RESUMO
Langerhans cell histiocytosis (LCH) is characterized by an expansion and accumulation of pathological histiocytes expressing langerin (CD207) and CD1a in different organs under an inflammatory milieu. The origin of pathognomonic precursors of LCH is widely debated, but monocytes and pre-dendritic cells (pre-DC) play a significant role. Remarkably, we found an expansion of AXLhigh cells in the CD11c+ subset of patients with active LCH, which also express the pathognomonic CD207 and CD1a. Moreover, we obtained a monocyte-derived LC-like (mo-LC-like) expressing high levels of AXL when treated with inflammatory cytokine, or plasma of patients with active disease. Intriguingly, inhibiting the mTOR pathway at the initial stages of monocyte differentiation to LC-like fosters the pathognomonic LCH program, highly increasing CD207 levels, together with NOTCH1 induction. We define here that AXLhigh could also be taken as a strong pathognomonic marker for LCH, and the release of Langerin and NOTCH1 expression depends on the inhibition of the mTOR pathway.
Assuntos
Antígenos CD , Receptor Tirosina Quinase Axl , Histiocitose de Células de Langerhans , Lectinas Tipo C , Lectinas de Ligação a Manose , Proteínas Proto-Oncogênicas , Receptores Proteína Tirosina Quinases , Serina-Treonina Quinases TOR , Feminino , Humanos , Masculino , Antígenos CD/metabolismo , Antígenos CD1/metabolismo , Biomarcadores , Diferenciação Celular , Histiocitose de Células de Langerhans/metabolismo , Lectinas Tipo C/metabolismo , Lectinas de Ligação a Manose/metabolismo , Monócitos/metabolismo , Monócitos/imunologia , Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/metabolismo , Receptor Notch1/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismoRESUMO
Langerhans cell histiocytosis (LCH) is a disorder characterized by an abnormal accumulation of CD207+ and CD1a+ cells in almost any tissue. Currently, there is a lack of prognostic markers to follow up patients and track disease reactivation or treatment response. Putative myeloid precursors CD207+ and CD1a+ cells were previously identified circulating in the blood. Therefore, we aim to develop a sensitive tracing method to monitor circulating CD207+ and CD1a+ cells in a drop of blood sample of patients with LCH. A total of 202 blood samples from patients with LCH and 23 controls were tested using flow cytometry. A standardized cellular score was defined by quantifying CD207+ and CD1a+ expression in monocytes and dendritic cells, based on CD11b, CD14, CD11c, and CD1c subpopulations, resulting in a unique value for each sample. The scoring system was validated by a receiver operating characteristic curve showing a reliable discriminatory capacity (area under the curve of 0.849) with a threshold value of 14, defining the presence of circulating CD207+ and CD1a+ cells. Interestingly, a fraction of patients with no evident clinical manifestation at the time of sampling also showed presence of these cells (29.6%). We also found a differential expression of CD207 and CD1a depending on the organ involvement, and a positive correlation between the cellular score and plasma inflammatory markers such as soluble CD40L, soluble IL-2Ra, and CXCL12. In conclusion, the analysis of circulating CD207 and CD1a cells in a small blood sample will allow setting a cellular score with minimal invasiveness, helping with prognostic accuracy, detecting early reactivation, and follow-up.
Assuntos
Histiocitose de Células de Langerhans , Lectinas de Ligação a Manose , Antígenos CD/metabolismo , Antígenos CD1/metabolismo , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/metabolismo , Humanos , Células de Langerhans , Lectinas Tipo C/metabolismo , Lectinas de Ligação a Manose/metabolismoRESUMO
Cellular senescence is more than a proliferative arrest in response to various stimuli. Senescent cells (SC) participate in several physiological processes, and their adequate removal is essential to maintain tissue and organism homeostasis. However, SC accumulation in aging and age-related diseases alters the tissue microenvironment leading to deterioration. The immune system clears the SC, but the specific scenarios and mechanisms related to recognizing and eliminating them are unknown. Hence, we aimed to evaluate the existence of three regulatory signals of phagocytic function, CD47, major histocompatibility complex class I (MHC-I), and calreticulin, present in the membrane of SC. Therefore, primary fibroblasts were isolated from CD1 female mice lungs, and stress-induced premature senescence (SIPS) was induced with hydrogen peroxide. Replicative senescence (RS) was used as a second senescent model. Our results revealed a considerable increment of CD47 and MHC-I in RS and SIPS fibroblasts. At the same time, no significant changes were found in calreticulin, suggesting that those signals might be associated with evading immune system recognition and thus averting senescent cells clearance.
