Increase In Plasma Cells Research Articles

REACTION OF THE LOCAL PROTECTIVE BARRIER IN THE DUODENAL MUCOSA OF RATS TO A COMPLEX OF FOOD ADDITIVES

Introduction: The use of food additives continues to be a topic of significant debate, primarily due to the limited research on their effects on the human body, especially in conditions involving combined exposure. Commonly used additives in the food industry include monosodium glutamate, sodium nitrite, and Ponceau-4R. These substances, widely incorporated into food products, enter the body as haptens and, when binding to proteins such as serum albumin, form complete antigens, which can trigger the synthesis of antibodies. Objective: To investigate the dynamics of quantitative changes in lymphoid cell populations in the lamina propria of the duodenal mucosa under normal conditions and following combined exposure to the food additives monosodium glutamate, sodium nitrite, and Ponceau-4R. Materials and Methods. The study involved 84 mature male rats. The animals in the experimental group, with free access to water, were administered 0.6 mg/kg of sodium nitrite, 20 mg/kg of monosodium glutamate, and 5 mg/kg of Ponceau 4R in 0.5 ml of distilled water orally once daily. These doses were twice lower than the permissible norm. The animals were euthanized after 1, 4, 8, 12, and 16 weeks. Histological sections, stained with hematoxylin and eosin, were studied under a light microscope. Quantitative parameters of lymphoid cells in the lamina propria of the duodenal mucosa were evaluated using a Levenhuk D740T digital microscope with microphotography attachment and specialized software adapted for the study. Results. The average number of lymphocytes in the lamina propria of the duodenal mucosa in rats at the 16th week of the experiment was 5.02±0.09 per field of view, which was 5.02 times significantly higher than in the control group (p<0.05). Prolonged intake of the additive complex led to an increase in plasma cells, reaching 20.04±0.17 per field of view at week 16, remaining 5.04 times higher than control values (p<0.05). The average number of macrophages was 8.96±0.17 per field of view, 4.48 times higher than in the control group (p<0.05). The number of granulocytes increased significantly, being 6.12 times higher than the control value at 3.98±0.09 per field of view (p<0.05). Conclusion. The complex of food additives monosodium glutamate, sodium nitrite, and Ponceau - 4R activates both nonspecific immune response processes and antigen-dependent cell differentiation in a wave-like manner.

Integrative bioinformatics analysis of immune activation and gene networks in pediatric septic arthritis

BackgroundPediatric septic arthritis, driven by Staphylococcus aureus, leads to substantial morbidity due to the host’s complex inflammatory response. This study integrates bioinformatics analyses to map the genomic and immune profiles of pediatric septic arthritis, aiming to identify key biomarkers and therapeutic targets. MethodsAn integrative bioinformatics approach was adopted to analyze gene expression datasets from the GEO database, focusing on pediatric septic arthritis. DEGs were identified using GEO2R, and gene co-expression networks were generated via GeneMANIA. STRING database and Cytoscape software facilitated PPI network construction. DAVID enabled functional enrichment analysis to elucidate biological processes and pathways, while iRegulon predicted transcription factor regulation. CIBERSORT provided a detailed profile of immune cell alterations in the condition. ResultsFrom the datasets analyzed, 576 DEGs were extracted, with 35 shared between the two datasets, revealing an innate immunity signature with notable hub genes such as MPO and ELANE, indicative of a pronounced neutrophilic response. Functional enrichment analysis highlighted pathways pertinent to antimicrobial defense and NET formation. Key transcription factors, including PBX1, POLR2A, and STAT3, were identified as potential modulators of these pathways. Immune profiling demonstrated significant shifts in cell populations, with increased plasma cells and reduced CD4+ naïve T cells. ConclusionsThis study elucidates the complex genomic and immunological milieu of pediatric septic arthritis, uncovering potential biomarkers and signaling pathways for targeted therapeutic intervention. These findings underscore the preeminence of innate immune mechanisms in the disease's pathology and offer a foundation for future research to explore diagnostic and treatment innovations. Translation of these bioinformatics discoveries into clinical applications requires further validation and consideration of the limitations inherent to gene expression data and its interpretation.

