibit joint destruction. However, these biological products are not effective for osteoporosis. Conversely, anti-RANKL antibody inhibits osteoporosis and bone destruction, but exerts no influence on RA disease activity. Such differences in therapeutic efficacy may indicate the necessity for rethinking current theories on the mechanism of bone metabolism abnormality and joint destruction. Understanding the mechanisms underlying these pathologies via commonalities existing between the immune system and the metabolic system may lead to the development of new treatments.


Assuntos
Osso e Ossos/imunologia , Articulações/imunologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/terapia , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Diferenciação Celular , Humanos , Articulações/patologia , Modelos Biológicos , Osteoclastos/patologia
8.
Biofactors ; 45(1): 69-74, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30496633

RESUMO

Resveratrol, a phytochemical, acts several cellular signaling pathways and has anti-inflammatory potentials. The purpose of this study is to research the therapeutic effect of resveratrol in collagen-induced arthritis (CIA) model in rats and whether resveratrol affects the activities of signaling pathways those are potent pathogenic actors of rheumatoid arthritis. Arthritis was induced by intradermal injection of chicken type II collagen combined with incomplete Freund's adjuvant in Wistar albino rats. One day after the onset of arthritis (day 14), resveratrol (20 mg/kg/day) was given via oral gavage, until day 29. The paws of the rats were obtained for further analysis. Tissue Wnt5a, mitogen-activated protein kinase (MAPK), Src tyrosine kinase and signal transducer, and activator of transcription-3 (STAT3) mRNA expressions were determined by real-time polymerase chain reaction. Resveratrol ameliorated the clinical and histopathological (perisynovial inflammation and cartilage-bone destruction) findings of inflammatory arthritis. The tissue mRNA expressions of Wnt5a, MAPK3, Src kinase, and STAT3 were increased in the sham group compared to the control group. Resveratrol supplement decreased their expressions. The present study shows that Src kinase, STAT3, and Wnt signaling pathway are active in the CIA model. Resveratrol inhibits these signaling pathways and ameliorates inflammatory arthritis. © 2018 BioFactors, 45(1):69-74, 2019.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Resveratrol/farmacologia , Fator de Transcrição STAT3/genética , Via de Sinalização Wnt/efeitos dos fármacos , Quinases da Família src/genética , Administração Oral , Animais , Artrite Experimental/genética , Artrite Experimental/imunologia , Artrite Experimental/patologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/imunologia , Osso e Ossos/patologia , Cartilagem/efeitos dos fármacos , Cartilagem/imunologia , Cartilagem/patologia , Esquema de Medicação , Feminino , Regulação da Expressão Gênica , Membro Posterior , Inflamação , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/imunologia , Ratos , Ratos Wistar , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/imunologia , Proteína Wnt-5a/genética , Proteína Wnt-5a/imunologia , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/imunologia
9.
Microsurgery ; 39(4): 340-348, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30556929

RESUMO

BACKGROUND: Skin is considered to be the most antigenic component of all vascularized composite allotransplantation tissues. However, no studies have used methods other than histological assessment to analyze the relative antigenicity of various components. In this study, we analyzed gene expression to investigate the relative antigenicity of each component in the transplanted limb. METHODS: Seven Brown Norway rats and 31 Lewis rats were assigned to two groups: an allograft group and a syngeneic (control) group. Brown Norway rats were used as the allogeneic donors, and Lewis rats were used as the syngeneic donors and recipients. About 13 recipients in the allograft group and 12 recipients in the control group were analyzed. Histological assessment was performed in 5 of the recipients in each group, and microRNA expression was analyzed in the remaining recipients, except for 1 recipient in the syngeneic group. RESULTS: In the allograft group, the relative microRNA-146a expression was significantly higher in skin (2.34 ± 0.44) than in muscle (1.25 ± 0.22; p = .034) and bone (1; p = .0081). In the allograft group, microRNA-155 expression was significantly higher in skin (1.91 ± 0.18) than in bone (1; p = .010). Histological assessment showed that some skin tissue in the allograft group showed evidence of severe acute rejection. CONCLUSIONS: The microRNA-146a and microRNA-155 seemed to reflect the relative antigenicity during acute rejection of transplanted limbs. Skin seemed to be more antigenic than muscle and bone in both the histological assessment and gene expression analysis.


