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1.
Intern Med ; 58(14): 2101-2105, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30918176

RESUMO

A 43-year-old man with malignant lymphoma who had been treated with the cyclosphamide, vincrstine, procarbazine, and prednisolone (C-MOPP) regimen was admitted to our hospital with skin eruption. He was diagnosed to have varicella, and treatment with acyclovir and immune globulin was started. Chest computed tomography revealed multiple nodules in the both lung fields. Diagnostic thoracoscopic lung biopsy specimens revealed granuloma formation, and polymerase chain reaction testing revealed the presence of varicella-zoster virus DNA in the granulomatous tissue. It was unusual for the lung nodule in varicella pneumonia to increase in size over time in a patient who had undergone antiviral therapy, while also demonstrating multiple granulomas.


Assuntos
Granuloma/genética , Granuloma/virologia , Pneumonia/patologia , Pneumonia/virologia , Infecção pelo Vírus da Varicela-Zoster/complicações , Infecção pelo Vírus da Varicela-Zoster/tratamento farmacológico , Infecção pelo Vírus da Varicela-Zoster/genética , Aciclovir/uso terapêutico , Adulto , Antivirais/uso terapêutico , Ciclofosfamida/uso terapêutico , DNA Viral/isolamento & purificação , Humanos , Masculino , Pneumonia/etiologia , Reação em Cadeia da Polimerase , Prednisolona/uso terapêutico , Procarbazina/uso terapêutico , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Infecção pelo Vírus da Varicela-Zoster/diagnóstico , Vincristina/uso terapêutico
2.
Clin Immunol ; 200: 55-63, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30639167

RESUMO

Ataxia-Telangiectasia (AT) is an immunodeficiency most often associated with T cell abnormalities. We describe a patient with a hyper-IgM phenotype and immune cell abnormalities that suggest a distinct clinical phenotype. Significant B cell abnormalities with increased unswitched memory B cells, decreased naive transitional B cells, and an elevated frequency of CD19+CD38loCD27-CD10-CD21-/low B cells expressing high levels of T-bet and Fas were demonstrated. The B cells were hyporesponsive to in vitro stimulation through the B cell receptor, Toll like receptors (TLR) 7 and 9, and CD40. T cell homeostasis was also disturbed with a significant increase in γδ T cells, circulating T follicular helper cells (Tfh), and decreased numbers of T regulatory cells. The ATM mutations in this patient are posited to have resulted in the perturbations in the frequencies and distributions of B and T cell subsets, resulting in the phenotype in this patient. KEY MESSAGES: A novel mutation creating a premature stop codon and a nonsense mutation in the ATM gene are postulated to have resulted in the unique clinical picture characterized by abnormal B and T cell populations, lymphocyte subset dysfunction, granuloma formation, and a hyper-IgM phenotype. CAPSULE SUMMARY: A patient presented with ataxia-telangiectasia, cutaneous granulomas, and a hyper-IgM phenotype; a novel combination of mutations in the ATM gene was associated with abnormal distributions, frequencies, and function of T and B lymphocyte subsets.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/genética , Subpopulações de Linfócitos B/imunologia , Granuloma/genética , Síndrome de Imunodeficiência com Hiper-IgM/genética , Dermatopatias/genética , Subpopulações de Linfócitos T/imunologia , Ataxia Telangiectasia/imunologia , Linfócitos B/imunologia , Pré-Escolar , Códon sem Sentido , Feminino , Granuloma/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Síndrome de Imunodeficiência com Hiper-IgM/imunologia , Memória Imunológica , Análise de Sequência de DNA , Dermatopatias/imunologia , Linfócitos T/imunologia
3.
J Clin Immunol ; 39(1): 81-89, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30607663

RESUMO

The association of immunodeficiency-related vaccine-derived rubella virus (iVDRV) with cutaneous and visceral granulomatous disease has been reported in patients with primary immunodeficiency disorders (PIDs). The majority of these PID patients with rubella-positive granulomas had DNA repair disorders. To support this line of inquiry, we provide additional descriptive data on seven previously reported patients with Nijmegen breakage syndrome (NBS) (n = 3) and ataxia telangiectasia (AT) (n = 4) as well as eight previously unreported patients with iVDRV-induced cutaneous granulomas and DNA repair disorders including NBS (n = 1), AT (n = 5), DNA ligase 4 deficiency (n = 1), and Artemis deficiency (n = 1). We also provide descriptive data on several previously unreported PID patients with iVDRV-induced cutaneous granulomas including cartilage hair hypoplasia (n = 1), warts, hypogammaglobulinemia, immunodeficiency, myelokathexis (WHIM) syndrome (n = 1), MHC class II deficiency (n = 1), Coronin-1A deficiency (n = 1), X-linked severe combined immunodeficiency (X-SCID) (n = 1), and combined immunodeficiency without a molecular diagnosis (n = 1). At the time of this report, the median age of the patients with skin granulomas and DNA repair disorders was 9 years (range 3-18). Cutaneous granulomas have been documented in all, while visceral granulomas were observed in six cases (40%). All patients had received rubella virus vaccine. The median duration of time elapsed from vaccination to the development of cutaneous granulomas was 48 months (range 2-152). Hematopoietic cell transplantation was reported to result in scarring resolution of cutaneous granulomas in two patients with NBS, one patient with AT, one patient with Artemis deficiency, one patient with DNA Ligase 4 deficiency, one patient with MHC class II deficiency, and one patient with combined immunodeficiency without a known molecular etiology. Of the previously reported and unreported cases, the majority share the diagnosis of a DNA repair disorder. Analysis of additional patients with this complication may clarify determinants of rubella pathogenesis, identify specific immune defects resulting in chronic infection, and may lead to defect-specific therapies.