Infiltrations of plasma cells in synovium predict inadequate response to Adalimumab in Rheumatoid Arthritis patients

ObjectiveRheumatoid arthritis (RA) is a clinically heterogeneous and complex autoimmune disease, making the prediction of therapeutic responses a significant challenge. This study aims to assess the role of clinical and synovial biomarkers in predicting poor response to adalimumab treatment in RA patients.MethodsThis single-center prospective study included 56 RA patients who had an inadequate response to methotrexate (MTX). At baseline, comprehensive assessments including complete blood count, liver and kidney function tests, blood glucose levels, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA), as well as counts of swollen and tender joints, Health Assessment Questionnaire (HAQ) score, pain visual analogue scale (VAS) scores, and DAS28-CRP scores were conducted. Synovial biopsies were performed, followed by an efficacy evaluation at 12 weeks of adalimumab treatment. Patients not meeting the ACR20 criteria were classified into the non-responder group, with the remainder categorized as the responder group.ResultsOut of the participants, 24 (42.9%) failed to achieve ACR20 with adalimumab treatment. Non-responders exhibited higher infiltration of plasma cells in the synovium. Multivariate logistic regression analysis identified the presence of plasma cells as an independent risk factor for inadequate response to adalimumab.ConclusionInadequate responses to adalimumab in RA patients were associated with increased plasma cell infiltrations in the synovium. These findings suggest a promising target for tailored therapies in rheumatoid arthritis.

A Complex Case of Extrahepatic Biliary Obstruction: Syphilitic abdominal lymphadenitis

Abstract Introduction/Objective Syphilis, a sexually transmitted disease that is caused by spirochete Treponema pallidum, can vary widely in presentation. Infective lymphadenitis due to syphilis have been reported before in cervical and inguinal lymph nodes.Here we present an interesting case of syphilitic lymphadenitis with unusual presentation and location. Methods/Case Report A 30-year-old male with no past medical history presented with epigastric pain, fever, jaundice, weight loss, and night sweats. Computed tomography imaging revealed a 4.1 cm solid mass at the porta hepatis with involvement of perihepatic lymph nodes, raising suspicion of malignancy. All serological tumor markers were negative. The patient underwent ERCP with biliary drainage to relieve obstructive jaundice. Bile duct brushing and liver biopsy at that time were non-diagnostic. Later the patient underwent laparoscopic lymph node excision. Histological examination of the lymph node showed intact follicular architecture with an increase in plasma cells and sinus histiocytes, without evidence of carcinoma or lymphoma cells. Flow cytometry on the lymph node showed polytypic B-cells and antigenically normal T-cells with CD4: CD8 ratio of 0.5 showing relatively excess of CD8 positive cytotoxic cells. Positive staining for Treponema pallidum with appropriate control highlighted micro-organisms suggestive of secondary syphilitic infection. This evidence was later supported by positive rapid plasma reagin (RPR) test. He subsequently tested positive for Human immunodeficiency virus (HIV-1). Results (if a Case Study enter NA) NA Conclusion In summary, appropriate histologic and serological testing lead to timely diagnosis in this case. This case contributes to the limited literature on syphilitic lymphadenitis and reports the first documented case of isolated intra- abdominal lymph node involvement.

Flower-Shaped Plasma Cells in Multiple Myeloma with Morphological Heterogeneity.

Flower-shaped nuclei in plasma cells are rare in multiple myeloma. We report on an 88-year-old male who presented with a mass lesion in the clavicular region. A biopsy of the mass revealed an increase in mature plasma cells with round nuclei. In contrast, a bone marrow examination showed increased plasma cells with flower-shaped nuclei. The patient tested negative for human T-lymphotropic virus type-1 and was diagnosed with multiple myeloma. While multiple myeloma is known for intra-tumor heterogeneity, reports of morphological heterogeneity based on the site of tumor sampling are limited. In this case, the presence of plasma cells with flower-shaped nuclei enabled the identification of site-dependent morphological tumor heterogeneity.

Survival benefit and spatial properties of tertiary lymphoid structures in esophageal squamous cell carcinoma with neoadjuvant therapies