Assuntos
Antígenos CD1/metabolismo , Antígeno CD47/metabolismo , Senescência Celular/fisiologia , Fibroblastos/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Pulmão/metabolismo , Animais , Calbindina 2/metabolismo , Senescência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Fibroblastos/citologia , Peróxido de Hidrogênio/toxicidade , Camundongos , Cultura Primária de CélulasRESUMO
Pulmonary fibrosis is an emerging disease with a poor prognosis and high mortality rate that is even surpassing some types of cancer. This disease has been linked to the concomitant appearance of liver cirrhosis. Bleomycin-induced pulmonary fibrosis is a widely used mouse model that mimics the histopathological and biochemical features of human systemic sclerosis, an autoimmune disease that is associated with inflammation and expressed in several corporal systems as fibrosis or other alterations. To determine the effects on proliferation, redox and inflammation protein expression markers were analyzed by immunohistochemistry. Analyses showed a significant increase in protein oxidation levels by lipoperoxidation bio-products and in proliferation and inflammation processes. These phenomena were associated with the induction of the redox status in mice subjected to 100 U/kg bleomycin. These findings clearly show that the bleomycin model induces histopathological alterations in the liver and partially reproduces the complexity of systemic sclerosis. Our results using the bleomycin-induced pulmonary fibrosis model provide a protocol to investigate the mechanism underlying the molecular alteration found in the liver linked to systemic sclerosis.
Assuntos
Bleomicina , Modelos Animais de Doenças , Hepatopatias/etiologia , Fibrose Pulmonar/complicações , Actinas/metabolismo , Animais , Antígenos CD1/metabolismo , Colágeno/metabolismo , Antígeno Ki-67/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Antígeno Nuclear de Célula em Proliferação/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Escleroderma Sistêmico , Pele/efeitos dos fármacos , Pele/patologiaRESUMO
Obesity-associated hypothalamic inflammation plays an important role in the development of defective neuronal control of whole body energy balance. Because dietary fats are the main triggers of hypothalamic inflammation, we hypothesized that CD1, a lipid-presenting protein, may be involved in the hypothalamic inflammatory response in obesity. Here, we show that early after the introduction of a high-fat diet, CD1 expressing cells gradually appear in the mediobasal hypothalamus. The inhibition of hypothalamic CD1 reduces diet-induced hypothalamic inflammation and rescues the obese and glucose-intolerance phenotype of mice fed a high-fat diet. Conversely, the chemical activation of hypothalamic CD1 further increases diet-induced obesity and hypothalamic inflammation. A bioinformatics analysis revealed that hypothalamic CD1 correlates with transcripts encoding for proteins known to be involved in diet-induced hypothalamic abnormalities in obesity. Thus, CD1 is involved in at least part of the hypothalamic inflammatory response in diet-induced obesity and its modulation affects the body mass phenotype of mice.
Assuntos
Antígenos CD1/metabolismo , Hipotálamo/imunologia , Obesidade/metabolismo , Animais , Antígenos CD1/imunologia , Biologia Computacional/métodos , Dieta Hiperlipídica , Gorduras na Dieta , Metabolismo Energético , Inflamação/metabolismo , Linfócitos/metabolismo , Masculino , Camundongos , Obesidade/imunologiaRESUMO
Langerhans cell histiocytosis (LCH) is a rare disease with an unknown etiology characterized by heterogeneous lesions containing CD207+CD1a+ cells that can arise in almost any tissue and cause significant morbidity and mortality. Precursors of pathological Langerhans cells have yet to be defined. Our aim was to identify circulating CD207+CD1a+ cells and their inducers in LCH. Expression of CD207 and CD1a in the blood myeloid compartment as well as thymic stromal lymphopoietin (TSLP) and transforming growth factor ß (TGF-ß) plasma levels were measured in 22 pediatric patients with active disease (AD) or nonactive disease (NAD). In patients with AD vs those with NAD, the myeloid compartment showed an increased CD11b (CD11bhigh plus CD11b+) fraction (39.7 ± 3.6 vs 18.6 ± 1.9), a higher percentage of circulating CD11bhighCD11c+CD207+ cells (44.5 ± 11.3 vs 3.2 ± 0.5), and the presence of CD11chighCD207+CD1a+ cells (25.0 ± 9.1 vs 2.3 ± 0.5). Blood CD207+CD1a+ cells were not observed in adult controls or umbilical cord. Increased TSLP and TGF-ß levels were detected in patients with AD. Interestingly, plasma from patients with AD induces CD207 expression on CD14+ monocytes. We conclude that CD207+CD1a+ cells are circulating in patients with active LCH, and TSLP and TGF-ß are potential drivers of Langerhans-like cells in vivo.
