RESUMO
Connective tissue diseases-related pulmonary arterial hypertension (CTD-PAH) is a disease characterized by an elevated pulmonary artery pressure that arises as a complication of connective tissue diseases. The number of patients with CTD-PAH accounts for 25.3% of all PAH patients. The main pathological features of CTD-PAH are thickening of intima, media and adventitia of pulmonary arterioles, increased pulmonary vascular resistance, autoimmune activation and inflammatory reaction. It is worth noting that abnormal immune activation will produce autoantibodies and release cytokines, and abnormal immune cell recruitment will promote inflammatory environment and vascular remodeling. Therefore, almost all forms of connective tissue diseases are related to PAH. In addition to general therapy and targeted drug therapy for PAH, high-dose glucocorticoid combined with immunosuppressant can quickly alleviate and stabilize the basic CTD-PAH disease. Given this, the development of therapeutic approaches targeting immune dysregulation and heightened inflammation is recognized as a promising strategy to prevent or reverse the progression of CTD-PAH. This review explores the potential mechanisms by which immune cells contribute to the development of CTD-PAH and examines the clinical application of immunosuppressive therapies in managing CTD-PAH.
Assuntos
Doenças do Tecido Conjuntivo , Hipertensão Arterial Pulmonar , Humanos , Doenças do Tecido Conjuntivo/imunologia , Doenças do Tecido Conjuntivo/complicações , Hipertensão Arterial Pulmonar/etiologia , Hipertensão Arterial Pulmonar/imunologia , Hipertensão Arterial Pulmonar/tratamento farmacológico , Animais , Imunossupressores/uso terapêutico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/imunologia , Hipertensão Pulmonar/tratamento farmacológicoRESUMO
BACKGROUND: Systemic sclerosis (SSc) often overlaps with other autoimmune diseases. More complex autoantibody profiles may be observed in SSc overlap syndrome (SSc OS). To determine the clinical significance of autoantibodies in SSc OS and classify the patients more accurately for better disease assessments, we analysed the correlation between serological profiles, organ involvements and outcomes. METHODS: A retrospective cohort study was conducted in Peking University People's Hospital. Chi-square tests and analysis of variance were used to analyse univariate comparisons of clinical symptoms, organ involvement and laboratory indicators. Survival was evaluated using Cox proportional hazards model. RESULTS: Among 141 cases, anti-Ro-52 was the most common antibody, followed by anti-centromere antibody and anti-Scl-70 antibody. We analysed the correlation between autoantibodies and vital organ damage in SSc OS patients, and compared the differences across four SSc OS subgroups (SSc SLE, SSc RA, SSc PM/DM and SSc SS) to demonstrate the correlation between autoantibodies and clinical characteristics and organ damage. Cox regression analysis showed that scleroderma renal crisis (SRC) (p = .004) and pulmonary arterial hypertension (PH) (p = .010) were independent risk factors for survival. CONCLUSIONS: Autoantibodies are associated with clinical features, organ involvement and prognosis in SSc OS patients. Anti-Scl-70 antibody is associated with interstitial lung disease (ILD) and SRC, while ACA is a protective factor of ILD. SRC and PH are risk factors associated with death.
Assuntos
Autoanticorpos , Escleroderma Sistêmico , Humanos , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/mortalidade , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/complicações , Feminino , Masculino , Estudos Retrospectivos , Pessoa de Meia-Idade , Autoanticorpos/sangue , Autoanticorpos/imunologia , Adulto , Modelos de Riscos Proporcionais , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Fatores de Risco , Idoso , Hipertensão Pulmonar/imunologia , Hipertensão Pulmonar/mortalidade , PrognósticoRESUMO
BACKGROUND: Schistosomiasis is a parasitic infection that can cause pulmonary hypertension (PH). Th2 CD4 T cells are necessary for experimental Schistosoma-PH. However, if T cells migrate to the lung to initiate, the localized inflammation that drives vascular remodeling and PH is unknown. METHODS: Mice were sensitized to Schistosoma mansoni eggs intraperitoneally and then challenged using tail vein injection. FTY720 was administered, which blocks lymphocyte egress from lymph nodes. T cells were quantified using flow cytometry, PH severity via heart catheterization, and cytokine concentration through ELISA. RESULTS: FTY720 decreased T cells in the peripheral blood, and increased T cells in the mediastinal lymph nodes. However, FTY720 treatment resulted in no change in PH or type 2 inflammation severity in mice sensitized and challenged with S. mansoni eggs, and the number of memory and effector CD4 T cells in the lung parenchyma was also unchanged. Notably, intraperitoneal Schistosoma egg sensitization alone resulted in a significant increase in intravascular lymphocytes and T cells, including memory T cells, although there was no significant change in parenchymal cell density, IL-4 or IL-13 expression, or PH. CONCLUSION: Blocking T cell migration did not suppress PH following Schistosoma egg challenge. Memory CD4 T cells, located in the lung intravascular space following egg sensitization, appear sufficient to cause type 2 inflammation and PH.