Assuntos
Aloenxertos Compostos/imunologia , Expressão Gênica/genética , Membro Posterior/transplante , MicroRNAs/genética , Animais , Osso e Ossos/imunologia , Rejeição de Enxerto/imunologia , Membro Posterior/imunologia , Músculo Esquelético/imunologia , Ratos , Ratos Endogâmicos BN , Pele/imunologia
10.
Joint Bone Spine ; 86(1): 43-47, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29654948

RESUMO

The gut microbiome is now viewed as a tissue that interacts bidirectionally with the gastrointestinal, immune, endocrine and nervous systems, affecting the cellular responses in numerous organs. Evidence is accumulating of gut microbiome involvement in a growing number of pathophysiological processes, many of which are linked to inflammatory responses. More specifically, data acquired over the last decade point to effects of the gut microbiome on bone mass regulation and on the development of bone diseases (such as osteoporosis) and of inflammatory joint diseases characterized by bone loss. Mice lacking a gut microbiome have bone mass alteration that can be reversed by gut recolonization. Changes in the gut microbiome composition have been reported in mice with estrogen-deficiency osteoporosis and have also been found in a few studies in humans. Probiotic therapy decreases bone loss in estrogen-deficient animals. The effect of the gut microbiome on bone tissue involves complex mechanisms including modulation of CD4+T cell activation, control of osteoclastogenic cytokine production and modifications in hormone levels. This complexity may contribute to explain the discrepancies observed betwwen some studies whose results vary depending on the age, gender, genetic background and treatment duration. Further elucidation of the mechanisms involved is needed. However, the available data hold promise that gut microbiome manipulation may prove of interest in the management of bone diseases.


Assuntos
Osso e Ossos/imunologia , Microbioma Gastrointestinal/imunologia , Osteoclastos/imunologia , Osteogênese/imunologia , Osteoporose/imunologia , Animais , Osso e Ossos/microbiologia , Diferenciação Celular/imunologia , Humanos , Camundongos , Osteoporose/microbiologia , Osteoporose/fisiopatologia
11.
Immunol Res ; 66(6): 696-709, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30498956

RESUMO

Currently, it is well recognized that in the natural history of rheumatoid arthritis (RA), an at-risk phase, characterized by the development of autoimmunity, precedes the onset of clinical symptoms in a large proportion of patients. For individuals who later develop seropositive RA, this manifests as autoantibodies directed against proteins that have undergone specific post-translational modifications (PTM). These anti-PTM autoantibodies (APMA) are an important biomarker and risk factor for future RA. However, the triggers of autoimmunity remain unknown. This review summarizes data supporting the view that the transition from the at-risk stage to clinical RA is governed by a link between autoimmunity, inflammation, and dysbiosis. In particular, dysbiosis was shown to enhance the generation of PMT-peptides, create an antigenic mimicry with self-antigens, and establish the pro-inflammatory immune profile, all of which lead to the initiation of APMA production. Moreover, we present data supporting a major role of the autoimmunity-inflammation-dysbiosis axis in the development of bone damage and atherosclerosis-associated cardiovascular morbidity in at-risk RA individuals, and we describe potential mechanisms underlying these events. We believe that clarification of the mechanisms triggering the transition from a preclinical to clinical RA stage will pay the way to new prophylactic interventions that will prevent development of classified RA. Graphical abstract.


Assuntos
Artrite Reumatoide/imunologia , Autoimunidade/imunologia , Disbiose/imunologia , Inflamação/imunologia , Animais , Autoanticorpos/imunologia , Autoantígenos/imunologia , Osso e Ossos/imunologia , Humanos , Processamento de Proteína Pós-Traducional/imunologia
12.
BMC Musculoskelet Disord ; 19(1): 327, 2018 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-30205831

RESUMO

BACKGROUND: Formation of lamellar bone in non-osseus tissue is a pathological process called heterotopic ossification. It is the aim of this study to analyse the morphology and immunological status of patients with heterotopic ossification compared to individual healthy persons. METHODS: Human bone marrow and blood samples were obtained from 6 systemically healthy individuals and 4 patients during resection of heterotopic ossification from bone at hip arthroplasty. Bone was fragmented and treated with purified collagenase. Immunofluorescence surface staining was performed and analyzed with flow cytometry. Microcomputed tomography scanning was done performed at a resolution of 11 and 35 µm isometric voxel size respectively using a two different cone beam X-computer tomography systems and a microfocus X-ray tube. Subsequently the volume data was morphometrically analysed. RESULTS: The monocytes, stem cells, stroma cells and granulocytes progenitor cells were strongly reduced in the heterotopic ossification patient. Additionally a significant reduction of stromal stem cells cells and CD34 positive stem cells was observed. The frequency of NK-cells, B cells and T cells were not altered in the patients with heterotopic ossification compared to a healthy person. Micromorphometric parameters showed a lower content of mineralized bone tissue compared to normal bone. Mean trabecular thickness showed a high standard deviation, indicating a high variation in trabecular thickness, anisotropy and reducing bone strength. CONCLUSIONS: This work shows altered immunological distribution that is accompanied by a low decrease in bone volume fraction and tissue mineral density in the heterotopic ossification sample compared to normal bone. Compared to healthy subjects, this might reflect an immunological participation in the development of this entity.


