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Frontiers in Immunology 2024Sialic acids are found as terminal sugars on glycan structures on cellular surfaces. T cells carry these sialoglycans abundantly, and they are thought to serve multiple...
Sialic acids are found as terminal sugars on glycan structures on cellular surfaces. T cells carry these sialoglycans abundantly, and they are thought to serve multiple functions in cell adhesion, cell migration, and protection from complement attack. We studied the role of sialoglycans on T cells in a mouse model with a T cell-specific deletion of cytidine monophosphate-sialic acid synthase (CMAS), the enzyme that is crucial for the synthesis of sialoglycans. These mice showed a T-cell deficiency in peripheral lymphoid organs. Many T cells with an undeleted allele were found in the periphery, suggesting that they escaped the Cre-mediated deletion. The remaining peripheral T cells of T cell-specific KO mice had a memory-like phenotype. Additional depletion of the complement factor C3 could not rescue the phenotype, showing that the T-cell defect was not caused by a host complement activity. -deficient T cells showed a high level of activated caspase 3, indicating an ongoing apoptosis. In bone marrow chimeric cellular transfer experiments, we observed a strong competitive disadvantage of -deficient T cells compared to wild-type T cells. These results show that sialoglycans on the surface of T cells are crucial for T-cell survival and maintenance. This function has not been recognized before and is similar to the function of sialoglycans on B cells.
Topics: Animals; Mice; Mice, Knockout; T-Lymphocytes; Sialic Acids; Cell Survival; Mice, Inbred C57BL; Apoptosis; Complement C3; Mixed Function Oxygenases
PubMed: 38947328
DOI: 10.3389/fimmu.2024.1359494 -
Frontiers in Immunology 2024Traumatic and thermal injuries result in a state of systemic immune suppression, yet the mechanisms that underlie its development are poorly understood. Released from...
Severe thermal and major traumatic injury results in elevated plasma concentrations of total heme that are associated with poor clinical outcomes and systemic immune suppression.
BACKGROUND
Traumatic and thermal injuries result in a state of systemic immune suppression, yet the mechanisms that underlie its development are poorly understood. Released from injured muscle and lysed red blood cells, heme is a damage associated molecular pattern with potent immune modulatory properties. Here, we measured plasma concentrations of total heme in over 200 traumatic and thermally-injured patients in order to examine its relationship with clinical outcomes and post-injury immune suppression.
METHODS
Blood samples were collected from 98 burns (≥15% total body surface area) and 147 traumatically-injured (injury severity score ≥8) patients across the ultra-early (≤1 hour) and acute (4-72 hours) post-injury settings. Pro-inflammatory cytokine production by lipopolysaccharide (LPS) challenged whole blood leukocytes was studied, and plasma concentrations of total heme, and its scavengers haptoglobin, hemopexin and albumin measured, alongside the expression of heme-oxygenase-1 (HO-1) in peripheral blood mononuclear cells (PBMCs). LPS-induced tumour necrosis factor-alpha (TNF-α) production by THP-1 cells and monocytes following heme treatment was also examined.
RESULTS
Burns and traumatic injury resulted in significantly elevated plasma concentrations of heme, which coincided with reduced levels of hemopexin and albumin, and correlated positively with circulating levels of pro and anti-inflammatory cytokines. PBMCs isolated from trauma patients 4-12 and 48-72 hours post-injury exhibited increased HO-1 gene expression. Non-survivors of burn injury and patients who developed sepsis, presented on day 1 with significantly elevated heme levels, with a difference of 6.5 µM in heme concentrations corresponding to a relative 52% increase in the odds of post-burn mortality. On day 1 post-burn, heme levels were negatively associated with LPS-induced TNF-α and interleukin-6 production by whole blood leukocytes. THP-1 cells and monocytes pre-treated with heme exhibited significantly reduced TNF-α production following LPS stimulation. This impairment was associated with decreased gene transcription, reduced activation of extracellular signal-regulated kinase 1/2 and an impaired glycolytic response.
CONCLUSIONS
Major injury results in elevated plasma concentrations of total heme that may contribute to the development of endotoxin tolerance and increase the risk of poor clinical outcomes. Restoration of the heme scavenging system could be a therapeutic approach by which to improve immune function post-injury.
PubMed: 38947312
DOI: 10.3389/fimmu.2024.1416820 -
The Yale Journal of Biology and Medicine Jun 2024: Chronic rhinosinusitis (CRS) is an inflammatory condition classified into chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal...
