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Scientific Reports Dec 2023The functionally pleiotropic ectoenzyme CD38 is a glycohydrolase widely expressed on immune and non-hematopoietic cells. By converting NAD to ADP-ribose and...
The functionally pleiotropic ectoenzyme CD38 is a glycohydrolase widely expressed on immune and non-hematopoietic cells. By converting NAD to ADP-ribose and nicotinamide, CD38 governs organismal NAD homeostasis and the activity of NAD-dependent cellular enzymes. CD38 has emerged as a major driver of age-related NAD decline underlying adverse metabolic states, frailty and reduced health span. CD38 is upregulated in systemic sclerosis (SSc), a chronic disease characterized by fibrosis in multiple organs. We sought to test the hypothesis that inhibition of the CD38 ecto-enzymatic activity using a heavy-chain monoclonal antibody Ab68 will, via augmenting organismal NAD, prevent fibrosis in a mouse model of SSc characterized by NAD depletion. Here we show that treatment of mice with a non-cytotoxic heavy-chain antibody that selectively inhibits CD38 ectoenzyme resulted in NAD boosting that was associated with significant protection from fibrosis in multiple organs. These findings suggest that targeted inhibition of CD38 ecto-enzymatic activity could be a potential pharmacological approach for SSc fibrosis treatment.
Topics: Mice; Animals; ADP-ribosyl Cyclase 1; Antigens, CD; Antigens, Differentiation; NAD+ Nucleosidase; NAD; ADP-ribosyl Cyclase; Membrane Glycoproteins; Glycoside Hydrolases; Fibrosis
PubMed: 38086958
DOI: 10.1038/s41598-023-49450-1 -
Cells Jun 2022We assessed immune cell infiltrates to develop an immunoscore for prognosis and to investigate its correlation with the clinical data of patients with head and neck...
We assessed immune cell infiltrates to develop an immunoscore for prognosis and to investigate its correlation with the clinical data of patients with head and neck cancer. CD8, FoxP3, and CD68 markers were evaluated by immunohistochemistry in 258 carcinoma samples and positive cells were counted in stromal and intra-tumoral compartments. The RStudio software was used to assess optimal cut-offs to divide the population according to survival while the prognostic value was established by using Kaplan-Meier curves and Cox regression models for each immune marker alone and in combination. We found with univariate analysis that the infiltration of immune cells in both compartments was predictive for recurrence-free survival and overall survival. Multivariate analysis revealed that CD8+ density was an independent prognostic marker. Additionally, the combination of CD8, FoxP3, and CD68 in an immunoscore provided a significant association with overall survival ( = 0.002, HR = 9.87). Such an immunoscore stayed significant ( = 0.018, HR = 11.17) in a multivariate analysis in comparison to tumor stage and histological grade, which had lower prognostic values. Altogether, our analysis indicated that CD8, FoxP3, and CD68 immunoscore was a strong, independent, and significant prognostic marker that could be introduced into the landscape of current tools to improve the clinical management of head and neck cancer patients.
Topics: Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers; CD8-Positive T-Lymphocytes; Carcinoma; Disease Progression; Forkhead Transcription Factors; Head and Neck Neoplasms; Humans; Immunohistochemistry; Lymphocytes, Tumor-Infiltrating
PubMed: 35805132
DOI: 10.3390/cells11132050 -
Blood May 2020
Topics: Animals; Antigens, Differentiation; Disease Models, Animal; Hematopoietic Stem Cell Transplantation; Heterografts; Humans; Mice; Neoplasms; Neoplastic Stem Cells; Receptors, Immunologic; Xenograft Model Antitumor Assays
PubMed: 32379878
DOI: 10.1182/blood.2020005554 -
Oncoimmunology 2021Immune checkpoint inhibitors (ICIs) have improved the survival of patients with non-small cell lung cancer (NSCLC) by reinvigorating tumor-specific T cell responses....