Tertiary lymphoid structures (TLSs) were associated with survival in esophageal squamous cell carcinoma (ESCC) undergoing surgery alone (SA). However, their clinical relevance in neoadjuvant therapies remains less known. Here, we firstly investigated the presence, maturation and spatial distribution of TLSs in 359 ESCC patients receiving neoadjuvant chemotherapy (NCT), neoadjuvant immunotherapy (NCI), neoadjuvant chemoradiotherapy (NCRT) or SA. We found mature TLS (MTLS) was an independent prognostic factor in ESCC. NCI group had the lowest immature TLS cases. NCRT group had the lowest MTLSs. MTLSs mostly located in stromal and normal compartments; these MTLSs were positively correlated with neoadjuvant therapy outcomes. NCI group displayed the highest T cells within 150 μm proximity of TLSs among the four groups. Most T cells were dispersed up to more than 150 μm from TLSs, while B cells remained concentrated within TLSs. Innate lymphoid cells and follicular dendritic cells infiltrated and connected with survival differently in NCRT and NCI groups compared with SA group. The novel PD-L1 combined positive score, NCPS, was positively connected with MTLSs and neoadjuvant therapy efficacy. ScRNA-seq analysis revealed TLS+ tumors had increased plasma cells, B cells, Th17, Tfh and Th1, and elevated exhausted CD8+ T cells that highly expressed checkpoint molecules and granzymes. Conclusively, MTLSs favored treatment outcome in ESCC patients receiving multiple neoadjuvant therapies. The spatial distribution of MTLSs was associated with multiregional immune status modified by the neoadjuvant therapies.

ICOS agonist vopratelimab modulates follicular helper T cells and improves B cell function in common variable immunodeficiency

Common variable immunodeficiency (CVID) is an immune defect characterized by hypogammaglobulinemia and impaired development of B cells into plasma cells. As follicular helper T cells (TFH) play a central role in humoral immunity, we examined TFH cells in CVID, and investigated whether an inducible T cell co-stimulator (ICOS) agonist, vopratelimab, could modulate TFH, B cell interactions and enhance immunoglobulin production. CVID subjects had decreased TFH17 and increased TFH1 subsets; this was associated with increased transitional B cells and decreased IgG+ B and IgD−IgM−CD27+ memory B cells. ICOS expression on CVID CD4+ T cells was also decreased. However, ICOS activation of CD4+ T cells by vopratelimab significantly increased total CVID TFH, TFH2, cell numbers, as well as IL-4, IL-10 and IL-21 secretion in vitro. Vopratelimab treatment also increased plasma cells, IgG+ B cells, reduced naïve & transitional B cells and significantly increased IgG1 secretion by CVID B cells. Interestingly, vopratelimab treatment also restored IgA secretion in PBMCs from several CVID patients who had a complete lack of endogenous serum IgA. Our data demonstrate the potential of TFH modulation in restoring TFH and enhancing B cell maturation in CVID. The effects of an ICOS agonist in antibody defects warrants further investigation. This biologic may also be of therapeutic interest in other clinical settings of antibody deficiency.

Plasma Cell Infiltrate in Liver Allograft Biopsy: Clinical and Histological Implications

Introduction: The relevance of plasma cells in the allograft liver is of utmost importance and objective assessment of these infiltrates and correlation with other ancillary findings needs to be evaluated. Materials and Methods: Three hundred and sixty-eight graft liver biopsies received in the department from 2012 to 2022 and 115 allograft liver biopsies with histopathological diagnosis of rejection were selected. Based on plasma cells percentage in the portal tracts, the biopsies were divided into three groups: Group 1 showing not more than an occasional plasma cell, Group 2 showing <10% plasma cells, and Group 3 showing >10% plasma cells. Rejection activity index (RAI), portal/lobular inflammation, interface activity, subendothelial inflammation (portal and central vein), duct damage/loss, presence of cholestasis, apoptosis, perivenulitis, necrosis, rosette along with serial liver function tests (LFTs), and patient status at 1 year of follow-up were recorded and compared between the groups. Results: Plasma cell infiltrates were observed in 52.6% of the specimens, with the mean percentage of plasma cells in the infiltrates being 4.9. Increased plasma cell infiltrates were associated with higher RAI scores, marked duct damage, marked portal and central vein endotheliitis, marked portal inflammation, and presence of interface activity. Higher levels of transaminitis were recorded at the time of biopsy, but no significant association was observed in the fall of serial LFTs over a 2-week period with the presence of plasma cells. Conclusion: Identifying plasma cell infiltrates in liver allografts can serve as a clue toward increased severity of rejection in liver allograft biopsies. Further studies with emphasis on correlation with the clinical outcome and response to treatment are needed to validate its utility as an objective tool.

212 Differential Immune Cell Recruitment Between Ruptured and Unruptured Intracranial Aneurysms

INTRODUCTION: Accumulating evidence implicates infiltrating inflammatory cells in intracranial aneurysms. However, few studies have examined immunological differences between aneurysm rupture statuses. METHODS: An established machine-learning deconvolution algorithm was applied on RNA-sequencing data developed from vessel wall tissue of 21 ruptured and 21 unruptured intracranial aneurysms. A validated gene signature matrix of human hematopoietic cell subsets was used to infer the relative fractions of immune cells present within the original aneurysm tissues. RESULTS: Deconvolution of the bulk gene expression data showed significantly increased plasma cells, CD8+ T cells, and activated natural killer cells in unruptured aneurysms compared to ruptured aneurysms. CONCLUSIONS: Specific lymphoid elements may be involved in an inflammatory reaction prior to intracranial aneurysm rupture.

