Immune Phenomena Research Articles

Theories of immune recognition: Is anybody right?

The clonal selection theory (CST) is the centrepiece of the current paradigm used to explain immune recognition and memory. Throughout the past decades, the original CST had been expanded and modified to explain new experimental evidences since its original publication by Burnet. This gave origin to new paradigms that govern experimental immunology nowadays, such as the associative recognition of antigen model and the stranger/danger signal model. However, these new theories also do not fully explain experimental findings such as natural autoimmune immunoglobulins, idiotypic networks, low and high dose tolerance, and dual-receptor T and B cells. To make sense of these empirical data, some authors have been trying to change the paradigm of immune cognition using a systemic approach, analogies with brain processing and concepts from second-order cybernetics. In the present paper, we review the CST and some of the theories/hypotheses derived from it, focusing on immune recognition. We point out their main weaknesses and highlight arguments made by their opponents and believers. We conclude that, until now, none of the proposed theories can fully explain the totality of immune phenomena and that a theory of everything is needed in immunology.

A Self-Cascade Penetrating Brain Tumor Immunotherapy Mediated by Near-Infrared II Cell Membrane-Disrupting Nanoflakes via Detained Dendritic Cells.

Immunotherapy can potentially suppress the highly aggressive glioblastoma (GBM) by promoting T lymphocyte infiltration. Nevertheless, the immune privilege phenomenon, coupled with the generally low immunogenicity of vaccines, frequently hampers the presence of lymphocytes within brain tumors, particularly in brain tumors. In this study, the membrane-disrupted polymer-wrapped CuS nanoflakes that can penetrate delivery to deep brain tumors via releasing the cell-cell interactions, facilitating the near-infrared II (NIR II) photothermal therapy, and detaining dendritic cells for a self-cascading immunotherapy are developed. By convection-enhanced delivery, membrane-disrupted amphiphilic polymer micelles (poly(methoxypoly(ethylene glycol)-benzoic imine-octadecane, mPEG-b-C18) with CuS nanoflakes enhances tumor permeability and resides in deep brain tumors. Under low-power NIR II irradiation (0.8 W/cm2), the intense heat generated by well-distributed CuS nanoflakes actuates the thermolytic efficacy, facilitating cell apoptosis and the subsequent antigen release. Then, the positively charged polymer after hydrolysis of the benzoic-imine bond serves as an antigen depot, detaining autologous tumor-associated antigens and presenting them to dendritic cells, ensuring sustained immune stimulation. This self-cascading penetrative immunotherapy amplifies the immune response to postoperative brain tumors but also enhances survival outcomes through effective brain immunotherapy.

Prospective, Randomized, Double-Blind Parallel Group Nutritional Study to Evaluate the Effects of Routine Intake of Fresh vs. Pasteurized Yogurt on the Immune System in Healthy Adults.

The immune system is affected by the dietary products humans intake. Immune system regulation by nutrition has uses in the clinical context, but it can also benefit healthy populations by delaying or preventing the emergence of immune-mediated chronic illnesses. In this study, the purpose was to describe and compare the modulator effects on the immune system of the routine ingestion of fresh vs. pasteurized yogurt. A unicentral, prospective, randomized, double-blind, parallel group 8-week nutritional study was carried out comparing the ingestion of 125 g of the products in healthy adults three times a day. A complete battery of in vitro tests on the activity of the immune system, processes and phenomena was performed. Exclusive immune-modulatory effects of fresh yogurt with respect to base line were found in terms of increased systemic IgM (primary immune responses), increased synthesis of IFN-gamma upon stimulation (Th1) and increased peripheral T cells (mainly "naive" CD4s). In the three interventions, we observed an increased phagocytic activity and burst test in granulocytes, together with increased secretion of IL-6, IL-1 β and IL-8 (pro-inflammatory) and increased CD16 expression (FcR favoring phagocytosis) in granulocytes. Overall, it is concluded that regardless of bacteria being alive or thermally inactivated, yogurt has common effects on the innate system, but the presence of live bacteria is necessary to achieve a potentiating effect on the specific immune response.

