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At least 19 recordsLinked to original sources
PubMed2026

Synovial short-lived plasma cells mediate adalimumab resistance in rheumatoid arthritis via MIF-CD74 axis-driven, partially TNF-α-independent inflammation.

OBJECTIVE: Synovial plasma cell infiltration predicts inadequate response to adalimumab in patients with rheumatoid arthritis (RA), yet the cellular and molecular mechanisms underlying this association remain unclear. This study aimed to dissect the functional heterogeneity of synovial plasma cells between adalimumab responders and non-responders at single-cell resolution, and to identify the molecular pathways driving treatment resistance. METHODS: This study was based on a prospective clinical cohort of 101 RA patients receiving adalimumab, from which synovial tissues of 8 patients (4 ACR20 responders and 4 non-responders) were profiled by 10x Genomics single-cell RNA sequencing (66,539 high-quality cells). A systematic ligand-receptor screening was performed to identify candidate signaling axes. Core findings were validated at four levels: an independent single-cell validation cohort (n = 4), external bulk RNA-seq cohorts (GSE15602, GSE47726), multiplex immunofluorescence on synovial tissues (n = 9 per group), and in vitro functional experiments using patient-derived peripheral blood monocyte-derived macrophages stimulated with recombinant human MIF under pharmacological intervention with adalimumab, the MIF inhibitor ISO-1, and an anti-CD74 neutralizing antibody. RESULTS: Plasma cells were significantly enriched in non-responder synovium, with a heterogeneous pattern characterized by quantitative accumulation of long-lived plasma cells (LLPCs) and functional dominance of short-lived plasma cells (SLPCs): SLPCs contributed 58.15% of total ribosomal module activity and preferentially overexpressed MIF. Systematic screening of 145 candidate ligand-receptor pairs identified MIF-CD74 as the only axis satisfying all four independent evidence layers. Tissue-level immunofluorescence confirmed that approximately 95% of synovial CD138+ plasma cells in non-responders co-expressed MIF, compared with approximately 45% in responders. In vitro, rh-MIF upregulated macrophage activation markers (CD74, CD80, CD86, HLA-DR) and induced IL-6 and TNF-α secretion. Adalimumab neutralized supernatant TNF-α but failed to suppress MIF-driven IL-6 and IL-1β activation, whereas ISO-1 and anti-CD74 effectively blocked MIF-induced effects at all levels examined. These findings were replicated in patient-derived PBMC macrophages. CONCLUSION: In adalimumab-resistant RA, a functionally active SLPC subset drives partially TNF-α-independent macrophage inflammation through the MIF-CD74 axis, representing a resistance pathway not fully addressed by anti-TNF therapy. Targeting MIF or CD74 blocked this axis in vitro, supporting MIF-CD74-directed precision intervention.

Adalimumab↗
PubMed2026

MIF-CD74 axis facilitates MDSC infiltration in the tumor microenvironment of pancreatic ductal adenocarcinoma.

Immune checkpoint inhibitors show insufficient efficacy against pancreatic ductal adenocarcinoma (PDAC). The tumor microenvironment (TME) has a remarkable influence on responsiveness to cancer immunotherapy. The aim of this study was to investigate immunosuppressive characteristics of TME in PDAC tissues. The flow cytometry (FCM) of PDAC surgical specimens revealed that the profile of tumor-infiltrating leukocytes was classified into myeloid cell- and T-cell-dominant subtypes; the myeloid subtype was associated with poorer patient outcomes. Myeloid-derived suppressor cells (MDSCs) showed the highest hazard ratio among various myeloid cell types. Single-cell RNA sequencing and FCM revealed that most MDSCs, but not lymphocytes, in PDAC tissues characteristically express CD74. Macrophage migration inhibitory factor (MIF), a CD74 ligand, was highly expressed in cancer-associated fibroblasts (CAFs) and cancer cells. Spatial transcriptomics demonstrated that the MIF-CD74+ myeloid cell interaction was recognized in CAF-dominant areas in PDAC tissue. CAFs expressing immune suppressor molecules such as MFAP5 and LRRC15 were consistent with MIF+ CAFs. Furthermore, MIF+ CAFs enhanced the migratory activity of MDSCs and promoted MDSC induction and activation. In the murine model, MDSCs were significantly increased in MIF-expressing PDAC tumors, as were CD74+ M-MDSCs per M-MDSC, confirming in vivo interaction between CD74 and MIF. MDSCs play a crucial role in creating an immunosuppressive TME in PDAC; the MIF-CD74 axis drives interactions between MDSCs and CAFs.

