Search Results (159)

Systemic lupus erythematosus (SLE) is a severe autoimmune disease characterized by autoantibody production and multi-organ involvement. Anifrolumab, a monoclonal antibody targeting the type I interferon (IFN) receptor, has been approved for the treatment of SLE. Our aim was to investigate the long-term effects of inhibited type I IFN signaling on circulating follicular helper T subsets (T_FH), follicular regulatory T cells (T_FR), and B lymphocyte subpopulations, reflecting the ongoing germinal center reactions in SLE patients. Peripheral blood samples were obtained from ten SLE patients before the initiation of anifrolumab treatment, and at months 6 and 12 of the intervention period. Flow cytometry analysis was performed to assess the frequencies of circulating T_FH cell subsets, T_FR cells, and certain B cell subpopulations. Serological parameters, including autoantibody levels and complement components, were determined as part of the routine diagnostic evaluation. We observed a significant and sustained reduction in the percentage of activated circulating T_FH cells. Notably, the frequency of CXCR3⁻CCR6⁺ T_FH17 cells decreased, whereas the proportion of CXCR3⁺CCR6⁻ T_FH1 cells increased significantly. Furthermore, the proportion of the IgD⁻CD27⁻ double-negative B lymphocytes was also significantly reduced. These findings suggest that anifrolumab therapy attenuates T_FH cell activation, which may contribute to its clinical efficacy by modulating germinal center responses in SLE. Full article

SLE is characterized by the generation of a variety of autoantibodies including anti-dsDNA autoantibodies, causing damage in various organs. If autoimmunity is defined by the generation of a variety of autoantibodies against the self, SLE is the only disease to qualify. Identification of the SLE-causing factor must fulfill the following criteria: (i) the factor induces SLE, (ii) the factor is operating in active SLE and (iii) SLE heals after removal of the factor. All candidate factors are reviewed from this viewpoint in this review. As to the cause of SLE, high levels of interferon α can induce SLE; however, interferon α in most patients did not reach this high level. BAFF (B cell activating factor of the TNF family) is increased in SLE. BAFF itself induced some manifestation of SLE, whereas removal of interferon α or BAFF by an antibody (Ab) did not heal SLE. BXSB male mice with a duplicated TLR7 gene develop SLE; however, the gene Sle1 is also required for the development of SLE. In addition, sanroque mice develop a variety of autoantibodies and SLE; the sanroque mutation, which disrupts one of the repressors of ICOS, results in increased CCR7^lo CXCR5⁺Tfh cells, IL-21 and SLE. ICOS⁺T follicular helper (Tfh) cells increase in SLE and SLE-model (NZBxNZW)F1 mice, and the blockade of Tfh development ameliorated SLE, indicating the importance of Tfh cells in the pathogenesis of SLE. Self-organized criticality theory shows that SLE is caused by repeated infection, wherein SLE-inducing pathogens can vary individually depending on one’s HLA; however, the pathogen presented on HLA stimulates the T cell receptor (TCR) strongly beyond self-organized criticality. This stimulation generates TCR-revised, autoreactive DOCK8⁺Tfh cells, which induced a variety of autoantibodies and SLE. The SARS-CoV-2 virus is an example pathogen because SLE occurs after SARS-CoV-2 infection and vaccination. DOCK8⁺Tfh cells and SLE decreased after conventional or anti-DOCK Ab therapies. Thus, DOCK8⁺Tfh cells newly generated after repeated infection fulfill the criteria (i), (ii) and (iii) as the cause of SLE. Full article

Myeloid/lymphoid neoplasms with tyrosine kinase gene fusions (MLN-TK) represent a distinct group of hematologic malignancies recognized in the latest WHO classification due to shared clinical, morphological, and molecular features, and their responsiveness to tyrosine kinase inhibitors (TKIs). Among these, fusions involving the SYK gene, such as ETV6::SYK and ITK::SYK, have emerged as rare but potentially targetable genetic events in both myeloid and lymphoid neoplasms. SYK, a non-receptor tyrosine kinase critical for hematopoietic signalling, can become constitutively activated through gene fusions, driving oncogenesis via the PI3K/AKT, MAPK, and JAK-STAT pathways. ETV6::SYK has been primarily associated with myeloid neoplasms, often presenting with eosinophilia, bone marrow dysplasia, and skin involvement. In vitro and in vivo models confirm its leukemogenic potential and identify SYK as a therapeutic target. Although SYK inhibitors like fostamatinib have shown transient efficacy, resistance mechanisms, possibly involving alternative pathway activation, remain a challenge. The ITK::SYK fusion, on the other hand, has been identified in peripheral T-cell lymphomas, particularly of the follicular helper T-cell subtype, with similar pathway activation and potential for targeted intervention. Additional rare SYK fusions, such as PML::SYK and CTLC::SYK, have been reported in myeloid neoplasms and juvenile xanthogranuloma, respectively, expanding the spectrum of SYK-driven diseases. Accumulating evidence supports the inclusion of SYK fusions in future classification systems and highlights the need for broader molecular screening and clinical evaluation of SYK-targeted therapies. Full article

