The mature plasmacytoid dendritic cell proliferation associated with myeloid neoplasm represents a clonal proliferation of plasmacytoid dendritic cells within myeloproliferative and myelodysplastic disorders. This entity was recently recognized as a distinct condition in the fifth edition of the World Health Organization classification of hematolymphoid tumors. It occurs in approximately 4.9% of acute myeloid leukemia cases. The pathogenic mechanisms underlying this proliferation and the role of these cells in disease progression remain poorly understood. Nevertheless, the plasmacytoid dendritic cell proliferation associated with acute myeloid leukemia is related to distinct genetic abnormalities, worse prognosis, reduced overall survival, lower sensitivity to conventional acute myeloid leukemia therapies, and an increased risk of relapse. It also displays distinct immunophenotypic features compared to other types of mature plasmacytoid dendritic cell proliferation, raising questions about its classification and diagnostic criteria. This review provides a comprehensive overview of current knowledge regarding the plasmacytoid dendritic cell proliferation associated with acute myeloid leukemia, including terminology inconsistencies; the role of plasmacytoid dendritic cells in this entity; associated genetic alterations; immunophenotypic and morphological characteristics of blasts and plasmacytoid dendritic cells; clinical outcomes and prognostic impact; and therapeutic approaches and perspectives. Synthesizing current evidence may help improve disease recognition and highlight gaps in knowledge to guide future research.

Dissecting the role of imiquimod and isostearic acid in Aldara-induced psoriasis mouse model.

Psoriasis is a chronic, immune-mediated inflammatory disorder with systemic implications beyond its cutaneous manifestations. Its pathogenesis involves a complex interplay between genetic predisposition, environmental triggers, and immune dysregulation. The sustained crosstalk between dendritic cells (DCs) and T cells, which orchestrates the initiation and perpetuation of psoriatic inflammation. Plasmacytoid DCs, activated by nucleic acid-LL37 complexes, produce interferon-α that promotes myeloid DC maturation. These DCs secrete IL-12, IL-23, and TNF-α, driving differentiation of naïve T cells into Th1, Th17, and Th22 subsets. Effector T cells subsequently release cytokines such as IFN-γ, IL-17, and IL-22, which promote keratinocyte hyperproliferation, impaired differentiation, neutrophil recruitment, and angiogenesis. This DC-T cell axis forms a self-amplifying inflammatory loop that underpins disease chronicity. Conventional systemic agents, including methotrexate, cyclosporine, and retinoids, have demonstrated efficacy but are limited by nonspecific immunosuppression and significant toxicities. Advances in immunology have identified the IL-23/Th17 pathway as a pivotal therapeutic target, enabling the development of biologics and small-molecule inhibitors. Monoclonal antibodies targeting TNF-α, IL-12/23, IL-17, and IL-23 have revolutionized management, achieving high rates of sustained clearance with improved safety profiles. Additional strategies, such as PDE4 and JAK/STAT inhibitors, offer oral alternatives with targeted immunomodulation. Novel approaches, including tolerogenic DC therapy and neuroimmune modulation, hold promise for refining treatment and addressing disease heterogeneity. Effective immunotherapeutic strategies must therefore balance skin clearance with reduction of systemic inflammation and long-term comorbidity risk. Integrating mechanistic insights into DC-T cell interactions with emerging therapies provides a framework for personalized, safer, and more durable disease control.

Mainzer-Saldino syndrome is a rare autosomal recessive ciliopathy characterized by cone-shaped epiphyses, chronic renal failure, and early-onset severe retinal dystrophy. Blastic plasmacytoid dendritic cell neoplasm is a rare hematologic malignancy. However, the association between these two diseases is unclear, and the coincidence of the two diseases has not been previously reported. We report a 5-year-5-month-old Chinese boy who experienced conical epiphysis, retinitis pigmentosa, and distinct cutaneous lesions. Renal ultrasound indicated morphological changes in the kidney. The whole exon sequencing revealed that the proband harbored compound heterozygous variants, including a novel variant c.2471T > C (p.Leu824Pro), a maternally inherited missense variant, and c.1990G > A (p.Glu664Lys) inherited from his father in the IFT140 gene. The proband was clinically and molecularly diagnosed as Mainzer-Saldino syndrome. Meanwhile, the diagnosis as blastic plasmacytoid dendritic cell neoplas (BPDCN) was confirmed by the biopsy of skin mass. This is the first case of Mainzer-Saldino syndrome combined with a rare tumor blastic plasmacytoid dendritic-cell neoplasm. Our research expands the mutation spectrum of the IFT140 gene, helping to refine the phenotypic diversity of Mainzer-Saldino syndrome.