Humans↗
PubMed1992

Bauhinia purpurea--a new paraffin section marker for Reed-Sternberg cells of Hodgkin's disease. A comparison with Leu-M1 (CD15), LN2 (CD74), peanut agglutinin, and Ber-H2 (CD30).

Thirty-three cases of Hodgkin's disease (thirteen nodular sclerosis, four diffuse, lymphocyte predominance, and sixteen mixed cellularity) were studied with Bauhinia purpurea (BPA), peanut agglutinin (PNA), anti-Leu-M1, LN2, and Ber-H2 by the avidinbiotin-peroxidase complex (ABC) method in paraffin sections. Reed-Sternberg (RS) cells and variants were stained positively with one or more of the reagents in all cases. BPA staining was positive in 32 of 33 cases (97.0%), PNA staining was positive in 23 of 33 cases (69.7%), Leu-M1 was positive in 13 of 33 cases (39.4%), LN2 was positive in 14 of 33 cases (42.4%), and Ber-H2 was positive in 24 of 33 cases (72.7%). Many RS cells were stained moderately to strongly and were readily recognized in 31 cases (96.9%) of BPA+, 10 (43.5%) of PNA+, 8 (61.5%) of Leu-M1+, 6 (42.9%) of LN2+, and 22 (91.7%) of Ber-H2+ cases; in the remaining positive cases, the RS cells were found only after careful searching. Three staining patterns were recognized: paranuclear, diffuse cytoplasmic, and membranous. These three patterns were obtained with all markers except for LN2. LN2 showed diffuse cytoplasmic staining in most of the positive cells, and a few cells showed paranuclear deposits. BPA reactivity was not affected by formalin fixation or paraffin embedding. Except for RS cells, BPA also showed dense cytoplasmic staining reaction with macrophage-histiocytes. Sixty cases of non-Hodgkin's diffuse lymphomas (30 T- and 30 B-cell origin) were also studied. Tumor cells were not stained with BPA, PNA, and Leu-M1, but stained positively with LN2 in six T-cell lymphomas and thirteen B-cell lymphomas, and with Ber-H2 in six T-cell lymphomas and one B-cell lymphoma. In conclusion, to facilitate the detection of RS cells and related variants in paraffin sections, BPA can be accepted as a useful marker due to its high-detection rate, reproducible staining pattern, and resistance to fixatives.

Antigens, CD↗
PubMed1991

Rapid intracellular pathway gives rise to cell surface expression of the MHC class II-associated invariant chain (CD74).

In previous investigations, it had been shown that class II and associated invariant polypeptides are sorted to an endocytic route where transport is delayed. Invariant chain (Ii) is degraded in a post-Golgi compartment, presumably an endosomal vesicle, and only class II molecules emerge on the cell surface. By using a mAb against the extracytoplasmic domain of human Ii, we demonstrate, by electron microscopy and by cytofluorometry, surface expression of Ii on lymphoma cells and on human B lymphocytes. We examined surface expression of Ii upon inhibition by brefeldin A of intracellular transport from the endoplasmic reticulum to the Golgi stack. This treatment rapidly depletes the cell surface of Ii. In the subsequent absence of brefeldin A, Ii appears rapidly at the cell surface. Within 5 h, the previous level of surface Ii (sIi) is reconstituted. Chloroquine abrogates depletion of sIi by brefeldin A, apparently by inhibition of internalization of sIi. Because on its route to the cell surface Ii is not proteolytically digested, it was possible that Ii and associated class II molecules are not separated on this pathway. Immunochemical studies reveal that on the cell surface of a B lymphoma cell line a proportion of Ii and class II polypeptides are associated.