Background: Allergic rhinitis (AR) is triggered by immunoglobulin E (IgE)-mediated immune responses to airborne allergens. Recent studies highlight the pivotal role of T follicular helper 2 (Tfh2) cells in IgE production. Interleukin-37 (IL-37) has emerged as an intrinsic modulator of innate immunity and inflammatory processes. We aimed to investigate the regulatory effect of IL-37 on Tfh2 cells in the pathogenesis of AR. Methods: Blood samples were collected from AR patients and controls. The IL-37 levels and the frequency of Tfh2 cells were detected by enzyme-linked immunosorbent assay (ELISA) and flow cytometry, respectively. The isolated Tfh2 cells were cultured or cocultured with naive B cells. The regulatory effects of IL-37 on Tfh2/B cells were assessed using ELISA, quantitative real-time polymerase chain reaction (qRT-PCR). Mouse models of ovalbumin (OVA)-induced AR were established to explore the effect of IL-37 in vivo. Results: IL-37 suppressed the production of IL-4 and IL-21 by Tfh2 cells and downregulated C-X-C chemokine receptor type 5 (CXCR5) and B-cell lymphoma 6 protein (Bcl6) mRNA expression while upregulating B lymphocyte-induced maturation protein 1 (Blimp1) and signal transducers and activators of transduction5 (STAT5) mRNA. IL-37 decreased IgE production by B cells significantly, and the addition of anti-IL-18 receptor α alleviated this effect. In mouse models, IL-37 reduced nasal rubbing, sneezing, eosinophil counts, OVA-specific IgE, and Tfh2 proportions. Conclusions: IL-37 plays a crucial role in modulating Tfh2 cell responses in AR, suggesting a potential therapeutic target for this condition. Full article

Background: Primary cutaneous peripheral T-cell lymphoma, not otherwise specified (pcPTCL-NOS), is a rare and aggressive form of lymphoma. Its characteristics and treatment outcomes remain poorly understood. Methods: We identified 15 patients who were diagnosed with pcPTCL-NOS between January 2014 and August 2024 at Tianjin Medical University Cancer Institute and Hospital (TMUCIH) in this retrospective study. The clinical and immunophenotypic features, treatment regimens, and outcomes of these patients were investigated. Results: All patients (4 men, 11 women; median age 54 years) presented with skin lesions, including five stage T1, four stage T2 and six stage T3 lesions. pcPTCL-NOS manifests clinically either with solitary or disseminated rapidly growing nodules/tumors and papules and, less often, ulcers. The lesion sites in patients presenting with solitary/localized tumors (stage T1 and T2) were the head and limbs, and those in patients presenting with disseminated lesions (stage T3) were the trunk, head, and limbs. The CD4/CD8 immunophenotypic characteristics were as follows: CD4+/CD8− 53.33%; CD4+/CD8+ 26.67%; CD4−/CD8− 13.33%; and CD4−/CD8+ 6.67%. One patient had a T follicular helper (TFH) phenotype. Five patients had aberrant expression of the B-cell marker CD20 by tumor cells. All patients received CHOP or CHOP-like regimens as the initial treatment, with three patients undergoing complete lesion resection before chemotherapy, seven patients receiving treatment combined with chidamide (tucidinostat), two patients receiving treatment combined with brentuximab vedotin, two patients receiving treatment combined with mitoxantrone liposomes (Lipo-Mit), three patients receiving treatment combined with radiotherapy, and two patients receiving ASCT after the first-line treatment. The OS rates at 1 year, 2 years, and 3 years were 80%, 77.8%, and 77.8%, respectively; the PFS rates were 60%, 44.4%, and 33.3%, respectively. With a median follow-up of 40 months, the median PFS was 21 months, and the median OS was not reached. Univariate analyses revealed that patients with B symptoms and the CD4−/CD8− phenotype had inferior outcomes (p < 0.05). Age, sex, tumor stage, PIT score, Ki-67 index, elevated β2-MG levels, expression of CD20 or PD1, and treatment selection were not associated with the prognosis. A trend of a survival benefit in patients with solitary (T1) tumors compared with patients with disseminated (T2, T3) tumors was observed, suggesting that it is possible to reduce the intensity of treatment in patients with T1 tumors in the future. Conclusions: pcPTCL-NOS is an aggressive but poorly characterized lymphoma that may require early and active systemic treatment. However, for patients with T1 tumors, reducing the intensity of treatment with CHOP should be appropriately considered. Full article

