-
Cellular and Molecular Gastroenterology... 2024Functional cure is achieved by a limited number of patients with chronic hepatitis B (CHB) after nucleotide analogue(s) and interferon treatment. It is urgent to develop...
BACKGROUND & AIMS
Functional cure is achieved by a limited number of patients with chronic hepatitis B (CHB) after nucleotide analogue(s) and interferon treatment. It is urgent to develop therapies that can help a larger proportion of patients achieve functional cure. The present study was designed to explore the anti-hepatitis B virus (HBV) potency of interleukin-6 family cytokines and to characterize the underlying mechanisms of the cytokine displaying the highest anti-HBV potency.
METHODS
HBV-infected cells were used to screened the anti-HBV potency of interleukin-6 family cytokines. The concentration of oncostatin M (OSM) in patients with chronic HBV infection was examined by enzyme-linked immunosorbent assay. The underlying mechanism of OSM anti-HBV was explored through RNA-seq. C57BL/6 mice injected with rAAV8-1.3HBV were used to explore the suppression effect of OSM on HBV in vivo.
RESULTS
OSM is the most effective of the interleukin-6 family cytokines for suppression of HBV replication (percentage of average inhibition: hepatitis B surface antigen, 34.44%; hepatitis B e antigen, 32.52%; HBV DNA, 61.57%). Hepatitis B e antigen-positive CHB patients with high OSM levels had lower hepatitis B surface antigen and hepatitis B e antigen than those with low levels. OSM activated JAK-STAT signaling pathway promoting the formation of STAT1-IRF9 transcription factor complex. Following this, OSM increased the expression of various genes with known functions in innate and adaptive immunity, which was higher expression in patients with CHB in immune clearance phase than in immune tolerance phase (data from GEO: GSE65359). Interferon-induced transmembrane protein 1, one of the most differentially expressed genes, was identified as an HBV restriction factor involved in OSM-mediated anti-HBV effect. In vivo, we also found OSM significantly inhibited HBV replication and induced expression of antiviral effector interferon-induced transmembrane protein 1.
CONCLUSIONS
Our study shows that OSM remodels the immune response against HBV and exerts potent anti-HBV activity, supporting its further development as a potential therapy for treating CHB.
Topics: Mice; Animals; Humans; Hepatitis B virus; Hepatitis B Surface Antigens; Oncostatin M; Hepatitis B e Antigens; Interleukin-6; Mice, Inbred C57BL; Signal Transduction; Hepatitis B; Interferons; Virus Replication
PubMed: 37879404
DOI: 10.1016/j.jcmgh.2023.10.003 -
Frontiers in Immunology 2024MICA and MICB are Class I MHC-related glycoproteins that are upregulated on the surface of cells in response to stress, for instance due to infection or malignant...
MICA and MICB are Class I MHC-related glycoproteins that are upregulated on the surface of cells in response to stress, for instance due to infection or malignant transformation. MICA/B are ligands for NKG2D, an activating receptor on NK cells, CD8 T cells, and γδ T cells. Upon engagement of MICA/B with NKG2D, these cytotoxic cells eradicate MICA/B-positive targets. MICA is frequently overexpressed on the surface of cancer cells of epithelial and hematopoietic origin. Here, we created nanobodies that recognize MICA. Nanobodies, or VHHs, are the recombinantly expressed variable regions of camelid heavy chain-only immunoglobulins. They retain the capacity of antigen recognition but are characterized by their stability and ease of production. The nanobodies described here detect surface-disposed MICA on cancer cells by flow cytometry and can be used therapeutically as nanobody-drug conjugates when fused to the Maytansine derivative DM1. The nanobody-DM1 conjugate selectively kills MICA positive tumor cells
Topics: Humans; CD8-Positive T-Lymphocytes; Single-Domain Antibodies; Histocompatibility Antigens Class I; NK Cell Lectin-Like Receptor Subfamily K; Neoplasms; Immunotherapy
PubMed: 38550583
DOI: 10.3389/fimmu.2024.1368586 -
Scientific Reports Oct 2023Rare individuals with Bombay and para-Bombay phenotypes lack or have weak expression of the ABO(H) antigens on surface of red blood cells due to no or very weak H-type...