Exploitation of multiple host-derived nutrients by the yellow catfish epidermal environment facilitates Vibrio mimicus to sustain infection potency and susceptibility

Infection with Vibrio mimicus in the Siluriformes has demonstrated a rapid and high infectivity and mortality rate, distinct from other hosts. Our earlier investigations identified necrosis, an inflammatory storm, and tissue remodeling as crucial pathological responses in yellow catfish (Pelteobagrus fulvidraco) infected with V. mimicus. The objective of this study was to further elucidate the impact linking these pathological responses within the host during V. mimicus infection. Employing metabolomics and transcriptomics, we uncovered infection-induced dense vacuolization of perimysium; Several genes related to nucleosidase and peptidase activities were significantly upregulated in the skin and muscles of infected fish. Concurrently, the translation processes of host cells were impaired. Further investigation revealed that V. mimicus completes its infection process by enhancing its metabolism, including the utilization of oligopeptides and nucleotides. The high susceptibility of yellow catfish to V. mimicus infection was associated with the composition of its body surface, which provided a microenvironment rich in various nucleotides such as dIMP, dAMP, deoxyguanosine, and ADP, in addition to several amino acids and peptides. Some of these metabolites significantly boost V. mimicus growth and motility, thus influencing its biological functions. Furthermore, we uncovered an elevated expression of gangliosides on the surface of yellow catfish, aiding V. mimicus adhesion and increasing its infection risk. Notably, we observed that the skin and muscles of yellow catfish were deficient in over 25 polyunsaturated fatty acids, such as Eicosapentaenoic acid, 12-oxo-ETE, and 13-Oxo-ODE. These substances play a role in anti-inflammatory mechanisms, possibly contributing to the immune dysregulation observed in yellow catfish. In summary, our study reveals a host immune deviation phenomenon that promotes bacterial colonization by increasing nutrient supply. It underscores the crucial factors rendering yellow catfish highly susceptible to V. mimicus, indicating that host nutritional sources not only enable the establishment and maintenance of infection within the host but also aid bacterial survival under immune pressure, ultimately completing its lifecycle.

#2324 Do urinary tract infections trigger chronic inflammation in the kidney allograft? Interleukin 17 levels in the urine of kidney recipients

Abstract Background and Aims Urinary tract infections (UTI) represent the most common complication following kidney transplantation. Their role in triggering immune phenomena in kidney allograft remains unclear. Interleukin 17 (IL17) represents the significant branch in antimicrobial immunity. At the same time IL17 has been found associated with autoimmune inflammatory disorders. The triggering role of infections in autoimmunity as well as the similarities between autoimmunity and post-transplant immunity have been postulated. The aim of the study was to analyze the levels of urine IL 17A levels in relation to prior UTI history and the timeframe after the last UTI episode. Method The group of 91 kidney recipients who received kidney transplantation between 2016 and 2019 was analyzed. The set of 233 urine samples (109 from females and 124 from males) obtained within first 24 months post-transplant was investigated, among these 144 samples from the patients with no previous UTI history and 89 samples from the patients with previous UTI history (1-22 months after the last episode, average 6.7 ± SD 5.7). Furthermore, 18 samples obtained at the time of an UTI episode and 29 samples from healthy controls were included. Urine IL 17A levels were measured with Human IL 17 ELISA Kit (Sigma Aldrich) and urine IL/creatinine concentrations ratio was calculated for each value. Szapiro-Wilk test was used to assess data distribution, Kruskal-Wallis test was used to assess the differences between independent groups and two proportions Z test was used to compare the groups compositions. Results Interleukin 17A appeared detectable in 105 out of the 233 investigated samples (45%), with significantly higher frequency in samples from the recipients with previous UTI history (p = 0.02). The difference was not significant in the group who underwent recurrent UTI episodes vs. these after a single UTI episode. Among the samples in which IL 17A was detected, the period between the last UTI episode and sample collection was divided into three timeframes: 1-3 months, 4-12 months and 12-24 months. Urine IL17A levels appeared significantly higher independently in each timeframe post-UTI when compared to the samples from the recipients without UTI history and controls (p = 0.0001). Fig. 1 It was apparent within the whole group but also in males and females separately. Further, urine IL17A levels were significantly higher in males 1-3 months after the last UTI episode than in females in the analogous period (p = 0.001). Conclusion Interleukin 17A was more frequently detected in urine samples from kidney recipients with previous UTI history. UTI history impacted IL17A urine levels in the analyzed kidney recipients. Within the first 24 months post-transplant, these were higher in the recipients with UTI history prior to the sample collection and it was independent on the timeframe between the last UTI episode and the sample collection. The factors other than UTI history which influence urine IL17A detectability are not fully recognized and remain under investigation.