Assuntos
Reparo do DNA/genética , Granuloma/complicações , Granuloma/virologia , Síndromes de Imunodeficiência/complicações , Vírus da Rubéola/patogenicidade , Dermatopatias/etiologia , Dermatopatias/virologia , Adolescente , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/virologia , Criança , Pré-Escolar , Feminino , Granuloma/genética , Cabelo/anormalidades , Cabelo/virologia , Transplante de Células-Tronco Hematopoéticas/métodos , Doença de Hirschsprung/genética , Doença de Hirschsprung/virologia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/virologia , Masculino , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/virologia , Osteocondrodisplasias/congênito , Osteocondrodisplasias/genética , Osteocondrodisplasias/virologia , Rubéola (Sarampo Alemão)/genética , Rubéola (Sarampo Alemão)/virologia , Pele/virologia , Dermatopatias/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/virologia
4.
Basic Clin Pharmacol Toxicol ; 124(2): 211-227, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30168672

RESUMO

Multi-walled carbon nanotubes (MWCNT) are widely used nanomaterials that cause pulmonary toxicity upon inhalation. The physicochemical properties of MWCNT vary greatly, which makes general safety evaluation challenging to conduct. Identification of the toxicity-inducing physicochemical properties of MWCNT is therefore of great importance. We have evaluated histological changes in lung tissue 1 year after a single intratracheal instillation of 11 well-characterized MWCNT in female C57BL/6N BomTac mice. Genotoxicity in liver and spleen was evaluated by the comet assay. The dose of 54 µg MWCNT corresponds to three times the estimated dose accumulated during a work life at a NIOSH recommended exposure limit (0.001 mg/m3 ). Short and thin MWCNT were observed as agglomerates in lung tissue 1 year after exposure, whereas thicker and longer MWCNT were detected as single fibres, suggesting biopersistence of both types of MWCNT. The thin and entangled MWCNT induced varying degree of pulmonary inflammation, in terms of lymphocytic aggregates, granulomas and macrophage infiltration, whereas two thick and straight MWCNT did not. By multiple regression analysis, larger diameter and higher content of iron predicted less histopathological changes, whereas higher cobalt content significantly predicted more histopathological changes. No MWCNT-related fibrosis or tumours in the lungs or pleura was found. One thin and entangled MWCNT induced increased levels of DNA strand breaks in liver; however, no physicochemical properties could be related to genotoxicity. This study reveals physicochemical-dependent difference in MWCNT-induced long-term, pulmonary histopathological changes. Identification of diameter size and cobalt content as important for MWCNT toxicity provides clues for designing MWCNT, which cause reduced human health effects following pulmonary exposure.


Assuntos
Pulmão/efeitos dos fármacos , Nanotubos de Carbono/toxicidade , Pneumonia/induzido quimicamente , Amiloide/biossíntese , Animais , Comportamento Animal/efeitos dos fármacos , DNA/genética , Dano ao DNA , Feminino , Granuloma/sangue , Granuloma/induzido quimicamente , Granuloma/genética , Granuloma/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Testes de Mutagenicidade , Pneumonia/sangue , Pneumonia/genética , Pneumonia/patologia , Baço/efeitos dos fármacos , Baço/patologia
5.
Am J Respir Cell Mol Biol ; 60(1): 84-95, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30134122

RESUMO

The mechanisms underlying abnormal granuloma formation in patients with sarcoidosis are complex and remain poorly understood. A novel in vitro human granuloma model was used to determine the molecular mechanisms of granuloma genesis in patients with sarcoidosis in response to putative disease-causing mycobacterial antigens. Peripheral blood mononuclear cells (PBMCs) from patients with active sarcoidosis and from normal, disease-free control subjects were incubated for 7 days with purified protein derivative-coated polystyrene beads. Molecular responses, as reflected by differential expression of genes, extracellular cytokine patterns, and cell surface receptor expression, were analyzed. Unbiased systems biology approaches were used to identify signaling pathways engaged during granuloma formation. Model findings were compared with human lung and mediastinal lymph node gene expression profiles. Compared with identically treated PBMCs of control subjects (n = 5), purified protein derivative-treated sarcoidosis PBMCs (n = 6) were distinguished by the formation of cellular aggregates resembling granulomas. Ingenuity Pathway Analysis of differential expression gene patterns identified molecular pathways that are primarily regulated by IL-13, which promotes alternatively activated (M2) macrophage polarization. M2 polarization was further demonstrated by immunohistochemistry performed on the in vitro sarcoidosis granuloma-like structures. IL-13-regulated gene pathways were confirmed in human sarcoidosis lung and mediastinal lymph node tissues. The in vitro human sarcoidosis granuloma model provides novel insights into early granuloma formation, particularly IL-13 regulation of molecular networks that regulate M2 macrophage polarization. M2 macrophages are predisposed to aggregation and multinucleated giant cell formation, which are characteristic features of sarcoidosis granulomas. Clinical trial registered with www.clinicaltrials.gov (NCT01857401).