Assuntos
Hipertensão Pulmonar , Pulmão , Schistosoma mansoni , Animais , Camundongos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/parasitologia , Hipertensão Pulmonar/imunologia , Pulmão/parasitologia , Pulmão/imunologia , Pulmão/patologia , Schistosoma mansoni/imunologia , Cloridrato de Fingolimode/farmacologia , Feminino , Linfócitos T CD4-Positivos/imunologia , Esquistossomose mansoni/imunologia , Esquistossomose mansoni/complicações , Esquistossomose mansoni/patologia , Modelos Animais de Doenças , Interleucina-4/metabolismo , Citocinas/metabolismo , Camundongos Endogâmicos C57BL , Linfócitos T/imunologia , Linfócitos T/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Esquistossomose/complicações , Esquistossomose/imunologia , Esquistossomose/parasitologiaRESUMO
Pulmonary hypertension (PH) is a progressive cardiovascular disease, which may lead to severe cardiopulmonary dysfunction. As one of the main PH disease groups, pulmonary artery hypertension (PAH) is characterized by pulmonary vascular remodeling and right ventricular dysfunction. Increased pulmonary artery resistance consequently causes right heart failure, which is the major reason for morbidity and mortality in this disease. Although various treatment strategies have been available, the poor clinical prognosis of patients with PAH reminds us that further studies of the pathological mechanism of PAH are still needed. Inflammation has been elucidated as relevant to the initiation and progression of PAH, and plays a crucial and functional role in vascular remodeling. Many immune cells and cytokines have been demonstrated to be involved in the pulmonary vascular lesions in PAH patients, with the activation of downstream signaling pathways related to inflammation. Consistently, this influence has been found to correlate with the progression and clinical outcome of PAH, indicating that immunity and inflammation may have significant potential in PAH therapy. Therefore, we reviewed the pathogenesis of inflammation and immunity in PAH development, focusing on the potential targets and clinical application of anti-inflammatory and immunosuppressive therapy.
Assuntos
Imunoterapia , Hipertensão Arterial Pulmonar , Humanos , Hipertensão Arterial Pulmonar/terapia , Hipertensão Arterial Pulmonar/etiologia , Imunoterapia/métodos , Animais , Inflamação/terapia , Inflamação/patologia , Hipertensão Pulmonar/terapia , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/imunologia , Remodelação VascularRESUMO
Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a serious pulmonary vascular disease characterized by residual thrombi in the pulmonary arteries and distal pulmonary microvascular remodeling. The pathogenesis of CTEPH remains unclear, but many factors such as inflammation, immunity, coagulation and angiogenesis may be involved. Monocytes are important immune cells that can differentiate into macrophages and dendritic cells and play an important role in thrombus formation. However, the distribution, gene expression profile and differentiation trajectory of monocyte subsets in CTEPH patients have not been systematically studied. This study aims to reveal the characteristics and functions of monocytes in CTEPH patients using single-cell sequencing technology, and to provide new insights for the diagnosis and treatment of CTEPH. Methods: Single-cell RNA sequencing (scRNA-seq) were performed to analyze the transcriptomic features of peripheral blood mononuclear cells (PBMCs) from healthy controls, CTEPH patients and the tissues from CTEPH patients after the pulmonary endarterectomy (PEA). We established a CTEPH rat model with chronic pulmonary embolism caused by repeated injection of autologous thrombi through a central venous catheter, and used flow cytometry to detect the proportion changes of monocyte subsets in CTEPH patients and CTEPH rat model. We also observed the infiltration degree of macrophage subsets in thrombus tissue and their differentiation relationship with peripheral blood monocyte subsets by immunofluorescence staining. Results: The results showed that the monocyte subsets in peripheral blood of CTEPH patients changed significantly, especially the proportion of CD16+ monocyte subset increased. This monocyte subset had unique functional features at the transcriptomic level, involving processes such as cell adhesion, T cell activation, coagulation response and platelet activation, which may play an important role in pulmonary artery thrombus formation and pulmonary artery intimal remodeling. In addition, we also found that the macrophage subsets in pulmonary endarterectomy tissue of CTEPH patients showed pro-inflammatory and lipid metabolism reprogramming features, which may be related to the persistence and insolubility of pulmonary artery thrombi and the development of pulmonary hypertension. Finally, we also observed that CD16+ monocyte subset in peripheral blood of CTEPH patients may be recruited to pulmonary artery intimal tissue and differentiate into macrophage subset with high expression of IL-1ß, participating in disease progression. Conclusion: CD16+ monocytes subset had significant gene expression changes in CTEPH patients, related to platelet activation, coagulation response and inflammatory response. And we also found that these cells could migrate to the thrombus and differentiate into macrophages with high expression of IL-1ß involved in CTEPH disease progression. We believe that CD16+ monocytes are important participants in CTEPH and potential therapeutic targets.