Antigens, Differentiation, B-Lymphocyte↗
PubMed2025

Computational network biology analysis revealed COVID-19 severity markers: Molecular interplay between HLA-II with CIITA.

COVID-19, severe acute respiratory syndrome coronavirus 2, rapidly spread worldwide. Severe and critical patients are expected to rapidly deteriorate. Although several studies have attempted to uncover the mechanisms underlying COVID-19 severity, most have focused on the perturbations of single genes. However, the complex mechanism of COVID-19 involves numerous perturbed genes in a molecular network rather than a single abnormal gene. Thus, we aimed to identify COVID-19 severity-specific markers in the Japanese population using gene network analysis. In order to reveal the severity-specific molecular interplays, we developed a novel computational network biology strategy that measures dissimilarity between networks based on the comprehensive information of gene network (i.e., expression levels of genes and network structure) by using Kullback-Leibler divergence. Monte Carlo simulations demonstrated the effectiveness of our strategy for differential gene network analysis. We applied this method to publicly available whole blood RNA-seq data from the Japan coronavirus disease 2019 Task Force and identified differentially regulated molecular interplays between 368 severe and 105 non-severe samples. Our analysis suggests the gene network between HLA class II, CIITA, and CD74 as a COVID-19 severity specific molecular marker. Although the association between HLA class II and COVID-19 has been demonstrated, our data analysis revealed that the molecular interplay of HLA class II with its target and/or regulator is a crucial marker for COVID-19 severity. Our findings from computational network biology analysis suggest that suppression and activation of the molecular interplay between HLA class II, CIITA, and CD74 provide crucial clues to uncover the mechanisms of COVID-19 severity.

Humans↗
PubMed1992

Inconsistency of the immunophenotype of Reed-Sternberg cells in simultaneous and consecutive specimens from the same patients. A paraffin section evaluation in 56 patients.

Both immunophenotypic overlaps between Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL), and evolution of one into the other have been reported. However, the underlying assumption that the antigenic expression of Reed-Sternberg (RS) cells is consistent in the same patient has not been evaluated. Such an evaluation was undertaken by immunophenotyping paraffin-embedded lymphoid tissue biopsies with HD from 56 patients in whom multiple specimens were obtained, either simultaneously from different sites or at different times. The panel of antibodies we used included: CD3 polyclonal antiserum, DAKO-M1 (CD15), L26 (CD20), BerH2 (CD30), MT1 (CD43), DAKO-LCA (CD45RB), UCHL1 (CD45R0), LN2 (CD74), and DAKO-EMA. The phenotype of RS cells was identical in simultaneous biopsies in only 11 of 39 patients (28%) and remained constant in consecutive biopsies in only 4 of 21 patients (19%). Major differences (relative to cell lineage specific antigens) were observed in 10 of 39 patients with simultaneous biopsies and in 10 of 21 patients over time; they mainly involved expression of T-cell antigens. Minor differences (relative to any other antigen) were observed in 22 of 39 patients with simultaneous biopsies and in 15 of 21 patients over time; these mainly involved CD15 or CD74. This striking variability of the immunophenotype of RS cells in the same patient may be due to aberrant marker expression, as a result of the neoplastic state, and/or to modulation of antigenic expression in relation to the host environment. This inconsistency suggests caution when interpreting the relationship between HD and NHL by paraffin immunophenotyping alone.

Antibodies↗
PubMed1990

Histopathologic, immunophenotypic, and genotypic analysis of Ki-1 anaplastic large cell lymphomas that express histiocyte-associated antigens.