Assuntos
Osso e Ossos/diagnóstico por imagem , Osso e Ossos/imunologia , Imunofluorescência , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/imunologia , Ossificação Heterotópica/diagnóstico por imagem , Ossificação Heterotópica/imunologia , Microtomografia por Raio-X , Adulto , Idoso , Biomarcadores/análise , Densidade Óssea , Osso e Ossos/patologia , Osso e Ossos/cirurgia , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Músculo Esquelético/cirurgia , Ossificação Heterotópica/patologia , Ossificação Heterotópica/cirurgia , Fenótipo
13.
Cell Immunol ; 331: 168-177, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30103869

RESUMO

Macrophages are represented in all tissues by phenotypically distinct resident populations that show great functional diversity. Macrophages generally play a protumoral role, and they are attractive targets for cancer therapy. In this study, we found that CD169+ macrophages depletion inhibited the growth of established Lewis lung carcinoma tumors in mice. Benefits must be weighed against potential adverse effects in cancer therapy. Here, we investigated the adverse effects of CD169+ macrophages depletion on bone and bone marrow in mice bearing Lewis lung carcinoma tumors. Our studies showed that depletion of CD169+ macrophages in LLC tumor-bearing mice disrupted bone homeostasis, including bone weight loss and bone mineral density decrease. Further studies revealed that bone marrow erythropoiesis was severely impaired after depletion of CD169+ macrophages in LLC tumor-bearing mice. Our findings suggest that depletion of macrophages for cancer therapy may be associated with potential adverse effects that need to be recognized, prevented, and optimally managed.


Assuntos
Medula Óssea/imunologia , Osso e Ossos/imunologia , Carcinoma Pulmonar de Lewis/imunologia , Eritropoese/imunologia , Homeostase/imunologia , Macrófagos/imunologia , Animais , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/imunologia , Medula Óssea/metabolismo , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/genética , Linhagem Celular Tumoral , Células Cultivadas , Toxina Diftérica/administração & dosagem , Toxina Diftérica/farmacologia , Eritropoese/genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/imunologia , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Homeostase/efeitos dos fármacos , Homeostase/genética , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo
14.
Immunobiology ; 223(12): 761-771, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30107932

RESUMO

Complement system is an important arm of the immune system that promotes inflammation. Complement Factor H (FH) is a critical regulator of the alternative complement pathway. Its absence causes pathology in different organs resulting in diseases such as age related macular degeneration and dense deposit disease. Recent studies suggest that the complement system plays a role in bone development and homeostasis. To determine the role of FH in bone architecture, we studied the FH knockout (fh-/-) mice. 3D reconstructions of femur from 16 week old fh-/- mice reveal significant changes, such as decreased BV/TV (4.5%, p < 0.02), trabecular number (22%, p < 0.01), tissue mineral density (16%, p < 0.04), and increased marrow area (16% p < 0.01), compared to their wild type (WT) counterparts. Kidney function and histology remained normal indicating that bone changes occurred prior to kidney dysfunction. Next we examined cultured osteoblasts and osteoclasts isolated from bone marrow. FH is expressed ubiquitously in the osteoblasts and in the cytoplasm of osteoclasts. The changes caused by absence of FH include: increase in number of osteoblasts (362%) and osteoclasts (342%), increase in RNA (180%) and protein expression of cathepsin K and increased osteoclast function (pit formation, 233%). Actin rearrangement in both osteoblasts and osteoclasts was altered, with a loss of integrity of the F-actin ring at the periphery of the osteoclasts. For the first time our studies demonstrate a direct role of FH in the maintenance of bone structure and function and is highlighted as a promising therapeutic target in bone diseases.