Assuntos
Hipertensão Pulmonar , Monócitos , Embolia Pulmonar , Receptores de IgG , Análise de Célula Única , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/imunologia , Hipertensão Pulmonar/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Receptores de IgG/metabolismo , Embolia Pulmonar/imunologia , Embolia Pulmonar/metabolismo , Animais , Masculino , Doença Crônica , Ratos , Feminino , Pessoa de Meia-Idade , Proteínas Ligadas por GPI/metabolismo , Modelos Animais de Doenças , Transcriptoma , Idoso , Artéria Pulmonar/metabolismo , Artéria Pulmonar/imunologia , Artéria Pulmonar/patologiaRESUMO
Introduction: Schistosomiasis (SM) is a parasitic disease caused by Schistosoma mansoni. SM causes chronic inflammation induced by parasitic eggs, with collagen/fibrosis deposition in the granuloma process in the liver, spleen, central nervous system, kidneys, and lungs. Pulmonary arterial hypertension (PAH) is a clinical manifestation characterized by high pressure in the pulmonary circulation and right ventricular overload. This study investigated the production of functional autoantibodies (fAABs) against the second loop of the G-protein-coupled receptor (GPCR) in the presence of hepatic and PAH forms of human SM. Methods: Uninfected and infected individuals presenting acute and chronic manifestations (e.g., hepatointestinal, hepato-splenic without PAH, and hepato-splenic with PAH) of SM were clinically evaluated and their blood was collected to identify fAABs/GPCRs capable of recognizing endothelin 1, angiotensin II, and a-1 adrenergic receptor. Human serum was analyzed in rat cardiomyocytes cultured in the presence of the receptor antagonists urapidil, losartan, and BQ123. Results: The fAABs/GPCRs from chronic hepatic and PAH SM individuals, but not from acute SM individuals, recognized the three receptors. In the presence of the antagonists, there was a reduction in beating rate changes in cultured cardiomyocytes. In addition, binding sites on the extracellular domain functionality of fAABs were identified, and IgG1 and/or IgG3 antibodies were found to be related to fAABs. Conclusion: Our data suggest that fAABs against GPCR play an essential role in vascular activity in chronic SM (hepatic and PAH) and might be involved in the development of hypertensive forms of SM.
Assuntos
Autoanticorpos , Receptores Acoplados a Proteínas G , Autoanticorpos/imunologia , Autoanticorpos/sangue , Humanos , Animais , Receptores Acoplados a Proteínas G/imunologia , Receptores Acoplados a Proteínas G/metabolismo , Ratos , Masculino , Feminino , Adulto , Hipertensão Pulmonar/imunologia , Hipertensão Pulmonar/etiologia , Pessoa de Meia-Idade , Miócitos Cardíacos/imunologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/parasitologia , Esquistossomose mansoni/imunologia , Schistosoma mansoni/imunologia , Esquistossomose/imunologiaRESUMO
BACKGROUND: Adaptive immunity is an important disease mediator of pulmonary vascular remodeling during pulmonary hypertension (PH) development, especially T-cells lymphocytes. However, data for bibliometric analysis of T cell immunity in PH is currently vacant. This aimed to provide a comprehensive and visualized view of T-cells research in PH pathogenesis and to lay a solid foundation for further studies. METHODS: The data was acquired from the Web of Science Core Collection database. Web of Science analytic tool was used to analysis the publication years, authors, journals, countries, and organizations. CiteSpace 6.2.R3, VOSviewer 1.6.16, and Scimago Graphica 1.0.35.0 were applied to conduct a visualization bibliometric analysis about authors, countries, institutions, journals, references, and keywords. RESULTS: Nine hundred and eight publications from 1992 to 2022 were included in the analysis. The results showed that Humbert Marc was the most prolific author. American Journal of Physiology Lung Cellular and Molecular Physiology had the most related articles. The institution with the most articles was Udice French Research University. The United States was far ahead in the article output. Keywords analysis showed that "Pulmonary hypertension" was the most usually appeared keyword in the relevant literature, and included "T-cells", "Regulatory T cells", and "Activated T cell." "miRNA" of reference co-citation clustering analysis demonstrated the possible T-cell immunity activation mechanisms in PH. The most cited literature was published in the European Heart Journal by Galie N in 2016. The strongest citation burst of keyword is "gene expression" and terms such as "vascular remodeling," "growth," "proliferation," and "fibrosis" are among the list, indicating that T-cells interact with stromal vascular cells to induce pulmonary vascular remodeling. The strongest burst of cited reference is "Galie N, 2016." CONCLUSIONS: T-cell immunity is an important pathogenesis mechanism for PH development, which may have interaction with miRNAs and stromal vascular cells, but the possible T-cell immunity activation mechanisms in PH need to be investigated further.
