Immunoglobulin Receptor Research Articles

Use of immune repertoire sequencing analysis to detect differences in treatment responses for advanced esophageal squamous cell carcinoma treated with camrelizumab and platinum-based chemotherapy.

488 Background: The study evaluated the efficacy and safety of camrelizumab combined with platinum-based chemotherapy (platinum plus paclitaxel [TP] or fluorouracil [FP] agents) as first-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC), and explored potential biomarkers for treatment response using immune repertoire (IR) sequencing. Methods: In this multi-center, prospective cohort study, advanced ESCC patients were treated with camrelizumab and TP or FP chemotherapy. Primary outcome was 1-year progression free survival (PFS). Secondary outcomes included 1-year overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Patients were categorized based on their treatment responses into the non-ORR and ORR groups. IR sequencing was exploratorily performed on the peripheral blood mononuclear cells from 15 patients in each group. Results: From June 2020 to April 2023, 88 out of 98 screened patients were enrolled, with a median follow-up of 15.9 months. The 1-year PFS was 56.8%, OS was 68.2%, ORR was 64.8%, and DCR was 91.1%. Most treatment-related adverse events were grade 1-2, though 12.5% experienced grade ≥3 toxicities. The FP regimen's efficacy was comparable to the TP regimen. The analysis of the complementarity-determining region 3 polypeptide sequences revealed significant differences in amino acid composition between the non-ORR and ORR groups in T-cell receptor beta-chain (TRB) and immunoglobulin heavy chain (IGH) repertoire. Furthermore, the ORR group exhibited a more concentrated distribution of clones within TRB. Two V genes (TRBV29-1 and TRBV4-1) and one J gene (TRBJ1-3) in the TRB region, along with six V genes (IGHV1-45, IGHV3-20, IGHV3-48, IGHV3-49, IGHV4-4, and IGHV5-51) in the IGH region, were differentially expressed between the two groups. Conclusions: Camrelizumab with platinum-based chemotherapy is effective and well-tolerated as first-line treatment in advanced ESCC. IR sequencing may provide insights into the underlying mechanisms influencing treatment response. Clinical trial information: ChiCTR2000037942. Objective response and disease response. Efficacy evaluation Total (N=88) Camrelizumab plus T（n=69） Camrelizumab plus FP (n=19) p 1-year PFS rate 50/88 (56.8%) 39/69 (56.5%) 11/19 (57.9%) 1.000 1-year OS rate 60/88 (68.2%) 47/69 (68.1%) 13/19 (68.4%) 1.000 ORR 57/88 (64.8%) 43/69 (62.3%) 11/19 (57.9%) 0.793 DCR 81/88 (91.1%) 63/69 (91.3%) 15/19 (79.0%) 0.213 ORR group, n (%) 54/88 (61.4%) 43/69 (62.3%) 11/19 (57.89%) 0.793 Non-ORR Group, n (%) 34/88 (38.6%) 26/69 (37.7%) 8/19 (42.1%) 1.000 2-year PFS rate 38/88 (43.2%) 30/69 (43.5%) 8/19 (42.1%) 1.000 2-year OS rate 42/88 (47.7%) 33/69 (47.8%) 9/19 (47.4%) 1.000 *p<0.05, a statistically difference.

Silibinin, a PLC-β3 inhibitor, inhibits mast cell activation and alleviates OVA-induced asthma.

The immunoglobulin E (IgE) receptor FcεRI (Fc epsilon RI) plays a crucial role in allergic reactions. Recent studies have indicated that the interaction between FcεRIβ and the downstream protein phospholipase C beta 3 (PLCβ3) leads to the production of inflammatory cytokines. The aim of this study was to develop small molecules that inhibit the protein-protein interactions between FcεRIβ and PLCβ3 to treat allergic inflammation. Additionally, PLCβ3 has emerged as a potential target protein for treating allergic inflammation. In this study, we employed a virtual screening technique to search the Taiwan Traditional Chinese Medicine Database, followed by a second screening using absorption, distribution, metabolism, excretion, and toxicity (ADMET). Among the compounds screened, silibinin exhibited the best performance, forming strong hydrogen bond interactions with residues of PLCβ3, with a binding free energy of -119.277 kcal/mol. Therefore, silibinin effectively blocked the interaction between FcεRIβ and PLCβ3. Silibinin reduced the production of allergic inflammatory cytokines, including cytokine-induced neutrophil chemoattractant 2a (CINC-2a), interleukin-2 (IL-2), cytokine-induced neutrophil chemoattractant 1 (CINC-1), interleukin 1α (IL-1α), macrophage inflammatory protein 3 alpha (MIP3α), interferon γ (IFN-γ), activin A, granulocyte macrophage colony stimulating factor (GM-CSF), intercellular adhesion molecule-1 (ICAM-1), interleukin 4 (IL-4), interleukin 13 (IL-13), Fas ligand (FasL) and tumor necrosis factor alpha (TNF-α), without inducing cytotoxicity. Furthermore, in studies of IgE-mediated allergic responses, silibinin also decreased the expression of surface IgE receptors (FcεRIs). Moreover, silibinin effectively alleviated allergen-induced asthma responses and reduced the infiltration of inflammatory immune cells into the lungs of an OVA-induced allergic airway inflammation mouse model. Taken together, these results demonstrate the potential antiallergic mechanism of silibinin both in vitro and in vivo, making it a promising candidate for the development of asthma therapeutics.