Flaviviruses are a group of viruses transmitted mainly by mosquitoes and ticks, causing severe diseases in humans. Examples include dengue, Zika, West Nile virus, and yellow fever. They primarily affect individuals in tropical and subtropical regions, causing public health problems such as epidemic outbreaks and significant economic burdens due to hospitalizations and treatments. They share antigens, leading to cross-reactivity where antibodies generated against one flavivirus can react with others, complicating the accurate diagnosis of individual infections and making the development of treatments or vaccines more challenging. The role of T cells in the immune response to flaviviruses is a complex topic debated by scientists. On one hand, T cells help control infection by eliminating infected cells and protecting against disease. However, there is evidence that an excessive or dysregulated T cell response can cause tissue damage and worsen the disease, as seen in severe dengue cases. This duality underscores the complexity of the immune response to flavivirus infections, posing a significant challenge for researchers. Gaining a deeper understanding of the immune response at the cellular level, particularly the role of T follicular helper cells, can reveal new avenues of investigation that could lead to novel strategies for disease management. This review explores the dynamics of T cell responses, focusing on circulatory T follicular helper cells (cT_FH), to enhance our understanding of flavivirus immunity and inform future interventions. Full article

T-follicular helper (Tfh) cells, a specialized subset of CD4⁺ cells, are the immune mediators connecting cellular and humoral immunity, as they lead B-cell proliferation within germinal centers, and orchestrate their response, including activation, class switching, and production of a diverse array of high-affinity antibodies. Their interactions with B cells is regulated by a wide complex of transcriptional and cytokine-driven pathways. A major contribution of Tfh cells to autoimmune diseases is through their production of cytokines, particularly IL-21, which supports the proliferation and differentiation of autoreactive B cells. Elevated levels of circulating Tfh-like cells and IL-21 have been observed in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) correlating strongly with disease severity and autoantibody levels. The feedback loop between Tfh cells and IL-21 or other signal pathways, such as Bcl-6, ICOS, and PD-1, not only sustains Tfh cell function but also drives the continuous expansion of autoreactive B cells, leading to chronic inflammation through the production of high-affinity pathogenic autoantibodies. By understanding these interactions, Tfh pathways may serve as potential therapeutic targets, with IL-21, ICOS, and PD1 blockades emerging as promising innovative therapeutic strategies to manage autoimmune diseases. Although a variety of studies have been conducted investigating the role of Tfh cells in SLE and RA, this review aims to reveal the gap in the literature regarding the role of such subpopulations in the pathogenesis of other autoimmune diseases, such as Anca-associated vasculitis (AAV), and express the need to conduct similar studies. Tfh cell-related biomarkers can be used to assess disease activity and transform autoimmune disease treatment, leading to more personalized and effective care for patients with chronic autoimmune conditions. Full article

IgG4 is an unusual immunoglobulin (Ig) and is the least component of IgG in humans. It is often asymmetrical and heterobivalent with weak Fc (fragment crystallizable region)-dependent effector function and ineffective complement activation, thus playing an unclear role in immune functions. IgE is an uncommon Ig, being important mostly in allergy and type 2 immunity. There are two rare chronic Ig-related fibroinflammatory diseases, namely IgG4-related disease (IgG4RD) and Kimura disease (KD), characterized by prominent IgG4- or IgE-positive plasma cells in the affected tissues, with or without blood elevations of the same Ig. The etiology of these two Ig-related diseases is unclear, though it appears that the pathogenesis in both is related to polarized Ig heavy chain isotype switching, concomitant with other cellular, cytokine and chemotaxin interactions that culminates in the characteristic pathologic manifestations of inflammation and fibrosis. IgG4RD and KD, despite having overlapping and differing features, may be connected by the similar pathogenetic polarized Ig isotype switching. Full article