Assuntos
Bibliometria , Hipertensão Pulmonar , Linfócitos T , Hipertensão Pulmonar/imunologia , Humanos , Linfócitos T/imunologia , AnimaisRESUMO
Cell migration regulated by Thrombospondin 2 (THSB2) is important for the development of pulmonary artery remodeling, but the mechanism by which THBS2-mediated cell migration regulates the development of pulmonary artery remodeling in broiler ascites syndrome (AS) is unclear. In addition, the lack of chicken THBS2 antibodies makes it difficult to study the mechanism in depth. In our study, we used recombinant gene technology, protein purification, and other techniques to obtain mouse anti-chicken THBS2 antibody and analyze its expression in broilers, ascites broilers and other animals. The results showed that we immunized mouse with recombinant THBS2 protein and obtained an antibody titer of 1:204,800, and the addition of astragalus polysaccharide as an immunomodulator during immunization significantly increased the titer of the antibody. Western blotting (WB) and immunofluorescence results showed that the THBS2 was significantly down-regulated in the ascites broiler. The THBS2 antibody we prepared can also detect THBS2 protein in duck, mouse, goat, and rabbit tissues. These results provide a foundation for further investigation of the role of THBS2 in pulmonary artery remodeling in broiler ascites syndrome and a powerful tool for studying the role of THBS2 in AS.
Assuntos
Anticorpos , Galinhas , Hipertensão Pulmonar , Proteínas Recombinantes , Trombospondinas , Animais , Proteínas Recombinantes/imunologia , Trombospondinas/imunologia , Trombospondinas/genética , Camundongos , Hipertensão Pulmonar/imunologia , Anticorpos/imunologia , Ascite/imunologia , Artéria Pulmonar , Doenças das Aves Domésticas/imunologiaRESUMO
Introduction: Hypoxia is a common pathological driver contributing to various forms of pulmonary vascular diseases leading to pulmonary hypertension (PH). Pulmonary interstitial macrophages (IMs) play pivotal roles in immune and vascular dysfunction, leading to inflammation, abnormal remodeling, and fibrosis in PH. However, IMs' response to hypoxia and their role in PH progression remain largely unknown. We utilized a murine model of hypoxia-induced PH to investigate the repertoire and functional profiles of IMs in response to acute and prolonged hypoxia, aiming to elucidate their contributions to PH development. Methods: We conducted single-cell transcriptomic analyses to characterize the repertoire and functional profiles of murine pulmonary IMs following exposure to hypobaric hypoxia for varying durations (0, 1, 3, 7, and 21 days). Hallmark pathways from the mouse Molecular Signatures Database were utilized to characterize the molecular function of the IM subpopulation in response to hypoxia. Results: Our analysis revealed an early acute inflammatory phase during acute hypoxia exposure (Days 1-3), which was resolved by Day 7, followed by a pro-remodeling phase during prolonged hypoxia (Days 7-21). These phases were marked by distinct subpopulations of IMs: MHCIIhiCCR2+EAR2+ cells characterized the acute inflammatory phase, while TLF+VCAM1hi cells dominated the pro-remodeling phase. The acute inflammatory phase exhibited enrichment in interferon-gamma, IL-2, and IL-6 pathways, while the pro-remodeling phase showed dysregulated chemokine production, hemoglobin clearance, and tissue repair profiles, along with activation of distinct complement pathways. Discussion: Our findings demonstrate the existence of distinct populations of pulmonary interstitial macrophages corresponding to acute and prolonged hypoxia exposure, pivotal in regulating the inflammatory and remodeling phases of PH pathogenesis. This understanding offers potential avenues for targeted interventions, tailored to specific populations and distinct phases of the disease. Moreover, further identification of triggers for pro-remodeling IMs holds promise in unveiling novel therapeutic strategies for pulmonary hypertension.
Assuntos
Perfilação da Expressão Gênica , Hipertensão Pulmonar , Hipóxia , Análise de Célula Única , Transcriptoma , Animais , Camundongos , Hipóxia/metabolismo , Hipóxia/imunologia , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/imunologia , Hipertensão Pulmonar/genética , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Masculino , Pulmão/imunologia , Pulmão/patologia , Pulmão/metabolismoRESUMO
Background: Schistosomiasis is a common cause of pulmonary hypertension (PH) worldwide. Type 2 inflammation contributes to the development of Schistosoma-induced PH. Specifically, interstitial macrophages (IMs) derived from monocytes play a pivotal role by producing thrombospondin-1 (TSP-1), which in turn activates TGF-ß, thereby driving the pathology of PH. Resident and recruited IM subpopulations have recently been identified. We hypothesized that in Schistosoma-PH, one IM subpopulation expresses monocyte recruitment factors, whereas recruited monocytes become a separate IM subpopulation that expresses TSP-1. Methods: Mice were intraperitoneally sensitized and then intravenously challenged with S. mansoni eggs. Flow cytometry on lungs and blood was performed on wildtype and reporter mice to identify IM subpopulations and protein expression. Single-cell RNA sequencing (scRNAseq) was performed on flow-sorted IMs from unexposed and at day 1, 3 and 7 following Schistosoma exposure to complement flow cytometry based IM characterization and identify gene expression. Results: Flow cytometry and scRNAseq both identified 3 IM subpopulations, characterized by CCR2, MHCII, and FOLR2 expression. Following Schistosoma exposure, the CCR2+ IM subpopulation expanded, suggestive of circulating monocyte recruitment. Schistosoma exposure caused increased monocyte-recruitment ligand CCL2 expression in the resident FOLR2+ IM subpopulation. In contrast, the vascular pathology-driving protein TSP-1 was greatest in the CCR2+ IM subpopulation. Conclusion: Schistosoma-induced PH involves crosstalk between IM subpopulations, with increased expression of monocyte recruitment ligands by resident FOLR2+ IMs, and the recruitment of CCR2+ IMs which express TSP-1 that activates TGF-ß and causes PH.