Mechanism and endoscopic-treatment-induced evolution of biliary non-anastomotic stricture after liver transplantation revealed by single-cell RNA sequencing.

Biliary complications, especially non-anastomotic stricture (NAS), are the main complications after liver transplantation. Insufficient sampling and no recognized animal models obstruct the investigation. Thus, the mechanisms and alterations that occur during endoscopic treatment (ET) of NAS remain unclear. Samples were obtained with endoscopic forceps from the hilar bile ducts of NAS patients receiving continuous biliary stent implantation after diagnosis. Retrospective analysis of multiple studies indicated that the duration of ET for NAS was approximately 1-2 years. Thus, we divided the patients into short-term treatment (STT) and long-term treatment (LTT) groups based on durations of less or more than 1 year. Samples were subjected to single-cell RNA sequencing. Transcriptomic differences between STT and normal groups were defined as the NAS mechanism. Similarly, alterations from STT to LTT groups were regarded as endoscopic-treatment-induced evolution. In NAS, inflammation and immune-related pathways were upregulated in different cell types, with nonimmune cells showing hypoxia pathway upregulation and immune cells showing ATP metabolism pathway upregulation, indicating heterogeneity. We confirmed a reduction in bile acid metabolism-related SPP1+ epithelial cells in NAS. Increases in proinflammatory and profibrotic fibroblast subclusters indicated fibrotic progression in NAS. Furthermore, immune disorders in NAS were exacerbated by an increase in plasma cells and dysfunction of NK and NKT cells. ET downregulated multicellular immune and inflammatory responses and restored epithelial and endothelial cell proportions. This study reveals the pathophysiological and genetic mechanisms and evolution of NAS induced by ET, thereby providing preventive and therapeutic insights into NAS. For the first time, single-cell transcriptome sequencing was performed on the bile ducts of patients with biliary complications. scRNA-seq analysis revealed distinct changes in the proportion and phenotype of multiple cell types during Nonanastomotic stricture (NAS) and endoscopic treatment. A reduction in bile acid metabolism-related SPP1+ epithelial cells and VEGFA+ endothelial cells, along with explosive infiltration of plasma cells and dysfunction of T and NK cells in NAS patients. SPP1+ macrophages and BST2+ T cells might serve as a surrogate marker for predicting endoscopic treatment.

Immune Cell Alterations and PI3K-PKB Pathway Suppression in Patients with Allergic Rhinitis Undergoing Sublingual Immunotherapy.

Our prior clinical study assessed the efficacy and safety of sublingual immunotherapy (SLIT) with standardized Dermatophagoides farina drops on patients with allergic rhinitis (AR) while analyzing the characteristics of adverse reactions. This study was conducted to evaluate the immune cell composition alterations in AR patients before and after SLIT, and to comprehensively investigate the role and changes of antigen-specific immune cells associated with treatment efficacy. A total of 68 AR patients who completed 12months of SLIT were included in the study. Before the trial's initiation and after 1year of SLIT, 10ml of venous blood was collected. Peripheral blood mononuclear cells were isolated using the Ficoll gradient method. The mRNA transcriptome was analyzed using an Affymetrix microarray. The proportions of 22 immune cell types were calculated via the CIBERSORTx platform. Correlations between each immune cell type and SLIT were analyzed. PI3K-PKB pathway dysregulation were analyzed using quantitative PCR and Western blot. Flow cytometry was utilized to assess the percentages of Th1 and Th2 cells. Mono-sensitized AR patients exhibited marked increases in plasma cells, activated memory T cells, regulatory T cells, and activated dendritic cells, while experiencing decreased neutrophils and resting dendritic cells. In poly-sensitized AR patients, the most notable change was an increase in regulatory T cells, coupled with decreased T follicular helper cells, resting dendritic cells, and activated mast cells. These findings indicated that SLIT reshaped immune cell profiles in AR patients, and, notably, the specific changes differed between mono-sensitized and poly-sensitized individuals. Furthermore, SLIT appeared to shift the immune response towards a Th2 decrease profile in both groups. Importantly, suppression of the PI3K-PKB pathway was evidenced as inhibition of PKB phosphorylation and the decrease of glycogen synthase kinase 3 β (GSKβ) and mammalian target of rapamycin (mTOR) expression after SLIT. Our study has demonstrated that SLIT treatment led to distinct changes in immune cell profiles between mono-sensitized and poly-sensitized AR patients. Furthermore, SLIT appeared to reduce a Th2 immune response, highlighting its efficacy in AR treatment. Importantly, the study revealed the suppression of the PI3K-PKB pathway, shedding light on the immunological mechanisms underlying SLIT's effectiveness.