CD30/Ki-1 antigen expression in 243 cases of malignant lymphomas was examined using Ber-H2 monoclonal antibody. Among them 20 cases were categorized as Ki-1 anaplastic large cell lymphoma. In two of these cases histiocyte-associated markers were also expressed. In these cases histopathologic and extensive in situ immunophenotypic analyses were used with genotypic studies in the determination of cell lineage. A sinusoid histologic pattern of involvement with partial lymph node infiltration by pleomorphic neoplastic cells was noticed in the nodes from both patients. Solid areas of node replacement resembling metastatic carcinoma were seen in Patient 1. Immunohistologically, tumor cells of both cases were positive for CD30, CD25, CD71, LN3 (HLA-DR), EMA, CD45, CD74, vimentin, alpha-1-antichymotrypsin, and CD68. Patient 1 was also CD45RO+, CD43+, whereas Patient 2 was positive for alpha-1-antitrypsin and CD4 tumor cells. Genotypic studies revealed that TCR beta and TCR gamma chain genes were clonally rearranged in Patient 1, whereas no rearrangements were detected in Patient 2. This study supports the view that some Ki-1 anaplastic large cell lymphomas may express multiple histiocyte-associated antigens and confirms that this group of neoplasms have immunophenotypic heterogeneity. The results of genotypic analyses used with immunophenotyping does not exclude that the tumor cells in these cases may be of true histiocytic origin despite the Ki-1-positive phenotype.

Adolescent↗
PubMed1991

Primary cutaneous B-cell lymphoma: a unique type of low-grade lymphoma. Clinicopathologic and immunologic study of 83 cases.

The clinical presentation and course, and the morphoimmunologic features of primary cutaneous B-cell lymphoma (CBCL) were investigated in a series of 83 patients. Fifty-one patients were male and 32 were female (male-to-female ratio of 1.6:1); CBCL primarily involved the elderly (median age, 58 years). A locoregional extension of the disease was quite frequent (86.7%). The neoplastic cells showed a range of appearances reminiscent of the whole spectrum of follicular/parafollicular cells. The antigenic phenotype of tumor cells (CD19+, CD20+, CD22+, CD28+, CD10-, CD5-, MB2+, CD74+/-, CDw75+/-, MT2+/-, surface immunoglobulin + monoclonal/-) plus the presence of admixed CD14- dendritic reticulum cells suggest a mantle-zone nature for CBCL. The nonaggressive clinical behavior with a substantial tendency to remain localized to a limited area of the skin, the quite good response to nonaggressive treatment, and the dichotomy existing between the enhancement of morphoimmunologic atypism--which parallels the increasing age and growth rate of lesions--and the constant benign overall prognosis on long-term follow-up make CBCL a unique type of lymphoma of low-grade malignancy. Proper recognition of CBCL is mandatory to avoid possible undertreatment or overtreatment of the patients affected.

Adult↗
PubMed1992

CD30 (Ki-1)-positive, anaplastic large cell lymphoma mimicking gastrointestinal carcinoma.

BACKGROUND: There is great diversity in the clinical presentation of CD30 (Ki-1)-positive, anaplastic large cell lymphoma (ALCL). The authors report two patients in whom the clinical and morphologic features mimicked gastrointestinal carcinoma. METHODS: Surgical pathology specimens were examined using standard histologic techniques. Paraffin- and frozen-section immunohistochemistry was performed by an avidin-biotin-peroxidase method. RESULTS: The first patient is a 58-year-old man who presented with a constricting mass of the sigmoid colon. Immunohistochemical staining for CD45 (LCA) was negative in formalin-fixed paraffin sections. However, CD45 and CD74 (LN2) were detectable in B5 postfixed material. The second patient is a 44-year-old woman who presented with dysphagia and back pain. Endoscopic examination revealed an ulcerated luminal mass in the proximal esophagus and a gastric ulcer. Mucosal biopsy specimens of the esophagus and stomach contained ALCL, which was CD45 positive. Retroperitoneal lymph nodes contained ALCL infiltrating the sinuses, interfollicular areas, and blood vessel lumina. In addition to CD45 and pan-T-cell antigens, the neoplastic cells expressed CD68 (KP1) and epithelial membrane antigen (EMA). Monoclonal antikeratins were negative, but a polyclonal antikeratin stain was positive. CONCLUSIONS: These findings indicate that clinical, morphologic, and some immunologic features of ALCL may mimic gastrointestinal carcinoma.