Assuntos
Hipertensão Pulmonar , Macrófagos , Animais , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/parasitologia , Hipertensão Pulmonar/imunologia , Hipertensão Pulmonar/patologia , Camundongos , Macrófagos/imunologia , Macrófagos/parasitologia , Fenótipo , Schistosoma mansoni/imunologia , Camundongos Endogâmicos C57BL , Esquistossomose/imunologia , Esquistossomose/complicações , Esquistossomose/parasitologia , Modelos Animais de Doenças , Esquistossomose mansoni/imunologia , Esquistossomose mansoni/parasitologia , Esquistossomose mansoni/complicações , Esquistossomose mansoni/patologia , Trombospondina 1/genética , Trombospondina 1/metabolismo , Monócitos/imunologia , Receptores CCR2/genética , Receptores CCR2/metabolismo , Feminino , Schistosoma/imunologia , Schistosoma/fisiologia , Pulmão/imunologia , Pulmão/parasitologia , Pulmão/patologiaRESUMO
Chronic thromboembolic pulmonary hypertension (CTEPH) is a debilitating disease characterized by thrombotic occlusion of pulmonary arteries and vasculopathy, leading to increased pulmonary vascular resistance and progressive right-sided heart failure. Thrombotic lesions in CTEPH contain CD68+ macrophages, and increasing evidence supports their role in disease pathogenesis. Macrophages are classically divided into pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages, which are involved in wound healing and tissue repair. Currently, the phenotype of macrophages and their localization within thrombotic lesions of CTEPH are largely unknown. In our study, we subclassified thrombotic lesions of CTEPH patients into developing fresh thrombi (FT) and organized thrombi (OT), based on the degree of fibrosis and remodeling. We used multiplex immunofluorescence histology to identify immune cell infiltrates in thrombotic lesions of CPTEH patients. Utilizing software-assisted cell detection and quantification, increased proportions of macrophages were observed in immune cell infiltrates of OT lesions, compared with FT. Strikingly, the proportions with a CD206+INOS- M2 phenotype were significantly higher in OT than in FT, which mainly contained unpolarized macrophages. Taken together, we observed a shift from unpolarized macrophages in FT toward an expanded population of M2 macrophages in OT, indicating a dynamic role of macrophages during CTEPH pathogenesis.
Assuntos
Hipertensão Pulmonar , Macrófagos , Embolia Pulmonar , Trombose , Humanos , Macrófagos/imunologia , Hipertensão Pulmonar/imunologia , Hipertensão Pulmonar/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/imunologia , Embolia Pulmonar/patologia , Doença Crônica , Trombose/imunologia , Trombose/patologia , Idoso , Antígenos CD/metabolismoRESUMO
There is an unmet need for new therapeutic strategies that target alternative pathways to improve the prognosis of patients with pulmonary arterial hypertension (PAH). As immunity has been involved in the development and progression of vascular lesions in PAH, we review the potential contribution of B-cells in its pathogenesis and evaluate the relevance of B-cell-targeted therapies. Circulating B-cell homeostasis is altered in PAH patients, with total B-cell lymphopenia, abnormal subset distribution (expansion of naïve and antibody-secreting cells, reduction of memory B-cells) and chronic activation. B-cells are recruited to the lungs through local chemokine secretion, and activated by several mechanisms: 1) interaction with lung vascular autoantigens through cognate B-cell receptors; 2) costimulatory signals provided by T follicular helper cells (interleukin (IL)-21), type 2 T helper cells and mast cells (IL-4, IL-6 and IL-13); and 3) increased survival signals provided by B-cell activating factor pathways. This activity results in the formation of germinal centres within perivascular tertiary lymphoid organs and in the local production of pathogenic autoantibodies that target the pulmonary vasculature and vascular stabilisation factors (including angiotensin-II/endothelin-1 receptors and bone morphogenetic protein receptors). B-cells also mediate their effects through enhanced production of pro-inflammatory cytokines, reduced anti-inflammatory properties by regulatory B-cells, immunoglobulin (Ig)G-induced complement activation, and IgE-induced mast cell activation. Precision-medicine approaches targeting B-cell immunity are a promising direction for select PAH conditions, as suggested by the efficacy of anti-CD20 therapy in experimental models and a trial of rituximab in systemic sclerosis-associated PAH.