Influence of HLA-B Leader (-21M/T) Dimorphism With Bw4/Bw6 Epitopes on Graft Versus Host Disease After Allogenic Haematopoietic Stem Cell Transplantation in North Indians.

High degree of variability in human leukocyte antigens (HLAs) system restricts availability of histocompatible HLA-matched-related donors, thus increasing reliance on worldwide bone marrow registries network. Nevertheless, due to limited coverage/accessibility/affordability of some ethnicities in these registries, haploidentical haematopoietic stem cell transplantation (HSCT) emerged as an alternative option, though with allorecognition-mediated graft versus host disease (GvHD) (>40% cases). A dimorphism [-21 methionine (M) or threonine (T)] in HLA-B leader peptide (exon 1) which differentially influences its HLA-E binding, plausibly regulates natural killer cell functionality, affecting GvHD vulnerability and clinically in practice for donor selection. Here, we analysed population-specific influence of this functionally relevant dimorphism on post HSCT GvHD occurrence and clinical utility (if any) towards defining donor permissibility. High resolution HLA-B genotyping data were analysed in 178 study participants, including 89 HSCT patient-donor pairs, for the frequency distribution of -21 leader dimorphism. Distribution of HLA-Bw4/Bw6 was deduced with killer cell immunoglobulin receptor ligand calculator tool in IPD-IMGT/HLA database. Though -21T (∼85%) was over represented in the study participants, no significant influence is observed for this variant between HLA-identical v/s haplo HSCT either with or without GvHD, at allelic and genotypic levels as well as in BLEAT (HLA-B Leader Assessment Tool)-based donor-recipient matching. Stratified analysis of -21M/T into Bw4/Bw6 groups revealed a higher frequency of -21T+Bw4 in GvHD (+) group compared to GvHD (-) (p<0.05), plausibly linking this haplotype with occurrence of GvHD post HSCT and importance of HLA class I-mediated NK cell functionality in GvHD.

Characterization of TCRβ and IGH Repertoires in the Spleen of Two Chicken Lines with Differential ALV-J Susceptibility Under Normal and Infection Conditions

This study investigates the immunological factors underlying the differential susceptibility of two chicken strains, E- and M-lines, to avian leukosis virus subgroup J (ALV-J). During the eradication of avian leukosis at a chicken breeder farm in Guangdong, we observed strain-specific differences in susceptibility to ALV-J. Moreover, E-line chickens exhibited a slower antibody response to ALV-J compared to M-line chickens. As the T cell receptor (TCR) and B cell receptor (BCR) are critical for antigen recognition, their activation triggers specific immune responses, including antibody production. Using high-throughput sequencing, we characterized the T cell receptor beta (TCRβ) and immunoglobulin heavy chain (IGH) repertoires in spleen tissues from both chicken strains. The M-line demonstrated higher clonal diversity in both TCRβ and IGH repertoires under normal conditions compared to the E-line, suggesting a broader baseline antigen recognition capacity. Following ALV-J infection, the TCRβ repertoire diversity remained unchanged, while the IGH repertoire displayed distinct clonal expansion patterns and complementarity-determining region 3 (CDR3) length distributions between the two lines, potentially affecting their ability to recognize ALV-J antigens. Our study provides the first comprehensive comparison of TCRβ and IGH repertoire dynamics in chickens with different ALV-J susceptibilities, offering new insights into the molecular and immunological mechanisms underlying resistance to ALV-J.

Presence of minimal residual disease determined by next-generation sequencing is not a reliable prognostic biomarker in children with acute lymphoblastic leukemia

The role of next-generation sequencing (NGS) for minimal residual disease (MRD) assessment in pediatric acute lymphoblastic leukemia (ALL) is still under consideration. Fifty pediatric patients were prospectively evaluated for specific clonal rearrangements of immunoglobulin and T-cell receptor genes using NGS analysis at diagnosis and on days 33 and 78 from therapy onset. The prognostic value or the NGS-MRD status was analyzed after a median follow-up of 4 years. All but one patient with negative NGS-MRD status on day 33 are in clinical remission. A total of 29 (58%) patients were NGS-MRD positive on day 33, of which 9 (18%) patients remained positive on day 78. However, only a small percentage of the patients with positive NGS-MRD status on day 33 and day 78 relapsed: 21% (6/29) and 33% (3/9), respectively. Positive NGS-MRD status is not a reliable prognostic biomarker in children with ALL and warrants careful consideration in disease stratification.

