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Immunity, Inflammation and Disease May 2024Thyroid-associated ophthalmopathy (TAO) is the most common orbital disease in adults, potentially leading to disfigurement and visual impairment. However, the causes of...
BACKGROUND
Thyroid-associated ophthalmopathy (TAO) is the most common orbital disease in adults, potentially leading to disfigurement and visual impairment. However, the causes of TAO are not fully understood. IL-35B cells are a newly identified regulatory B cells (Bregs) in maintaining immune balance in various autoimmune diseases. Yet, the influence of IL-35Bregs in TAO remains unexplored.
METHODS
This study enrolled 36 healthy individuals and 14 TAO patients. We isolated peripheral blood mononuclear cells and stimulated them with IL-35 and CpG for 48 h. Flow cytometry was used to measure the percentages of IL-35Bregs.
RESULTS
The percentage of circulating IL-35Bregs was higher in TAO patients, and this increase correlated positively with disease activity. IL-35 significantly increased the generation of IL-35Bregs in healthy individuals. However, B cells from TAO patients exhibited potential impairment in transitioning into IL-35Breg phenotype under IL-35 stimulation.
CONCLUSIONS
Our results suggest a potential role of IL-35Bregs in the development of TAO, opening new avenues for understanding disease mechanisms and developing therapeutic approaches.
Topics: Humans; B-Lymphocytes, Regulatory; Interleukins; Female; Male; Adult; Middle Aged; Graves Ophthalmopathy; Aged
PubMed: 38804861
DOI: 10.1002/iid3.1304 -
Heliyon May 2024The high heterogeneity of lung squamous cell carcinomas (LUSC) and the complex tumor microenvironment lead to non-response to immunotherapy in many patients. Therefore,...
The high heterogeneity of lung squamous cell carcinomas (LUSC) and the complex tumor microenvironment lead to non-response to immunotherapy in many patients. Therefore, characterizing the heterogeneity of the tumor microenvironment in patients with LUSC and further exploring the immune features and molecular mechanisms that lead to immune resistance will help improve the efficacy of immunotherapy in such patients. Herein, we retrospectively analyzed the RNA sequencing (RNA-seq) data of 513 LUSC samples with other multiomics and single-cell RNA-seq data and validated key features using multiplex immunohistochemistry. We divided these samples into six subtypes (CS1-CS6) based on the RNA-seq data and found that CS3 activates the immune response with a high level of lymphocyte infiltration and gathers a large number of patients with advanced-stage disease but increases the expression of exhausted markers cytotoxic T-lymphocyte associated protein 4, lymphocyte-activation gene 3, and programmed death-1. The prediction of the response to immunotherapy showed that CS3 is potentially resistant to immune checkpoint blockade therapy, and multi-omic data analysis revealed that CS3 specifically expresses immunosuppression-related proteins B cell lymphoma 2, GRB2-associated binding protein, and dual-specificity phosphatase 4 and has a high mutation ratio of the driver gene ATP binding cassette subfamily A member 13. Furthermore, single-cell RNA-seq verified lymphocyte infiltration in the CS3 subtype and revealed a positive relationship between the expression of LAMC2-CD44 and immune resistance. LAMC2 and CD44 are epithelial-mesenchymal transition-associated genes that modulate tumor proliferation, and multicolor immunofluorescence validated the negative relationship between the expression of LAMC2-CD44 and immune infiltration. Thus, we identified a lymphocyte-infiltrated subtype (CS3) in patients with LUSC that exhibited resistance to immune checkpoint blockade therapy, and the co-hyperexpression of LAMC2-CD44 contributed to immune resistance, which could potentially improve immunological efficacy by targeting this molecule pair in combination with immunotherapy.
PubMed: 38803944
DOI: 10.1016/j.heliyon.2024.e31299 -
Cureus Apr 2024The link between the Epstein-Barr virus (EBV) and the development of certain types of lymphomas in patients with human immunodeficiency virus (HIV) is of noteworthy...
A Newly Diagnosed Patient With Human Immunodeficiency Virus (HIV)-Associated Epstein-Barr Virus (EBV)-Positive Diffuse Large B-cell Lymphoma and Esophageal Candidiasis: A Case Report.