Assuntos
Linfócitos B , Hipertensão Arterial Pulmonar , Humanos , Linfócitos B/imunologia , Hipertensão Arterial Pulmonar/imunologia , Animais , Pulmão/imunologia , Autoanticorpos/imunologia , Hipertensão Pulmonar/imunologiaRESUMO
OBJECTIVES: Systemic sclerosis (SSc) is characterized by multiple clinical manifestations. Vasculopathy is a main disease hallmark and ranges in severity from an exacerbated Raynaud phenomenon to pulmonary arterial hypertension (PAH). The potential involvement of the immune system in SSc-associated vascular abnormalities is not clear. Here, we set out to study SSc-related immune parameters and determine whether and which peripheral T cell subsets associate with vascular severity in SSc patients. METHODS: Peripheral blood and clinical data were collected from 30 SSc patients, 5 patients with idiopathic PAH and 15 age and sex-matched healthy donors (HD). In this cross-sectional cohort, SSc patients with PAH (n = 15) were matched for their age, sex and medication with SSc patients with no signs of PAH (n = 15). Lymphocyte subsets were quantified by multi-colour flow cytometry. RESULTS: SSc patients exhibited elevated percentages of T peripheral helper cells (Tph), CD4+GZMB+ T cells and decreased levels of Th1 cells compared with HD. Increased presence of both CD4+ and CD8+ exhausted-like (CD28-) T cells, characterized by raised cytokine and cytotoxic signature, was also observed in SSc compared with HD blood. Furthermore, IL-4 expressing CD4+CD8+ T cells were significantly increased in SSc peripheral blood. Interestingly, the presence of PAH in SSc was accompanied by a distinct T helper profile, characterized by raised percentages of Th17 and Tph cells. CONCLUSION: SSc patients with severe vasculopathy (presence of PAH) exhibited a distinct T cell profile, suggesting a potential role of auto-immune inflammation in SSc vascular complications.
Assuntos
Escleroderma Sistêmico , Humanos , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/complicações , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Transversais , Adulto , Linfócitos T Auxiliares-Indutores/imunologia , Hipertensão Arterial Pulmonar/imunologia , Hipertensão Arterial Pulmonar/etiologia , Estudos de Casos e Controles , Idoso , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/imunologia , Citometria de FluxoAssuntos
Doenças Pulmonares Intersticiais , Hipertensão Arterial Pulmonar , Escleroderma Sistêmico , Humanos , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/diagnóstico , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/classificação , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico , Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/fisiopatologia , Hipertensão Arterial Pulmonar/imunologia , Hipertensão Arterial Pulmonar/classificação , Hipertensão Arterial Pulmonar/tratamento farmacológico , Autoanticorpos/sangue , Hipertensão Pulmonar/imunologia , Hipertensão Pulmonar/classificação , Hipertensão Pulmonar/diagnóstico , FemininoRESUMO
Pre-capillary pulmonary arterial hypertension (PAH) is hemodynamically characterized by a mean pulmonary arterial pressure (mPAP) ≥ 20 mmHg, pulmonary capillary wedge pressure (PAWP) ≤15 mmHg and pulmonary vascular resistance (PVR) > 2. PAH is classified in six clinical subgroups, including idiopathic PAH (IPAH) and PAH associated to connective tissue diseases (CTD-PAH), that will be the main object of this review. The aim is to compare these two PAH subgroups in terms of epidemiology, histological and pathogenic findings in an attempt to define disease-specific features, including autoimmunity, that may explain the heterogeneity of response to therapy between IPAH and CTD-PAH.