DOP030 Mucosal deficiency of mitochondria-driven humoral immunity is linked to Crohn’s Disease

Abstract Background Secretory IgA (sIgA) is critical for the maintenance of the mucosal barrier function, preventing bacterial translocation and reducing the risk of chronic inflammation. Several decades of research have revealed a dysregulation of the B-cell compartment in inflammatory bowel disease (IBD) of yet unknown origin1,2. While increased serum levels of (auto)antibodies against S. cerevisiae or the intestinal M-cell expressed FimH receptor glycoprotein 2 (GP2) are observed in patients with Crohn’s disease (CD)3, some studies indicated an impaired generation of intestinal immunoglobulin-secreting plasma cells (PCs)4. To unravel the role of mucosal humoral immunity in CD pathogenesis, we aimed to provide an in-depth characterisation of colonic PC differentiation in patients with CD. Methods In-depth phenotyping of patients with CD in remission and non-IBD controls (hospitalised normals) was performed using multi-omics analyses (spatial single-cell proteomics, proteomics, metabolomics, and transcriptomics) of plasma or colon biopsy samples. Colonic switched memory B cells (sMBCs) were sorted from lamina propria mononuclear cells (LPMNCs) by magnetic-activated cell sorting and ex vivo differentiated into PCs. The impact of mitochondrial function on colonic PC maturation was studied in mitochondrial respiratory chain complex V-deficient ATP8 mutant mice and mice that underwent nutritional intervention. Results Despite a hyperactive colonic B-cell compartment, patients with CD displayed significantly diminished mucosal dimeric IgA (dIgA) and fecal IgA compared to non-IBD controls. Polymeric immunoglobulin receptor (PIGR) expression did not differ, excluding a defective epithelial transcytosis of dIgA. Spatial single-cell proteomics uncovered that colonic plasmablasts and immature CD19+CD45+ PCs were increased at the expense of the fully mature CD19-CD45- phenotype. Consistently, PCs generated ex vivo from CD-derived sMBCs revealed impaired capacity to differentiate into IgA-secreting PCs. Metabolic phenotyping indicated a colonic mitochondrial dysfunction in patients with CD that was also reflected in colonic PCs by increased expression of the cell-surface NADase CD38 in concert with decreased expression of mitochondrially encoded transcripts. Of note, splenic PCs isolated from ATP8 mutant mice displayed a hyperproliferative and low-differentiated phenotype, while colonic IgA-secreting PCs were reduced. Conversely, feeding mice an isocaloric glucose-free, high-protein diet, which promotes mitochondrial activity, increased colonic IgA levels. Conclusion In summary, this study links mitochondrial dysfunction to impaired PC differentiation in patients with CD, resulting in reduced levels of sIgA and thereby compromised mucosal barrier integrity.

Characterization of the colostrum proteome of primiparous Holstein cows and its association with colostrum immunoglobulin G concentrations

BackgroundThe objective was to characterize the colostrum proteome of primiparous Holstein cows in association with immunoglobulin G (IgG) content. Immediately after calving, colostrum samples were collected from 18 cows to measure IgG concentration. Based on colostrum IgG content, samples were classified through cluster analysis and were identified as poor, average, and excellent quality. The proteome was assessed with quantitative shotgun proteomics; abundance data were compared among the colostrum types; enrichment analysis of metabolic processes and proteins classes was performed as well. We also tested correlations between this proteome and blood globulin level of cows and passive immunity level of calves.ResultsOn average, 428 proteins were identified per sample, which belonged mainly to cellular process, biological regulation, response to stimulus, metabolic process, and immune system process. Most abundant proteins were complement C3 (Q2UVX4), alpha-S1-casein (P02662), Ig-like domain-containing protein (A0A3Q1M032), albumin (A0A140T897), polymeric immunoglobulin receptor (P81265), lactotransferrrin (P24627), and IGHG1*01 (X16701_4). Colostrum of excellent quality had greater (P < 0.05) abundance of serpin A3-7 (A2I7N3), complement factor I (A0A3Q1MIF4), lipocalin/cytosolic fatty-acid binding domain-containing protein (A0A3Q1MRQ2), complement C3 (E1B805), complement component 4 binding protein alpha (A0AAF6ZHP5), and complement component C6 (F1MM86). However, colostrum of excellent quality had lower (P < 0.05) abundance of HGF activator (E1BCW0), alpha-S1-casein (P02662), and xanthine dehydrogenase/oxidase (P80457). This resulted in enrichment of the biological processes predominantly for complement activation alternative pathway, complement activation, complement activation classical pathway, humoral immune response, leukocyte mediated immunity, and negative regulation of endopeptidase activity in excellent-quality colostrum. Additionally, some colostrum proteins were found to be correlated with the blood globulin level of cows and with the passive immunity level of calves (P < 0.05; r ≥ 0.57).ConclusionsThis study provides new insights into the bovine colostrum proteome, demonstrating associations between IgG levels and the abundance of other proteins, as well as the enrichment of metabolic processes related to innate immune response. Thus, results suggest that the colostrum proteomic profile is associated with the content of IgG. Future research should deeply explore the association of these findings with pre-calving nutrition status and blood composition of the cow, and with passive immunity transfer to the calf.