Adult↗
PubMed2025

Genetic Architecture of Idiopathic Inflammatory Myopathies From Meta-Analyses.

OBJECTIVE: Idiopathic inflammatory myopathies (IIMs, myositis) are rare systemic autoimmune disorders that lead to muscle inflammation, weakness, and extramuscular manifestations, with a strong genetic component influencing disease development and progression. Previous genome-wide association studies identified loci associated with IIMs. In this study, we imputed data from two prior genome-wide myositis studies and analyzed the largest myositis data set to date to identify novel risk loci and susceptibility genes associated with IIMs and its clinical subtypes. METHODS: We performed association analyses on 14,903 individuals (3,206 patients and 11,697 controls) with genotypes and imputed data from the Trans-Omics for Precision Medicine reference panel. Fine-mapping and expression quantitative trait locus colocalization analyses in myositis-relevant tissues indicated potential causal variants. Functional annotation and network analyses using the random walk with restart (RWR) algorithm explored underlying genetic networks and drug repurposing opportunities. RESULTS: Our analyses identified novel risk loci and susceptibility genes, such as FCRLA, NFKB1, IRF4, DCAKD, and ATXN2 in overall IIMs; NEMP2 in polymyositis; ACBC11 in dermatomyositis; and PSD3 in myositis with anti-histidyl-transfer RNA synthetase autoantibodies (anti-Jo-1). We also characterized effects of HLA region variants and the role of C4. Colocalization analyses suggested putative causal variants in DCAKD in skin and muscle, HCP5 in lung, and IRF4 in Epstein-Barr virus (EBV)-transformed lymphocytes, lung, and whole blood. RWR further prioritized additional candidate genes, including APP, CD74, CIITA, NR1H4, and TXNIP, for future investigation. CONCLUSION: Our study uncovers novel genetic regions contributing to IIMs, advancing our understanding of myositis pathogenesis and offering new insights for future research.

Humans↗
PubMed1992

B-zone small lymphocytic lymphoma: a morphologic, immunophenotypic, and clinical study with comparison to "well-differentiated" lymphocytic disorders.

The pathologic, immunologic, and clinical features of five cases of B-zone small lymphocytic lymphoma (BZSLL), characterized by a nondestructive growth pattern with a selective and complete replacement of the B-zone areas of lymph nodes, were examined. These findings were compared with those of 13 cases of intermediate differentiated lymphoma/mantle zone lymphoma (ILL/MZL) and 20 cases of typical small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL). B-zone SLL was characterized histologically by a deceptively benign pattern at a low magnification, the lymph node architecture being substantially preserved, in contrast to the ILL/MZL and SLL/CLL cases, in which complete effacement of the normal architecture usually could be observed. Moreover, in BZSLL the cellular population was rather uniform and lacked either a prolymphocytic component or the small-cleaved lymphoid cells often seen in SLL/CLL and ILL/MZL cases, respectively. The phenotypic profile of the BZSLL clonal cell population studied by the immunoperoxidase method and by single- and double-labeling flow cytometric analyses (SIg+, CD19+, CD20+, CD21+, CD22+, CD24+, CD35+, CD37+, CD74+, CD45+, CD45R+, MB2+, HLA-DR+, Leu-8+, CD9+/-, CDw75+/-, CD5-/+, CD23-/+, CD10-, FMC7-, PCA-1-, CD25-, CD38-, CD43-, CD3-) appeared to be fairly homogeneous and sufficiently distinct from that of ILL/MZL, based on the absence of FMC7 and CD38 molecules, and from that of SLL/CLL due to significantly stronger expression of SIgs (P less than .05), the higher reactivity with anti-CD9 and -CD22 antibodies (P less than .05), the lower reactivity with anti-CD5 and -CD23 antibodies (P less than .05), and the absence of CD25 determinants. Several clinical features of patients with BZSLL, including age group, advanced stage disease, and high frequency of bone marrow and peripheral blood involvement, were similar to those found in the other patients with ILL/MZL and SLL/CLL, but none of the BZSLL patients had an absolute lymphocyte count higher than 15.0 x 10(9)/L at presentation. Based on the architectural pattern, cytologic features, immunophenotypes, and hematologic findings, we conclude that BZSLL is an unusual variant of SLL that is primary in the lymph nodes and should be distinguished from ILL/MZL and CLL.