Rare individuals with Bombay and para-Bombay phenotypes lack or have weak expression of the ABO(H) antigens on surface of red blood cells due to no or very weak H-type α(1,2)fucosyltransferase activity encoded by FUT1. These phenotypes are clinically important because subjects with these phenotypes can only accept transfusions of autologous blood or blood from subjects with the same phenotypes due to the anti-H antibody. To survey FUT1 alleles involved in Bombay and para-Bombay phenotypes, the effect of 22 uncharacterized nonsynonymous SNPs in the Erythrogene database on the α(1,2)fucosyltransferase activity were examined by transient expression studies and in silico analysis using four different online software tools. Two nonfunctional alleles (FUT1 with c.503C>G and c.749G>C) and one weakly functional allele (with c.799T>C) were identified in transient expression studies, while the software predicted that the proteins encoded by more alleles including these would be impaired. Because both nonfunctional FUT1 alleles appear to link to the nonsecretor alleles, homozygotes of these alleles would be of the Bombay phenotype. The present results suggest that functional assays are useful for characterization of nonsynonymous SNPs of FUT1 when their phenotypes are not available.
Topics: Humans; Fucosyltransferases; ABO Blood-Group System; Phenotype; Alleles; Genotype
PubMed: 37838738
DOI: 10.1038/s41598-023-44731-1 -
Frontiers in Immunology 2023The transcription factor HELIOS is primarily known for its expression in CD4 regulatory T cells, both in humans and mice. In mice, HELIOS is found in exhausted CD8 T...
INTRODUCTION
The transcription factor HELIOS is primarily known for its expression in CD4 regulatory T cells, both in humans and mice. In mice, HELIOS is found in exhausted CD8 T cells. However, information on human HELIOS CD8 T cells is limited and conflicting.
METHODS
In this study, we characterized by flow cytometry and transcriptomic analyses human HELIOS CD8 T cells.
RESULTS
These T cells primarily consist of memory cells and constitute approximately 21% of blood CD8 T cells. In comparison with memory HELIOS T-BET CD8 T cells that displayed robust effector functions, the memory HELIOS T-BET CD8 T cells produce lower amounts of IFN-γ and TNF-α and have a lower cytotoxic potential. We wondered if these cells participate in the immune response against viral antigens, but did not find HELIOS cells among CD8 T cells recognizing CMV peptides presented by HLA-A2 and HLA-B7. However, we found HELIOS CD8 T cells that recognize a CMV peptide presented by MHC class Ib molecule HLA-E. Additionally, a portion of HELIOS CD8 T cells is characterized by the expression of CD161, often used as a surface marker for identifying T cells. These CD8 T cells express T/T-related genes encoding RORgt, RORa, PLZF, and CCL20.
DISCUSSION
Our findings emphasize that HELIOS is expressed across various CD8 T cell populations, highlighting its significance beyond its role as a transcription factor for Treg or exhausted murine CD8 T cells. The significance of the connection between HELIOS and HLA-E restriction is yet to be understood.