Assuntos
Regulação da Expressão Gênica , Granuloma/imunologia , Interleucina-13/metabolismo , Leucócitos Mononucleares/imunologia , Pulmão/imunologia , Macrófagos/imunologia , Sarcoidose Pulmonar/imunologia , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Granuloma/genética , Granuloma/metabolismo , Granuloma/patologia , Humanos , Técnicas In Vitro , Interleucina-13/genética , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Sarcoidose Pulmonar/genética , Sarcoidose Pulmonar/metabolismo , Sarcoidose Pulmonar/patologia , Transcriptoma
6.
Front Immunol ; 9: 2717, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30534124

RESUMO

Lipocalin-2 is a constituent of the neutrophil secondary granules and is expressed de novo by macrophages and epithelium in response to inflammation. Lipocalin-2 acts in a bacteriostatic fashion by binding iron-loaded siderophores required for bacterial growth. Mycobacterium tuberculosis (M.tb) produces siderophores that can be bound by lipocalin-2. The impact of lipocalin-2 in the innate immune response toward extracellular bacteria has been established whereas the effect on intracellular bacteria, such as M.tb, is less well-described. Here we show that lipocalin-2 surprisingly confers a growth advantage on M.tb in the early stages of infection (3 weeks post-challenge). Using mixed bone marrow chimeras, we demonstrate that lipocalin-2 derived from granulocytes, but not from epithelia and macrophages, leads to increased susceptibility to M.tb infection. In contrast, lipocalin-2 is not observed to promote mycobacterial growth at later stages of M.tb infection. We demonstrate co-localization of granulocytes and mycobacteria within the nascent granulomas at week 3 post-challenge, but not in the consolidated granulomas at week 5. We hypothesize that neutrophil-derived lipocalin-2 acts to supply a source of iron to M.tb in infected macrophages within the immature granuloma, thereby facilitating mycobacterial growth.


Assuntos
Granulócitos/imunologia , Granuloma/imunologia , Imunidade Inata , Lipocalina-2/imunologia , Macrófagos/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Animais , Granulócitos/patologia , Granuloma/genética , Granuloma/microbiologia , Granuloma/patologia , Lipocalina-2/genética , Macrófagos/microbiologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Tuberculose/genética , Tuberculose/patologia
7.
J Cutan Pathol ; 45(12): 940-943, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30203448

RESUMO

Cutaneous granulomas without detectable infectious etiology rarely occur in children and adults with primary immunodeficiency disorders. These cutaneous granulomas are primarily seen in combined variable immunodeficiency, ataxia-telangiectasia, and severe combined immunodeficiency (SCID) and can emulate the reaction patterns seen in sarcoidosis and granuloma annulare. To date, the literature has described only six cases of non-infectious cutaneous granulomas in SCID. We report an unusual case of cutaneous granuloma, mimicking a sarcoma, in a 40-year old male with recombinase activating gene 1-deficient SCID, who presented with a slow-growing globus mass over the lateral aspect of the right elbow. There was heterogeneous enhancement on MRI, which was concerning for neoplasm but no malignancy was found on frozen or permanent sections. GMS, PAS with diastase, and AFB stains, as well as microbiology cultures, were negative. An AE1/AE3 stain was negative and a CD163 stain highlighted histiocytes. No infectious etiology was identified and histopathology revealed palisaded granulomatous dermatitis, most closely resembling a rheumatoid nodule. Although cutaneous manifestations have been reported in nearly half of primary immunodeficiency disorder cases, non-infectious cutaneous granulomas are exceedingly rare in SCID. To our knowledge, this is the first case report of cutaneous palisaded granulomatous dermatitis mimicking a rheumatoid nodule in a major joint.


Assuntos
Dermatite , Granuloma , Proteínas de Homeodomínio/genética , Nódulo Reumatoide , Imunodeficiência Combinada Severa , Adulto , Dermatite/genética , Dermatite/metabolismo , Dermatite/patologia , Granuloma/genética , Granuloma/metabolismo , Granuloma/patologia , Humanos , Masculino , Nódulo Reumatoide/genética , Nódulo Reumatoide/metabolismo , Nódulo Reumatoide/patologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/metabolismo , Imunodeficiência Combinada Severa/patologia
8.
J Pathol ; 246(3): 300-310, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30062795