Adult↗
PubMed1992

Antigenic phenotypes of hairy cell leukemia and monocytoid B-cell lymphoma: an immunohistochemical evaluation of 66 cases.

Using a large panel of antibodies on multi-tumor block sections of routinely processed, paraffin-embedded fixed tissue, we compared the antigenic phenotype of 42 clinically, morphologically, and immunologically well-characterized cases of hairy cell leukemia (HCL) with 24 cases of monocytoid B-cell lymphoma (MBCL) selected from the Monocytoid B-Cell Lymphoma Registry at the City of Hope National Medical Center. The predominant antigenic phenotype of hairy cells was CD45 (leukocyte common antigen)+, CD45Ra (4KB5, MB1, MT2)+, L26+, CDw75 (LN1)+, CD74 (LN2)+, LN3+, MB2+, CD45RO (UCHL1)-, MT1-, CD15 (Leu-M1)-, neuron-specific enolase (NSE)-, epithelial membrane antigen-, and CD30 (Ber-H2)-. The immunophenotype of neoplastic monocytoid B lymphocytes was essentially identical to that of the hairy cells, with one exception: the neoplastic monocytoid B lymphocytes were stained by epithelial membrane antigen in seven cases. An interesting observation was the staining by anti-muscle-specific actin of the neoplastic cells of MBCL in 53% of cases, but of none of the cases of HCL. The results of our study (1) indicate that HCL and MBCL can be immunophenotyped reliably on fixed tissue samples, (2) further confirm the proposed lineage relationship between these two lymphoproliferative disorders, and (3) indicate that decalcification of bone marrow biopsies does not adversely affect the immunoreactivity of hematopoietic-associated antigens.

Antigens, Neoplasm↗
PubMed1992

Immunoarchitecture of normal human bone marrow: a study of frozen and fixed tissue sections.