The link between the Epstein-Barr virus (EBV) and the development of certain types of lymphomas in patients with human immunodeficiency virus (HIV) is of noteworthy clinical importance. Their immunocompromised state increases the risk of cancers such as lymphomas. Gastrointestinal (GI) lymphomas, though, can occur due to the immunosuppression caused by HIV, with diffuse large B-cell lymphoma (DLBCL) being common in this group. This case report describes a case of a patient with a newly diagnosed HIV who initially presented with symptoms associated with EBV-associated DLBCL and with esophageal candidiasis. This case report highlights the need for increased awareness of HIV-related complications and the importance of close follow-up. In addition, despite advancements in highly active antiretroviral therapy (HAART), acquired immunodeficiency syndrome (AIDS)-related lymphomas continue to be a concern requiring treatment approaches.
PubMed: 38803735
DOI: 10.7759/cureus.59106 -
Frontiers in Immunology 2024Primary immunodeficiencies are heritable defects in immune system function. Antibody deficiency is the most common form of primary immunodeficiency in humans, can be...
BACKGROUND
Primary immunodeficiencies are heritable defects in immune system function. Antibody deficiency is the most common form of primary immunodeficiency in humans, can be caused by abnormalities in both the development and activation of B cells, and may result from B-cell-intrinsic defects or defective responses by other cells relevant to humoral immunity. Inflammatory gastrointestinal complications are commonly observed in antibody-deficient patients, but the underlying immune mechanisms driving this are largely undefined.
METHODS
In this study, several mouse strains reflecting a spectrum of primary antibody deficiency (IgA, Aicda, CD19 and J ) were used to generate a functional small-bowel-specific cellular atlas using a novel high-parameter flow cytometry approach that allows for the enumeration of 59 unique cell subsets. Using this cellular atlas, we generated a direct and quantifiable estimate of immune dysregulation. This estimate was then used to identify specific immune factors most predictive of the severity of inflammatory disease of the small bowel (small bowel enteropathy).
RESULTS
Results from our experiments indicate that the severity of primary antibody deficiency positively correlates with the degree of immune dysregulation that can be expected to develop in an individual. In the SI of mice, immune dysregulation is primarily explained by defective homeostatic responses in T cell and invariant natural killer-like T (iNKT) cell subsets. These defects are strongly correlated with abnormalities in the balance between protein (MHCII-mediated) versus lipid (CD1d-mediated) antigen presentation by intestinal epithelial cells (IECs) and intestinal stem cells (ISCs), respectively.
CONCLUSIONS
Multivariate statistical approaches can be used to obtain quantifiable estimates of immune dysregulation based on high-parameter flow cytometry readouts of immune function. Using one such estimate, we reveal a previously unrecognized tradeoff between iNKT cell activation and type 1 immunity that underlies disease in the small bowel. The balance between protein/lipid antigen presentation by ISCs may play a crucial role in regulating this balance and thereby suppressing inflammatory disease in the small bowel.
Topics: Animals; Mice; Disease Models, Animal; Flow Cytometry; Intestine, Small; Mice, Knockout; Primary Immunodeficiency Diseases; Mice, Inbred C57BL; B-Lymphocytes; Intestinal Diseases
PubMed: 38803492
DOI: 10.3389/fimmu.2024.1278197 -
Life Science Alliance Aug 2024The merozoite surface protein 1 (MSP1) is the most abundant protein on the surface of the invasive merozoite stages of and has long been considered a key target of...
The merozoite surface protein 1 (MSP1) is the most abundant protein on the surface of the invasive merozoite stages of and has long been considered a key target of protective immunity. We used samples from a single controlled human malaria challenge study to test whether the full-length version of MSP1 (MSP1) induced antibodies that mediated Fc-IgG functional activity in five independent assays. We found that anti-MSP1 antibodies induced complement fixation via C1q, monocyte-mediated phagocytosis, neutrophil respiratory burst, and natural killer cell degranulation as well as IFNγ production. Activity in each of these assays was strongly associated with protection. The breadth of MSP1-specific Fc-mediated effector functions was more strongly associated with protection than the individual measures and closely mirrored what we have previously reported using the same assays against merozoites. Our findings suggest that MSP1 is an important target of functional antibodies that contribute to a protective immune response against malaria.