RESUMO

Metastasis is the leading cause of death in cancer patients, and successful colonisation of a secondary organ by circulating tumour cells (CTCs) is the rate-limiting step of this process. We used tail-vein injection of B16-F10 melanoma cells into mice to mimic the presence of CTCs and to allow for the assessment of host (microenvironmental) factors that regulate pulmonary metastatic colonisation. We found that mice deficient for the individual subunits of the NADPH oxidase of myeloid cells, NOX2 (encoded by Cyba, Cybb, Ncf1, Ncf2, and Ncf4), all showed decreased pulmonary metastatic colonisation. To understand the role of NOX2 in controlling tumour cell survival in the pulmonary microenvironment, we focused on Cyba-deficient (Cybatm1a ) mice, which showed the most significant decrease in metastatic colonisation. Interestingly, histological assessment of pulmonary metastatic colonisation was not possible in Cybatm1a mice, owing to the presence of large granulomas composed of galectin-3 (Mac-2)-positive macrophages and eosinophilic deposits; granulomas of variable penetrance and severity were also found in Cybatm1a mice that were not injected with melanoma cells, and these contributed to their decreased survival. The decreased pulmonary metastatic colonisation of Cybatm1a mice was not due to any overt defects in vascular permeability, and bone marrow chimaeras confirmed a role for the haematological system in the reduced metastatic colonisation phenotype. Examination of the lymphocyte populations, which are known key regulators of metastatic colonisation, revealed an enhanced proportion of activated T and natural killer cells in the lungs of Cybatm1a mice, relative to controls. The reduced metastatic colonisation, presence of granulomas and altered immune cell populations observed in Cybatm1a lungs were mirrored in Ncf2-deficient (Ncf2tm1a ) mice. Thus, we show that NOX2 deficiency results in both granulomas and the accumulation of antitumoural immune cells in the lungs that probably mediate the decreased pulmonary metastatic colonisation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Movimento Celular , Grupo dos Citocromos b/deficiência , Granuloma/patologia , Neoplasias Pulmonares/secundário , Melanoma Experimental/secundário , NADPH Oxidase 2/deficiência , NADPH Oxidases/deficiência , Células Neoplásicas Circulantes/patologia , Animais , Linhagem Celular Tumoral , Grupo dos Citocromos b/genética , Granuloma/enzimologia , Granuloma/genética , Granuloma/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Melanoma Experimental/enzimologia , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Camundongos Knockout , NADPH Oxidase 2/genética , NADPH Oxidases/genética , Invasividade Neoplásica , Células Neoplásicas Circulantes/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Microambiente Tumoral
9.
Clin Immunol ; 197: 1-5, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30121298

RESUMO

V(D)J recombination, during which recognition and repair of broken DNA chains are accomplished by non-homologous end joining pathway, is a critical process in B and T cell development.Null mutations of each enzyme or protein of this pathway result in T- B- NK+ severe combined immunodeficiency whereas hypomorphic mutations result in atypical(leaky)severe combined immunodeficiency forms. We present two siblings with PRKDC (Protein Kinase, DNA-Activated, Catalytic Polypeptide) mutation who presented with granulomatous skin lesions and recurrent lung infections. Primary immune deficiencies may initially present with skin findings. Disruption in central and peripheral B-cell tolerance and impaired intrathymic T-cell maturation,a central player in T-cell tolerance, have been identified as the mechanism of autoimmunity and granuloma seen in patients. The variation in clinical phenotypes of patients with PRKDC mutation suggests that additional factors such as modifying genes, epigenetic and environmental factors may affect the severity and clinical phenotype of the disease. Functional studies during the follow-up and evaluation before and after hematopoeitic stem cell transplantation will hopefully increase our knowledge about the autoimmune and inflammatory process of the disease spectrum.


Assuntos
Proteína Quinase Ativada por DNA/genética , Granuloma/genética , Histiocitose de Células não Langerhans/genética , Proteínas Nucleares/genética , Imunodeficiência Combinada Severa/genética , Dermatopatias/genética , Pré-Escolar , Feminino , Granuloma/imunologia , Granuloma/patologia , Transplante de Células-Tronco Hematopoéticas , Histiocitose de Células não Langerhans/imunologia , Histiocitose de Células não Langerhans/patologia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Lactente , Recém-Nascido , Pneumonia Bacteriana/genética , Pneumonia Bacteriana/imunologia , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Imunodeficiência Combinada Severa/terapia , Irmãos , Dermatopatias/imunologia , Dermatopatias/patologia
10.
J Bone Miner Res ; 33(11): 2071-2080, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29933504

RESUMO

Pediatric granulomatous arthritis (PGA) refers to two formerly separate entities: autosomal dominant Blau syndrome (BS) and its sporadic phenocopy early-onset sarcoidosis (EOS). In 2001 BS and in 2005 EOS became explained by heterozygous mutations within the gene that encodes nucleotide-binding oligomerization domain-containing protein 2 (NOD2), also called caspase recruitment domain-containing protein 15 (CARD15). NOD2 is a microbe sensor in leukocyte cytosol that activates and regulates inflammation. PGA is characterized by a triad of autoinflammatory problems (dermatitis, uveitis, and arthritis) in early childhood, which suggests the causal NOD2/CARD15 mutations are activating defects. Additional complications of PGA were recognized especially when NOD2 mutation analysis became generally available. However, in PGA, hypercalcemia is only briefly mentioned, and generalized osteosclerosis is not reported, although NOD2 regulates NF-κB signaling essential for osteoclastogenesis and osteoclast function. Herein, we report a 4-year-old girl with PGA uniquely complicated by severe 1,25(OH)2 D-mediated hypercalcemia, nephrocalcinosis, and compromised renal function together with radiological and histopathological features of osteopetrosis (OPT). The classic triad of PGA complications was absent, although joint pain and an antalgic gait accompanied wrist, knee, and ankle swelling and soft non-tender masses over her hands, knees, and feet. MRI revealed tenosynovitis in her hands and suprapatellar effusions. Synovial biopsy demonstrated reactive synovitis without granulomas. Spontaneous resolution of metaphyseal osteosclerosis occurred while biochemical markers indicated active bone turnover. Anti-inflammatory medications suppressed circulating 1,25(OH)2 D, corrected the hypercalcemia, and improved her renal function, joint pain and swelling, and gait. Mutation analysis excluded idiopathic infantile hypercalcemia, type 1, and known forms of OPT, and identified a heterozygous germline missense mutation in NOD2 common in PGA (c.1001G>A, p.Arg334Gln). Thus, radiological and histological findings of OPT and severe hypercalcemia from apparent extrarenal production of 1,25(OH)2 D can complicate NOD2-associated PGA. Although the skeletal findings seem inconsequential, treatment of the hypercalcemia is crucial to protect the kidneys. © 2018 American Society for Bone and Mineral Research.