Immune checkpoint inhibitors (ICIs) have improved the survival of patients with non-small cell lung cancer (NSCLC) by reinvigorating tumor-specific T cell responses. However, the specificity of such T cells and the human leukocyte antigen (HLA)-associated epitopes recognized, remain elusive. In this study, we identified NSCLC T cell epitopes of recently described NSCLC-associated antigens, termed keratinocyte differentiation antigens. Epitopes of these antigens were presented by HLA-A 03:01 and HLA-C 04:01 and were associated with responses to ICI therapy. Patients with CD8 T cell responses to these epitopes had improved overall and progression-free survival. T cells specific for such epitopes could eliminate HLA class I-matched NSCLC cells and were enriched in patient lung tumors. The identification of novel lung cancer HLA-associated epitopes that correlate with improved ICI-dependent treatment outcomes suggests that keratinocyte-specific proteins are important tumor-associated antigens in NSCLC. These findings improve our understanding of the mechanisms of ICI therapy and may help support the development of vaccination strategies to improve ICI-based treatment of these tumors.
Topics: Antigens, Differentiation; Carcinoma, Non-Small-Cell Lung; Humans; Immune Checkpoint Inhibitors; Keratinocytes; Lung Neoplasms
PubMed: 34858733
DOI: 10.1080/2162402X.2021.2006893 -
Journal of Virology Oct 2023Mouse models of viral infection play an especially large role in virology. In 1960, a mouse virus, lactate dehydrogenase-elevating virus (LDV), was discovered and found...
Mouse models of viral infection play an especially large role in virology. In 1960, a mouse virus, lactate dehydrogenase-elevating virus (LDV), was discovered and found to have the peculiar ability to evade clearance by the immune system, enabling it to persistently infect an individual mouse for its entire lifespan without causing overt disease. However, researchers were unable to grow LDV in culture, ultimately resulting in the demise of this system as a model of failed immunity. We solve this problem by identifying the cell-surface molecule CD163 as the critical missing component in cell-culture systems, enabling the growth of LDV in immortalized cell lines for the first time. This advance creates abundant opportunities for further characterizing LDV in order to study both failed immunity and the family of viruses to which LDV belongs, (aka, arteriviruses).
Topics: Animals; Mice; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Cell Culture Techniques; Cell Line; Ectopic Gene Expression; Lactate dehydrogenase-elevating virus; Receptors, Cell Surface; Time Factors
PubMed: 37792000
DOI: 10.1128/jvi.00930-23 -
Frontiers in Immunology 2021Immune-mediated necrotizing myopathy (IMNM) is characterized by manifestation of myonecrosis and regeneration of muscle fibers; however, the underlying pathogenesis... (Clinical Trial)
Clinical Trial
Immune-mediated necrotizing myopathy (IMNM) is characterized by manifestation of myonecrosis and regeneration of muscle fibers; however, the underlying pathogenesis remains unclear. This study aimed to investigate the role and mechanism of miR-18a-3p and its target RNA-binding protein HuR in IMNM. HuR and miR-18a-3p levels were detected in the skeletal muscles of 18 patients with IMNM using quantitative reverse-transcription real-time polymerase chain reaction (qRT-PCR) and western blotting analysis. Human myoblasts were transfected with small interfering RNA targeting HuR and miR-18a-3p mimic or inhibitor. Myogenic differentiation markers, myogenin and myosin heavy chain, were analyzed by qRT-PCR, western blotting analysis, and immunofluorescence staining. The results showed that miR-18a-3p was upregulated (p=0.0002), whereas HuR was downregulated (p=0.002) in the skeletal muscles of patients with IMNM. The expression of miR-18a-3p in patients with IMNM was negatively correlated with those of HuR (r = -0.512, p = 0.029). We also found that disease activity was positively correlated with HuR expression ( = 0.576, = 0.012) but muscle activity was negatively correlated with miR-18a-3p expression ( = -0.550, = 0.017). Besides, bioinformatics analysis and dual-luciferase reporter assays suggested that miR-18a-3p could directly target HuR. Cellular experiments showed that overexpression of miR-18a-3p inhibited myogenic differentiation by targeting HuR, whereas inhibition of miR-18a-3p led to opposite results. Therefore, miR-18a-3p and its target protein HuR may be responsible for modulating the myogenic process in IMNM and can thus be therapeutic targets for the same.
