Afatinib, an oral molecular-targeted anticancer agent, is effective but causes significant gastrointestinal side effects. These effects are associated with EGFR inhibition in intestinal cells and changes in the microbiota.

To investigate the effects of afatinib on intestinal mucosal immunity in rats, focusing on IgA levels in the intestine and saliva, and to understand the innate and acquired immune responses to these side effects.

Male Wistar rats received afatinib (5.2 mg/kg) daily for 24 h (Day 1) and for 2 weeks (Day 14). Gene expression in the intestine was analyzed using quantitative polymerase chain reaction. IgA levels in the intestine and saliva were measured using enzyme-linked immunosorbent assay.

Afatinib suppressed α-defensin 5 and pIgR in the jejunum and ileum, indicating reduced innate immunity. It increased IgA levels in the intestine and saliva, suggesting altered acquired immunity. Salivary IgA levels significantly correlated with intestinal IgA levels.

Afatinib affects gastrointestinal mucosal immunity, suppresses innate defense, and alters IgA production. Salivary IgA could serve as a marker for monitoring these effects, aiding cancer therapy management.

A previous study identified a novel sulfated-rhamnoglucuronan structure in Ulva pertusa polysaccharide (UPP). The present study evaluates the intestinal immunostimulatory effects of UPP in naïve C3H/HeN mice. Oral administration of UPP significantly enhanced the secretion of IgA and associated cytokines, including interleukin (IL)-6, IL-10, and transforming growth factor (TGF)-β, from Peyer's patch (PP) cells in vivo. Additionally, the supernatant from PP cell cultures stimulated the proliferation of bone marrow cells. Histological analysis revealed strong stimulation of PP by UPP, as evidenced by hematoxylin and eosin staining. Serum analysis indicated that UPP triggered TGF-β secretion, which subsequently promoted IgA production. Furthermore, UPP administration enhanced IgA-related cytokine production in ileum tissues and was linked to the activation of the mitogen-activated protein kinase and nuclear factor kappa B signaling pathways. The secretion of A proliferation-inducing ligand (tumor necrosis factor superfamily member 13; TNFSF13) and B-cell activating factor (TNFSF13B) was also upregulated in the ileum. Additionally, fecal analysis demonstrated an increase in short-chain fatty acids, including acetic, propionic, and butyric acids, in a dose- and administration period-dependent manner. These findings suggest that UPP administration contributes IgA-related immune responses and intestinal immune system modulation via PP cells.

Mucosal delivery of vaccine boosters induces robust local protective immune responses even without any adjuvants. Yet, the mechanisms by which antigen alone induces mucosal immunity in the respiratory tract remain unclear. Here we show that an intranasal booster with an unadjuvanted recombinant SARS-CoV-2 spike protein, after intramuscular immunization with 1 μg of mRNA-LNP vaccine encoding the full-length SARS-CoV-2 spike protein (Pfizer/BioNTech BNT162b2), elicits protective mucosal immunity by retooling the lymph node-resident immune cells. On intranasal boosting, peripheral lymph node-primed B cells rapidly migrated to the lung through CXCR3-CXCL9 and CXCR3-CXCL10 signaling and differentiated into antigen-specific IgA-secreting plasma cells. Memory CD4+ T cells in the lung served as a natural adjuvant for developing mucosal IgA by inducing the expression of chemokines CXCL9 and CXCL10 for memory B cell recruitment. Furthermore, CD40 and TGFβ signaling had important roles in mucosal IgA development. Repeated mucosal boosting with an unadjuvanted protein amplified anamnestic IgA responses in both the upper and the lower respiratory tracts. These findings help explain why nasal boosters do not require an adjuvant to induce robust mucosal immunity at the respiratory mucosa and can be used to design safe and effective vaccines against respiratory pathogens.

IgA nephropathy (IgAN), as the most common chronic glomerulonephritis worldwide, is often triggered by mucosal infections and follows a chronic progression, with the majority of patients ultimately progressing to end-stage renal disease (ESRD) during their lifetimes. Since the mystery of its complete pathogenesis has not been fully solved, the resulting lack of effective early diagnosis and treatment greatly affects the prognosis of patients. Given the well-defined pathological feature of IgA deposition in the mesangial region, the source and role of pathogenic IgA has been focused on. Starting from the microbiology and immunity of the gut, we systematically review both the physiological and the pathological process of microbiome-B cell-IgA axis, from microbial-induced IgA production to the role of IgA in the intestinal immune milieu, and ultimately end up with the various aspects of microbiome-B cell-IgA axis in the pathogenesis of IgAN as well as the corresponding therapeutic initiatives available. Our retrospective review helps researchers to systematically understand the complex role between intestinal flora dysbiosis and pathogenic IgA in IgAN. This understanding provides a foundation for in-depth explorations to uncover more detailed pathogenic mechanisms and to develop more precise and effective diagnostic and therapeutic approaches.

IgA nephropathy (IgAN), also known as Berger's disease, is a prevalent kidney disorder caused by the accumulation of IgA antibodies in the glomerular tissue. Long noncoding RNAs (lncRNAs), a class of noncoding RNAs longer than 200 nucleotides, play crucial roles in regulating various cellular and molecular processes, including translation, chromatin remodeling, and transcriptional efficiency. Research has highlighted the significant impact of lncRNA imbalances on the development and progression of kidney diseases, including IgAN. These molecules influence several key signaling pathways, such as PI3K/AKT/mTOR, PTEN, Notch, JNK, and immune-related pathways, with their dysregulation contributing to IgAN pathogenesis. This review aims to provide a comprehensive analysis of the molecular signaling pathways involving lncRNAs in IgAN, underscoring their potential as biomarkers for screening, diagnosis, and prevention. Furthermore, it explores the therapeutic potential of lncRNAs as precise targets for personalized treatment strategies.