Assuntos
Osso e Ossos/imunologia , Osso e Ossos/metabolismo , Fator H do Complemento/imunologia , Actinas/metabolismo , Animais , Biomarcadores , Reabsorção Óssea/genética , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Fator H do Complemento/genética , Fator H do Complemento/metabolismo , Imunofluorescência , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Osteoblastos/imunologia , Osteoblastos/metabolismo , Osteoclastos/imunologia , Osteoclastos/metabolismo , Fenótipo , Microtomografia por Raio-X
15.
J Autoimmun ; 94: 70-82, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30064915

RESUMO

Genetic investigations on ancient human remains affected by rheumatological pathologies are a research field of particular interest for identifying the pathogenesis of diseases, especially those having an autoimmune background such as spondyloarthopaties (SpA). Reliable studies concerning this topic require collaboration between multiple disciplines, usually starting from paleopathologic observations up to molecular genetic screening. Here, we focused our investigation in a medieval necropolis in the Basque Country (13th-15th century, N = 163), which presents a high frequency of joint pathologies through two approaches: on the one hand, the analysis of joint manifestations for the differential diagnosis of the SpA and, on the other hand, the determination of the alleles of the HLA-B gene. The morphological analysis allowed determining that 30% of the individuals had rheumatic bone manifestations, with SpA being the most frequent (45%). The genetic analysis of individuals with and without pathologies, based on the study of the HLA-B gene, allowed finding 17 alleles for this gene, with HLA-B40, HLA-B27 and HLA-B35 being the most frequent. Although these alleles have been traditionally described as genetic markers associated to the development of SpA, in this study they were also found in individuals with other rheumatic diseases (osteoarthritis and rheumatoid arthritis) and even in individuals without pathologies. These data confirm the complexity of the relationship of the HLA-B gene variants with SpA, since it is not possible to establish a diagnosis of SpA with these variants alone. However, we suggest that allele HLA-B40, in combination with some specific rheumatic bone manifestations, facilitates the diagnosis of SpA.


Assuntos
Artrite Reumatoide/diagnóstico , Antígeno HLA-B27/genética , Antígeno HLA-B35/genética , Antígeno HLA-B40/genética , Osteoartrite/diagnóstico , Polimorfismo Genético , Espondiloartropatias/diagnóstico , Alelos , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Restos Mortais , Osso e Ossos/imunologia , Osso e Ossos/patologia , Clima , Temperatura Baixa , DNA Antigo/análise , Diagnóstico Diferencial , Feminino , Predisposição Genética para Doença , Antígeno HLA-B27/imunologia , Antígeno HLA-B35/imunologia , Antígeno HLA-B40/imunologia , História Medieval , Humanos , Articulações/imunologia , Articulações/patologia , Masculino , Osteoartrite/genética , Osteoartrite/imunologia , Osteoartrite/patologia , Paleopatologia/métodos , Espanha , Espondiloartropatias/genética , Espondiloartropatias/imunologia , Espondiloartropatias/patologia
16.
Food Funct ; 9(9): 4791-4801, 2018 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-30128468

RESUMO

Milk contains various bioactive components with osteoanabolic properties. This study investigates the comparative effect of the whey-derived antioxidative (YVEEL) and angiotensin-converting enzyme inhibitory (YLLF) bioactive peptides on bone remodelling in ovariectomised (OVX) osteoporotic rat model. OVX animals were administered with antioxidative (AO) (500 µg kg-1 day-1) and angiotensin-converting enzyme inhibitory (ACE inhibitory) (50 µg kg-1 day-1) peptides for eight weeks. Trabecular microarchitectural parameters of femoral and tibiae bone were determined using micro-CT scan. Bone formation, resorption, turnover markers (ALP, RANKL, OCN) and inflammatory cytokines (TNF-α, TGF-ß, IFN-γ) were determined by ELISA. Both AO and ACE inhibitory peptides inhibited the increase in bone turnover and inflammatory cytokines while increased the bone formation markers. The altered morphometric parameters of femoral and tibiae bones due to OVX were strikingly attenuated by the peptide administration. The results indicated that AO peptide exerts more osteoprotective potential than ACE inhibitory peptide by suppressing inflammatory status and enhancing bone formation markers.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Suplementos Nutricionais , Oligopeptídeos/uso terapêutico , Osteoporose Pós-Menopausa/prevenção & controle , Fragmentos de Peptídeos/uso terapêutico , Proteínas do Soro do Leite/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides , Antioxidantes/química , Antioxidantes/uso terapêutico , Biomarcadores/sangue , Conservadores da Densidade Óssea/química , Remodelação Óssea , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/imunologia , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/imunologia , Feminino , Humanos , Mediadores da Inflamação/sangue , Oligopeptídeos/química , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/diagnóstico por imagem , Osteoporose Pós-Menopausa/imunologia , Ovariectomia/efeitos adversos , Fragmentos de Peptídeos/química , Distribuição Aleatória , Ratos Wistar , Tomografia Computadorizada por Raios X , Proteínas do Soro do Leite/química
17.
J Immunol ; 200(12): 3871-3880, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29866769