Topics: Humans; Animals; Mice; HLA-E Antigens; CD8-Positive T-Lymphocytes; Tumor Necrosis Factor-alpha; Transcription Factors; Cytomegalovirus Infections
PubMed: 38187391
DOI: 10.3389/fimmu.2023.1308539 -
Journal of Translational Medicine Jul 2023Chimeric antigen receptors (CARs) are engineered to target T cells specifically to tumor cells, resulting in the engineered T cell killing the tumor cell. This... (Review)
Review
Chimeric antigen receptors (CARs) are engineered to target T cells specifically to tumor cells, resulting in the engineered T cell killing the tumor cell. This technology has been developed to target a range of cancers, with the most notable successes in the treatment of B-cell malignancies where four approved therapies, all targeting CD19, are on the market. These four products differ in the costimulation domains, with axicabtagene ciloleucel (Yescarta) and brexucabtagene autoleucel (Tecartus) both utilizing the CD28 costimulation domain whilst tisagenlecleucel (Kymriah) and lisocabtagene maraleucel (Breyanzi) both utilizing the 4-1BB costimulation domain. There are clearly defined differences in how the CD28 and 4-1BB domains signal, yet it is difficult to ascertain which domain affords a superior mechanism of action given many other differences between these products, including overall CAR architecture and manufacturing methods. Additionally, while in vitro and preclinical in vivo studies have compared CARs with different costimulation domains, it remains a challenge to extrapolate differences observed in this biology across different experimental systems to the overall product performance. While there has been extensive preclinical and clinical work looking at CARs with a variety of targeting domains and architectures, this review will focus on the differences between the four marketed anti-CD19 CAR-Ts, with an additional focus on the impact of hinge and transmembrane domain on CAR activity and interaction with the target cell as well as other proteins on the surface of the T-cell.
Topics: Adaptor Proteins, Signal Transducing; Antigens, CD19; CD28 Antigens; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; T-Lymphocytes; Humans
PubMed: 37518011
DOI: 10.1186/s12967-023-04372-4 -
Chinese Medical Journal Nov 2023Hepatitis B surface antigen (HBsAg) clearance is vital for a functional cure of hepatitis B virus (HBV) infection. However, the incidence and predictors of HBsAg...
BACKGROUND
Hepatitis B surface antigen (HBsAg) clearance is vital for a functional cure of hepatitis B virus (HBV) infection. However, the incidence and predictors of HBsAg seroclearance in patients co-infected with HBV and human immunodeficiency virus (HIV) remain largely unknown in Guangdong, China.
METHODS
Between 2009 and 2019, patients co-infected with HBV/HIV undergoing antiretroviral therapy (ART) in Guangzhou Eighth People's Hospital affiliated to Guangzhou Medical University were retrospectively reviewed with the endpoint on December 31, 2020. The incidence and risk factors for HBsAg seroclearance were evaluated using Kaplan-Meier and multivariate Cox regression analyses.
RESULTS
A total of 1550 HBV/HIV co-infected patients were included in the study, with the median age of 42 years and 86.0% (1333/1550) males. Further, 98.3% (1524/1550) received ART containing tenofovir disoproxil fumarate (TDF) plus lamivudine (3TC). HBV DNA was examined in 1283 cases at the last follow-up. Over the median 4.7 years of follow-up, 8.1% (126/1550) patients achieved HBsAg seroclearance, among whom 50.8% (64/126) obtained hepatitis B surface antibody, 28.1% (137/488) acquired hepatitis B e antigen seroconversion, and 95.9% (1231/1283) undetectable HBV DNA. Compared with patients who maintained HBsAg positive, cases achieving HBsAg seroclearance showed no differences in age, gender, CD4 + T cell count, alanine aminotransferase (ALT) level, or fibrosis status; however, they presented lower HBV DNA levels, lower HBsAg levels, and higher rates of HBV genotype B at the baseline. Multivariate analysis showed that baseline HBsAg <1500 cutoff index (COI) (adjusted hazard ratio [aHR], 2.74, 95% confidence interval [95% CI]: 1.48-5.09), ALT elevation >2 × upper limit of normal during the first six months after receiving ART (aHR, 2.96, 95% CI: 1.53-5.77), and HBV genotype B (aHR, 3.73, 95% CI: 1.46-9.59) were independent predictors for HBsAg seroclearance (all P <0.01).
CONCLUSIONS
Long-term TDF-containing ART has high anti-HBV efficacy including relatively high overall HBsAg seroclearance in HBV/HIV co-infected patients. Lower baseline HBsAg levels, HBV genotype B, and elevated ALT levels during the first six months of ART are potential predictors of HBsAg seroclearance.