T follicular helper (Tfh) cells are a specialized subset of CD4+ T lymphocytes that are essential for the development of long-lasting humoral immunity. Tfh cells facilitate B lymphocyte maturation, promote germinal center formation, and drive high-affinity antibody production. Our current knowledge of Tfh interactions with the humoral immune system effectors suggests that they have a critical role in supporting the immune response against viral infections. This review discusses the mechanisms through which Tfh cells influence anti-viral immunity, highlighting their interactions with B cells and their impact on antibody quality and quantity. We explore the role of Tfh cells in viral infections and examine how vaccine design can be improved to enhance Tfh cell responses. Innovative vaccine platforms, such as mRNA vaccines and self-assembling protein nanoplatforms (SAPNs), are promising strategies to enhance Tfh cell activation. Their integration and synergistic combination could further enhance immunity and Tfh responses (SAPN-RNA vaccines). In summary, we provide a comprehensive overview of the current insights into Tfh cells’ role during viral infections, emphasizing their potential as strategic targets for innovative vaccine development. Full article

Peripheral T-cell lymphomas (PTCLs) present a significant clinical challenge despite recent advances in the development of novel therapeutic agents, guided by a deeper understanding of the pathobiology and the genetic and molecular characteristics underlying this complex and heterogeneous group of aggressive non-Hodgkin lymphomas (NHLs) [...] Full article

Background: Lung adenocarcinoma (LUAD) is a common histopathological variant of non-small cell lung cancer. Individuals with type 2 diabetes (T2DM) face an elevated risk of developing LUAD. We examined the common genomic characteristics between LUAD and T2DM through bioinformatics analysis. Methods: We acquired the GSE40791, GSE25724, GSE10072, and GSE71416 datasets. Differentially expressed genes (DEGs) were identified through R software, particularly its version 4.1.3 and analyzed via gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Subsequently, we analyzed the relationship between immune cell infiltration and DEGs. we constructed a protein–protein interaction network using STRING and visualized it with Cytoscape. Moreover, gene modules were identified utilizing the MCODE plugin, and hub genes were selected through the CytoHubba plugin. Additionally, we evaluated the predictive significance of hub genes using receiver operating characteristic curves and identified the final central hub genes. Finally, we forecasted the regulatory networks of miRNA and transcription factors for the central hub genes. Results: A total of 748 DEGs were identified. Analysis of immune infiltration showed a notable accumulation of effector-memory CD8 T cells, T follicular helper cells, type 1 T helper cells, activated B cells, natural killer cells, macrophages, and neutrophils in both LUAD and T2DM. Moreover, these DEGs were predominantly enriched in immune-related pathways, including the positive regulation of I-κB kinase/NF-κB signaling, positive regulation of immunoglobulin production, cellular response to interleukin-7, and cellular response to interleukin-4. The TGF-β signaling pathway was significantly important among them. Additionally, seven hub genes were identified, including ATR, RFC4, MCM2, NUP155, NUP107, NUP85, and NUP37. Among them, ATR, RFC4, and MCM2 were identified as pivotal hub genes. Additionally, hsa-mir147a, hsa-mir16-5p, and hsa-mir-1-3p were associated with LUAD and T2DM. SP1 (specific protein 1) and KDM5A (lysine-specific demethylase 5A) regulated MCM2, ATR, and RFC4. Conclusions: Our study elucidates the common mechanisms of immune response, TGF-β signaling pathway, and natural killer cells in LUAD and T2DM, and identifies ATR, RFC4, and MCM2 as key potential biomarkers and therapeutic targets for the comorbidity of these two conditions. Full article

T follicular helper (Tfh) and T follicular regulatory cells (Tfr) are required for antibody production and are dysregulated in SLE. Genetic variants within or near interferon regulatory factor 5 (IRF5) are associated with SLE risk. We previously reported higher plasma cells and autoantibodies in healthy IRF5-SLE homozygous risk carriers. Here, we report the dysregulation of circulating Tfh and Tfr in both SLE patients and presymptomatic IRF5-SLE homozygous risk carriers. Full article