Determination of Reference Values of Hematopoetic CELLS in Normal BONE Marrow By 10 Colors FLOW Cytometry in Brazilian Population

Purpose: To determine relative and absolute reference values of normality in individuals with no hematologic disease bone marrow, as well as normal patterns of maturation for the different hematopoietic lineages. Methods: Bone marrow samples were collected from 46 healthy patients (16 women and 30 men) undergoing orthopedic surgery and were aged between 18 and 87 years (median 36 years). The analysis of 8 tubes performed in an equipment with 10 colors configuration enabled to evaluate and quantify (% and mm³) B lymphocytes (immature and mature), T lymphocytes (helper, cytotoxic, double negative, double positive), natural killer cells, granulocytes (myeloblasts, promyelocytes, myelocytes, metamyelocytes, rods and neutrophils), monocytes (monoblasts, promonocytes, mature monocytes, classical, intermediate and non-classical), erythroblasts (immature and mature), plasma cells, basophils, mast cells, myeloid dendritic cells and plasmacytoid dendritic cells. The results were evaluated according to sex (female and male), age group (<40, 40 to 60, >60 years), and described as median percentage and absolute values. Results: In evaluating the results according to age group, we identified that older individuals presented an increase in plasma cells that expressed CD56 (p=0.031 in absolute values). In addition, they also had increase relation of CD4/CD8 ratio (p=0.002), mast cells (p=0.004 in percentages), non-classical monocytes (p=0.016 in percentages), as well as a decrease in cytotoxic T lymphocytes (p=0.031 in absolute values), double negative T lymphocytes (p=0.018 in absolute values), and natural killer cells that express CD56 (p =0.002 in absolute values and p=0.012 in percentages). Moreover, these individuals also presented higher natural killer cells that expressed CD56 and CD16 (p=0.024 in absolute values), myeloblasts (p=0.048 in absolute values), metamyelocytes/Rods (p=0.038 in absolute values), neutrophils (p=0.006 in absolute values), monoblasts (p=0.030 in absolute values), mature monocytes (p=0.024 in absolute values), classical monocytes (p=0.017), plasmacytoid dendritic cells (p=0.027 in absolute values), and mature erythroblasts (p=0.004 in absolute values). In the evaluation of the results according to sex, we identified that the population of mature B lymphocytes (p=0.013) and B lymphocytes that expressed CD5 (p=0.014) was higher in women, while the percentage of natural killer cells was relatively higher than in men (p=0.007), particularly in the population of cells that expressed CD56 and CD16 (p=0.013). Conclusion: This study established reference values (absolute and relative) of B lymphocytes (immature and mature), T lymphocytes (helper, cytotoxic, double negative, double positive), natural killer cells, granulocytes (myeloblasts, promyelocytes, myelocytes, metamyelocytes, rods and neutrophils), monocytes (monoblasts, promonocytes, mature monocytes, classical, intermediate and non-classical), erythroblasts (immature and mature), plasma cells, basophils, mast cells, myeloid dendritic cells and plasmacytoid dendritic cells according sex and age group in bone marrow samples from individuals with no hematologic disease Maturational stages of B lymphocytes, granulocytes, monocytes and erythroblasts was shown to be stable regardless of sex and age.

Th1/17 polarization and potential treatment by an anti-interferon-γ DNA aptamer in Hunner-type interstitial cystitis

Hunner-type interstitial cystitis (HIC) is a rare, enigmatic inflammatory disease of the urinary bladder with no curative treatments. In this study, we aimed to characterize the unique cellular and immunological factors specifically involved in HIC by comparing with cystitis induced by Mycobacterium bovis bacillus Calmette-Guérin, which presents similar clinicopathological features to HIC. Here, we show that T helper 1/17+polarized immune responses accompanied by prominent overexpression of interferon (IFN)-γ, enhanced cGAS-STING cytosolic DNA sensing pathway, and increased plasma cell infiltration are the characteristic inflammatory features in HIC bladder. Further, we developed a mouse anti-IFN-γ DNA aptamer and observed that the intravesical instillation of the aptamer significantly ameliorated bladder inflammation, pelvic pain and voiding dysfunction in a recently developed murine HIC model with little migration into the blood. Our study provides the plausible basis for the clinical translation of the anti-IFN-γ DNA aptamer in the treatment of human HIC.