Topics: Humans; Merozoite Surface Protein 1; Malaria, Falciparum; Plasmodium falciparum; Antibodies, Protozoan; Phagocytosis; Immunoglobulin G; Killer Cells, Natural; Interferon-gamma; Female; Merozoites; Neutrophils
PubMed: 38803222
DOI: 10.26508/lsa.202301910 -
Journal of Cellular and Molecular... May 2024The current era we experience is full with pandemic infectious agents that no longer threatens the major local source but the whole globe. Almost the most emerging...
The current era we experience is full with pandemic infectious agents that no longer threatens the major local source but the whole globe. Almost the most emerging infectious agents are severe acute respiratory syndrome coronavirus-2 (SARS CoV-2), followed by monkeypox virus (MPXV). Since no approved antiviral drugs nor licensed active vaccines are yet available, we aimed to utilize immunoinformatics approach to design chimeric vaccine against the two mentioned viruses. This is the first study to deal with design divalent vaccine against SARS-CoV-2 and MPXV. ORF8, E and M proteins from Omicron SARS-CoV-2 and gp182 from MPXV were used as the protein precursor from which multi-epitopes (inducing B-cell, helper T cells, cytotoxic T cells and interferon-ɣ) chimeric vaccine was contrived. The structure of the vaccine construct was predicted, validated, and docked to toll-like receptor-2 (TLR-2). Moreover, its sequence was also used to examine the immune simulation profile and was then inserted into the pET-28a plasmid for in silico cloning. The vaccine construct was probable antigen (0.543) and safe (non-allergen) with strong binding energy to TLR-2 (-1169.8 kcal/mol) and found to have significant immune simulation profile. In conclusion, the designed chimeric vaccine was potent and safe against SARS-CoV-2 and MPXV, which deserves further consideration.
Topics: SARS-CoV-2; Humans; COVID-19; COVID-19 Vaccines; Molecular Docking Simulation; Toll-Like Receptor 2; Epitopes, T-Lymphocyte; Epitopes, B-Lymphocyte; Epitopes
PubMed: 38801408
DOI: 10.1111/jcmm.18452 -
JBRA Assisted Reproduction May 2024Bisphenol F (BPF) is an endocrinedisrupting chemical, but information about its effect on thyroid hormones has not been fully explored. Omega 3 fatty acids (O3FA), on...
OBJECTIVE
Bisphenol F (BPF) is an endocrinedisrupting chemical, but information about its effect on thyroid hormones has not been fully explored. Omega 3 fatty acids (O3FA), on the other hand, are antioxidant and antiapoptotic agents. Therefore, this study explored the role and associated molecular mechanism of O3FA in BPF-induced hypothyroidism-mediated testicular dysfunction in male Wistar rats.
METHODS
Twenty (20) male Wistar rats were randomized into four groups (n=5/group), namely: the control group; the BPF treated group (30 mg/kg of BPF); and the intervention groups (30mg/kg BPF + 100mg/kg O3FA (BPF+O3FA-L) and 30mg/kg BPF + 300mg/kg of O3FA for 28 days).
RESULTS
Low and high doses of O3FA ameliorated BPF-induced hypothyroidism-mediated reduction in sperm quality, testosterone, luteinizing hormone, follicle-stimulating hormone, catalase, superoxide dismutase, total antioxidant capacity, and nuclear factor erythroid 2-related factor 2 and increases in estrogen, malondialdehyde, c-reactive protein, interleukin 1 beta, caspase 3. Furthermore, O3FA prevented BPF-induced Na+/K+-ATPase and Ca2+-ATPase dysfunction, estrogen receptor beta overexpression, and tumor protein P53 (p53)/ b-cell lymphoma 2 (Bcl-2) imbalance.
CONCLUSIONS
This study showed that O3FA ameliorated BPF-induced dysthyroidism-mediated testicular dysfunction by preventing proton pump dysfunction and p53/BCl-2 imbalance.