Assuntos
Artrite/genética , Granuloma/complicações , Granuloma/genética , Hipercalcemia/complicações , Mutação/genética , Proteína Adaptadora de Sinalização NOD2/genética , Osteosclerose/complicações , Vitamina D/análogos & derivados , Sequência de Aminoácidos , Artrite/complicações , Artrite/diagnóstico por imagem , Sequência de Bases , Medula Óssea/diagnóstico por imagem , Medula Óssea/patologia , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Pré-Escolar , Análise Mutacional de DNA , Feminino , Granuloma/diagnóstico por imagem , Humanos , Hipercalcemia/diagnóstico por imagem , Proteína Adaptadora de Sinalização NOD2/química , Osteosclerose/diagnóstico por imagem , Membrana Sinovial/patologia , Vitamina D/efeitos adversos
11.
Biochem Biophys Res Commun ; 503(2): 684-690, 2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-29908181

RESUMO

Peroxisome proliferator activated receptor gamma (PPARγ), a ligand activated nuclear transcription factor, is constitutively expressed in alveolar macrophages of healthy individuals. PPARγ deficiencies have been noted in several lung diseases including the alveolar macrophages of pulmonary sarcoidosis patients. We have previously described a murine model of multiwall carbon nanotubes (MWCNT) induced pulmonary granulomatous inflammation which bears striking similarities to pulmonary sarcoidosis, including the deficiency of alveolar macrophage PPARγ. Further studies demonstrate alveolar macrophage PPARγ deficiency exacerbates MWCNT-induced pulmonary granulomas. Based on these observations we hypothesized that activation of PPARγ via administration of the PPARγ-specific ligand rosiglitazone would limit MWCNT-induced granuloma formation and promote PPARγ-dependent pathways. Results presented here show that rosiglitazone significantly limits the frequency and severity of MWCNT-induced pulmonary granulomas. Furthermore, rosiglitazone attenuates alveolar macrophage NF-κB activity and downregulates the expression of the pro-inflammatory mediators, CCL2 and osteopontin. PPARγ activation via rosiglitazone also prevents the MWCNT-induced deficiency of PPARγ-regulated ATP-binding cassette lipid transporter-G1 (ABCG1) expression. ABCG1 is crucial to pulmonary lipid homeostasis. ABCG1 deficiency results in lipid accumulation which promotes pro-inflammatory macrophage activation. Our results indicate that restoration of homeostatic ABCG1 levels by rosiglitazone correlates with both reduced pulmonary lipid accumulation, and decreased alveolar macrophage activation. These data confirm and further support our previous observations that PPARγ pathways are critical in regulating MWCNT-induced pulmonary granulomatous inflammation.


Assuntos
Granuloma/patologia , Pneumopatias/patologia , Pulmão/patologia , PPAR gama/metabolismo , Sarcoidose/patologia , Transdução de Sinais , Animais , Modelos Animais de Doenças , Dislipidemias/etiologia , Dislipidemias/genética , Dislipidemias/metabolismo , Dislipidemias/patologia , Regulação da Expressão Gênica , Granuloma/etiologia , Granuloma/genética , Granuloma/metabolismo , Pulmão/metabolismo , Pneumopatias/etiologia , Pneumopatias/genética , Pneumopatias/metabolismo , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Camundongos Endogâmicos C57BL , Nanotubos de Carbono/efeitos adversos , PPAR gama/agonistas , Sarcoidose/etiologia , Sarcoidose/genética , Sarcoidose/metabolismo
12.
J Autoimmun ; 87: 82-96, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29310925