Topics: Male; Humans; Adult; Hepatitis B Surface Antigens; Hepatitis B virus; HIV Infections; HIV; DNA, Viral; Incidence; Coinfection; Retrospective Studies; Tenofovir; Lamivudine; Hepatitis B, Chronic
PubMed: 37881959
DOI: 10.1097/CM9.0000000000002886 -
Current Treatment Options in Oncology Feb 2024PSMA-PET has been a practice-changing imaging biomarker for the management of men with PCa. Research suggests improved accuracy over conventional imaging and other PET... (Review)
Review
PSMA-PET has been a practice-changing imaging biomarker for the management of men with PCa. Research suggests improved accuracy over conventional imaging and other PET radiotracers in many contexts. With multiple approved PSMA-targeting radiotracers, PSMA PET will become even more available in clinical practice. Its increased use requires an understanding of the prospective data available and caution when extrapolating from prior trial data that utilized other imaging modalities. Future trials leveraging PSMA PET for treatment optimization and management decision-making will ultimately drive its clinical utility.
Topics: Humans; Male; Antigens, Surface; Neoplasm Staging; Positron Emission Tomography Computed Tomography; Prospective Studies; Prostatic Neoplasms; Radiopharmaceuticals; Prostate-Specific Antigen
PubMed: 38270802
DOI: 10.1007/s11864-024-01181-9 -
Journal of Translational Medicine Jan 2024Idiopathic pulmonary fibrosis (IPF) is a globally prevalent, progressive disease with limited treatment options and poor prognosis. Because of its irreversible disease... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a globally prevalent, progressive disease with limited treatment options and poor prognosis. Because of its irreversible disease progression, IPF affects the quality and length of life of patients and imposes a significant burden on their families and social healthcare services. The use of the antifibrotic drugs pirfenidone and nintedanib can slow the progression of the disease to some extent, but it does not have a reverse effect on the prognosis. The option of lung transplantion is also limited owing to contraindications to transplantation, possible complications after transplantation, and the risk of death. Therefore, the discovery of new, effective treatment methods is an urgent need. Over recent years, various studies have been undertaken to investigate the relationship between interstitial pneumonia and lung cancer, suggesting that some immune checkpoints in IPF are similar to those in tumors. Immune checkpoints are a class of immunosuppressive molecules that are essential for maintaining autoimmune tolerance and regulating the duration and magnitude of immune responses in peripheral tissues. They can prevent normal tissues from being damaged and destroyed by the immune response. While current studies have focused on PD-1/PD-L1 and CTLA-4, PD-1/PD-L1 may be the only effective immune checkpoint IPF treatment. This review discusses the application of PD-1/PD-L1 checkpoint in IPF, with the aim of finding a new direction for IPF treatment.
Topics: Humans; Programmed Cell Death 1 Receptor; B7-H1 Antigen; Idiopathic Pulmonary Fibrosis; Contraindications; Immune Tolerance
PubMed: 38263193
DOI: 10.1186/s12967-024-04884-7 -
BMC Medicine Feb 2024The coexistence of hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (HBsAb) represents an uncommon serological pattern observed in patients with...
BACKGROUND
The coexistence of hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (HBsAb) represents an uncommon serological pattern observed in patients with hepatitis B virus (HBV) infection, and its underlying mechanism and clinical significance have not been well established. The aim of this study was to investigate the association between this serological profile and clinical treatment outcomes in children with chronic hepatitis B (CHB).
METHODS
This retrospective cohort study included 372 treatment-naïve CHB children from the Hunan Children's Hospital. The participants were categorized into HBsAb-positive group and HBsAb-negative group. The associations between HBsAb positive status to clinical outcomes were assessed using Cox proportional hazard regression. Receiver operating characteristic curve was conducted to evaluate the prediction ability in HBsAg loss.