RESUMO

Staphylococcus aureus causes a wide range of diseases that together embody a significant public health burden. Aided by metabolic flexibility and a large virulence repertoire, S. aureus has the remarkable ability to hematogenously disseminate and infect various tissues, including skin, lung, heart, and bone, among others. The hallmark lesions of invasive staphylococcal infections, abscesses, simultaneously denote the powerful innate immune responses to tissue invasion as well as the ability of staphylococci to persist within these lesions. In this article, we review the innate immune responses to S. aureus during infection of skin and bone, which serve as paradigms for soft tissue and bone disease, respectively.


Assuntos
Osso e Ossos/imunologia , Osso e Ossos/microbiologia , Imunidade Inata/imunologia , Pele/imunologia , Pele/microbiologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Animais , Humanos
18.
J Immunol Res ; 2018: 8173983, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29850639

RESUMO

Following severe tissue injury, patients are exposed to various danger- and microbe-associated molecular patterns, which provoke a strong activation of the neutrophil defense system. Neutrophils trigger and modulate the initial posttraumatic inflammatory response and contribute critically to subsequent repair processes. However, severe trauma can affect central neutrophil functions, including circulation half-life, chemokinesis, phagocytosis, cytokine release, and respiratory burst. Alterations in neutrophil biology may contribute to trauma-associated complications, including immune suppression, sepsis, multiorgan dysfunction, and disturbed tissue regeneration. Furthermore, there is evidence that neutrophil actions depend on the quality of the initial stimulus, including trauma localization and severity, the micromilieu in the affected tissue, and the patient's overall inflammatory status. In the present review, we describe the effects of severe trauma on the neutrophil phenotype and dysfunction and the consequences for tissue repair. We particularly concentrate on the role of neutrophils in wound healing, lung injury, and bone fractures, because these are the most frequently affected tissues in severely injured patients.


Assuntos
Osso e Ossos/imunologia , Fraturas Ósseas/imunologia , Pulmão/imunologia , Neutrófilos/imunologia , Sepse/imunologia , Pele/imunologia , Ferimentos e Lesões/imunologia , Animais , Osso e Ossos/patologia , Citocinas/metabolismo , Humanos , Pulmão/patologia , Ativação de Neutrófilo , Estresse Oxidativo , Fagocitose , Pele/patologia , Cicatrização
19.
Arthritis Res Ther ; 20(1): 80, 2018 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-29720243

RESUMO

BACKGROUND: Osteoclast-mediated bone erosion is a central feature of rheumatoid arthritis (RA). Immune complexes, present in a large percentage of patients, bind to Fcγ receptors (FcγRs), thereby modulating the activity of immune cells. In this study, we investigated the contribution of FcγRs, and FcγRIV in particular, during antigen-induced arthritis (AIA). METHODS: AIA was induced in knee joints of wild-type (WT), FcγRI,II,III-/-, and FcγRI,II,III,IV-/- mice. Bone destruction, numbers of tartrate-resistant acid phosphatase-positive (TRAP+) osteoclasts, and inflammation were evaluated using histology; expression of the macrophage marker F4/80, neutrophil marker NIMPR14, and alarmin S100A8 was evaluated using immunohistochemistry. The percentage of osteoclast precursors in the bone marrow was determined using flow cytometry. In vitro osteoclastogenesis was evaluated with TRAP staining, and gene expression was assessed using real-time PCR. RESULTS: FcγRI,II,III,IV-/- mice showed decreased bone erosion compared with WT mice during AIA, whereas both the humoral and cellular immune responses against methylated bovine serum albumin were not impaired in FcγRI,II,III,IV-/- mice. The percentage of osteoclast precursors in the bone marrow of arthritic mice and their ability to differentiate into osteoclasts in vitro were comparable between FcγRI,II,III,IV-/- and WT mice. In line with these observations, numbers of TRAP+ osteoclasts on the bone surface during AIA were comparable between the two groups. Inflammation, a process that strongly activates osteoclast activity, was reduced in FcγRI,II,III,IV-/- mice, and of note, mainly decreased numbers of neutrophils were present in the joint. In contrast to FcγRI,II,III,IV-/- mice, AIA induction in knee joints of FcγRI,II,III-/- mice resulted in increased bone erosion, inflammation, and numbers of neutrophils, suggesting a crucial role for FcγRIV in the joint pathology by the recruitment of neutrophils. Finally, significant correlations were found between bone erosion and the number of neutrophils present in the joint as well as between bone erosion and the number of S100A8-positive cells, with S100A8 being an alarmin strongly produced by neutrophils that stimulates osteoclast resorbing activity. CONCLUSIONS: FcγRs play a crucial role in the development of bone erosion during AIA by inducing inflammation. In particular, FcγRIV mediates bone erosion in AIA by inducing the influx of S100A8/A9-producing neutrophils into the arthritic joint.