Clinicohematological Profile of Visceral Leishmaniasis in the Pediatric Population

Abstract Background Visceral leishmaniasis (VL) is a major public health problem worldwide. In addition to the clinical manifestations, varied hematological abnormalities have also been observed. We aim to study morphology both in peripheral smear and bone marrow aspirates (BMAs) along with clinicohematological correlation in the pediatric age group. Materials and Methods: A retrospective analysis of clinicohematological findings of 47 pediatric patients (0–18 years) diagnosed with leishmaniasis on BMAs from 2006 to 2017 was undertaken. All the results were tabulated and compared for evaluation. Results: From the 47 VL patients, the following abnormalities were noted. Pancytopenia 44.7% (21/47), bicytopenia 42.5% (20/47), anemia 10.6% (5/47), leukopenia 81% (38/47), and thrombocytopenia 53.2% (25/47). On peripheral smear, shift to left (48.3%), nucleated red blood cells (19.4%), toxic granules (6.7%), and Leishmania donovani (LD) bodies (5.7%) were noted. About 5.7% were seen. Bone marrow examination revealed erythroid hyperplasia in 44.6% of cases showing normoblastic (88.8%), megaloblastic (4.4%), and mixed (10.6%) reactions. Dyserythropoiesis (15.5%), drug-induced karyorrhexis (2.1%), dysmyelopoiesis (17%), giant stabs and metamyelocytes (6.3%), coarse granulation (2.1%), intrahistiocytic organisms (100%), increased plasma cells (3.4%), granulomas (25.5%), parasitophorous vacuoles (25.5%), nonhistiocytic intracellular organisms (15%), intracellular granule-like organism (8.5%), hemophagocytosis (8.5%), Reed–Sternberg-like cells (2.1%). Conclusion: BMA findings such as increased plasma cells, granulomas, hemophagocytosis, and granule-like organisms are important clues for suspecting leishmaniasis and further searching for LD bodies in patients with fever and splenomegaly.

Anti-IFNg DNA aptamer for Hunner Type Interstitial Cystitis

There is no widely accepted definition for Interstitial cystitis (IC)/bladder pain syndrome (BPS) and very few effective diagnostic biomarkers. Chizuko Koseki is combining her deep knowledge of both urology and nucleic acid/oligonucleotides to develop innovative treatments for Hunner-type IC (HIC). Patients with IC/BPS are classified as either HIC, presenting with a specific Hunner lesion, or BPS presenting without Hunner lesion. There is a distinct lack of treatments, with only one approved drug; 50% dimethyl sulfoxide (DMSO) as intravesical instillation therapy, with the drug put directly into the bladder. An important study enabled scientists to surmise that HIC is a distinct inflammatory disorder that is characterised by pancystitis with an increase in plasma cells and frequent expansion of clonal B-cells, and epithelial denudation. Koseki is the CEO of TAGCyx Biotechnologies, a pre-clinical stage drug development company based in Komaba Open Laboratory, The University of Tokyo, Japan focused on developing novel nucleic acid-based drugs for therapeutic applications. The company focuses on: autoimmune disease; womenâ–™s disease; apheresis; thrombosis; and chronic kidney disease. Oligonucleotides are key to Kosekiâ–™s work; she is using the advantages and characteristics of single strand DNA oligonucleotides to develop some focused disease areas, such as autoimmune diseases, topical applications and womenâ–™s diseases. The team has established a technology platform called Xenoligo® that can screen and stabilise drug candidates utilising oligonucleotide drug discovery. The platform can generate highly potent and efficacious single strand DNA aptamers.