Clonal mature plasmacytoid dendritic cell proliferations (MPDCP) are a recently recognized entity in the WHO fifth edition, but their pathologic spectrum remains poorly characterized. Cases with extensive MPDCP in the bone marrow (BM) are rare and can exhibit overlapping features with blastic plasmacytoid dendritic cell neoplasm (BPDCN). We compared clinicopathologic and genomic features of 11 patients with myeloid neoplasm-associated MPDCP to 5 patients with secondary BPDCN arising from clonally-related myeloid neoplasms. MPDCP exhibited variable degrees of BM involvement (5% to 50%) and architectural patterns, were uniformly positive for CD123, CD4, TCF4, and IRF8, variably positive for TCL1 (7/11), CD5 (7/11), and CD7 (2/11), and negative for SOX4, CD56, and TdT. MPDCP skin involvement was rare (1/11), with no CNS involvement. MPDCP heralded myeloid disease progression in a subset of patients, with increased blasts or progression to AML (4/11). In contrast, secondary BPDCN was uniformly positive for SOX4 and TCL1, with frequent CD56 (4/5) and subset/weak TdT (3/4). All BPDCN patients had characteristic skin lesions, and a subset with CNS involvement (2/5). The underlying myeloid neoplasms associated with MPDCP or BPDCN were enriched in TET2 , SRSF2 , ASXL1 , RUNX1 , and RAS pathway mutations. While karyotypic abnormalities were uncommon in MPDCP, all BPDCN showed chromosomal structural abnormalities and copy number variants, including deletions of 3p, 9p, and 12p. Our findings expand the histopathologic, immunophenotypic, and genetic characterization of MPDCP, and highlight pathologic features that distinguish it from BPDCN. Utilization of SOX4 immunohistochemistry, combined with careful clinical and molecular correlation, can aid in resolving these diagnostic challenges.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive malignancy characterized by skin involvement and frequent systemic dissemination. We report a case of a 32-year-old man with multiple violaceous cutaneous nodules who underwent F-18 FDG PET/CT for staging. PET/CT demonstrated extensive metabolic activity in cutaneous sites and revealed previously unsuspected inguinal and cervical lymph-node involvement. Histopathology confirmed BPDCN. This case highlights the crucial role of FDG PET/CT in detecting subclinical nodal disease, delineating total disease burden, and improving staging accuracy in BPDCN, thereby supporting its value in guiding management and future response assessment.

Complete pathologic response (CPR) correlates with long-term survival after perioperative chemoimmunotherapy (ChIO) in resectable non-small cell lung cancer (NSCLC). We provide a multiomic characterization of B cells and tertiary lymphoid structures (TLS) to dissect the immune landscape associated with CPR. We integrated B-cell receptor (BCR) repertoire profiling (n = 87 tissue, n = 25 blood), multiplex immunofluorescence (n = 67), and bulk (n = 15), spatial (n = 12), and single-cell transcriptomics (n = 15) from tumor tissue and blood (baseline, surgery, and at 6 months of adjuvant therapy) in 123 patients (NADIM/NADIM II trials, NCT03081689/NCT03838159). CPR tumors exhibited a more clonal baseline BCR repertoire (AUC 0.775; P = 0.030) that was better conserved and reinvigorated during neoadjuvant ChIO. In blood, patients with CPR tumors displayed a repertoire enriched in class-switched clones (AUC 0.833; P = 0.008), characterized by higher diversity, lower clonality, and upregulation of activation-related transcriptional programs. Neoadjuvant ChIO was associated with the induction of B-cell-related genes within TLS regions and with higher TLS density at surgery compared with Ch (P = 0.034). TLS density was not associated with CPR (P = 0.129); however, mature TLS in CPR tumors were enriched in immune activation and antigen-presenting pathways, estimated T follicular helper cells, plasmacytoid dendritic cells, and plasma cells, whereas low B-cell regions from CPR tumors displayed higher inferred infiltration of CD8+ T cells, NK cells, and macrophages, with reduced neutrophils and Tregs. Patients with CPR tumors exhibit a preexisting and more mature B-cell response that develops further during neoadjuvant ChIO. Our findings link B-cell-related features to CPR and highlight BCR metrics as promising predictive biomarkers in NSCLC.