To provide baseline information on the immunoarchitecture of normal bone marrow, we studied cryostat-cut, frozen, and paraffin-embedded, fixed tissue sections prepared from 21 core biopsies of normal bone marrow obtained during bone marrow harvests for transplantation. A large panel of antibodies was applied that included, for frozen tissue, Leu-6 (CD1), T11 (CD2), Leu-3a (CD4), Leu-1 (CD5), Leu-2a (CD8), J5 (CD10), My7 (CD13), Leu-11 (CD16), B4 (CD19), B1 (CD20), B2 (CD21), Tac (CD25), My9 (CD33), T200 (CD45), NKH-1 (CD56), kappa and lambda chains, beta F1, Ki-67, HLA-DR, TQ1, and keratin, and for fixed tissue, leukocyte common antigen (CD45), L26 (CD20), LN1 (CDw75), LN2 (CD74), LN3, LN4, LN5, MB1 (CD45R), MB2, MT1 (CD43), MT2 (CD45R), UCHL1 (CD45R0), BM1, Ki-1 (CD30), Leu-M1 (CD15), lysozyme, KP1 (CD68), actin, S100, neuron-specific enolase, vimentin, and keratin. On fresh-frozen sections CD19 and CD2 were the most reliable and sensitive markers for B and T cells, staining 5% and 9% of marrow cells, respectively. Immunoglobulins generally showed heavy background staining, which frequently precluded an accurate assessment. The CD4 to CD8 ratio in the bone marrow was reversed from that of peripheral blood. On fixed tissues, leukocyte common antigen was found in 14% of the marrow cells, corresponding roughly to the lymphocyte population. L26, a pan-B-cell marker, stained 3% of the marrow cells. Among the other B-cell markers, LN1 and MB2 stained a large number of cells (40% to 70%), indicating reactivity with cells of the myeloid or erythroid series in addition to lymphocytes. Among the T-cell markers, UCHL1 and MT1 stained 66% and 50% of the cells, respectively, which could be explained by their cross-reactivity with myeloid cells. Nonspecific myelomonocytic markers (Leu-M1, KP1, and lysozyme) also showed reactivity in a high percentage of cells. No particular architectural distribution patterns of B or T lymphocytes were noted in either frozen or fixed bone marrow specimens. The results of this study provide normal baseline data for the immunohistologic application of hematopoietic and lymphoid markers on frozen or fixed bone marrow biopsy specimens.

Adult↗
PubMed2026

Proteomics combined with single-cell sequencing reveals key genes and computational lead compound related to ligamentum flavum hypertrophy, lactate metabolism and lactate modification.

Ligamentum flavum hypertrophy (LFH) is a hallmark pathological feature of lumbar spinal stenosis; however, its underlying molecular mechanisms remain incompletely understood. Lactate metabolism and related lactylation modifications have emerged as critical links between cellular metabolism and epigenetic regulation, with established roles in various fibrotic and inflammatory diseases. Nevertheless, the specific contribution of lactylation to LFH pathogenesis remains unexplored. In this study, we integrated proteomic profiling of ligamentum flavum tissues with single-cell transcriptomic data to identify differentially expressed proteins associated with LFH. Cross-referencing these genes with genes involved in lactate metabolism and lactylation yielded 16 candidate genes. Through functional enrichment analysis, protein-protein interaction network construction, and GraphBAN model prediction, we identified five hub genes (NDUFS2, HMOX1, SPR, FABP5, and PFKP) and two potential lead compounds (ZINC000014879975 and ZINC000242437513). Molecular docking analysis confirmed favorable binding affinities between these compounds, suggesting that they may serve as potential lead compounds worthy of further experimental investigation. Single-cell analysis further revealed that macrophages occupy a central position in the LFH microenvironment, resulting in pronounced metabolic reprogramming and remodeling of intercellular communication networks, particularly via the MIF-CD74/CD44 axis, under pathological conditions.

Proteomics↗
PubMed2026

Cell-type signatures of Alzheimer's disease shared across population groups.

Genomic studies at single-cell resolution have identified several cell types associated with clinical and pathological traits in Alzheimer's disease1-9, but have not examined associations that are shared across populations. To bridge this gap, here we use single-nucleus RNA sequencing and assay for transposase-accessible chromatin with sequencing to profile cortical and subcortical regions in post-mortem brain-tissue samples from Latin, white (excluding Latin) and African American (excluding Latin) individuals. Using discrete and continuous dissections of molecular programs, we identify cell-type-specific clusters associated with Alzheimer's disease in a region-specific manner across all three population groups, including microglial (GPNMB+ and CD74+ subgroups), astrocytic (SERPINH1+, CD44+ and WIF1+ subgroups) and neuronal (SST+ GABAergic and superficial-layer glutamatergic) signatures. We also report continuous gene-expression factors in astrocytes and oligodendrocytes that are not captured by discrete cluster assignments, but which show strong associations with disease phenotypes; these factors are enriched for genes associated with annotated functions such as lipid processing and neurotransmitter reuptake. Finally, we find that molecular programs reveal six distinct subgroups of individuals with cognitive impairment that span all three populations, are not captured by neuropathology, and are instead distinguished by molecular signatures that are not universally present but are nonetheless associated with ante-mortem impairment. Overall, our study identifies key cell types and gene programs implicated in Alzheimer's disease that are shared across population groups, and underscores how representative sampling can capture both shared signatures and disease heterogeneity, thereby enabling better prioritization of key cell types for further investigation.