Assuntos
Autoimunidade , Doenças do Tecido Conjuntivo , Humanos , Doenças do Tecido Conjuntivo/imunologia , Doenças do Tecido Conjuntivo/complicações , Hipertensão Arterial Pulmonar/imunologia , Hipertensão Arterial Pulmonar/etiologia , Hipertensão Arterial Pulmonar/fisiopatologia , Hipertensão Pulmonar/imunologia , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar Primária Familiar/fisiopatologia , Hipertensão Pulmonar Primária Familiar/imunologiaRESUMO
BACKGROUND: Pathogenesis of pulmonary hypertension (PH) is a multifactorial process driven by inflammation and pulmonary vascular remodeling. To target these two aspects of PH, we recently tested a novel treatment: Interleukin-9 (IL9) fused to F8, an antibody that binds to the extra-domain A of fibronectin (EDA+ Fn). As EDA+ Fn is not found in healthy adult tissue but is expressed during PH, IL9 is delivered specifically to the tissue affected by PH. We found that F8IL9 reduced pulmonary vascular remodeling and attenuated PH compared with sham-treated mice. PURPOSE: To evaluate possible F8IL9 effects on PH-associated inflammatory processes, we analysed the expression of genes involved in pulmonary immune responses. METHODS: We applied the monocrotaline (MCT) model of PH in mice (n = 44). Animals were divided into five experimental groups: sham-induced animals without PH (control, n = 4), MCT-induced PH without treatment (PH, n = 8), dual endothelin receptor antagonist treatment (dual ERA, n = 8), F8IL9 treatment (n = 12, 2 formats with n = 6 each), or with KSFIL9 treatment (KSFIL9, n = 12, 2 formats with n = 6 each, KSF: control antibody with irrelevant antigen specificity). After 28 days, a RT-PCR gene expression analysis of inflammatory response (84 genes) was performed in the lung. RESULTS: Compared with the controls, 19 genes exhibited relevant (+2.5-fold) upregulation in the PH group without treatment. Gene expression levels in F8IL9-treated lung tissue were reduced compared to the PH group without treatment. This was the case especially for CCL20, CXCL5, C-reactive protein, pentraxin related (CRPPR), and Kininogen-1 (KNG1). CONCLUSION: In accordance with the hypothesis stated above, F8IL9 treatment diminished the upregulation of some genes associated with inflammation in a PH animal model. Therefore, we hypothesize that IL9-based immunocytokine treatment will likely modulate various inflammatory pathways.
Assuntos
Hipertensão Pulmonar , Interleucina-9 , Animais , Camundongos , Anticorpos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/imunologia , Imunoconjugados/uso terapêutico , Inflamação/tratamento farmacológico , Interleucina-9/imunologia , Interleucina-9/uso terapêutico , Pulmão , Remodelação Vascular , Modelos Animais de DoençasRESUMO
Mast cells are responsible for IgE-dependent allergic responses, but they also produce various bioactive mediators and contribute to the pathogenesis of various cardiovascular diseases, including pulmonary hypertension (PH). The importance of lipid mediators in the pathogenesis of PH has become evident in recent years, as exemplified by prostaglandin I2, the most central therapeutic target in pulmonary arterial hypertension. New bioactive lipids other than eicosanoids have also been identified that are associated with the pathogenesis of PH. However, it remains largely unknown how mast cell-derived lipid mediators are involved in pulmonary vascular remodeling. Recently, it has been demonstrated that mast cells produce epoxidized n-3 fatty acid (n-3 epoxides) in a degranulation-independent manner, and that n-3 epoxides produced by mast cells regulate the abnormal activation of pulmonary fibroblasts and suppress the progression of pulmonary vascular remodeling. This review summarizes the role of mast cells and bioactive lipids in the pathogenesis of PH. In addition, we introduce the pathophysiological role and therapeutic potential of n-3 epoxides, a mast cell-derived novel lipid mediator, in the pulmonary vascular remodeling in PH. Further knowledge of mast cells and lipid mediators is expected to lead to the development of innovative therapies targeting pulmonary vascular remodeling.
Assuntos
Remodelação das Vias Aéreas , Ácidos Graxos Insaturados , Hipertensão Pulmonar , Lisofosfolipídeos , Mastócitos , Artéria Pulmonar , Mastócitos/metabolismo , Remodelação das Vias Aéreas/imunologia , Hipertensão Pulmonar/imunologia , Hipertensão Pulmonar/patologia , Artéria Pulmonar/imunologia , Artéria Pulmonar/patologia , Lisofosfolipídeos/biossíntese , Ácidos Graxos Insaturados/biossíntese , Humanos , AnimaisRESUMO
Impaired proteasome activity due to genetic variants of certain subunits might lead to proteasome-associated autoinflammatory syndromes (PRAAS). Here we report a de novo heterozygous missense variant of the PSMB9 proteasome subunit gene in two unrelated Japanese infants resulting in amino acid substitution of the glycine (G) by aspartic acid (D) at position 156 of the encoded protein ß1i. In addition to PRAAS-like manifestations, these individuals suffer from pulmonary hypertension and immunodeficiency, which are distinct from typical PRAAS symptoms. The missense variant results in impaired immunoproteasome maturation and activity, yet ubiquitin accumulation is hardly detectable in the patients. A mouse model of the heterozygous human genetic variant (Psmb9G156D/+) recapitulates the proteasome defects and the immunodeficiency phenotype of patients. Structurally, PSMB9 G156D interferes with the ß-ring-ßring interaction of the wild type protein that is necessary for 20S proteasome formation. We propose the term, proteasome-associated autoinflammatory syndrome with immunodeficiency (PRAAS-ID), to indicate a separate category of autoinflammatory diseases, similar to, but distinct from PRAAS, that describes the patients in this study.