PubMed: 38801312
DOI: 10.5935/1518-0557.20240033 -
Frontiers in Oncology 2024Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment landscape of relapsed/refractory multiple myeloma. The current Food and Drug Administration... (Review)
Review
Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment landscape of relapsed/refractory multiple myeloma. The current Food and Drug Administration approved CAR T cell therapies idecabtagene vicleucel and ciltacabtagene autoleucel both target B cell maturation antigen (BCMA), which is expressed on the surface of malignant plasma cells. Despite deep initial responses in most patients, relapse after anti-BCMA CAR T cell therapy is common. Investigations of acquired resistance to anti-BCMA CAR T cell therapy are underway. Meanwhile, other viable antigenic targets are being pursued, including G protein-coupled receptor class C group 5 member D (GPRC5D), signaling lymphocytic activation molecule family member 7 (SLAMF7), and CD38, among others. CAR T cells targeting these antigens, alone or in combination with anti-BCMA approaches, appear to be highly promising as they move from preclinical studies to early phase clinical trials. This review summarizes the current data with novel CAR T cell targets beyond BCMA that have the potential to enter the treatment landscape in the near future.
PubMed: 38800372
DOI: 10.3389/fonc.2024.1398902 -
IScience Jun 2024Germline pathogenic variants in and (gpath(/)) represent genetic susceptibility for hereditary breast and ovarian cancer syndrome. Tumor-immune interactions are key...
Germline pathogenic variants in and (gpath(/)) represent genetic susceptibility for hereditary breast and ovarian cancer syndrome. Tumor-immune interactions are key contributors to breast cancer pathogenesis. Although earlier studies confirmed pro-tumorigenic immunological alterations in breast cancer patients, data are lacking in healthy carriers of gpath(/). Peripheral blood mononuclear cells of 66 women with or without germline predisposition or breast cancer were studied with a mass cytometry panel that identified 4 immune subpopulations of altered frequencies between healthy controls and healthy gpath() carriers, while no difference was observed in healthy gpath() carriers compared to controls. Moreover, 3 (one IgD-CD27CD95 B cell subpopulation and two CD45RA-CCR7+CD38 CD4 T cell subpopulations) out of these 4 subpopulations were also elevated in triple-negative breast cancer patients compared to controls. Our results reveal an activated peripheral immune phenotype in healthy carriers of gpath() that needs to be further elucidated to be leveraged in risk-reducing strategies.
PubMed: 38799565
DOI: 10.1016/j.isci.2024.109882 -
Frontiers in Immunology 2024Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, a rare autosomal recessive disorder, manifests with hypoglobulinemia and chromosomal... (Review)
Review
Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, a rare autosomal recessive disorder, manifests with hypoglobulinemia and chromosomal instability accompanied by DNA hypomethylation. Pathological variants in the , , , or genes underlie its etiology. Activated lymphocytes from patients often display distinctive multiradial chromosomes fused via pericentromeric regions. Recent studies have provided deeper insights into how pathological variants in ICF-related proteins cause DNA hypomethylation and chromosome instability. However, the understanding of the molecular pathogenesis underlying immunodeficiency is still in its nascent stages. In the past half-decade, the roles of CDCA7, HELLS, and ZBTB24 in classical non-homologous end joining during double-strand DNA break repair and immunoglobulin class-switch recombination (CSR) have been unveiled. Nevertheless, given the decreased all classes of immunoglobulins in most patients, CSR deficiency alone cannot fully account for the immunodeficiency. The latest finding showing dysregulation of immunoglobulin signaling may provide a clue to understanding the immunodeficiency mechanism. While less common, a subgroup of patients exhibits T-cell abnormalities alongside B-cell anomalies, including reduced regulatory T-cells and increased effector memory T- and follicular helper T-cells. The dysregulation of immunoglobulin signaling in B-cells, the imbalance in T-cell subsets, and/or satellite RNA-mediated activation of innate immune response potentially explain autoimmune manifestations in a subset of patients. These findings emphasize the pivotal roles of ICF-related proteins in both B- and T-cell functions. ICF syndrome studies have illuminated many fundamental mechanisms. Further investigations will certainly continue to unveil additional mechanisms and their interplay.
Topics: Humans; DNA Repair; Immunologic Deficiency Syndromes; Epigenesis, Genetic; DNA Methylation; Animals; Immunoglobulin Class Switching; Primary Immunodeficiency Diseases
PubMed: 38799442
DOI: 10.3389/fimmu.2024.1405022