SUGT1 is a prognostic biomarker and is associated with immune infiltrates in ovarian cancer

BackgroundOvarian cancer (OC) is a prevalent gynecological malignancy with a relatively dismal prognosis. The SGT1 homolog (SUGT1) protein, which interacts with heat shock protein 90 and is essential for the G1/S and G2/M transitions, was formerly thought to be a cancer promoter, but its precise role in OC remains unknown.MethodsWe conducted a comprehensive bioinformatics analysis of SUGT1 expression in patients with OC compared with their normal controls, including the data from the cancer genome atlas (TCGA), genotype–tissue expression (GTEx) databases, gene ontology (GO) analysis, Kyoto Encylopedia of Genes and Genomes (KEGG) analysis, gene set enrichment analysis (GSEA), single sample gene set enrichment analysis (ssGSEA). In addition, Kaplan–Meier (KM) analysis, univariate and multivariate Cox analyses were applied to investigate the prognostic role of SUGT1 in ovarian cancer. Furthermore, we validated the expression of SUGT1 in OC and normal tissues through immunohistochemistry.ResultsSUGT1 was significantly overexpressed in OC than in normal tissues. In addition, the GO, KEGG and GSEA analysis revealed that SUGT1 was associated with the functions related to immunoglobulin complex, antigen binding, immunoglobulin receptor binding, among others. Besides, ssGSEA demonstrated a positive correlation between SUGT1 expression and the abundance of T central memory cells, natural killer cells, and T gamma delta cells, although it showed a negative association with activated dendritic cells, cytotoxic cells, T cells, and T helper 1 cells. Subsequently, KM survival analysis revealed that high SUGT1 expression indicated a shorter overall survival, disease specific survival and progression free interval in OC patients. Univariate and multivariate Cox regression revealed that SUGT1 could serve as an independent risk factor for prognosis of patients with OC.ConclusionsAll these results of this study show that SUGT1 is an important molecular component in immune infiltration in OC and may have a new significant prognostic role in OC.

Stereotyped B-Cell Receptor Immunoglobulins in B-Cell Lymphomas.

Thorough examination of clonotypic B-cell receptor immunoglobulin (BcR IG) gene rearrangement sequences in patients with mature B-cell malignancies has revealed significant repertoire restrictions, leading to the identification of subsets of patients expressing highly similar, stereotyped BcR IG. This discovery strongly suggests selection by common epitopes or classes of structurally similar epitopes in the development of these tumors. Initially observed in chronic lymphocytic leukemia (CLL), where the stereotyped fraction accounts for a substantial fraction of patients, stereotyped BcR IGs have also been identified in other mature B-cell malignancies, including mantle cell lymphoma (MCL) and splenic marginal zone lymphoma (SMZL).Further comparisons across different entities have indicated that stereotyped IGs are predominantly "disease-biased," indicating distinct immune pathogenetic trajectories. Notably, accumulating evidence suggests that molecular subclassification of mature B-cell malignancies based on BcR IG stereotypy holds biological and clinical relevance. Particularly in CLL, patients belonging to the same subset due to the expression of a specific stereotyped BcR IG exhibit consistent biological backgrounds and clinical courses, especially for major and extensively studied subsets. Therefore, robust assignment to stereotyped subsets may aid in uncovering mechanisms underlying disease initiation and progression, as well as refining patient risk stratification. In this chapter, we offer an overview of recent studies on BcR IG stereotypy in mature B-cell malignancies and delineate past and present methodological approaches utilized for the identification of stereotyped BcR IG.