Assuntos
Antígenos CD1/metabolismo , Antígenos CD/metabolismo , Histiocitose de Células de Langerhans/metabolismo , Histiocitose de Células de Langerhans/patologia , Lectinas Tipo C/metabolismo , Lectinas de Ligação a Manose/metabolismo , Criança , Pré-Escolar , Citocinas/sangue , Feminino , Histiocitose de Células de Langerhans/sangue , Humanos , Lactente , Masculino , Fator de Crescimento Transformador beta/sangue , Linfopoietina do Estroma do TimoRESUMO
BACKGROUND: There may be differences in the antitumor immunity induced by dendritic cells (DCs) during the development of squamous cell carcinoma (SCC) located in the lip rather than in the oral cavity. The aim of this study was to evaluate the number of immature and mature DCs in SCC and potentially malignant disorders of the oral cavity and lip. METHODS: Immunohistochemistry was used to identify the number (cells/mm(2) ) of immature (CD1a(+) ) or mature (CD83(+) ) DCs in samples of oral cavity SCC (OCSCC) (n = 39), lip SCC (LSCC) (n = 23), leukoplakia (LK) (n = 21), actinic cheilitis (AC) (n = 13), and normal mucosa of the oral cavity (OC control, n = 12) and the lip (lip control, n = 11). RESULTS: The number of CD1a(+) cells tended to be higher in the OC control samples compared with the LK (P = 0.04) and OCSCC (P = 0.21). Unlike, this cell population was lower in the lip control than in AC or LSCC (P < 0.05). The number of CD83(+) cells was increased in the LSCC samples compared with the AC and lip control (P = 0.0001) and in OCSCC compared with both the LK (P = 0.001) and OC control (P = 0.0001) samples. LSCC showed an elevated number of CD1a(+) and CD83(+) cells compared with OCSCC (P = 0.03). The population of mature DCs was lower than the population of immature DCs in all of the tested groups (P < 0.05). CONCLUSION: There were a greater number of both mature and immature DC populations in the LSCC samples than in the OCSCC, which could contribute to establishing a more effective immune antitumor response for this neoplasm.
Assuntos
Carcinoma de Células Escamosas/patologia , Células Dendríticas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias Labiais/patologia , Neoplasias Bucais/patologia , Antígenos CD/metabolismo , Antígenos CD1/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Queilite/metabolismo , Queilite/patologia , Estudos Transversais , Células Dendríticas/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Imunoglobulinas/metabolismo , Leucoplasia/metabolismo , Leucoplasia/patologia , Neoplasias Labiais/diagnóstico , Neoplasias Labiais/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Mucosa Bucal/metabolismo , Mucosa Bucal/patologia , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço , Taxa de Sobrevida , Antígeno CD83RESUMO
BACKGROUND: Mesenchymal stem cells have prominent immune modulatory properties, which may have clinical applications; however their major source, bone marrow, is of limited availability. On the other hand, mesenchymal stem cells derived from human exfoliated deciduous teeth (SHEDs) are readily accessible, but their immune regulatory properties have not been completely investigated. This study was designed, therefore, to evaluate the SHEDs influence on DCs differentiation, maturation, ability to activate T cells and to expand CD4(+)Foxp3(+) T cells. METHODOLOGY/PRINCIPAL FINDINGS: The experiments were based in cellular co-culture during differentiation and maturation of monocyte derived-DCs (moDCs), with, or not, presence of SHEDs. After co-culture with SHEDs, (moDCs) presented lower expression of BDCA-1 and CD11c, in comparison to DC cultivated without SHEDs. CD40, CD80, CD83 and CD86 levels were also decreased in mature DCs (mDCs) after co-cultivation with SHEDs. To assess the ability of SHEDs-exposed moDCs to modulate T cell responses, the former were separated from SHEDs, and co-cultured with peripheral blood lymphocytes. After 5 days, the proliferation of CD4(+) and CD8(+) T cells was evaluated and found to be lower than that induced by moDCs cultivated without SHEDs. In addition, an increase in the proportion of CD4(+)Foxp3(+)IL-10(+) T cells was observed among cells stimulated by mature moDCs that were previously cultivated with SHEDs. Soluble factors released during co-cultures also showed a reduction in the pro-inflammatory cytokines (IL-2, TNF-α and IFN-γ), and an increase in the anti-inflammatory molecule IL-10. CONCLUSION/SIGNIFICANCE: This study shows that SHEDs induce an immune regulatory phenotype in moDCs cells, evidenced by changes in maturation and differentiation rates, inhibition of lymphocyte stimulation and ability to expand CD4(+)Foxp3(+) T cells. Further characterization and validation of this phenomenon could support the use of SHEDs, directly or indirectly for immune modulation in the clinical practice.