Systemic application of Toll-like receptor 7/8 (TLR7/8) agonists against cancer is severely limited due to uncontrolled immune activation. In this study, a platinum(IV)-based prodrug strategy is developed for the systemic administration of a TLR7/8 agonist, selectively activated in the malignant tissue simultaneously with the immunogenic cell death inducer oxaliplatin. Two oxaliplatin(IV)-based complexes are synthesized comprising the TLR7/8 agonist gardiquimod: Ox-Gardi-PEG, containing polyethylene glycol as the second axial ligand, and Ox-Gardi-Mal, a maleimide-bearing derivative to exploit the tumor-targeting effects of serum albumin. In vitro, cytotoxicity and immune pathway-inducing potency of Ox-Gardi-PEG and Ox-Gardi-Mal are diminished under standard cell culture conditions compared to free oxaliplatin and gardiquimod, respectively, and markedly enhanced under reducing conditions, underscoring the activation-by-reduction concept. In vivo, Ox-Gardi-Mal shows superior and TLR7/8 signaling-dependent anticancer efficacy and prolongs overall survival of cancer-bearing mice, while mitigating hematotoxic effects associated with oxaliplatin. Therapy significantly elevates expression of MHC-I on antigen-presenting immune cell subsets, increases the frequency of activated plasmacytoid dendritic cells and tumor-infiltrating CD8+ T cells, as well as depleted primarily immunosuppressive M2 macrophages. These results demonstrate that tumor-targeted oxaliplatin(IV)-based prodrugs carrying TLR7/8 agonists offer a potent dual-release strategy for improved immunochemotherapy, while minimizing excessive immune responses associated with systemic TLR7/8 activation.

Ischemic stroke (IS) is a leading cause of morbidity and mortality worldwide, with emerging evidence suggesting that immune cell characteristics may play a crucial role in its pathogenesis. This study aimed to investigate the causal relationship between 731 immune cell signatures and IS via a two-sample Mendelian randomization approach, thereby elucidating the potential immunological mechanisms underlying IS. We conducted a two-sample Mendelian randomization analysis using genome-wide association study summary statistics for IS and immune traits. Instrumental variables were selected based on stringent criteria, including genome-wide significance thresholds and quality control measures. Causal estimates were derived via inverse-variance weighted regression, supplemented by sensitivity analyses to assess robustness and address potential pleiotropy. Our findings indicate that IS may causally influence the activation of immune cells, specifically increasing absolute counts and relative proportions of CD86+ plasmacytoid dendritic cells and increasing B-cell activating factor receptor expression on CD20-CD38- B cells. Conversely, we identified 6 immunophenotypes associated with reduced IS risk, including elevated CD62L-HLA-DR+ monocyte counts and decreased CD28 expression on regulatory T cells. Sensitivity analyses confirmed the robustness of these associations, with no evidence of horizontal pleiotropy. This study provides compelling evidence for the causal roles of specific immune cell characteristics in the pathogenesis of IS. These findings suggest that immune modulation, particularly through the CD86 and B-cell activating factor receptor signaling pathways, may influence IS risk and highlight the potential for targeted immunotherapeutic strategies in stroke prevention. Future research should further explore these mechanisms and their implications for clinical practice.

Endosomal function is essential for pattern recognition receptor signaling, through endosomal Toll-like receptor (TLR) sensing of nonself RNA and DNA. The specific interaction of the calcium sensor Munc13-4 with syntaxin 7 (STX7) regulates endosomal flux and Munc13-4 depletion decreases the systemic inflammatory response to unmethylated DNA. Using high-throughput screening and orthogonal cell-based validation, we identified small-molecule inhibitors of the Munc13-4-STX7 interaction, ENDOtollins (ENDOs). ENDOs inhibit extracellular signal-regulated kinase signaling in neutrophils and interferon (IFN) regulatory factor signaling in plasmacytoid dendritic cells (DCs) in response to endosomal TLR ligands but not to plasma membrane agonists, highlighting specificity for the endocytic pathway. Mechanistically, ENDOs inhibit endolysosomal flux and decrease endolysosomal cargo degradation. Chemical optimization identified ENDO12 as the most potent inhibitor. ENDO12 inhibited primary DC responses to TLR3, TLR7 and TLR9 and reduced CpG-induced systemic inflammation, manifested as decreased levels of the proinflammatory mediators myeloperoxidase, interleukin 6 and IFNγ. Our findings have significant implications for immunodeficiency, inflammation and innate immunity.