Cardiovascular Risk Biomarkers in Women with and Without Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder with an increased risk for cardiovascular disease (CVD) that is enhanced by obesity. This study sought to determine whether a panel of cardiovascular risk proteins (CVRPs) would be dysregulated in overweight/obese PCOS patients, highlighting potential biomarkers for CVD in PCOS. In this exploratory cross-sectional study, plasma levels of 54 CVRPs were analyzed in women with PCOS (n = 147) and controls (n = 97). CVRPs were measured using the SOMAscan proteomic platform (version 3.1), with significant proteins identified through linear models, regression analysis, and receiver operating characteristic (ROC) analysis. Analysis on BMI-matched subsets of the cohort were undertaken. Functional enrichment and protein-protein interaction analyses elucidated the pathways involved. Eleven CVRPs were dysregulated in PCOS (whole set, without matching for body mass index (BMI) or insulin resistance (IR)): leptin, Interleukin-1 receptor antagonist protein (IL-1Ra), polymeric immunoglobulin receptor (PIGR), interleukin-18 receptor (IL-18Ra), C-C motif chemokine 3 (MIP-1a), and angiopoietin-1 (ANGPT1) were upregulated whilst advanced glycosylation end product-specific receptor, soluble (sRAGE), bone morphogenetic protein 6 (BMP6); growth/differentiation factor 2 (GDF2), superoxide dismutase [Mn] mitochondrial (MnSOD), and SLAM family member 5 (SLAF5) were downregulated versus the controls. In BMI-matched (overweight/obese, BMI ≥ 26 kg/m2) subset analysis, six CVRPs were common to the whole set: ANGPT1 and IL-1Ra were upregulated; and sRAGE, BMP6, GDF2, and Mn-SOD were downregulated. In addition, lymphotactin (XCL1) was upregulated and placenta growth factor (PIGF), alpha-L-iduronidase (IDUA), angiopoietin-1 receptor, and soluble (sTie-2) and macrophage metalloelastase (MMP12) were downregulated. A subset analysis of BMI-matched plus insulin resistance (IR)-matched women revealed only upregulation of tissue factor (TF) and renin in PCOS, potentially serving as biomarkers for cardiovascular risk in overweight/obese women with PCOS. A combination of upregulated obesity-related CVRPs (ANGPT1/IL/1Ra/XCL1) and downregulated cardioprotective proteins (sRAGE/BMP6/Mn-SOD/GDF2) in overweight/obese PCOS women may contribute to the increased risk for CVD. TF and renin upregulation observed in the BMI- and IR-matched limited sample PCOS subgroup indicates their potential risk of CVD.

Ganoderma lucidum (Curtis) P. Karst. Immunomodulatory Protein Has the Potential to Improve the Prognosis of Breast Cancer Through the Regulation of Key Prognosis-Related Genes.

Background/Objectives: Breast cancer in women is the most commonly diagnosed and most malignant tumor. Although luminal A breast cancer (LumA) has a relatively better prognosis, it still has a persistent pattern of recurrence. Ganoderma lucidum (Curtis) P. Karst. is a kind of traditional Chinese medicine and has antitumor effects. In this study, we aimed to identify the genes relevant to prognosis, find novel targets, and investigate the function of the bioactive protein from G. lucidum, called FIP-glu, in improving prognosis. Methods: Gene expression data and clinical information of LumA breast cancer patients were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Using bioinformatics methods, a predictive risk model was constructed to predict the prognosis for each patient. The cell counting kit-8 (CCK8) and clone formation assays were used to validate gene function. The ability of FIP-glu to regulate RNA levels of risk genes was validated. Results: Six risk genes (slit-roundabout GTPase-activating protein 2 (SRGAP2), solute carrier family 35 member 2 (SLC35A2), sequence similarity 114 member A1 (FAM114A1), tumor protein P53-inducible protein 11 (TP53I11), transmembrane protein 63C (TMEM63C), and polymeric immunoglobulin receptor (PIGR)) were identified, and a prognostic model was constructed. The prognosis was worse in the high-risk group and better in the low-risk group. The receiver operating characteristic (ROC) curve confirmed the model's accuracy. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that the differentially expressed genes (DEGs) between the high- and low-risk groups were significantly enriched in the immune responses. TMEM63C could promote tumor viability, growth, and proliferation in vitro. FIP-glu significantly regulated these risk genes, and attenuated the promoting effect of TMEM63C in breast cancer cells. Conclusions: SRGAP2, SLC35A2, FAM114A1, TP53I11, TMEM63C, and PIGR were identified as the potential risk genes for predicting the prognosis of patients. TMEM63C could be a potential novel therapeutic target. Moreover, FIP-glu was a promising drug for improving the prognosis of LumA breast cancer.

Molecular biomarkers involved in the progression of gallbladder inflammatory lesions to invasive cancer: A proteomic approach.