LAG-3 : recent developments in combinational therapies in cancer.

The study of anticancer immune responses and in particular the action of immune checkpoint inhibitors that overcome T cell inhibition has revolutionized metastatic patients' care. Unfortunately, many patients are resistant to these innovative immunotherapies. Over the last decade, several immune checkpoint inhibitors, currently available in the clinic, have been developed, such as anti-PD-1/PD-L1 or anti-CTLA-4. More recently, other immune checkpoints have been characterized, among them lymphocyte activation gene 3 (LAG-3). LAG-3 has been the subject of numerous therapeutic studies and may be involved in cancer-associated immune resistance phenomena. This review summarizes the latest knowledge on LAG-3 as an immunotherapeutic target, particularly in combination with standard or innovative therapies. Indeed, many studies are looking at combining LAG-3 inhibitors with chemotherapeutic, immunotherapeutic, radiotherapeutic treatments, or adoptive cell therapies to potentiate their antitumor effects and/or to overcome patients' resistance. We will particularly focus on the association therapies that are currently in phase III clinical trials and innovative combinations in preclinical phase. These new discoveries highlight the possibility of developing other types of therapeutic combinations currently unavailable in the clinic, which could broaden the therapeutic spectrum of personalized medicine.

Comprehensive analysis and prognostic assessment of senescence-associated genes in bladder cancer

BackgroundThe prevalence and mortality of bladder cancer (BLCA) present a significant medical challenge. While the function of senescence-related genes in tumor development is recognized, their prognostic significance in BLCA has not been thoroughly explored.MethodsBLCA transcriptome datasets were sourced from the TCGA and GEO repositories. Gene groupings were determined through differential gene expression and non-negative matrix factorization (NMF) methodologies. Key senescence-linked genes were isolated using singular and multivariate Cox regression analyses, combined with lasso regression. Validation was undertaken with GEO database information. Predictive models, or nomograms, were developed by merging risk metrics with clinical records, and their efficacy was gauged using ROC curve methodologies. The immune response’s dependency on the risk metric was assessed through the immune phenomenon score (IPS). Additionally, we estimated IC50 metrics for potential chemotherapeutic agents.ResultsReviewing 406 neoplastic and 19 standard tissue specimens from the TCGA repository facilitated the bifurcation of subjects into two unique clusters (C1 and C2) according to senescence-related gene expression. After a stringent statistical evaluation, a set of ten pivotal genes was discerned and applied for risk stratification. Validity tests for the devised nomograms in forecasting 1, 3, and 5-year survival probabilities for BLCA patients were executed via ROC and calibration plots. IC50 estimations highlighted a heightened responsiveness in the low-risk category to agents like cisplatin, cyclopamine, and sorafenib.ConclusionsIn summation, our research emphasizes the prospective utility of risk assessments rooted in senescence-related gene signatures for enhancing BLCA clinical oversight.

Abstract 3962: A CCR6+Th1-like CD4+T-cell cluster involved in HEV formation predicted lung cancer patients requiring anti-CTLA-4 therapy