Topics: Adult; Antigens, Differentiation; Cell Differentiation; ELAV-Like Protein 1; Female; Humans; Male; MicroRNAs; Middle Aged; Muscle Development; Myositis
PubMed: 35069550
DOI: 10.3389/fimmu.2021.780237 -
PloS One 2020Hereditary nasal parakeratosis (HNPK) is an inherited disorder described in Labrador Retrievers and Greyhounds. It has been associated with breed-specific variants in...
Hereditary nasal parakeratosis (HNPK) is an inherited disorder described in Labrador Retrievers and Greyhounds. It has been associated with breed-specific variants in the SUV39H2 gene encoding a histone 3 methyltransferase involved in epigenetic silencing. Formalin-fixed biopsies of the nasal planum of Labrador Retrievers were screened by immunofluorescence microscopy for the presence and distribution of epidermal proliferation and differentiation markers. Gene expression of these markers was further analysed using RNA sequencing (RNA-seq) and ultrastructural epidermal differences were investigated by electron microscopy. Differentiation of the nasal planum in the basal and suprabasal epidermal layers of HNPK-affected dogs (n = 6) was similar compared to control dogs (n = 6). In the upper epidermal layers, clear modifications were noticed. Loricrin protein was absent in HNPK-affected nasal planum sections in contrast to sections of the same location of control dogs. However, loricrin was present in the epidermis of paw pads and abdominal skin from HNPK dogs and healthy control dogs. The patterns of keratins K1, K10 and K14, were not markedly altered in the nasal planum of HNPK-affected dogs while the expression of the terminal differentiation marker involucrin appeared less regular. Based on RNA-seq, LOR and IVL expression levels were significantly decreased, while KRT1, KRT10 and KRT14 levels were up-regulated (log2fold-changes of 2.67, 3.19 and 1.71, respectively) in HNPK-affected nasal planum (n = 3) compared to control dogs (n = 3). Electron microscopical analysis revealed structural alterations in keratinocytes and stratum corneum, and disrupted keratinocyte adhesions and distended intercellular spaces in lesional samples (n = 3) compared to a sample of a healthy control dog (n = 1). Our findings demonstrate aberrant keratinocyte terminal differentiation of the nasal planum of HNPK-affected Labrador Retrievers and provide insights into biological consequences of this inactive SUV39H2 gene variant.
Topics: Animals; Dogs; Female; Male; Antigens, Differentiation; Dog Diseases; Genetic Diseases, Inborn; Keratinocytes; Nose Diseases; Parakeratosis
PubMed: 32119674
DOI: 10.1371/journal.pone.0225901 -
Medecine Sciences : M/S Apr 2015During evolution, organisms developed adaptative mechanisms to survive continuous aggressions from a variety of pathogens. Among these lines of defence, many cellular... (Review)
Review
During evolution, organisms developed adaptative mechanisms to survive continuous aggressions from a variety of pathogens. Among these lines of defence, many cellular proteins have been described to modulate viral replication and are the subject of intense study. This review will focus on IFITM (interferon induced transmembrane protein), a family of proteins that act against a particularly wide range of viruses. We will summarize our knowledge of the antiviral mechanisms used by IFITM to interfere with the replication of several viruses, and more specifically HIV (human immunodeficiency virus).
Topics: Animals; Antigens, Differentiation; Antiviral Agents; HIV-1; Humans; Immunity, Innate; Membrane Proteins; Protein Transport; Viruses
PubMed: 25958755
DOI: 10.1051/medsci/20153104011 -
PloS One 2021The expression of programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) indicate the efficacy of anti-PD-1/PD-L1 therapy in colorectal cancer (CRC), but are...