Integrated single cell RNA sequencing and flow cytometry analysis identifies elevated S100A6+ and S100A8+ myeloid subsets in pancreatic ductal adenocarcinoma.

Reactive oxygen species and metabolic checkpoints shape plasmacytoid dendritic cell fate in infection and autoimmunity.

Metabolic reprogramming in lacrimal gland GVHD: Stage-specific shifts in acinar cells as drivers of disease progression.

Psoriasis is a cutaneous autoimmune disease with worldwide prevalence. In situ activation of skin-infiltrating plasmacytoid dendritic cells (pDCs) leading to local induction of type I interferons (IFNs) is a crucial innate initiation event in psoriasis. Psoriatic patients also have notable susceptibility to the development of metabolic syndrome, especially systemic insulin resistance. Interestingly, a crucial role of systemic and metabolic tissue-restricted induction of type I IFNs is now established in metabolic syndrome. We aimed at exploring whether systemic type I IFN abundance contributes to metabolic derangements in psoriatic patients as well. We developed a preclinical murine model of chronic psoriasis that develops systemic insulin resistance, accompanied by a chronic low-grade systemic inflammation. Then we showed that systemic ablation of type I IFN signaling, using a monoclonal antibody against type I IFN receptor IFNAR1, can mitigate the metabolic dysregulation in this preclinical model of psoriasis-associated insulin resistance. Thus, we report a hitherto unknown role of systemic type I IFN abundance in driving systemic insulin resistance and metabolic dysregulations in psoriasis.

EPR26-157: Blastic Plasmacytoid Dendritic Cell Neoplasm: Demographics, Outcomes, and Mortality-to-Incidence Ratio Trends.

Outer membrane vesicle (OMV)-based vaccines elicit strong immune responses and have emerged as a versatile platform for targeting multiple pathogens, yet the mechanisms underlying their efficacy remain incompletely understood. Here, we investigated the early immune response following intranasal administration of an OMV-based pneumococcal vaccine candidate in mice. Using in vivo bioluminescence imaging, spectral flow cytometry, and high-resolution microscopy, we tracked OMV biodistribution and immune activation throughout the respiratory tract from 1 to 72 h post-immunization. OMVs persisted in the nasal cavity for up to 48 h and rapidly recruited Ly6Ghi neutrophils and myeloid-derived suppressor cells, followed by activation of local T cells. MHCII expression was significantly upregulated on Ly6Ghi neutrophils in nasal tissue and coincided with a marked expansion at 24 h. In the lungs, alveolar macrophages and plasmacytoid dendritic cells emerged as early responders. OMV exposure also induced costimulatory molecule expression across multiple myeloid cell subsets. Together, these findings reveal distinct spatio-temporal patterns of innate and adaptive immune activation at mucosal sites, providing mechanistic insight into OMV-induced mucosal immunity and underscoring their potential as a versatile vaccine platform.

Primary Sjögren's disease (SjD) is achronic autoimmune disease that predominantly affects exocrine glands but can also show numerous systemic organ manifestations. Presentation of the current understanding of the pathogenesis of the disease, focusing on genetic predisposition, epithelial activation, interferon signature and the resulting B‑Tcell interaction, which form the basis for innovative treatment approaches. Selective literature review of current original articles, reviews and clinical studies. Current research postulates that SjD triggers epithelial dysregulation through acombination of genetic and epigenetic predispositions, hormonal influences and possible viral triggers. This leads to the release of dsDNA, dsRNA or ssRNA, which in turn activate the innate immune system. Salivary gland epithelial cells (SGECs), plasmacytoid dendritic cells (pDCs), and monocytes produce proinflammatory cytokines and additional immune cells are recruited. The pDCs produce massive amounts of typeI interferon. This results in the formation of an inflammatory microenvironment, which causes SGECs to undergo apoptosis, the release of further antigens and the recruitment of Tcells. In this context, myeloid cells and SGECs produce large amounts of the cytokine B‑cell activating factor (BAFF). This promotes the further recruitment of Bcells. Through Th1 cells and Tfh cells aT-Bcell interaction is formed, leading to the development of ectopic germinal centers, including the induction of autoreactive Bcells. The pathophysiology of SjD is amultistage process in which the early activation of the salivary epithelium and subsequent activation of the innate immune system with IFN play acrucial role in its initiation. This is followed by activation of the adaptive immune system with afocus on T‑Bcell interaction and pathological Bcell activation. The chronic inflammation in SjD can be understood as positive feedback from the activation of the innate and adaptive immune systems, which innovative therapeutic approaches aim to interrupt. These comprise TLR and IFN blockade, inhibition of T‑Bcell interaction via CD154/CD40 blockade (e.g., dazodalibep, iscalimab) or Bcell depletion strategies including. anti-BAFF‑R and anti-CD19 CAR-Tcells.