Assuntos
Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Esfoliação de Dente/imunologia , Esfoliação de Dente/metabolismo , Antígenos CD1/metabolismo , Biomarcadores/metabolismo , Antígenos CD40/metabolismo , Diferenciação Celular , Técnicas de Cocultura , Citocinas/metabolismo , Células Dendríticas/citologia , Fatores de Transcrição Forkhead/metabolismo , Glicoproteínas/metabolismo , Humanos , Imunomodulação , Interleucina-10/metabolismo , Ativação Linfocitária/imunologia , Monócitos/citologia , Fenótipo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
AIMS: The purpose of this study was to quantify and compare the density of dendritic cells (DCs) in cervical lymph nodes (LNs) and palatine tonsils (PTs) of AIDS and non-AIDS patients. METHODS AND RESULTS: Factor XIIIa, CD1a and CD83 antibodies were used to identify migratory DCs by immunohistochemistry in LNs and PTs of 32 AIDS patients and 21 HIV-negative control patients. Quantification was performed by the positive pixel count analytical method. AIDS patients presented a lower density of factor XIIIa(+) cells (P < 0.001), CD1a(+) cells (P < 0.05) and CD83(+) cells (P < 0.001) in cervical LNs and PTs compared to the non-AIDS control group. CONCLUSION: Overall depletion of DCs in lymphoid tissues of AIDS patients may be predictive of the immune system's loss of disease control.
Assuntos
Síndrome da Imunodeficiência Adquirida/patologia , Antígenos CD1/metabolismo , Antígenos CD/metabolismo , Células Dendríticas/patologia , Fator XIIIa/metabolismo , Imunoglobulinas/metabolismo , Linfonodos/patologia , Glicoproteínas de Membrana/metabolismo , Tonsila Palatina/patologia , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Humanos , Linfonodos/imunologia , Linfonodos/metabolismo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Pescoço , Tonsila Palatina/imunologia , Tonsila Palatina/metabolismo , Adulto Jovem , Antígeno CD83RESUMO
Tuberculosis (TB) is one of the world's most pernicious diseases mainly due to immune evasion strategies displayed by its causative agent Mycobacterium tuberculosis (Mtb). Blood monocytes (Mos) represent an important source of DCs during chronic infections; consequently, the alteration of their differentiation constitutes an escape mechanism leading to mycobacterial persistence. We evaluated whether the CD16(+)/CD16(-) Mo ratio could be associated with the impaired Mo differentiation into DCs found in TB patients. The phenotype and ability to stimulate Mtb-specific memory clones DCs from isolated Mo subsets were assessed. We found that CD16(-) Mos differentiated into CD1a(+) DC-SIGN(high) cells achieving an efficient recall response, while CD16(+) Mos differentiated into a CD1a(-) DC-SIGN(low) population characterized by a poor mycobacterial Ag-presenting capacity. The high and sustained phosphorylated p38 expression observed in CD16(+) Mos was involved in the altered DC profile given that its blockage restored DC phenotype and its activation impaired CD16(-) Mo differentiation. Furthermore, depletion of CD16(+) Mos indeed improved the differentiation of Mos from TB patients toward CD1a(+) DC-SIGN(high) DCs. Therefore, Mos from TB patients are less prone to differentiate into DCs due to their increased proportion of CD16(+) Mos, suggesting that during Mtb infection Mo subsets may have different fates after entering the lungs.