The expression of programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) indicate the efficacy of anti-PD-1/PD-L1 therapy in colorectal cancer (CRC), but are less useful for monitoring the efficacy of therapy of CRC liver metastasis (CRLM). This study investigated the effects of immune molecules on the prognosis of CRLM. We enrolled 71 patients with CRLM who underwent curative resection for CRC. We used immunohistochemistry to analyze the expression of PD-1, PD-L1, indoleamine-pyrrole 2,3-dioxygenase (IDO), and CD163 (a marker of tumor-associated macrophages [TAMs]) in metastatic tumors. The immune molecules PD-1, PD-L1, IDO, and TAMs were expressed in 32.3%, 47.8%, 45.0%, and 47.9% of metastatic CRC samples, respectively. The 5-year overall survival rates associated with immune molecule-positive groups were significantly better than in the negative groups (PD-1: 87.7% vs 53.2%, p = 0.023; PD-L1: 82.4% vs 42.3%, p = 0.007; IDO: 80.7% vs 43.5%, p = 0.007; TAMs: 82.6% vs 48.0%, p = 0.005). Multivariate analysis revealed PD-1 expression (p = 0.032, hazard ratio: 0.19), IDO expression (p = 0.049, hazard ratio: 0.37), and tumor differentiation (p<0.001, hazard ratio: 0.02) as independent prognostic indicators. PD-1 and TAMs in metastases were associated with less aggressive features such as smaller tumors. Furthermore, TAMs positively and significantly correlated with PD-1 expression (p = 0.011), PD-L1 expression (p = 0.024), and tended to correlate with IDO expression (p = 0.078). PD-1, PD-L1, IDO, and TAMs in CRLM were associated with less aggressive features and better prognosis of patients with CRC, indicating adaptive antitumor immunity vs immune tolerance. These molecules may therefore serve as prognostic markers for CRLM.
Topics: Adaptive Immunity; Adult; Aged; Aged, 80 and over; Antigens, CD; Antigens, Differentiation, Myelomonocytic; B7-H1 Antigen; Biomarkers, Tumor; Colonic Neoplasms; Colorectal Neoplasms; Diagnostic Tests, Routine; Female; Gene Expression; Humans; Immune Tolerance; Indoleamine-Pyrrole 2,3,-Dioxygenase; Japan; Liver; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Programmed Cell Death 1 Receptor; Receptors, Cell Surface; Rectal Neoplasms; Transcriptome; Tumor-Associated Macrophages
PubMed: 34797860
DOI: 10.1371/journal.pone.0259940 -
Journal of Immunology Research 2020The function of natural killer (NK) cells, defending against virus infection and tumour progression, is regulated by multiple activating and inhibiting receptors... (Review)
Review
The function of natural killer (NK) cells, defending against virus infection and tumour progression, is regulated by multiple activating and inhibiting receptors expressed on NK cells, among which sialic acid-bind immunoglobulin-like lectins (Siglecs) act as a vital inhibitory group. Previous studies have shown that Siglec7 and Siglec9 are expressed on NK cells, which negatively regulate the function of NK cells and modulate the immune response through the interaction of sialic acid-containing ligands. Siglec7 and Siglec9 are very similar in distribution, gene encoding, protein sequences, ligand affinity, and functions in regulating the immune system against virus and cancers, but differences still exist between them. In this review, we aim to discuss the similarities and differences between Siglec7 and Siglec9 and analyze their functions in virus infection and tumour progression in order to develop better anti-viral and anti-tumor immunotherapy in the future.
Topics: Antigens, CD; Antigens, Differentiation, Myelomonocytic; Disease Progression; Humans; Killer Cells, Natural; Lectins; Neoplasms; Sialic Acid Binding Immunoglobulin-like Lectins; Virus Diseases
PubMed: 32322597
DOI: 10.1155/2020/6243819