RESUMO

Sarcoidosis, a multisystem granulomatous disorder, has historically been classified as Th1-driven disease. However, increasing data demonstrate a key role of Th17-cell plasticity in granuloma formation and maintenance. In Löfgren's syndrome (LS), an acute and distinct phenotype of sarcoidosis with a favorable outcome, differences in Th17-lineage cell subsets, cytokine expression and T-cell suppressive mechanisms may account for differences in clinical presentation as well as prognosis compared to non-LS sarcoidosis. In contrast with LS, up to 20% of non-LS sarcoidosis patients may progress to irreversible pulmonary fibrosis. In non-LS sarcoidosis patients, IFN-γ-producing Th17.1-cells appear to be more pathogenic and possibly linked to disease progression, while a broader range of cytokines is found in bronchoalveolar lavage fluid (BALF) in LS patients. Differences in Cytotoxic T-lymphocyte antigen 4 (CTLA-4) expression on Th17-cells and regulatory T-cells (Treg) could contribute to Th17-cell pathogenicity and consequently to either disease resolution or ongoing inflammation in sarcoidosis. Furthermore, several genes and SNPs are associated with disease susceptibility and outcome in sarcoidosis, the majority of which are involved in antigen presentation, T-cell activation or regulation of T-cell survival. Novel insights into the role of Th17-cells in the pathogenesis of both LS and non-LS sarcoidosis will unravel pathogenic and benign Th17-lineage cell function and drivers of Th17-cell plasticity. This will also help identify new treatment strategies for LS and non-LS sarcoidosis patients by altering Th17-cell activation, suppress conversion into more pathogenic subtypes, or influence cytokine signaling towards a beneficial signature of Th17-lineage cells. In this review, we summarize new insights into Th17-cell plasticity in the complex pathogenesis of sarcoidosis and connect these cells to the different disease phenotypes, discuss the role of genetic susceptibility and autoimmunity and focus on possible treatment strategies.


Assuntos
Plasticidade Celular , Granuloma/imunologia , Sarcoidose Pulmonar/imunologia , Subpopulações de Linfócitos T/imunologia , Células Th17/imunologia , Animais , Diferenciação Celular , Linhagem da Célula , Autorrenovação Celular/genética , Predisposição Genética para Doença , Granuloma/genética , Humanos , Ativação Linfocitária/genética , Camundongos , Polimorfismo de Nucleotídeo Único , Síndrome
13.
Clin Immunol ; 187: 68-75, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29051008

RESUMO

Defects in DNA Recombination due to mutations in RAG1/2 or DCLRE1C result in combined immunodeficiency (CID) with a range of disease severity. We present the clinical, immunologic and molecular characteristics of 21 patients with defects in RAG1, RAG2 or DCLRE1C, who accounted for 24% of combined immune deficiency cases in the Kuwait National Primary Immunodeficiency Disorders Registry. The distribution of the patients was as follow: 8 with RAG1 deficiency, 6 with RAG2 deficiency and 7 with DCLRE1C deficiency. Nine patients presented with SCID, 6 with OS, 2 with leaky SCID and 4 with CID and granuloma and/or autoimmunity (CID-G/AI). Eight patients [(7 SCID and 1 OS) (38%)] received hematopoietic stem cell transplant (HSCT). The median age of HSCT was 11.5months and the median time from diagnosis to HSCT was 6months. Fifty percent of the transplanted patients are alive while only 23% of the untransplanted ones are alive.


Assuntos
Doenças Autoimunes/imunologia , Granuloma/imunologia , Imunodeficiência Combinada Severa/imunologia , Recombinação V(D)J/genética , Adolescente , Antibacterianos/uso terapêutico , Doenças Autoimunes/genética , Doenças Autoimunes/terapia , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Feminino , Perfil Genético , Granuloma/genética , Granuloma/terapia , Transplante de Células-Tronco Hematopoéticas , Proteínas de Homeodomínio/genética , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/terapia , Fatores Imunológicos/uso terapêutico , Lactente , Kuweit , Masculino , Proteínas Nucleares/genética , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/terapia
15.
Sci Rep ; 7(1): 2300, 2017 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-28536447

RESUMO

Tuberculosis, caused by Mycobacterium tuberculosis, affects the functions of the lung and causes high morbidity and mortality rates worldwide. MASP-2 is an executioner enzyme, which plays an essential role in the activation of lectin pathway. In our previous studies, the MASP-2 played a dual role in promoting the progress of lesions in BCG-infected rabbit skin models. However, the really effects of MASP-2 on tuberculosis are unknown. The aim of this study was to investigate the effects of MASP-2 in granuloma formation with BCG-infected mice. Compared to the control group, rAd-hMASP-2 treated group showed increasing in survival rate of BCG-infected mice (P = 0.042), and decreasing of bacteria loads (P = 0.005) in the lung tissue. MASP-2 displayed a protective efficacy in BCG-infected mice, which promoted the activation and recruitment of macrophages and lymphocytes to the granuloma. Moreover, the data obtained from the ELISA and RT-PCR demonstrated that mRNA expression for IL-6, CCL12, CCL2 and cytokines of IFN-γ, TNF-α in lung were significantly elevated by treatment of rAd-hMASP-2. Those findings provided an evidence that MASP-2 may be as a newly immunomodulatory in targeting granuloma formation, which displayed a potential protective role in control of tuberculosis.