: Chronic rhinosinusitis (CRS) is an inflammatory condition classified into chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP). Th cells manage inflammatory cells in CRS. Suppressor of Cytokine Signaling (SOCS) proteins regulate Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in Th cells by polarizing toward Th1, Th2, and Th17 cells. This study evaluated the levels of SOCS1,3,5 in CRS patients to find associations with Th cells. : In this cross-sectional study, 20 CRSwNP patients, 12 CRSsNP patients, and 12 controls participated. The infiltration of CD4 T cells was determined using immunohistochemistry. The expression of specific transcription factors and SOCS proteins was assessed using real-time PCR. Cytokine levels were evaluated using ELISA. SOCS protein levels were investigated using western blot analysis. : The expression of SOCS3 increased in the CRSwNP group compared to CRSsNP and control groups ( <0.001). SOCS3 protein levels increased in the CRSwNP group compared to CRSsNP ( <0.05) and control ( <0.001) groups. Although there was a significant difference in SOCS5 expression between CRSsNP and control groups, SOCS5 protein levels were significantly different between CRSsNP and control ( <0.001) and CRSwNP ( <0.05) groups. : Targeted therapies may be suggested for CRS by modulating SOCS3 and SOCS5 proteins that are responsible for polarization of Th cells toward Th2 or Th1 cells, respectively. JAK-STAT pathway targeting, which encompasses numerous cells, can be limited to SOCS proteins to more effectively orchestrate Th cell differentiation.
Topics: Humans; Sinusitis; Suppressor of Cytokine Signaling Proteins; Chronic Disease; Male; Suppressor of Cytokine Signaling 3 Protein; Rhinitis; Female; Adult; Middle Aged; T-Lymphocytes, Helper-Inducer; Cross-Sectional Studies; Nasal Polyps; Cytokines; Suppressor of Cytokine Signaling 1 Protein; Signal Transduction; Rhinosinusitis
PubMed: 38947108
DOI: 10.59249/HZFN2950 -
Gynecological Endocrinology : the... Dec 2024Telomeres maintain chromosome stability, while telomerase counteracts their progressive shortening. Telomere length varies between cell types, with leukocyte telomere...
BACKGROUND
Telomeres maintain chromosome stability, while telomerase counteracts their progressive shortening. Telomere length varies between cell types, with leukocyte telomere length (LTL) decreasing with age. Reduced telomerase activity has been linked to reproductive issues in females, such as low pregnancy rates and premature ovarian failure, with recent studies indicating correlations between telomere length in granulosa cells and IVF outcomes.
OBJECTIVES
The study aims to explore the relationship between telomere length, telomerase activity, and euploid blastocyst rate in infertile women undergoing IVF/ICSI PGT-A cycles.
METHODS
This prospective study involves 108 patients undergoing controlled ovarian stimulation and PGT-A. Telomere length and telomerase activity were measured in peripheral mononuclear cells and granulosa cells (GC), respectively.
RESULTS
The telomere repeat copy number to single gene copy number ratio (T/S) results respectively 0.6 ± 0.8 in leukocytes and 0.7 ± 0.9 in GC. An inverse relationship was found between LTL and the patient's age ( < .01). A higher aneuploid rate was noticed in patients with short LTL, with no differences in ovarian reserve markers ( = .15), number of oocytes retrieved ( = .33), and number of MII ( = 0.42). No significant association was noticed between telomere length in GC and patients' age ( = 0.95), in ovarian reserve markers ( = 0.32), number of oocytes retrieved ( = .58), number of MII ( = .74) and aneuploidy rate ( = .65).
CONCLUSION
LTL shows a significant inverse correlation with patient age and higher aneuploidy rates. Telomere length in GCs does not correlate with patient age or reproductive outcomes, indicating differential telomere dynamics between leukocytes and granulosa cells.
Topics: Humans; Female; Adult; Telomerase; Telomere; Prospective Studies; Pregnancy; Aneuploidy; Fertilization in Vitro; Granulosa Cells; Infertility, Female; Ovulation Induction; Blastocyst; Telomere Homeostasis; Sperm Injections, Intracytoplasmic
PubMed: 38946430
DOI: 10.1080/09513590.2024.2373742 -
Cancer Discovery Jul 2024Despite its long history of toxicity and limited efficacy, IL2 has re-entered the clinic as a companion to the recently FDA-approved tumor infiltrating lymphocyte...
Despite its long history of toxicity and limited efficacy, IL2 has re-entered the clinic as a companion to the recently FDA-approved tumor infiltrating lymphocyte therapy. In back-to-back articles, Moynihan and Kaptein introduce a new fusion protein that delivers a biased IL2 mutein to CD8 T cells. See related article by Moynihan et al., p. 1206 (6). See related article by Kaptein et al., p. 1226 (7).