Abstract PO-092: Molecular characterization of the salivary adenoid cystic carcinoma tumor immune landscape by anatomic subsite

Abstract Introduction: Adenoid cystic carcinoma (AdCC) is typically indolent, however tends to behave more aggressively and present with perineural invasion and distant metastasis. Despite an improved understanding of AdCC pathobiology, the impact of anatomic tumor subsite (e.g., major versus minor salivary glands) on survival and response to treatment is relatively understudied. We recently discovered that submandibular AdCC’s exhibit unique differences in prognosis and treatment response to adjuvant radiotherapy. However, the impact of anatomic subsites on gene expression and immune cell composition, has not been investigated. Materials and methods: We used 4 publicly available AdCC molecular datasets (n = 37 AdCCs of different origin: 27 primary and 10 metastatic; 7 parotid (PG), 5 submandibular (SMG), 4 sublingual (SLG), 21 minor salivary gland (mG) and 21 normal salivary gland tissue samples). Data were harmonized between datasets using identical quantification procedures, followed by filtering and normalization performed simultaneously on the pooled data from all cohorts. Gene set enrichment analysis (GSEA) was performed Human Molecular Signatures Database (MSigDB) Hallmark and Oncologic signatures. Tumor immune microenvironment (TIME) decomposition was performed using a non-negative matrix factorization-based approach. GSEA and TIME differences between AdCC subsites were evaluated using Wilcoxon rank-sum and nonparametric equality-of-medians tests. Results: We identified different levels of enrichment for several key tumorigenic pathways between AdCCs arising within different anatomic subsites. Among AdCCs, major glands overexpressed the HALLMARK_SPERMATOGENESIS signature (parotid and sublingual glands), while the HALLMARK_REACTIVE_OXYGEN_SPECIES_PATHWAY (ROS) signature was significantly underexpressed in SMG AdCCs. In addition, the HALLMARK_EPITHELIAL_MESENCHYMAL_TRANSITION (EMT) signature was significantly underexpressed in both SMG and PG AdCCs. These pathway signatures were not seen in control tissue comparison samples, indicating that these features are AdCC-specific. Additionally, TIME decomposition identified differences in CD4-T cell populations (minor > major gland AdCC) and natural killer (NK) cells (increased in PG and SLG). Meanwhile, normal control comparisons revealed a significant increase in plasma cells only within SM glands. Conclusions: AdCC subsites exhibit survival and treatment-response differences, and in this study demonstrate that these anatomical sites are associated with distinct molecular features. Specifically, these different anatomical sites vary in the expression of spermatogenesis, ROS, and EMT signature-related genes. Also, CD4-T and NK cell populations vary by anatomical site, suggesting that the SMG AdCC tumor-intrinsic pathway differences observed may be responsible for influencing the TIME composition and increased prognosis associated with these tumors following adjuvant radiotherapy. Validation with additional cohorts of primary AdCCs with accurate clinical annotation are required. Citation Format: Jason Tasoulas, Travis Schrank, Steven Johnson, Kimon Divaris, Stamatios Theocharis, Trevor Hackman, Siddharth Sheth, Kedar Kirtane, Juan Hernandez-Prera, Christine Chung, Wendell Gray Yarbrough, Natalia Issaeva, Antonio Amelio. Molecular characterization of the salivary adenoid cystic carcinoma tumor immune landscape by anatomic subsite [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-092.

Morphological Spectrum of Bone Marrow Aspirates in Infections: A Clinico-Hematological Analysis.

Bone marrow examination (BME) is an invaluable tool for cases with pyrexia of unknown origin and pancytopenia. However, it is under-utilized for diagnosing infectious etiology and there is a paucity of literature regarding its role in infective pathology. This study aims to bring to light the role of BME in diagnosing infectious pathology. A retrospective study was carried out on bone marrow aspirates (BMAs) sent to the hematology department over the past 4 years. Clinical details, peripheral smears and BMA were retrieved from the records and analyzed. Leishman-stained peripheral smears and BMA were studied along with bone marrow biopsy wherever feasible. A total of 52 cases were studied. The most common clinical presentation was fever, clinical finding was splenomegaly and hematological finding was anemia. Based on the morphological findings in combination with clinical history, cases were categorized into-parasitic (26.9%), viral (23.1%), tubercular (11.5%), and nonspecific infections (38.5%). Parasites such as Leishmania donovani, microfilaria, plasmodium falciparum, and vivax were reported in 14/52 (27%) cases. Associated BMA findings were plasmacytosis, eosinophilia, reactive lymphocytosis, or dyserythopoiesis. In 38% (20/52) cases, no specific cause of infection was found in the bone marrow. These patients showed histiocytosis, hemophagocytosis, maturation arrest in myeloid lineage, relative myeloid hyperplasia, dysmyelopoiesis, toxic granulation/vacuolation in myeloid cells, lymphocytosis, increased plasma cells or monocytosis in marrow. Increased histiocytes, hemophagocytosis, dysplastic changes, maturation arrest, relative myeloid hyperplasia or reactive plasmacytosis, lymphocytosis, and monocytosis are BMA features which must alert the pathologist towards an infectious disease process, a knowledge of these changes can help extend the scope of BME beyond hemato-lymphoid malignancies.