Assuntos
Granuloma/genética , Serina Proteases Associadas a Proteína de Ligação a Manose/genética , Mycobacterium bovis/fisiologia , Tuberculose/microbiologia , Adenoviridae/genética , Animais , Terapia Genética/métodos , Vetores Genéticos/genética , Granuloma/etiologia , Granuloma/terapia , Humanos , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Serina Proteases Associadas a Proteína de Ligação a Manose/metabolismo , Camundongos Endogâmicos BALB C , Análise de Sobrevida , Tuberculose/complicações , Tuberculose/veterinária
16.
Sci Rep ; 7(1): 2343, 2017 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-28539607

RESUMO

Liver granulomatous inflammation and fibrosis were the primary pathological changes observed during Schistosoma japonicum (S. japonicum) infection. In the present study, the characteristics of IL-9 were investigated in the liver of S. japonicum infection C57BL/6 mice. Immunofluorescence, qRT-PCR, and ELISA results demonstrated that the expression of IL-9 significantly increased after infection (P < 0.01). FACS results indicated that the peak of IL-9+ Th9 cells in the liver mononuclear cells appeared at the early phase of infection (week 5), except that Th9 cells, CD8+ Tc cells, NKT and γδT cells could secrete IL-9 in this model. Although IL-9 neutralization has a limited effect on liver granulomatous inflammation, it could decrease the level of fibrosis-associated factor, PC-III, in the serum of infected mice (P < 0.05). Taken together, our results indicated that IL-9 was an important type of cytokine involved in the progression of S. japonicum infection-induced hepatic damage.


Assuntos
Interleucina-9/genética , Fígado/metabolismo , Fígado/parasitologia , Schistosoma japonicum/fisiologia , Esquistossomose Japônica/parasitologia , Animais , Células Cultivadas , Feminino , Expressão Gênica , Granuloma/genética , Granuloma/metabolismo , Granuloma/parasitologia , Interações Hospedeiro-Parasita , Inflamação/genética , Inflamação/metabolismo , Inflamação/parasitologia , Interleucina-9/sangue , Interleucina-9/metabolismo , Fígado/patologia , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/parasitologia , Linfócitos/metabolismo , Linfócitos/parasitologia , Camundongos Endogâmicos C57BL , Esquistossomose Japônica/genética , Esquistossomose Japônica/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Auxiliares-Indutores/parasitologia
17.
Hum Pathol ; 64: 198-206, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28442268

RESUMO

Palisaded neutrophilic and granulomatous dermatitis (PNGD) is characterized by erythematous papules or plaques on trunk or limbs and is frequently associated with rheumatologic, autoimmune, or hematologic malignancies. Histopathology shows interstitial granulomas composed of epitheloid histiocytes in the reticular dermis with surrounding foci of collagen degeneration and variable neutrophilic inflammation. We report 3 cases of generalized PNGD associated with chronic myelomonocytic leukemia (CMML), a myelodysplastic/myeloproliferative neoplasm, which may show a variety of cutaneous manifestations. SRSF2 P95 hotspot mutations, found in 40%-50% of CMML cases, were retrospectively detected in skin and bone marrow biopsies of all 3 patients, in 1 of them already 5 years before CMML diagnosis. Generalized PNGD may represent a type of cutaneous manifestation of CMML. Because diagnosis of CMML is frequently difficult in cases with isolated persistent monocytosis and minimal dysplasia in the bone marrow, patients with a generalized PNGD should be evaluated for the presence of hematologic disorders including CMML, ideally supported by mutational analyses.


Assuntos
Dermatite/diagnóstico , Granuloma/diagnóstico , Leucemia Mielomonocítica Crônica/diagnóstico , Neutrófilos/patologia , Pele/patologia , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Biópsia , Exame de Medula Óssea , Análise Mutacional de DNA , Dermatite/genética , Dermatite/imunologia , Dermatite/patologia , Feminino , Predisposição Genética para Doença , Granuloma/genética , Granuloma/imunologia , Granuloma/patologia , Humanos , Imuno-Histoquímica , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/imunologia , Leucemia Mielomonocítica Crônica/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Neutrófilos/imunologia , Fenótipo , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Processamento de Serina-Arginina/genética , Pele/imunologia
18.
Hum Immunol ; 78(5-6): 430-434, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28336310

RESUMO

Genetic variations in chemokine genes influence the chemoattractive properties of T cells which may be associated with outcome of infections. In present study, we have investigated the regulatory role played by In1.1T/C (rs2280789) polymorphism of CCL5 and -135G/A (rs56061981) polymorphism of CXCL10 gene on intracellular CCL5 and CXCL10 expression in T cells. Whole blood cell cultures were stimulated with culture filtrate antigen (CFA) and infected with live M. tuberculosis were used for intracellular CCL5 and CXCL10 expression using flow cytometry. Genotyping was performed using polymerase chain reaction based restriction fragment length polymorphism (PCR-RFLP). Significantly higher expression of CCL5 expressing CD3+ and CD3+ CD8+ T cells were observed in HCs with In1.1TT genotype compared to C allele carrier (TT+TC) under unstimulated and CFA induced cultures (p<0.05). In -135G/A (rs56061981) polymorphism, PTB patients with GG genotype showed a significantly decreased expression of CD3+ CXCL10+ and CD3+ CD4+ CXCL10+ T cells compared to A allele carrier (GA+AA) under unstimulated, CFA induced and M. tuberculosis infected cultures (P<0.05). The present study suggest that TT genotype of CCL5 In1.1T/C (rs2280789) polymorphism play an important role to increased CCL5 expression in T cell which may enhanced Th1 immunity and help in protection against tuberculosis. The study also suggests GG genotype of CXCL10 -135G/A (rs56061981) polymorphism decreased CXCL10 expression in T cells which may have defective recruitment of mononuclear cells at the site of infection as well granuloma formation and in turn contribute to progression of TB.