Topics: Humans; Interleukin-2; Neoplasms; CD8-Positive T-Lymphocytes; Lymphocytes, Tumor-Infiltrating
PubMed: 38946323
DOI: 10.1158/2159-8290.CD-24-0558 -
Journal of Immunotoxicology Dec 2024Per- and polyfluoroalkyl substances (PFAS) are anthropogenic organofluorine compounds that persist indefinitely in the environment and bioaccumulate throughout all...
Per- and polyfluoroalkyl substances (PFAS) are anthropogenic organofluorine compounds that persist indefinitely in the environment and bioaccumulate throughout all trophic levels. Biomonitoring efforts have detected multiple PFAS in the serum of most people. Immune suppression has been among the most consistent effects of exposure to PFAS. PFAS often co-occur as mixtures in the environment, however, few studies have examined immunosuppression of PFAS mixtures or determined whether PFAS exposure affects immune function in the context of infection. In this study, mixtures containing two or four different PFAS and a mouse model of infection with influenza A virus (IAV) were used to assess immunotoxicity of PFAS mixtures. PFAS were administered the drinking water as either a binary mixture of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) or quaternary mixture of PFOS, PFOA, perfluorohexane sulfonate (PFHxS), and perfluorononanoic acid (PFNA). The results indicated that the binary mixture affected the T-cell response, while the quaternary mixture affected the B-cell response to infection. These findings indicate that the immunomodulatory effects of PFAS mixtures are not simply additive, and that the sensitivity of immune responses to PFAS varies by cell type and mixture. The study also demonstrates the importance of studying adverse health effects of PFAS mixtures.
Topics: Fluorocarbons; Animals; Mice; Influenza A virus; Alkanesulfonic Acids; Orthomyxoviridae Infections; Caprylates; Humans; Female; Mice, Inbred C57BL; Influenza, Human; Disease Models, Animal; T-Lymphocytes
PubMed: 38946256
DOI: 10.1080/1547691X.2024.2340495 -
Acta Dermatovenerologica Croatica : ADC Mar 2024Plasma cell mucositis (PCM) is an unusual disorder most evident in the accessible mucosa and usually reported in the upper aerodigestive tract, although it is named... (Review)
Review
Plasma cell mucositis (PCM) is an unusual disorder most evident in the accessible mucosa and usually reported in the upper aerodigestive tract, although it is named according to its specific anatomical site of involvement such as plasma cell cheilitis, plasma cell gingivitis, plasma cell vulvitis, and Zoon's balanitis. PCM reflects a dense polyclonal rather than a monoclonal plasma cell proliferation of unclear and unknown etiology. This perplexing disorder tends to be treated by avoiding possible triggers and intralesional and/or systemic steroids. In this work, we provide a review and update on PCM, which often represents a clinical conundrum.
Topics: Humans; Mucositis; Plasma Cells
PubMed: 38946188
DOI: No ID Found -
Internal Medicine (Tokyo, Japan) 2024Objective Chimeric antigen receptor (CAR) T cell therapy is an emerging and effective therapy for relapsed or refractory diffuse large B cell lymphoma (R/R DLBCL). The...
Activated CD4 T Cell Proportion in the Peripheral Blood Correlates with the Duration of Cytokine Release Syndrome and Predicts Clinical Outcome after Chimeric Antigen Receptor T Cell Therapy.
Objective Chimeric antigen receptor (CAR) T cell therapy is an emerging and effective therapy for relapsed or refractory diffuse large B cell lymphoma (R/R DLBCL). The characteristic toxicities of CAR T cell therapy include cytokine release syndrome (CRS) and prolonged cytopenia. We investigated the factors associated with these complications after CAR T cell therapy by analyzing lymphocyte subsets following CAR T cell infusion. Methods We retrospectively analyzed peripheral blood samples on days 7, 14, and 28 after tisagenlecleucel (tisa-cel) infusion by flow cytometry at our institution between June 2020 and September 2022. Patients Thirty-five patients with R/R DLBCL who received tisa-cel therapy were included. Results A flow cytometry-based analysis of blood samples from these patients revealed that the proportion of CD4CD25CD127 T cells (hereafter referred to as "activated CD4 T cells" ) among the total CD4 T cells on day 7 after tisa-cel infusion correlated with the duration of CRS (r=0.79, p<0.01). In addition, a prognostic analysis of the overall survival (OS) using time-dependent receiver operating characteristic curves indicated a significantly more favorable OS and progression-free survival of patients with a proportion of activated CD4 T cells among the total CD4 T cells <0.73 (p=0.01, and p<0.01, respectively). Conclusion These results suggest that the proportion of activated CD4 T cells on day 7 after tisa-cel infusion correlates with the CRS duration and predicts clinical outcomes after CAR T cell therapy. Further studies with a larger number of patients are required to validate these observations.