Abstract Background: CD4+ T cells are known to help in cytotoxic T-cell priming, clonal proliferation, migratory and infiltrative capacity, and target cell killing function by licensing dendritic cells. Although CXCR3+ CCR6- classical Th1 CD4+ T cells are thought to be essential for acute cellular immunity, such as antiviral responses, the details of Th1-type CD4+ T cells required for anti-tumor immunity as a long-term chronic T cell immune responses over years remain unclear. We reported the Th7R, a CCR6 expressing Th1-like CD4+ T cell cluster predicted anti-PD-1 antibody therapy efficacy and postoperative recurrence-free survival. Objective: In this study, we focus on two Th1-like CD4+ T cell clusters, Th1 and Th7R, to determine their functions and roles in long-lasting anti-tumor immune phenomena. Methods: We studied patients with advanced stage lung cancer treated with immune checkpoint inhibitors (Pembrolizumab monotherapy n=63, Ipilimumab + Nivolumab n=148) and stage I-II lung cancer patients undergoing surgery (n=54). Mass cytometry, single cell RNA sequencing, and immunohistochemical staining were performed using peripheral blood, tumor-infiltrating lymphocytes and lymph node T cells. These studies were approved by the IRB of Saitama Medical University International Medical Center, and all patients gave written consent. Results: Unlike classical Th1, which highly expresses PRF1, GZMB, GNLY, and NKG7, Th7R expressed LTβ, CXCR6, CTLA-4, CD28, and CXCL13. Analysis of HEV index (MECA79+/CD31+ vessels) by MECA79 and CD31 staining of tumor tissues showed that Th7R in peripheral blood correlated with tumor tissue HEV index, suggesting that LTβ and CXCL13 expressed by Th7R are involved in HEV formation.Th1 mainly expressed PD-1 and did not express CTLA-4, whereas Th7R expressed both PD-1 and CTLA-4. When pre-treatment peripheral Th7R quartile was used to analyze OS after Ipilimumab + Nivolumab treatment, both the top 25% and intermediate 50% patients showed favorable prognosis, but the lower 25% had significantly poor OS. In contrast, only the top 25% Th7R patients but not the intermediate 50% and lower 25% patients who were treated with Pembrolizumab had favorable OS. Thus, it is likely that the Th7R intermediate 50% patients required anti-CTLA-4 therapy to achieve antitumor immune responses. These results may be useful for stratification of patients requiring anti-CTLA-4 antibody therapy as well as for predicting the therapeutic response of Ipilimumab + Nivolumab. Conclusion: Th7R exhibits LTβ and CXCL13 expression, which is absent in classical Th1, and may help maintain sustained T-cell immunity through HEV/TLS formation. Th7R may be a biomarker to select the patients who benefit from anti-CTLA-4 treatment. Citation Format: Hiroshi Kagamu, Satoshi Yamasaki, Atsuhito Mouri, Ou Yamaguchi, Ayako Shiono, Fuyumi Nishihara, Yu Miura, Kosuke Hashimoto, Hisao Imai, Kyoichi Kaira, Kunihiko Koabayashi, Katsuhisa Horimoto. A CCR6+Th1-like CD4+T-cell cluster involved in HEV formation predicted lung cancer patients requiring anti-CTLA-4 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3962.

Molecular insights into gastric cancer: The impact of TGFBR2 and hsa-mir-107 revealed by microarray sequencing and bioinformatics

BackgroundGastric carcinoma (GC) remains a significant therapeutic challenge, garnering widespread attention. Oxymatrine (OMT), an active component of the traditional Chinese medicine compound Kushen injection (CKI), has shown promising results in combination with chemotherapy for the treatment of GC. However, the molecular mechanisms underlying OMT's therapeutic effects in GC have yet to be elucidated. MethodsThe transcriptomic expression data of HGC-27 post-OMT intervention were obtained through microarray sequencing, while the miRNA and mRNA sequencing data for GC patients were sourced from the TCGA database. The mechanism of OMT intervention in GC is analyzed in multiple aspects, including Protein-Protein Interactions (PPI), Competitive Endogenous RNA (ceRNA) networks, correlation and co-expression analyses, immune infiltration, and clinical implications. ResultsBy analyzing key modules, five critical mRNAs were identified, and their interacting miRNAs were predicted to construct a ceRNA network. Among these, TGFBR2 and hsa-miR-107 have correlations or co-expression relationships with other genes in the network. They are differentially expressed in most other cancers, associated with prognosis, and have diagnostic value. TGFBR2 also exhibits immune infiltration phenomena, and its high expression is linked to poor patient prognosis. Low expression of hsa-miR-107 is associated with poor patient prognosis. OMT may act on the TGFβ/Smad signaling pathway or negatively regulate the WNT signaling pathway through the hsa-miR-107/BTRC axis, thereby inhibiting the onset and progression of GC. ConclusionThe mechanisms of OMT intervention in GC are diverse, TGFBR2 and hsa-miR-107 may serve as prognostic molecular biomarkers or potential therapeutic targets.