The progression of gallbladder inflammatory lesions to invasive cancer remains poorly understood, necessitating research on biomarkers involved in this transition. This study aims to identify and validate proteins associated with this progression, offering insights into potential diagnostic biomarkers for gallbladder cancer (GBC). Label-free liquid chromatography-assisted tandem mass spectrometry (LC-MS/MS) proteomics was performed on samples from ten cases each of GBC and inflammatory lesions, with technical duplicates. Validation was conducted through the enzyme-linked immunosorbent assay (ELISA) using 80 samples (40 GBC and 40 inflammatory lesions). Bioinformatics tools analyzed protein-protein interaction (PPI) networks and pathways. Statistical correlations with clinicopathological variables were assessed. Prognostic evaluation utilized Kaplan-Meier survival analysis and Cox regression analyses. mRNA expressions were studied using real-time-polymerase chain reaction (RT-PCR). Out of 5714 proteins analyzed, 621 were differentially expressed. Three upregulated (the S100 calcium-binding protein P [S100P], polymeric immunoglobulin receptor [PIGR], and complement C1q-binding protein [C1QBP]) and two downregulated (transgelin [TAGLN] and calponin 1 [CNN1]) proteins showed significant expression. Pathway analysis implicated involvement of proteoglycans in cancer and glycosaminoglycan metabolism. Significant correlations were observed between protein concentrations and clinicopathological variables. Prognostic factors, such as tumor size, lymph node metastasis, and preoperative bilirubin levels were associated with overall survival (OS). Protein-based assays demonstrated higher resolution compared to mRNA analysis, suggesting their utility in GBC risk stratification. S100P, PIGR, C1QBP, TAGLN, and CNN1 emerge as potential protein-based biomarkers involved in the progression from gallbladder inflammatory lesions to invasive cancer. These findings hold promise for improved diagnostic and prognostic strategies in GBC management.

MS4A superfamily molecules in tumors, Alzheimer's and autoimmune diseases.

MS4A (membrane-spanning 4-domain, subfamily A) molecules are categorized into tetraspanins, which possess four-transmembrane structures. To date, eighteen MS4A members have been identified in humans, whereas twenty-three different molecules have been identified in mice. MS4A proteins are selectively expressed on the surfaces of various immune cells, such as B cells (MS4A1), mast cells (MS4A2), macrophages (MS4A4A), Foxp3+CD4+ regulatory T cells (MS4A4B), and type 3 innate lymphoid cells (TMEM176A and TMEM176B). Early research confirmed that most MS4A molecules function as ion channels that regulate the transport of calcium ions. Recent studies have revealed that some MS4A proteins also function as chaperones that interact with various immune molecules, such as pattern recognition receptors and/or immunoglobulin receptors, to form immune complexes and transmit downstream signals, leading to cell activation, growth, and development. Evidence from preclinical animal models and human genetic studies suggests that the MS4A superfamily plays critical roles in the pathogenesis of various diseases, including cancer, infection, allergies, neurodegenerative diseases and autoimmune diseases. We review recent progress in this field and focus on elucidating the molecular mechanisms by which different MS4A molecules regulate the progression of tumors, Alzheimer's disease, and autoimmune diseases. Therefore, in-depth research into MS4A superfamily members may clarify their ability to act as candidate biomarkers and therapeutic targets for these diseases. Eighteen distinct members of the MS4A (membrane-spanning four-domain subfamily A) superfamily of four-transmembrane proteins have been identified in humans, whereas the MS4A genes are translated into twenty-three different molecules in mice. These proteins are selectively expressed on the surface of various immune cells, such as B cells (MS4A1), macrophages (MS4A4A), mast cells (MS4A2), Foxp3+CD4+ regulatory T cells (MS4A4B), type 3 innate lymphoid cells (TMEM176A and TMEM176B) and colonic epithelial cells (MS4A12). Functionally, most MS4A molecules function as ion channels that regulate the flow of calcium ions [Ca2+] across cell membranes. Recent studies have revealed that some MS4A proteins also act as molecular chaperones and interact with various types of immune receptors, including pattern recognition receptors (PRRs) and immunoglobulin receptors (IgRs), to form signaling complexes, thereby modulating intracellular signaling and cellular activity. Evidence from preclinical animal models and human genetic studies suggests that MS4A proteins play critical roles in various diseases (2). Therefore, we reviewed the recent progress in understanding the role of the MS4A superfamily in diseases, particularly in elucidating its function as a candidate biomarker and therapeutic target for cancer.

Asymmetric N-Glycosylation in the Tailpiece of Recombinant IgA1.

Here, we employed a variety of mass spectrometry (MS)-based approaches, both (glyco)peptide-centric and protein-centric, to resolve the complex glycoproteoform landscape of recombinant IgA1 produced in HEK293 cells. These key immunoglobulins harbor several N- and O-glycosylation sites, making them considerably more heterogeneous than their IgG counterparts. We provide quantitative data on the occupancy and glycan composition for each IgA1 glycosylation site. Combining all data, we revealed that IgA1 molecules consist of at least three distinct populations with varying N-glycosylation site occupancies at the C-terminal tailpiece, namely, one with both glycosylation sites occupied, another with both glycosylation sites unoccupied, and a third asymmetric population with one glycosylation site occupied and the other unoccupied, challenging the prevailing acceptance that IgA1 N-glycosylation is symmetrical. This finding is significant, given that the tailpiece is involved in interactions with the J-chain and the Polymeric Immunoglobulin Receptor, and in general as antibody glycosylation is a quality attribute that needs to be carefully monitored, as the presence and nature of these modifications can affect the antibody's efficacy, lifetime, stability, and binding and/or neutralizing capacities. Optimizing strategies to produce recombinant IgA1 requires efficient and specific quality control analytical strategies, as presented here, which is essential for therapeutic IgA1-based antibody development. We expect that the integrated MS-based strategy presented here may be beneficial to comprehensively characterize the glycoproteoform profiles of IgA1-based therapeutics, thereby improving their production and optimization processes and facilitating the pathway to bring more IgA1-based therapeutics into clinical applications.