Assuntos
Quimiocina CCL5/genética , Quimiocina CXCL10/genética , Genótipo , Granuloma/genética , Mycobacterium tuberculosis/imunologia , Células Th1/imunologia , Tuberculose Pulmonar/genética , Adulto , Movimento Celular/genética , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Células Th1/microbiologia
19.
Sci Rep ; 7: 45061, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28332618

RESUMO

CXC chemokine receptor 4 plays a critical role in chemotaxis and leukocyte differentiation. Furthermore, there is increasing evidence that links this receptor to angiogenesis. Using the well-established zebrafish-Mycobacterium marinum model for tuberculosis, angiogenesis was recently found to be important for the development of cellular aggregates called granulomas that contain the mycobacteria and are the hallmark of tuberculosis disease. Here, we found that initiation of the granuloma-associated proangiogenic programme requires CXCR4 signalling. The nascent granulomas in cxcr4b-deficient zebrafish embryos were poorly vascularised, which in turn also delayed bacterial growth. Suppressed infection expansion in cxcr4b mutants could not be attributed to an overall deficient recruitment of leukocytes or to different intramacrophage bacterial growth rate, as cxcr4b mutants displayed similar microbicidal capabilities against initial mycobacterial infection and the cellular composition of granulomatous lesions was similar to wildtype siblings. Expression of vegfaa was upregulated to a similar extent in cxcr4b mutants and wildtypes, suggesting that the granuloma vascularisation phenotype of cxcr4b mutants is independent of vascular endothelial growth factor.


Assuntos
Granuloma/metabolismo , Granuloma/patologia , Mycobacterium marinum , Neovascularização Patológica/etiologia , Receptores CXCR4/metabolismo , Animais , Movimento Celular/genética , Modelos Animais de Doenças , Expressão Gênica , Genes Reporter , Granuloma/genética , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Mutação , Neovascularização Patológica/metabolismo , Receptores CXCR4/genética , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Peixe-Zebra
20.
Gut ; 66(6): 1060-1073, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-26953272

RESUMO

OBJECTIVE: Patients with Niemann-Pick disease type C1 (NPC1), a lysosomal lipid storage disorder that causes neurodegeneration and liver damage, can present with IBD, but neither the significance nor the functional mechanism of this association is clear. We studied bacterial handling and antibacterial autophagy in patients with NPC1. DESIGN: We characterised intestinal inflammation in 14 patients with NPC1 who developed IBD. We investigated bacterial handling and cytokine production of NPC1 monocytes or macrophages in vitro and compared NPC1-associated functional defects to those caused by IBD-associated nucleotide-binding oligomerization domain-containing protein 2 (NOD2) variants or mutations in X-linked inhibitor of apoptosis (XIAP). RESULTS: Patients with the lysosomal lipid storage disorder NPC1 have increased susceptibility to early-onset fistulising colitis with granuloma formation, reminiscent of Crohn's disease (CD). Mutations in NPC1 cause impaired autophagy due to defective autophagosome function that abolishes NOD2-mediated bacterial handling in vitro similar to variants in NOD2 or XIAP deficiency. In contrast to genetic NOD2 and XIAP variants, NPC1 mutations do not impair NOD2-receptor-interacting kinase 2 (RIPK2)-XIAP-dependent cytokine production. Pharmacological activation of autophagy can rescue bacterial clearance in macrophages in vitro by increasing the autophagic flux and bypassing defects in NPC1. CONCLUSIONS: NPC1 confers increased risk of early-onset severe CD. Our data support the concept that genetic defects at different checkpoints of selective autophagy cause a shared outcome of CD-like immunopathology linking monogenic and polygenic forms of IBD. Muramyl dipeptide-driven cytokine responses and antibacterial autophagy induction are parallel and independent signalling cascades downstream of the NOD2-RIPK2-XIAP complex.


Assuntos
Acetilmuramil-Alanil-Isoglutamina/metabolismo , Autofagia/genética , Doença de Crohn/genética , Granuloma/genética , Macrófagos/efeitos dos fármacos , Doença de Niemann-Pick Tipo C/genética , Doença de Niemann-Pick Tipo C/fisiopatologia , Proteína Adaptadora de Sinalização NOD2/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Acetilmuramil-Alanil-Isoglutamina/farmacologia , Adolescente , Adulto , Antibacterianos/farmacologia , Autofagia/efeitos dos fármacos , Bactérias , Células Cultivadas , Criança , Pré-Escolar , Clorpromazina/farmacologia , Doença de Crohn/complicações , Doença de Crohn/patologia , Antagonistas de Dopamina/farmacologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Gentamicinas/farmacologia , Granuloma/patologia , Humanos , Imidazóis/farmacologia , Leucócitos Mononucleares , Lisossomos , Macrófagos/fisiologia , Masculino , Mutação , Doença de Niemann-Pick Tipo C/complicações , Proteína Adaptadora de Sinalização NOD2/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/farmacologia , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/antagonistas & inibidores , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/deficiência , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Adulto Jovem
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