COVID-19 Neuroimaging Update: Pathophysiology, Acute Findings, and Post-Acute Developments

COVID-19 has prominent effects on the nervous system with important manifestations on neuroimaging. In this review, we discuss the neuroimaging appearance of acute COVID-19 that became evident during the early stages of the pandemic. We highlight the underlying pathophysiology mediating nervous system effects and neuroimaging appearances including systemic inflammatory response such as cytokine storm, coagulopathy, and para/post-infections immune mediated phenomena. We also discuss the nervous system manifestations of COVID-19 and the role of imaging as the pandemic has evolved over time, including related to the development of vaccines and the emergence of post-acute sequalae such as long COVID.

Prognostic model development and molecular subtypes identification in bladder urothelial cancer by oxidative stress signatures.

Mounting studies indicate that oxidative stress (OS) significantly contributes to tumor progression. Our study focused on bladder urothelial cancer (BLCA), an escalating malignancy worldwide that is growing rapidly. Our objective was to verify the predictive precision of genes associated with overall survival (OS) by constructing a model that forecasts outcomes for bladder cancer and evaluates the prognostic importance of these genetic markers. Transcriptomic data were obtained from TCGA-BLCA and GSE31684, which are components of the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), respectively. To delineate distinct molecular subtypes, we employed the non-negative matrix factorization (NMF)method. The significance of OS-associated genes in predicting outcomes was assessed using lasso regression, multivariate Cox analysis, and univariate Cox regression analysis. For external validation, we employed the GSE31684 dataset. CIBERSORT was utilized to examine the tumor immune microenvironment (TIME). A nomogram was created and verified using calibration and receiver operating characteristic (ROC) curves, which are based on risk signatures. We examined variations in clinical characteristics and tumor mutational burden (TMB) among groups classified as high-risk and low-risk. To evaluate the potential of immunotherapy, the immune phenomenon score (IPS) was computed based on the risk score. In the end, the pRRophetic algorithm was employed to forecast the IC50 values of chemotherapy medications. In our research, we examined the expression of 275 genes associated with OS in 19 healthy and 414 cancerous tissues of the bladder obtained from the TCGA database. As a result, a new risk signature was created that includes 4 genes associated with OS (RBPMS, CRYAB, P4HB, and PDGFRA). We found two separate groups, C1 and C2, that showed notable variations in immune cells and stromal score. According to the Kaplan-Meier analysis, patients classified as high-risk experienced a considerably reduced overall survival in comparison to those categorized as low-risk (P<0.001). The predictive capability of the model was indicated by the area under the curve (AUC) of the receiver operating characteristic (ROC) curve surpassing 0.6. Our model showed consistent distribution of samples from both the GEO database and TCGA data. Both the univariate and multivariate Cox regression analyses validated the importance of the risk score in relation to overall survival (P < 0.001). According to our research, patients with a lower risk profile may experience greater advantages from using a CTLA4 inhibitor, whereas patients with a higher risk profile demonstrated a higher level of responsiveness to Paclitaxel and Cisplatin. In addition, methotrexate exhibited a more positive outcome in patients with low risk compared to those with high risk. Our research introduces a novel model associated with OS gene signature in bladder cancer, which uncovers unique survival results. This model can assist in tailoring personalized treatment approaches and enhancing patient therapeutic effect in the management of bladder cancer.