The Role of Leukocyte Immunoglobulin Receptor B2 Overexpression as a Novel Biomarker and Potential Therapeutic Agent for Colorectal Cancer

The Role of Leukocyte Immunoglobulin Receptor B2 Overexpression as a Novel Biomarker and Potential Therapeutic Agent for Colorectal Cancer

Proteomics and surface free fatty acid analysis of milk fat globule in the spray- and freeze-dried bovine, goat and horse milk powders.

Changes in the structure and composition of milk fat globules in spray- and freeze-dried milk powders have recently garnered significant attention. This study investigated changes in milk fat globular membrane (MFGM) proteins from bovine, goat, and horse milk powders, both spray- and freeze-dried, using a label-free proteomics approach, and quantified surface free fatty acids and their composition using gas chromatography. The results showed that several proteins of αS2-casein and β-lactoglobulin increased, while fibrinogen α, β chain, and mucin-1 decreased in the MFGM fractions of the studied spray-dried milk powders. Additionally, lactoperoxidase and polymeric immunoglobulin receptor levels were elevated in the studied freeze-dried milk powders. Several proteins exhibited variations in both dried milk powders depending on the species, of these, nucleobindin-1, complement C3, and sulfhydryl oxidase were increased in spray-dried bovine and goat milk powders, and lactoferrin was increased in freeze-dried horse milk powder, compared with their raw milk counterparts. Conversely, butyrophilin subfamily 1 member A1 and xanthine dehydrogenase/oxidase were decreased in spray-dried bovine and goat milk powders, S100 calcium-binding protein and aldehyde dehydrogenase were decreased in freeze-dried bovine and goat milk powders, and mucin-4 and paraoxonase were decreased in horse milk powder. Additionally, spray-dried milk powders had lower surface free fatty acid content compared with freeze-dried milk powders. The findings underscore that dried methods exert varied impacts on MFGM components of the studied milk sources, thereby providing a valuable reference for improving the nutritional quality of dried dairy products.

The impact of atmospheric ultrafine particulate matter on IgE-mediated type 1 hypersensitivity reaction

The effect of atmospheric ultrafine particulate matter (UPM) on respiratory allergic diseases has been investigated for decades; however, the precise molecular mechanisms underlying these effects remain poorly understood. In this study, we used a simulated UPM (sUPM) generated via the spark discharge method to refine black carbon, a core particle that closely mimics real-world UPM, including the size (i.e., size of agglomerates: 165 nm) and organic carbon/elemental carbon ratio (i.e., 2.62). When 25 μg/mouse of dispersed sUPM was instilled into the lungs of mice, it promoted the infiltration and degranulation response of pulmonary mast cells, and exposure to sUPM in an immunoglobulin E (IgE)-mediated passive anaphylaxis model intensified the degranulation response of peripheral mast cells. These effects of sUPM were demonstrated to amplify the downstream signaling mechanism of the high-affinity IgE receptor (FcεRI) mediated by IgE when tested using rat basophil leukemia (RBL)−2H3 and mouse bone marrow-derived mast cells (BMMCs) collected from the bone marrow of BALB/c mice. These results indicate that airborne UPM can exacerbate type 1 hypersensitivity reactions by enhancing the IgE-mediated signaling pathways within mast cells. Furthermore, this study provided mechanistic evidence on exacerbated allergic pulmonary diseases induced by UPM inhalation.

T-cell receptor and B-cell receptor repertoires profiling in pleural tuberculosis.