Neutrophil metalloproteinase driven spleen damage hampers infection control of trypanosomiasis

Recent blood transcriptomic analysis of rhodesiense sleeping sickness patients has revealed that neutrophil signature genes and activation markers constitute the top indicators of trypanosomiasis-associated inflammation. Here, we show that Trypanosoma brucei infection results in expansion and differentiation of four splenic neutrophil subpopulations, including Mki67+Birc5+Gfi1+Cebpe+ proliferation-competent precursors, two intermediate immature subpopulations and Cebpb+Spi1+Irf7+Mcl1+Csf3r+ inflammation reprogrammed mature neutrophils. Transcriptomic scRNA-seq profiling identified the largest immature subpopulation by Mmp8/9 positive tertiary granule markers. We confirmed the presence of both metalloproteinases in extracellular spleen homogenates and plasma. During infection, these enzymes digest extracellular matrix components in the absence of sufficient TIMP inhibitory activity, driving remodeling of the spleen follicular architecture. Neutrophil depletion prevents the occurrence of organ damage, resulting in increased plasma cell numbers and prolonged host survival. We conclude that trypanosomiasis-associated neutrophil activation is a major contributor to the destruction of the secondary lymphoid architecture, required for maintaining an efficient adaptive immune response.

Distribution of peripheral blood mononuclear cell subtypes in patients with West syndrome: Impact of synacthen treatment

BackgroundWest Syndrome (WS) is an epileptic encephalopathy that typically occurs in infants and is characterized by hypsarrhythmia, infantile spasms, and neurodevelopmental impairment. Demonstration of autoantibodies and cytokines in some WS patients and favorable response to immunotherapy have implicated inflammation as a putative trigger of epileptiform activity in WS. Our aim was to provide additional support for altered inflammatory responses in WS through peripheral blood immunophenotype analysis. MethodsEight WS cases treated with synacthen and 11 age- and sex-matched healthy volunteers were included. Peripheral blood mononuclear cells (PBMC) were isolated and immunophenotyping was performed in pre-treatment baseline (8 patients) and 3 months post-treatment (6 patients) samples. The analysis included PBMC expressing NFκB transcription and NLRP3 inflammasome factors. ResultsIn pre-treatment baseline samples, switched memory B cells (CD19+IgD−CD27+) were significantly reduced, whereas plasma cells (CD19+CD38+CD138+) and cytotoxic T cells (CD3+CD8+) were significantly increased. Regulatory T and B cell ratios were not significantly altered. Synacthen treatment only marginally reduced helper T cell ratios and did not significantly change other T, B, NK and NKT cell and monocyte ratios. ConclusionsOur findings lend further support for the involvement of inflammation-related mechanisms in WS. New-onset WS patients are inclined to display increased plasma cells in the peripheral blood. Synacthen treatment does not show a beneficial effect on most effector acquired and innate immunity subsets.

Hairy Cell Leukemia with Marrow Reactive Plasmacytosis and Mast Cell Hyperplasia: A Case Report and Brief Review of the Literature

Hairy cell leukemia (HCL) and HCL-like disorders, including HCL-variant, are disorders of heterogeneous mature lymphoid B-cells known for their hairy cell infiltration accompanied by a specific genetic profile, various clinical presentations, and, as they are uncommon hematological malignancies characterized by pancytopenia, the need for appropriate therapy. Sometimes HCL creates diagnostic challenges for clinicians, and its coincidence or association with mast cell and plasma cell infiltration is a rare condition. Herein, we report a case of HCL with confusing manifestations. A 44-year-old man was referred to the hospital for weakness, fatigue, and watery, non-bloody diarrhea. The laboratory tests showed pancytopenia, leading to a referral for bone marrow aspiration and biopsy. Medium to large cells exhibiting widespread cytoplasm, oval nuclei similar to monocyte nuclei (kidney-shaped) accompanied by an increased number of mast cells, and plasma cells were observed in the biopsy sample. In flow cytometry, the neoplastic cells were positive for CD19, FMC7, and the co-expression of the CD20/CD25, CD11C/CD22, and CD103 markers. In immunohistochemical staining, the mast cells were positive for CD117, the plasma cells were positive for CD138, and the hairy cells were positive for CD20. Overall, hematopathologists must be aware of various morphologic confounding factors such as lack of typical cell morphological features and increased plasma cell and mast cell infiltration in the diagnosis of patients with HCL.