IMMUNOTHERAPY OF CANCER: IMMUNE CHECKPOINT BLOCKERS, VACCINES AND ADOPTIVE T CELL THERAPIES

The clinical effectiveness of the three dominant forms of cancer immunotherapy (ITx): Immune checkpoint inhibition (ICI), adoptive cell therapies (ACT) and cancer vaccines (Vx) all require the ability of cancer tissues to attract tumor specific cytotoxic T cells (CTLs) and support their local effector function. For this reason, “cold” tumors, which lack CTL infiltration are uniformly nonresponsive to immune therapies and are less responsive to chemo- and radiotherapy, which effectiveness also involves immune phenomena. Our group has developed three groups of strategies to eliminate the “cold” tumor phenotype and to enhance allow effectiveness of the above forms of therapy of solid tumors: 1) Cell-based immunotherapies of cancer with dendritic cells (DC), used as live vaccines or intratumorally injected live adjuvants; 2) DC-induced multi-epitope-specific CTLs; and 3) Combinatorial reprograming of tumor microenvironments (TME), using different classes of adjuvants to enhance local infiltration of immune cells. Preclinical data and the results of the recently completed clinical trials will be discussed.

Polysaccharide of Asparagus cochinchinensis (Lour.) Merr regulates macrophage immune response and epigenetic memory through TLR4-JNK/p38/ERK signaling pathway and histone modification

BackgroundInnate immune memory of macrophages is closely linked to histone modifications. While various studies have demonstrated that the polysaccharide of Asparagus cochinchinensis (Lour.) Merr (ACMP), extracted through alcohol-alkali extraction, enhances macrophages' non-specific immune function; no literature currently addresses whether ACMP's regulatory effect is related to innate immune memory and histone modification. PurposeThis study aims to investigate if ACMP induces innate immune memory emergence in macrophages via pattern recognition receptor (PRR). Study designAfter co-incubating different doses of ACMP with RAW264.7 cells and BMDM cells, we observed changes in signaling pathways related to PRR and assessed the presence of innate immune memory phenomenon in the cells. MethodsWe observed the morphological characteristics of the ACMP using a scanning electron microscope, infrared spectrum, and HPLC pre-column derivatization method. We used q-PCR, Western blot, RNA-seq, and CUT&Tag-seq methods to examine ACMP's regulation of macrophage immune response and innate immune memory and explored its specific mechanism. ResultsACMP, primarily composed of Man, GlcN, Rha, Fuc, GalA, Xyl, Glc, Gal, Ara, and, exhibited a molar ratio of each monosaccharide (1.41: 0.35: 0.49: 0.18: 1.00: 97.12: 0.36: 3.58: 1.14). ACMP regulated immunological function in macrophages through the TLR4-MAPK-JNK/p38/ERK pathway. ACMP induced elevated levels of chromosomal H3K4me1, enhancing TNF-α, IL-1β, and other genes' responsiveness, allowing macrophages to develop innate immune memory to ACMP stimulation. ConclusionThis study first time demonstrates that ACMP regulates immunological function through the TLR4-MAPK-JNK/ERK/p38 signaling pathway, distinct from prior reports. ACMP induces innate immune memory in macrophages in response to its immune stimulation by promoting increased H3K4me1 on chromosomes. This mechanism may be crucial in how plant polysaccharides regulate macrophages and the body's immune function.

Curcuphenols facilitate the immune driven attenuation of metastatic tumour growth

One of the primary obstacles in current cancer treatments lies in the extensive heterogeneity of genetic and epigenetic changes that occur in each arising tumour. However, an additional challenge persists, as certain types of cancer display shared immune deficiencies in the antigen processing machinery (APM). This includes the downregulation of human leukocyte antigen (HLA) class I molecules, which serve as peptide antigen receptors for T lymphocyte recognition that plays a crucial role in killing emerging tumours. Consequently, this contributes to immune escape in metastatic disease. Notably, current cell-based immunotherapies primarily focusing on T lymphocytes and the implementation of immune checkpoint inhibitor modalities have largely ignored the crucial task of reversing immune escape. This oversight may explain the limited success of these approaches becoming more effective cancer immunotherapies. Hence, there is a critical need to prioritize the discovery of new therapeutic candidates that can effectively address immune escape and synergize with evolving immunotherapy strategies. In this context, we identified curcuphenol in a cell-based screen from a library of marine extracts as a chemical entity that reverses the immune-escape phenotype of metastatic cancers. To advance these findings toward clinical efficacy, the present study describes the synthesis of analogues of naturally occurring curcuphenol with enhanced chemical properties and biological efficacy. Here we test the hypothesis that these curcuphenol analogues can evoke the power of the immune system to reduce the growth of metastatic disease in tumour bearing animals. Our findings indicate that these compounds effectively restore the expression of APM genes in metastatic tumours and inhibit the growth of highly invasive tumours in preclinical models, thereby counteracting the common immune evasion phenomenon observed in metastatic cancers. We conclude that cancer immunotherapies capable of boosting APM expression, hold great potential in maximizing the effectiveness of immune blockade inhibitors and eradicating invasive tumours.