Background/Objectives: Acute otitis media is a common pediatric infection caused primarily by nontypeable Haemophilus influenzae. With rising antibiotic resistance, vaccines are essential for combating this public health issue. Although the PD-1/PD-L1 pathway has been extensively studied for its role in tumor immunity, its impact on mucosal immunity, particularly in vaccine responses, is unclear. Methods: BALB/c mice were intranasally immunized with nontypeable H. influenzae outer membrane protein and treated with anti-PD-L1 antibodies. Immune responses were evaluated in middle ear mucosa (MEM), the cervical lymph node, and the spleen using an enzyme-linked immunosorbent assay, an enzyme-linked immunospot assay, and flow cytometry. The effects on CD4⁺ T cells, T follicular helper (Tfh) cells, and B-cell differentiation were analyzed. Results: Anti-PD-L1 antibody treatment increased CD3⁺CD4⁺CD185⁺ (CXCR5⁺) Tfh cells in MEM, which play a crucial role in supporting B-cell activation and antibody production. This correlated with a significant increase in IgA- and IgG-producing cells in MEM, which enhanced local bacterial clearance. Although B-cell activation and differentiation into plasmablasts were observed in MEM, no significant changes were noted in the cervical lymph node and spleen, suggesting a localized enhancement of mucosal immunity. Conclusions: Anti-PD-L1 antibodies promoted Tfh cell expansion and B-cell differentiation in MEM, leading to enhanced antibody production and improved bacterial clearance. These findings suggest that PD-L1 blockade can potentiate mucosal vaccine-induced immunity by strengthening local humoral responses. This supports its potential application in developing intranasal vaccines for acute otitis media. Full article

Background: Although mRNA vaccines have the potential to be developed and deployed rapidly to combat infectious diseases, the ideal method of administration and boosting schedule strategy for generating optimal immunogenicity is an area of active research. We compared the immune responses resulting from different schedules for prime–boost and boosting either ipsilaterally or contralaterally in relation to the initial vaccine dose. Methods: Influenza hemagglutinin (HA) was used as a model antigen for different vaccination regimens in mice using both mRNA lipid nanoparticles (mRNA-LNP) and AF03-adjuvanted recombinant protein (rHA-AF03) vaccines. Results: Increasing the prime–boost interval resulted in higher levels of serum anti-HA IgG and functional antibody hemagglutination inhibition (HAI) responses in mRNA-LNP-vaccinated animals, which correlated with an induction of germinal center (GC) B cells and follicular helper T (Tfh) cells in lymph nodes. In addition, longer prime–boost intervals resulted in higher levels of IL-2 and TNF-α producing CD4+ T cells two weeks after boosting. The number of Ig-secreting long-lived plasma cells increased with the length of prime–boost intervals. Contralateral boosting resulted in an increase in HAI titers and GC B cells compared to an ipsilateral boost. However, significantly higher numbers of GC B cells were induced in the draining lymph nodes following ipsilateral boosting than in the non-draining lymph nodes. Conclusions: Overall, our data provides insights into the immune mechanisms of action of mRNA-LNP to develop the optimal vaccine regimen for mRNA vaccine platforms. Full article

Background: Influenza viruses with truncated NS1 proteins show promise as viral vectors and candidates for mucosal universal influenza vaccines. These mutant NS1 viruses, which lack the N-terminal half of the NS1 protein (124 a.a.), are unable to antagonise the innate immune response. This creates a self-adjuvant effect enhancing heterologous protection by inducing a robust CD8+ T-cell response together with immunoregulatory mechanisms. However, the effects of NS1 modifications on T-follicular helper (Tfh) and B-cell responses remain less understood. Methods: C57bl/6 mice were immunised intranasally with 10 μL of either an influenza virus containing a truncated NS1 protein (PR8/NS124), a cold-adapted influenza virus with a full-length NS1 (caPR8/NSfull), or a wild-type virus (PR8/NSfull). Immune responses were assessed on days 8 and 28 post-immunisation by flow cytometry, ELISA, and HAI assay. Results: In this study, we demonstrate that intranasal immunisation with PR8/NS124 significantly increases tissue-resident CD4+ and CD8+ T cells in the lungs and activates Tfh cells in regional lymph nodes as early as day 8 post-immunisation. These effects are not observed in mice immunised with caPR8/NSfull or PR8/NSfull. Notably, PR8/NS124 immunisation also leads to the development of inducible bronchus-associated lymphoid tissue (iBALT) in the lungs by day 28, characterised by the presence of antigen-specific Tfh cells and GL7+Fas+ germinal centre B cells. Conclusions: Our findings further underscore the potential of NS1-truncated influenza viruses to drive robust mucosal immune responses and enhance vaccine efficacy. Full article