Topics: Humans; Male; Female; Cytokine Release Syndrome; Immunotherapy, Adoptive; Middle Aged; Lymphoma, Large B-Cell, Diffuse; Aged; Retrospective Studies; CD4-Positive T-Lymphocytes; Adult; Treatment Outcome; Receptors, Chimeric Antigen; Prognosis; Receptors, Antigen, T-Cell
PubMed: 38945932
DOI: 10.2169/internalmedicine.2556-23 -
Journal For Immunotherapy of Cancer Jun 2024How distinct methods of host preconditioning impact the efficacy of adoptively transferred antitumor T helper cells is unknown.
BACKGROUND
How distinct methods of host preconditioning impact the efficacy of adoptively transferred antitumor T helper cells is unknown.
METHODS
CD4 T cells with a transgenic T-cell receptor that recognize tyrosinase-related peptide (TRP)-1 melanoma antigen were polarized to the T helper 17 (Th17) phenotype and then transferred into melanoma-bearing mice preconditioned with either total body irradiation or chemotherapy.
RESULTS
We found that preconditioning mice with a non-myeloablative dose of total body irradiation (TBI of 5 Gy) was more effective than using an equivalently dosed non-myeloablative chemotherapy (cyclophosphamide (CTX) of 200 mg/kg) at augmenting therapeutic activity of antitumor TRP-1 Th17 cells. Antitumor Th17 cells engrafted better following preconditioning with TBI and regressed large established melanoma in all animals. Conversely, only half of mice survived long-term when preconditioned with CTX and infused with anti-melanoma Th17 cells. Interleukin (IL)-17 and interferon-γ, produced by the infused Th17 cells, were detected in animals given either TBI or CTX preconditioning. Interestingly, inflammatory cytokines (granulocyte colony stimulating factor, IL-6, monocyte chemoattractant protein-1, IL-5, and keratinocyte chemoattractant) were significantly elevated in the serum of mice preconditioned with TBI versus CTX after Th17 therapy. The addition of fludarabine (FLU, 200 mg/kg) to CTX (200 mg/kg) improved the antitumor response to the same degree mediated by TBI, whereas FLU alone with Th17 therapy was ineffective.
CONCLUSIONS
Our results indicate, for the first time, that the antitumor response, persistence, and cytokine profiles resulting from Th17 therapy are impacted by the specific regimen of host preconditioning. This work is important for understanding mechanisms that promote long-lived responses by adoptive cellular therapy, particularly as CD4 based T-cell therapies are now emerging in the clinic.
Topics: Animals; Th17 Cells; Mice; Mice, Inbred C57BL; Immunotherapy, Adoptive; Whole-Body Irradiation; Melanoma, Experimental; Cyclophosphamide; Adoptive Transfer; Female; Melanoma
PubMed: 38945552
DOI: 10.1136/jitc-2023-008715 -
Advances in Gerontology = Uspekhi... 2024The aim of the study was to investigate the peculiarities of morphometric parameters of peripheral blood lymphocytes in chronic pyelonephritis in elderly patients in...
The aim of the study was to investigate the peculiarities of morphometric parameters of peripheral blood lymphocytes in chronic pyelonephritis in elderly patients in comparison with young and middle-aged patients. A total of 81 patients with chronic pyelonephritis in the exacerbation phase were examined. All patients were divided into three age groups according to WHO recommendations: the 1st - 42patients of young age (18-44 years); the 2nd - 17 patients of middle age (45-59 years); the 3rd - 22 elderly patients (60-74 years). Computer morphometry of lymphocytes was performed in all examined patients. In elderly patients with chronic pyelonephritis the size and сytoplasmic-nuclear ratio of lymphocytes increase. This indicates the preservation of lymphocyte defense responses at this age. In male patients with chronic pyelonephritis in the 1st and 2nd age groups the size of lymphocytes increases, and in female patients - decreases. The сytoplasmic-nuclear ratio increases in males of these age groups, while it remains unchanged or decreases in females. Indirect indications of reduced immunity in young and middle-aged women with chronic inflammation in the kidneys have been obtained.
Topics: Humans; Pyelonephritis; Middle Aged; Female; Male; Lymphocytes; Aged; Adult; Chronic Disease; Age Factors
PubMed: 38944771
DOI: No ID Found