Radiologically isolated syndrome (RIS) is a neurological condition in people with demyelinating lesions on brain and/or spinal cord magnetic resonance imaging (MRI) studies, but without clinical symptoms of disease. Elucidating the immune profile of people with RIS (pwRIS) who will display MRI or clinical features of advancing disease is critical to our understanding of disease pathogenesis. Our lab previously identified features of B cell dysregulation in people with clinically isolated syndrome (pwCIS), who have both demyelinating lesions and a first clinical event of disease. The goal of this study was to compare features of B cell dysregulation in pwRIS, pwCIS, and healthy controls (HC). The second goal was to determine if these features of B cell dysregulation would be evident in people who meet the new MS diagnostic criteria, particularly in the context of their disease course for 5 years post-sampling. Features of plasmablast responses that distinguish pwRIS from pwCIS include PB expansion, antigen-driven selection, VH4 and JH6 antibody gene over-usage, neuron reactivity by purified IgG and individually cloned antibodies. Furthermore, VH4:JH6 pairing in plasmablasts was higher in people with stable MS who do not show changes in MRI or clinical events from those with advancing disease activity.

Head and neck squamous cell carcinoma (HNSCC) is a major health concern with considerable morbidity and mortality worldwide. Previous studies have applied single-cell sequencing to characterize the tumor microenvironment in HNSCC, providing insights into immune cell composition, stromal interactions, and malignant cell states. However, there remains a gap in analyzing lymph node metastasis (LM) and normal lymph node tissues (LN) by using single-cell RNA sequencing (scRNA-seq) analysis. We performed comparative scRNA-seq analysis on seven lymph node metastatic tissues of HNSCC patients and five non-metastatic tissues. We identified several cell types with significantly altered expression levels, such as CD8+ Tex cells, Macrophages, and Cancer-associated fibroblasts (CAFs). Tumor cells were classified into seven clusters, with cluster2 strongly linked to tumorigenesis and metastasis. Specific subsets such as CD4_Tfh_CXCL13, CD4_Treg_RPL26, CD8_teff_CREM, NK_GZMB, Macrophages_OLFML3 and macrophages_SPP1 cells were also associated with HNSCC progression and metastasis. Based on these findings, we constructed and validated a prognostic model for HNSCC using the expression of INHBA, SFRP2, SPP1, and IFI27. This model provides a tool for risk stratification and informs potential therapeutic strategies for HNSCC.

The prognosis for hepatocellular carcinoma remains grim. Combining radiotherapy with immune checkpoint blockade (ICB) has shown potential to enhance therapeutic outcomes, yet there is a pressing need for further advancements. Our previous research demonstrated that this combined approach suppresses ALKBH5 gene expression and increases m6A modification levels in hepatocellular carcinoma tissues. High-throughput sequencing and detailed molecular analysis revealed that inhibiting ALKBH5 amplifies CIITA m6A modifications post-therapy. This modulation triggers MHC II molecule expression in tumors, facilitating the presentation of tumor-associated antigens to CD4 + T lymphocytes and the recruitment of CD8 + T cells for an anti-tumor immune response. Building on these findings, we engineered a CIITA vector with a specific site mutation to confirm that the regulation of CIITA by the combined radiotherapy and immunotherapy is mediated through m6A methylation. Consequently, we established a comprehensive network involving ALKBH5, CIITA, MHC II, and CD4+ and CD8 + T cells. To elucidate the role and underlying molecular mechanisms of this combined therapy in reshaping the tumor immune microenvironment for hepatocellular carcinoma, we employed multi-omics approaches across in vitro, animal model, and clinical multi-dimensional studies, offering novel insights for enhancing treatment efficacy.

Cyclic GMP-AMP synthase (cGAS) is critical for dendritic cell (DC) maturation. This study investigates how cGAS suppression in DCs influences graft immune tolerance. Bioinformatics analysis assessed cGAS involvement in transplant immunity. Immature DCs were transduced with an adenoviral vector to knockdown cGAS and divided into three groups: cGAS-shRNA-DCs, EGFP-DCs and PBS (control). These were administered intravenously before transplantation to establish a mouse model. Graft survival and histopathology were evaluated. Splenic T cell subsets were analyzed by flow cytometry. After lipopolysaccharide stimulation, MHC-II and co-stimulatory molecule expression, antigen uptake, and T cell proliferation were measured in three groups. Cytokine levels in supernatants were quantified. Western blotting was used to explore the mechanism of cGAS in DC maturation. Bioinformatics revealed elevated cGAS expression in allografts. cGAS-shRNA-DCs showed reduced MHC-II and co-stimulatory molecule expression, enhanced phagocytosis, and decreased T cell activation. IFN-γ, IL-1β, TNF-α, and IL-6 levels were lower, while IL-10 was higher. Mice receiving cGAS-shRNA-DCs exhibited prolonged graft survival and improved function. Flow cytometry showed increased regulatory T cells and reduced Th1 and Th17 cells. WB indicated that cGAS regulates DC maturation via NF-κB signaling. In conclusion, suppressing cGAS in DCs inhibits their maturation, thereby enhancing graft survival.

N6-methyladenosine (m6A) RNA modifications and reovirus infections have recently been implicated in the development of celiac disease. While viral infections are known to alter the RNA modification machinery of the host, their interplay in autoimmune tissue damage remains unexplored. In this study we employed an in vitro model combining a viral mimic with gliadin peptides to simulate celiac disease conditions, alongside the analysis of serum and intestinal biopsies from controls and patients to investigate the link between m6A methylation and viral infections in inducing autoimmune inflammation. We found elevated anti-reovirus reactivity in patients, increased antiviral gene expression and enhanced m6A levels. Notably, the expression of IRF7 was synergistically induced by the combined exposure to the viral mimic and gliadin peptides, and this is mediated through m6A methylation in its coding region and interaction with the reader protein YTHDC2. Furthermore, the reduction of m6A through METTL3 silencing or simvastatin treatment reduced IRF7 mRNA methylation and downstream proinflammatory gene expression both in vitro and ex vivo. These findings highlight m6A methylation as a modulator of antiviral responses and a potential therapeutic target in autoimmune disorders.