Assuntos
Cisteína Endopeptidases/genética , Doenças Hereditárias Autoinflamatórias/genética , Hipertensão Pulmonar/genética , Doenças da Imunodeficiência Primária/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Animais , Cisteína Endopeptidases/metabolismo , Modelos Animais de Doenças , Feminino , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/imunologia , Doenças Hereditárias Autoinflamatórias/patologia , Heterozigoto , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/imunologia , Recém-Nascido , Masculino , Camundongos , Camundongos Transgênicos , Mutação de Sentido Incorreto , Linhagem , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/imunologia , Doenças da Imunodeficiência Primária/patologia , Complexo de Endopeptidases do Proteassoma/genética , SíndromeRESUMO
BACKGROUND: Pulmonary arterial hypertension (PH) secondary to pulmonary fibrosis (PF) is one of the most common complications in PF patients, it causes severe disease and usually have a poor prognosis. Whether the combination of PH and PF is a unique disease phenotype is unclear. We aimed to screen the key modules associated with PH-PF immune infiltration based on WGCNA and identify the hub genes for molecular typing. METHOD: Using the gene expression profile GSE24988 of PF patients with or without PH from the Gene Expression Omnibus (GEO) database, we evaluated immune cell infiltration using Cibersortx and immune cell gene signature files. Different immune cell types were screened using the Wilcoxon test; differentially expressed genes were screened using samr. The molecular pathways implicated in these differential responses were identified using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analyses. A weighted co-expression network of the differential genes was constructed, relevant co-expression modules were identified, and relationships between modules and differential immune cell infiltration were calculated. The modules most relevant to this disease were identified using weighted correlation network analysis. From these, we constructed a co-expression network; using the STRING database, we integrated the values into the human protein-protein interaction network before constructing a co-expression interaction subnet, screening genes associated with immunity and unsupervised molecular typing, and analyzing the immune cell infiltration and expression of key genes in each disease type. RESULTS: Of the 22 immune cell types from the PF GEO data, 20 different immune cell types were identified. There were 1622 differentially expressed genes (295 upregulated and 1327 downregulated). The resulting weighted co-expression network identified six co-expression modules. These were screened to identify the modules most relevant to the disease phenotype (the green module). By calculating the correlations between modules and the differentially infiltrated immune cells, extracting the green module co-expression network (46 genes), extracting 25 key genes using gene significance and module-membership thresholds, and combining these with the 10 key genes in the human protein-protein interaction network, we identified five immune cell-related marker genes that might be applied as biomarkers. Using these marker genes, we evaluated these disease samples using unsupervised clustering molecular typing. CONCLUSION: Our results demonstrated that all PF combined with PH samples belonged to four categories. Studies on the five key genes are required to validate their diagnostic and prognostic value.
Assuntos
Hipertensão Pulmonar/genética , Fibrose Pulmonar/genética , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Marcadores Genéticos , Humanos , Hipertensão Pulmonar/imunologia , Tipagem Molecular , Fibrose Pulmonar/imunologia , TranscriptomaRESUMO
OBJECTIVE: High-altitude pulmonary hypertension (HAPH) is one of the diseases with higher occurrence among people living in plateau areas. The possible mechanism of angiotensin II receptor 1 inhibitor irbesartan in improving HAPH was explored from the perspective of intestinal bacterial flora in this study. MATERIALS AND METHODS: A HAPH rat model was established under simulated high-altitude hypobaric hypoxia. The levels of oxidative stress and vasoactive substances were detected after irbesartan intervention, and intestinal flora genomics analysis was performed. RESULTS: High-altitude hypobaric hypoxia-induced the increase in pulmonary artery pressure and left ventricular systolic dysfunction in HAPH model rats, but its effects were alleviated by irbesartan. Changes in the levels of oxidative damage in intestinal tissues, such as the increase in superoxide dismutase and glutathione peroxidase in intestinal tissues and the decrease in malondialdehyde content, were also reversed by irbesartan. The serum levels of angiotensin II, endothelin 1, interleukin-6, and C-reactive protein increased substantially whereas the level of nitric oxide decreased in HAPH model rats. The levels of these vasoconstriction and inflammatory indicators were also reversed after irbesartan intervention. The distribution of intestinal florae in rats was changed by the simulated high-altitude hypoxia environment as manifested by the increased Firmicutes-to-Bacteroidetes ratio (F/B), the increased abundance of Lactobacillaceae and Lachnospiraceae, and the decreased abundance of Prevotellaceae and Desulfovibrionaceae at the family level. However, the changes in F/B ratio and the abundance of these florae were reversed by irbesartan. CONCLUSIONS: Irbesartan can alleviate pulmonary artery pressure and left ventricular relaxation in HAPH model rats, reduce the oxidative damage caused by high-altitude hypoxia, and lower the release of vasoconstrictor factors and inflammatory mediators. These effects might be caused by the increased abundance of Lactobacillaceae and Lachnospiraceae and the decreased abundance of Prevotellaceae and Desulfovibrionaceae in the intestines.