Oxeiptosis core genes and their multi-omics analysis in hepatocellular carcinoma.

Oxeiptosis is a recently discovered caspase-independent, non-inflammatory programmed cell death modality. Current studies suggest that oxeiptosis has crucial effects on biological processes in a variety of diseases. However, the mechanism of oxeiptosis in hepatocellular carcinoma (HCC) remains unclear and no relevant studies have been published. Therefore, this study is intended to investigate the mechanism and prognostic role of oxeiptosis-related genes in HCC. We explored the mechanisms and molecular phenotypes underlying the role of oxeiptosis in HCC through multi-omics analysis. Firstly, we obtained RNA-sequencing and clinical data from public database and divided the samples into trial and validation cohorts in subsequent analyses. We then screened oxeiptosis core genes (OCGs) and screened prognosis-related genes. Based on different molecular markers, we identified the molecular phenotypes of HCC, and the potential OCGs molecular mechanisms were explored. Subsequently, we construct a prognostic prediction system for HCC. Finally, we analyzed the tumor microenvironment and the immune escape phenomenon. We screened a total of 69 OCGs, most of which were prognostic risk factors for HCC. A majority of OCGs were enriched in cell cycle regulation and mitotic processes, which were related to both tumor cell proliferation and death. We identified 2 different molecular typing options with significant differences in prognosis, function, and signaling pathway enrichment between different molecular subtypes. The prognostic prediction model combined with molecular phenotypes and had a good predictive effect. Finally, we found CD4 + T-cell exhaustion in samples with specific molecular phenotypes. Through multi-omics analysis of OCGs, we not only revealed the possible molecular mechanisms of OCGs in HCC but also provided a prognostic prediction system for clinical application through molecular typing and risk scoring model. Meanwhile, we found immune escape mechanisms in HCC.

P30 An unusual infective cause of inflammatory arthritis

P30 An unusual infective cause of inflammatory arthritis

Castleman's disease in the rheumatological practice

The term Castleman's disease encompasses agroup of rare lymphoproliferative diseases that show histopathological similarities in lymph node biopsy. Diagnostic criteria and aspecific ICD-10 code have been available for afew years. Case studies listed at the beginning illustrate that close cooperation between clinicians and pathologists is required to enable areliable diagnosis. For an optimal histopathological assessment, the pathologist is also dependent on the removal of acomplete lymph node. Before distinguishing apotentially fatal multicentric idiopathic Castleman's disease from the resectable unicentric form, which is important in terms of prognosis and treatment, early diagnosis presupposes that Castleman's disease is considered in the differential diagnosis. Various immune phenomena and overlaps with autoimmune diseases can increase the probability of misdiagnosis or undetected cases in the clinical routine of rheumatologists. The intention of the present overview is therefore to point out the similarities with autoimmune diseases that are relevant for differential diagnoses and to point out situations that justify areview of the previous diagnosis.