RESULTS
The coexistence of HBsAg and HBsAb accounted for 23.39% (87/372) of the participants. The crude incidence rates of HBsAg loss, hepatitis B e antigen (HBeAg) clearance, and HBV-DNA undetectability were higher in the HBsAb-positive group compared with the HBsAb-negative group (37.46 vs. 17.37, 49.51 vs. 28.66, 92.11 vs. 66.54 per 100 person-years, respectively, all P < 0.05). The Cox regression analysis revealed a significant association between this serological profile and an increased likelihood of HBsAg loss (HR = 1.78, P = 0.001), and HBeAg clearance (HR = 1.78, P = 0.001). In addition, a combination of HBsAb ≥ 0.84 log10 IU/L and age ≤ 5 years can help identify patients likely to achieve HBsAg loss after antiviral therapy, with an AUC of 0.71.
CONCLUSIONS
Children who are positive for both HBsAg and HBsAb demonstrate a higher probability of favorable outcomes after antiviral treatment. Thus, children with HBsAb-positive CHB should be actively treated to achieve functional cure.
Topics: Child; Humans; Child, Preschool; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Hepatitis B e Antigens; Retrospective Studies; Hepatitis B virus; Treatment Outcome; Hepatitis B Antibodies; Antiviral Agents
PubMed: 38378606
DOI: 10.1186/s12916-024-03294-2 -
Journal of Clinical Immunology Oct 2023The human CD19 antigen is expressed throughout B cell ontogeny with the exception of neoplastic plasma cells and a subset of normal plasma cells. CD19 plays a role in...
BACKGROUND
The human CD19 antigen is expressed throughout B cell ontogeny with the exception of neoplastic plasma cells and a subset of normal plasma cells. CD19 plays a role in propagating signals from the B cell receptor and other receptors such as CXCR4 in mature B cells. Studies of CD19-deficient patients have confirmed its function during the initial stages of B cell activation and the production of memory B cells; however, its role in the later stages of B cell differentiation is unclear.
OBJECTIVE
Using B cells from a newly identified CD19-deficient individual, we investigated the role of CD19 in the generation and function of plasma cells using an in vitro differentiation model.
METHODS
Flow cytometry and long-read nanopore sequencing using locus-specific long-range amplification products were used to screen a patient with suspected primary immunodeficiency. Purified B cells from the patient and healthy controls were activated with CD40L, IL-21, IL-2, and anti-Ig, then transferred to different cytokine conditions to induce plasma cell differentiation. Subsequently, the cells were stimulated with CXCL12 to induce signalling through CXCR4. Phosphorylation of key downstream proteins including ERK and AKT was assessed by Western blotting. RNA-seq was also performed on in vitro differentiating cells.
RESULTS
Long-read nanopore sequencing identified the homozygous pathogenic mutation c.622del (p.Ser208Profs*19) which was corroborated by the lack of CD19 cell surface staining. CD19-deficient B cells that are predominantly naïve generate phenotypically normal plasma cells with expected patterns of differentiation-associated genes and normal levels of CXCR4. Differentiated CD19-deficient cells were capable of responding to CXCL12; however, plasma cells derived from naïve B cells, both CD19-deficient and sufficient, had relatively diminished signaling compared to those generated from total B cells. Additionally, CD19 ligation on normal plasma cells results in AKT phosphorylation.
CONCLUSION
CD19 is not required for generation of antibody-secreting cells or the responses of these populations to CXCL12, but may alter the response other ligands that require CD19 potentially affecting localization, proliferation, or survival. The observed hypogammaglobulinemia in CD19-deficient individuals is therefore likely attributable to the lack of memory B cells.
Topics: Humans; Plasma Cells; Antigens, CD19; Proto-Oncogene Proteins c-akt; B-Lymphocytes; Receptors, Antigen, B-Cell; Adaptor Proteins, Signal Transducing; Chemokine CXCL12
PubMed: 37246174
DOI: 10.1007/s10875-023-01511-w