Tuberculosis (TB) is a leading cause of death worldwide from a single infectious agent. In China the most common extra-pulmonary TB (EPTB) is pleural tuberculosis (PLTB). An important clinical feature of PLTB is that the lymphocytes associated with TB will accumulate in the pleural fluid. The adaptive immune repertoires play important roles in Mycobacterium tuberculosis (Mtb) infection. In this study, 10 PLTB patients were enrolled, and their Peripheral Blood Mononuclear Cells(PBMCs) and Pleural Effusion Mononuclear Cells(PEMCs) were collected. After T cells were purified from PBMCs and PEMCs, high-throughput immunosequencing of the TCRβ chain (TRB), TCRγ chain(TRG), and B cell receptor(BCR) immunoglobulin heavy chain (IGH) were conducted on these samples. The TRB, TRG, and BCR IGH repertoires were characterized between the pleural effusion and blood in PLTB patients, and the shared clones were analyzed and collected. The binding activity of antibodies in plasma and pleural effusion to Mtb antigens was tested which indicates that different antibodies responses to Mtb antigens in plasma and pleural effusion in PLTB patients. Moreover, GLIPH2 was used to identify the specificity groups of TRB clusters and Mtb-specific TRB sequences were analyzed and collected by VJ mapping. We characterize the adaptive immune repertoires and identify the shared clones and Mtb-specific clones in pleural effusion and blood in PLTB patients which can give important clues for TB diagnosis, treatment, and vaccine development.

IL-17 signaling protects against Helicobacter pylori-induced gastric cancer

ABSTRACT Helicobacter pylori infection is the predominant risk factor for the development of gastric cancer. Risk is enhanced by specific H. pylori virulence factors, diet, and the inflammatory response. Chronic activation of T helper (Th) 1 and Th17 pathways contributes to prolonged inflammation; yet, higher expression of IL-17 receptor (IL-17RA) is a favorable prognostic marker for survival after gastric cancer diagnosis. The protective impact of IL-17RA signaling is not understood. To investigate if IL-17RA signaling protects during H. pylori-induced carcinogenesis, the transgenic InsGAS tg/tg mouse, which is prone to H. pylori-induced gastric cancer, was utilized. InsGAS tg/tg mice and InsGAS tg/tg Il17ra -/- mice were infected with a cag type 4 secretion system (T4SS) positive H. pylori strain for up to 6 months. Six weeks post-infection, IL-17RA deficiency led to increased bacterial burden, increased gastritis, and development of lymphoid follicles. Increased inflammation was associated with heightened cellular proliferation and earlier loss of parietal and chief cells in InsGAS tg/tg Il17ra -/- mice. Gastric cancers developed more frequently by 3- and 6-months post-infection in H. pylori-infected InsGAS tg/tg Il17ra -/- mice compared to InsGAS tg/tg mice. Chronic inflammation was exacerbated with IL-17RA deficiency, characterized by elevated Th1/Th17 cytokines, increased B cell infiltration, and enhanced IgA production, despite reduced expression of the polymeric immunoglobulin receptor. Further, paragastric lymph nodes of InsGAS tg/tg Il17ra -/- mice were enlarged relative to controls and displayed altered gene expression profiles. Increased inflammation was accompanied by a significant increase in Cybb expression, which encodes NADPH oxidase 2, suggesting that increased oxidative damage may occur in the absence of IL-17RA. Further, there is increased phosphorylation of histone 2AX in IL-17RA deficient mice, indicating that the DNA damage response is highly activated. These data suggest that IL-17RA signaling activates a protective pathway to prevent excessive inflammation which otherwise can lead to increased oxidative stress, DNA damage, and drive gastric carcinogenesis after H. pylori infection.

Supplementation of Parachlorella sp. in feed promote the gut microbiome colonization and fecal IgA response of broiler in both early and late period

This study evaluated the effects of Parachlorella sp. KSN1 (PA) supplementation on the gut microbiota and intestinal immunity of broilers of different ages. A total of 180 Ross 308 broiler chicks were weighed and divided into early (1 to 10 days post hatch) and late (11 to 28 days post hatch) periods, with six replicates of 10 chicks per cage assigned to two dietary groups. The experimental diets included a corn-soybean meal-based control diet and a treatment diet supplemented with 0.5% PA, replacing corn or corn starch, and fed ad libitum for the assigned experimental period. On days 10 and 28, two broilers from each of the six replicate cages, with 7 broilers per cage in each group, were selected and euthanized, and cecal feces and intestinal tissue samples were collected. PA supplementation did not significantly affect broilers growth performance during both the early and the late periods. However, PA supplementation altered the cecal microbiome, with Clostridiaceae and Clostridium exhibiting prominent and consistent changes. In terms of intestinal immunity, PA supplementation significantly increased the number of CD3+ and CD4+ T cells when administered only during the early period. Cecal IgA levels were significantly increased by PA supplementation during both the early and late periods. A significant positive correlation was observed between IgA, Clostridiaceae and Clostridium during the early and late periods. Gene expression analysis identified 40 upregulated genes, including polymeric immunoglobulin receptor (pIgR), and 142 downregulated genes, including marginal zone B and B1 cell specific protein and immunoglobulin lambda-like polypeptide 1 that were associated with the IgA response in PA-treated broilers during the early period. This study demonstrated that PA supplementation promotes gut microbial colonization and intestinal immunity development during the early age of broilers. These findings suggest that the early growth period of broilers is the optimal time for dietary immunomodulation to promote gut health in broilers.