Sequels of COVID-19: An integrative literature review

The strong affinity between the Spike protein of the SARS-CoV-2 virus and the angiotensin-converting enzyme 2 receptor is postulated as one of the main reasons for the high viral transmission rate, leading the WHO to declare COVID-19 as a Public Health Emergency of International Concern and to adopt measures to contain viral spread. Moreover, due to the virus’s pathophysiological mechanism, non-specific symptoms, atypical progression, especially in the elderly and immunocompromised, and a faster and more lethal progression are observed. Additionally, as knowledge about the natural history of the virus infection has advanced, persistent symptoms and/or sequelae causing organic dysfunctions and negatively impacting patients’ quality of life have been noted. In light of this, the objective of this article was to present an integrative review of the main sequels of COVID-19 in the years 2021 and 2022. To achieve this, full articles were searched in the Scientific Electronic Library Online, Biblioteca Virtual em Saúde, and PubMed research databases, in both Portuguese and English languages, using the PRISMA methodology (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), resulting in the selection of 14 articles. Among the results, the following stand out: the pathogenesis of persistent COVID-19 is based on the theory of immune phenomena secondary to infection, abnormal immune response, and the presence of the virus in immunologically privileged sites; prevalent complications include fatigue, dyspnea, subjective cognitive impairment, neurological sequelae, central nervous system inflammatory diseases, and post-viral olfactory dysfunction; evidence of a causal relationship between COVID-19 and subacute thyroiditis was presented; a higher number of complications and hospitalizations were demonstrated in vitamin D-deficient patients; as well as the presence of neuropsychiatric symptoms in the healthcare professional population. In conclusion, a scarcity of studies directly addressing COVID-19 sequelae was noted, highlighting the need for further research to create more specific diagnostic protocols.

Adenosine Methylation Level of miR-125a-5p Promotes Anti-PD-1 Therapy Escape through the Regulation of IGSF11/VSIG3 Expression.

Despite encouraging anti-tumour activity in lung cancer, anti-PD-1 therapy has encountered increasing resistance to treatment. Several companion diagnostic assays have been performed to identify patients who may benefit from this immunotherapy and to adapt this therapy in case of acquired resistance. A large panel of methods was used for the analysis of expression and methylation levels of miRNAs (qPCR, MemiRIP, …), protein/miRNA interactions (CLIP, oligo pull-down, …), and protein-protein interactions (CoIP) in cells and/or blood samples. Our work highlights that the saturation of PD-1 by anti-PD1 therapies induces an immune escape phenomenon due to the overexpression of IGSF11 following adenosine methylation of miR-125a-5p. Mechanistically, we identify METTL3/KHDRBS3 and HuR as two crucial players in the methylation and the loss of the repressive function of this miRNA. Finally, our work shows that the adenosine methylation of miR-125a-5p is analyzable from EVs/exosomes from longitudinal blood samples and that such EVs/exosomes modulate the IGSF11/VSIG3 expression in lung cancer cells to promote an immune escape phenomenon. Our data provide a biomarker (m6A-miR-125a-5p level) and two therapeutic solutions (anti-IGSF11 antibody and METTL3 inhibitor) that could potentially address the anti-PD1 therapy failure in the context of precision and personalized medicine.

Non-organ-specific autoantibodies with unspecific patterns are a frequent para-infectious feature of chronic hepatitis D.

Infections with hepatotropic viruses are associated with various immune phenomena. Hepatitis D virus (HDV) causes the most severe form of viral hepatitis. However, few recent data are available on non-disease-specific and non-organ-specific antibody (NOSA) titers and immunoglobulin G (IgG) levels in chronic hepatitis D (CHD) patients. Here, we examined the NOSA titers and IgG levels of 40 patients with CHD and different disease courses and compared them to 70 patients with chronic hepatitis B (CHB) infection. 43% of CHD patients had previously undergone treatment with pegylated interferon-α (IFN-α). The antibody display of 46 untreated patients diagnosed with autoimmune hepatitis (AIH) was used as a reference. The frequency of elevated NOSA titers (CHD 69% vs. CHB 43%, p < 0.01), and the median IgG levels (CHD 16.9 g/L vs. CHB 12.7 g/L, p < 0.01) were significantly higher in CHD patients than in patients with CHB, and highest in patients with AIH (96%, 19.5 g/L). Also, the antinuclear antibody pattern was homogeneous in many patients with AIH and unspecific in patients with viral hepatitis. Additionally, f-actin autoantibodies were only detectable in patients with AIH (39% of SMA). In CHD patients, IgG levels correlated with higher HDV viral loads, transaminases, and liver stiffness values. IgG levels and NOSA were similar in CHD patients irrespective of a previous IFN-α treatment. In summary, autoantibodies with an unspecific pattern are frequently detected in CHD patients with unclear clinical relevance.