Dendritic cells (DCs) orchestrate immune responses. Their development is controlled by transcription factors, but epigenetic mechanisms remain poorly understood. DOT1L emerges as a key epigenetic regulator in immune cells. Mapping DOT1L-mediated histone H3K79 methylation in canonical DC subsets revealed that DOT1L modified common and DC subset-specific genes. Deletion of Dot1l in vivo or in vitro decreased myeloid progenitors and increased cDC2s, whereas cDC1s remained unchanged. In addition, in vitro deletion of Dot1l led to loss of plasmacytoid DCs (pDCs) and of IFNα production upon stimulation. Upon in vivo deletion, a decrease in pDCs was only observed after subsequent in vitro expansion. This difference was likely related to insufficient replication-mediated loss of H3K79 methylation in vivo within the time frame studied. Transcriptomes of Dot1l-KO DC subsets exhibited enrichment of antigen presentation pathways, and MHC class II surface levels were up-regulated in pDCs. Mechanistically, inhibition of DOT1L linked the observed effects to its methyltransferase activity. Together, our data indicate that in DCs DOT1L differentially affects the development of canonical subsets and suppresses antigen presentation pathways.

Not available.

CD28 is a co-stimulatory molecule expressed on the surface of T cells. To date, three individuals with germline CD28 deficiency have been reported to develop recalcitrant, HPV-driven warts: one exhibited persistent lesions, another experienced disease resolution, and the third developed a chronic “tree-man” phenotype. In mice, we confirmed that CD28-knockout (CD28ko) animals on the C57BL/6 (B6) background are susceptible to cutaneous infection with mouse papillomavirus (MmuPV1); however, their skin warts regressed spontaneously approximately five weeks post-infection. Furthermore, we demonstrate that CD28ko mice are vulnerable to MmuPV1 infection at HPV-relevant mucosal sites, including the most HPV prevalent sites: anogenital tract and oral cavity. Virions recovered from vaginal lavage were infectious but could be neutralized by the neutralizing monoclonal antibody MPV.A4. Viral clearance at mucosal sites was delayed in CD28ko mice, persisting for up to six weeks in the lower genital tract. Blocking the CD28 ligands CD80 and CD86 in B6 mice reproduced the CD28ko phenotype following MmuPV1 infection and markedly reduced CD28 expression, implicating the CD28-CD80/CD86 axis in delayed viral clearance. Infected CD28ko mice showed a reduction in both CD4+ and CD8+ T cell population in the spleen compared to infected B6 mice, but an increase in CD11c+/F4-80+ cells, particularly the plasmacytoid dendritic cell (pDCs, SiglecH⁺) subset. Additionally, CD28ko mice exhibited delayed recruitment of activated CD4+ T cells to infected tissues. Accumulation of MmuPV1 E6/90–99-specific, tetramer-positive CD8+ cytotoxic T lymphocytes (CTLs) was slower in CD28ko than in B6 mice; these CTLs remained FoxP3 negative but displayed reduced efficacy in both in vitro killing and antiviral cytokine assays. Adoptive transfer of CTLs from either B6 or CD28ko mice into MmuPV1-infected Rag1ko mice induced viral clearance at mucosal (oral) sites, whereas B6-derived CTLs achieved more complete regression of cutaneous (tail) lesions. Collectively, these findings indicate that CD28 deficiency delays but does not prevent the clearance of papillomavirus infections at both cutaneous and mucosal sites in mice.