Myeloid cells, including monocytes, macrophages, and microglia, play major roles in innate and adaptive immune responses. Alzheimer's disease (AD) and inflammatory bowel disease (IBD) susceptibility loci are both enriched for genes expressed in myeloid cells, so we assessed whether these myeloid pathways may be shared. Leveraging genome-wide association study results, we investigated the causal effect of IBD (including ulcerative colitis and Crohn's disease) variants on AD and its endophenotypes. Microglia and monocyte expression Quantitative Trait Locus (eQTLs) were used to examine the functional consequences of IBD and AD variants. Our results revealed that the sets of genes and pathways implicated in AD and IBD susceptibility are largely distinct. Specifically, AD loci were enriched for microglial eQTLs, while IBD loci were enriched for monocyte eQTLs. Nonetheless, genetically determined IBD was associated with a modest protective effect against AD (p < 0.03), whereas CD susceptibility was linked to a modest increase in amyloid accumulation (β = 7.14, p = 0.02) and AD risk. UC susceptibility, on the other hand, was associated with increased TDP-43 deposition (β = 7.58, p value = 6.11 × 10-4). Thus, the relationship between gastrointestinal inflammatory diseases and AD is complex, but there is evidence for a modest role of IBD susceptibility on AD risk that could yield valuable therapeutic insights.

Lung cancer is the deadliest cancer globally. Non-small cell lung cancer (NSCLC), including adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, constitutes a significant portion of cases. Adenocarcinoma, the most prevalent type, has seen a rising incidence. Immune checkpoint inhibitors (ICIs) have improved outcomes in lung adenocarcinoma (LUAD), yet response rates remain unsatisfactory. PD-1/PD-L1 inhibitors are primary ICIs for LUAD, targeting the PD-1/PD-L1 pathway between CD8+ T cells and tumor cells. However, LUAD presents a "cold tumor" phenotype with fewer CD8+ T cells and lower PD-1 expression, leading to resistance to ICIs. Thus, understanding the function of other immune cell in tumor microenvironment is crucial for developing novel immunotherapies for LUAD. B cells, which is part of the adaptive immune system, have gained attention for its role in cancer immunology. While research on B cells lags behind T cells, recent studies reveal their close correlation with prognosis and immunotherapy effectiveness in various solid tumors, including lung cancer. B cells show higher abundance, activity, and prognostic significance in LUAD than that in LUSC. This review summarizes the difference of B cell immunity between LUAD and other lung cancers, outlines the role of B cell immunity in LUAD.

Tumor-Infiltrating Lymphocytes (TILs) immunotherapy is a highly promising treatment for Non-small Cell Lung Cancer (NSCLC), which is responsible for 18% of all cancer-related deaths. The heterogeneity of TILs remains poorly understood. Here, we utilized combined single-cell RNA (scRNA)/T cell receptor sequencing (scTCR-seq) data from lung adenocarcinoma (LUAD) patients. Naïve CD4+ and effector memory CD8+ T cells were increased in tumor tissue compared with circulating blood samples. Activated signaling pathways were detected, and GZMA was identified as a potential novel diagnostic biomarker. During the transitional phase, macrophages (FTL) and dendritic (AIF1) cells transported the most CD3 TCR clones to T cells, while cytotoxicity CD8+ T (NKG7) cells transported to terminal exhausted CD8+ T cells. In both transition and expansion phases, T helper cells (CXCL13) are transported to regulatory T cells (Tregs). Additionally, we investigated the expression profiles of key cytokines, checkpoint receptors, and their ligands. Cytotoxicity CD8+ T cells (CCL5 and IFNG), T helper cells (FTL, TNFRSF4, and TIGIT), and regulatory T cells (CTLA4, TIGIT and FTL) exhibited functional roles in both primary and metastatic tumor stages. Taken together, our study provides a single-cell resolution of the TIL immune landscape and suggests potential treatment strategies to overcome drug resistance.

Thyroid cancer (TC) is the most prevalent endocrine malignancy worldwide. This study aimed to explore the molecular subtypes and improve the selection of targeted therapies. We used multi-omics data from 539 patients with DNA methylation, gene mutations, mRNA, lncRNA, and miRNA expressions. This study employed consensus clustering algorithms to identify molecular subtypes and used various bioinformatics tools to analyze genetic alterations, signaling pathways, immune infiltration, and responses to chemotherapy and immunotherapy. Two prognostically relevant TC subtypes, CS1 and CS2, were identified. CS2 was associated with a poorer prognosis of shorter progression-free survival times (P < 0.001). CS1 exhibited higher copy number alterations but a lower tumor mutation burden than CS2. CS2 exhibited activation in cell proliferation and immune-related pathways. Drug sensitivity analysis indicated CS2's higher sensitivity to cisplatin, doxorubicin, paclitaxel, and sunitinib, whereas CS1 was more sensitive to bicalutamide and FH535. The different activated pathways and sensitivity to drugs for the subtypes were further validated in an external cohort. Twenty-four paired tumors and adjacent normal tissues by immunohistochemical staining further demonstrated the prognostic value of CXCL17. In conclusion, we identified two distinct molecular subtypes of TC with significant implications for prognosis, genetic alterations, pathway activation, and treatment response.