Assuntos
Artrite Experimental/imunologia , Osso e Ossos/imunologia , Calgranulina A/imunologia , Calgranulina B/imunologia , Neutrófilos/imunologia , Receptores de IgG/imunologia , Animais , Artrite Experimental/genética , Artrite Experimental/metabolismo , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Calgranulina A/metabolismo , Calgranulina B/metabolismo , Articulação do Joelho/imunologia , Articulação do Joelho/metabolismo , Articulação do Joelho/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/metabolismo , Osteoclastos/imunologia , Osteoclastos/metabolismo , Receptores de IgG/genética , Receptores de IgG/metabolismo , Fosfatase Ácida Resistente a Tartarato/imunologia , Fosfatase Ácida Resistente a Tartarato/metabolismo
20.
Arthritis Rheumatol ; 70(11): 1745-1756, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29750395

RESUMO

OBJECTIVE: It has been reported that ADAMTS-12 is a susceptibility gene for rheumatoid arthritis (RA) development, and its level is significantly increased in RA patients. In addition, ADAMTS-12 is reported to be required for inflammation in otherwise healthy subjects. This study was undertaken to determine the role of ADAMTS-12 and the underlying mechanisms in the pathogenesis of inflammatory arthritis. METHODS: The collagen-induced arthritis (CIA) model was established in ADAMTS-12-deficient mice and their control littermates to determine the role of ADAMTS-12 in vivo. Micro-computed tomography scanning was used to demonstrate the destruction of the ankle joint; histologic analysis illustrated synovitis, pannus formation, and bone and cartilage destruction; enzyme-linked immunosorbent assay was performed to measure serum levels of inflammatory cytokines; and protein-protein interaction assays were performed to detect the interactions of ADAMTS-12 and its various deletion mutants with connective tissue growth factor (CTGF). RESULTS: Deficiency of ADAMTS-12 led to accelerated inflammatory arthritis in the CIA mouse model. Loss of ADAMTS-12 caused enhanced osteoclastogenesis. In vitro and in vivo protein-protein interaction assays demonstrated that ADAMTS-12 bound and processed CTGF, a previously unrecognized substrate of ADAMTS-12. In addition, deletion of ADAMTS-12 enhanced, while overexpression of ADMATS-12 reduced, CTGF-mediated inflammation. Furthermore, ADAMTS-12 regulation of inflammation was largely lost in CTGF-deficient macrophages. Importantly, blocking of CTGF attenuated elevated inflammatory arthritis seen in the ADAMTS-12-deficient CIA mouse model. CONCLUSION: This study provides evidence that ADAMTS-12 is a critical regulator of inflammatory arthritis and that this is mediated, at least in part, through control of CTGF turnover.


Assuntos
Proteínas ADAMTS/genética , Artrite Experimental/genética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Citocinas/imunologia , Proteínas ADAMTS/imunologia , Proteínas ADAMTS/metabolismo , Animais , Artrite Experimental/diagnóstico por imagem , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/imunologia , Osso e Ossos/metabolismo , Cartilagem Articular/diagnóstico por imagem , Cartilagem Articular/imunologia , Cartilagem Articular/metabolismo , Ensaio de Imunoadsorção Enzimática , Articulações/diagnóstico por imagem , Articulações/imunologia , Articulações/metabolismo , Camundongos , Camundongos Knockout , Mapas de Interação de Proteínas , Sinovite/diagnóstico por imagem , Sinovite/genética , Sinovite/imunologia , Sinovite/metabolismo , Tarso Animal/diagnóstico por imagem , Tarso Animal/metabolismo , Microtomografia por Raio-X
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