Female↗
PubMed2026

Stage-specific ROMO1 in rheumatoid arthritis: predictive immune insights into the MIF pathway and HLA-DR/IL2RA axis via integrated GWAS, transcriptomic, single-cell, and spatial profiling.

Emerging evidence links reactive oxygen species modulator 1 (ROMO1), a key mitochondrial ROS regulator, to rheumatoid arthritis (RA) pathogenesis. However, its exact mechanism remains elusive given the conflicting evidence about its specific function. We used a four-level integrative framework combining multi-omics data and literature‑supported mechanistic inference. At the genetic level, Mendelian randomization (MR) was performed to explore potential causal relationships between ROMO1, IL2RA, HLA-DR, MIF, and RA risk, followed by differential expression analysis and machine learning-based feature selection to identify key mROS genes. The temporal expression dynamics of ROMO1 were assessed in RA progression. At the cellular and tissue levels, we integrated single-cell RNA sequencing and spatial transcriptomics to map cell-type-specific expression and synovial localization of ROMO1-related immune cells and pathways. Finally, our multi-omics findings were contextualized with literature-supported mechanistic inference. (1) MR results were consistent with a potential protective effect of ROMO1 on RA (OR = 0.52) and its potential regulation of risk factors IL2RA (OR = 0.46) and HLA-DR (OR = 0.40). Conversely, IL2RA (OR = 1.42), HLA-DR (OR = 1.88), and MIF (OR = 1.17) were positively associated with RA risk. Additionally, ROMO1 was identified as a top candidate diagnostic predictor with stage-specific dynamics: downregulated in the early but upregulated in the late/remission stages. (2) Single-cell RNA sequencing showed ROMO1's cell-specific expression in CD14+ HLA-DR+ CD74+ monocytes and CD4+ IL2RA+ T cells. Cell communication analysis further suggested that these cells may participate in MIF pathway regulation. Spatial transcriptomics subsequently identified that ROMO1-related cells localized to synovial pathological regions, with MIF pathway changes correlated with RA progression. (3) Finally, literature-supported mechanistic inference suggests that ROMO1 may modulate mROS levels to promote anti-inflammatory M2 macrophage polarization, which could theoretically contribute to reduced systemic inflammation and the alleviation of multi-organ decline in RA. This integrated multi-omics investigation, supported by literature-based mechanistic inference, suggests ROMO1 as a stage-dependent biomarker candidate and potential immune regulator in RA.

Humans↗
PubMed1991

Immunohistochemical differential diagnosis between lymphocytoma cutis and malignant lymphoma in paraffin-embedded sections.

A panel of monoclonal antibodies (Leucocyte Common Antigen [CD45], LN-1 [CDw75], LN-2 [CD74], LN-3, L-26, UCHL-1 [CD45RO] and MT-1) which identify B and T cell surface markers were applied to benign lymphocytoma cutis and malignant lymphoma of the skin in paraffin-embedded sections. In five cases of lymphocytoma cutis, both B and T cell markers were positive, consistent with the polyclonality of the proliferative lymphocytes. In contrast, in two cases of B cell lymphoma, only the B cell markers were positive, consistent with the monoclonality. Furthermore, the immunohistochemistry clarified lymph follicle structures of lymphocytoma cutis. These were occasionally not evident in routine hematoxylin and eosin stained sections. Thus an immunologic phenotyping study combined with other appropriate criteria for histologic evaluation and clonal gene rearrangement analysis appears to be useful in distinguishing reactive from neoplastic lymphoid lesions of the skin.

Aged↗