It is well known that infliximab is an anti-tumor necrosis factor chimeric factor that is effective in treating inflammatory bowel diseases, such as Crohn's disease. Recently, there have been reports of new onset or flare-ups of immunoglobulin A (IgA) nephropathy during infliximab therapy for Crohn's disease. Inflammatory bowel disease-associated IgA nephropathy has been associated with IgA2; However, its activation by infliximab is still unknown.

We report our experience with two patients who experienced acute exacerbations of pre-existing abnormal urinalysis and renal dysfunction 1-18 years following infliximab treatment for Crohn's disease. Renal biopsies at the time of renal disease flare-up revealed IgA nephropathy in one patient and mesangial proliferative nephropathy in the other. Immunostaining results showed no clear predominance of intraglomerular expression of IgA2, and the patient diagnosed with IgA nephropathy entered remission with high dose methylprednisolone pulse therapy and oral corticosteroids, without the need for tonsillectomy. In contrast, the patient with mesangial proliferative nephritis had many devastated glomeruli, thus corticosteroids were not administrated, and the patient was followed up.

The clinical course of our patients, along with similar cases reported in the literature, indicates that infliximab therapy for Crohn's disease is linked to a relatively high risk of new-onset IgA nephropathy or disease relapse. This report is notable because it is the first to compare the expression of IgA1 and IgA2 in glomeruli in nephritis associated with infliximab therapy.

Fatty acid metabolism plays a critical role in regulating immune cell function, including B cells, which are central to humoral immunity and the pathogenesis of autoimmune diseases. Emerging evidence suggests that fatty acid metabolism influences B cell development, activation, differentiation, and antibody production, thereby impacting B cell-related autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). In this review, we discuss the mechanisms by which fatty acid metabolism modulates B cell biology, including energy provision, membrane composition, and signaling pathways. We highlight how alterations in fatty acid synthesis, oxidation, and uptake affect B cell function and contribute to autoimmune pathogenesis. Additionally, we explore the therapeutic potential of targeting fatty acid metabolism in B cells to treat autoimmune diseases. Understanding the interplay between fatty acid metabolism and B cell immunity may provide novel insights into the development of precision therapies for B cell-mediated autoimmune disorders.

The mucosal system serves as the primary barrier against respiratory diseases and plays a crucial role in combating viral infections through mucosal immunity. The resident microbial community constitutes the main component of the mucosal system and exerts a significant inhibitory impact on the invasion of exogenous agents. However, the precise relationship between resident microbiota, mucosal immunity, and viral infections remains incomplete. This review aims to summarize the regulatory interactions between the resident microbiota of the mucosal system and innate immune components such as mucosal immunity and trained immunity. By clarifying these complex relationships, this review seeks to identify potential targets for augmenting respiratory disease prevention strategies and developing novel vaccine formulations. Furthermore, we propose the possibility of integrating the fields of microbiome-based therapeutics and vaccine development to create multifunctional vaccine formulations capable of targeting mucosal immunity induction. Such an approach holds great potential in offering novel pathways and strategies for the prevention and treatment of respiratory diseases.

Peptide immunotherapy (PIT) offers a safe and effective treatment with minimal side effects. This study aims to identify B-cell epitopes of a novel allergen from Blomia tropicalis (B. tropicalis), specifically the Chitin-binding domain type 2 (ChtBD2) protein, and evaluate the therapeutic effects of peptide treatment in a murine model.

Using Alphafold2, the 3D structure of ChtBD2 was constructed. AI-based and traditional computational tools predicted the predominant B-cell epitopes. Twelve synthesized peptides were assessed for allergenicity and immunogenicity. A murine model of B. tropicalis-induced allergic airway inflammation mimicking human atopic asthma was developed and analyzed.

Predominant B-cell epitopes of ChtBD2 were identified as promising IgE-binding domains. Peptide 1 (PT1: 1-15) showed significant IgE-binding activity and the highest inhibition rate in competitive IgE-binding assays. PT1 upregulated IL-4, IL-13, and CD63 in B. tropicalis-sensitized patients' PBMCs and basophils, respectively. Notably, IT groups showed reduced lung cellular infiltration and type 2 cytokine expression in BALF. Specific IgE levels were reduced, with a decline in the IgG1/IgG2a ratio.

This study represents the first AI-facilitated development of a B-cell epitope-based ChtBD2 PIT, showing promise as an immunotherapy for B. tropicalis-allergic patients with reduced allergenicity and high immunogenicity in inducing IgG-blocking antibodies.

Not applicable.

The acetyl group is a significant reactive component of Dendrobium officinale polysaccharide (DOP). In this study, we prepared DOPs with different degrees of acetyl substitution and investigated how the acetyl group, a naturally occurring characteristic of DOP, influences the immunomodulatory activity and the production of secretory IgA (sIgA) in the small intestine. Physical property measurements revealed significant changes in surface morphology and solubility of DOP caused by the addition or removal of acetyl groups. In vivo studies have demonstrated that DOP can mitigate Cyclophosphamide-induced immunosuppression by enhancing the immune organ index, promoting immunoglobulin secretion, and increasing the population of immune cells. Additionally, DOP can enhance sIgA production through multiple pathways, including enhanced IgA+ B cell class switch recombination, gut homing of IgA+ plasma cells, and upregulation of factors involved in sIgA composition and secretion. Correlation analysis revealed strong, piecewise-specific correlations between DOP acetylation and sIgA production at varying intervals of acetyl substitution. Based on this, we propose a theoretical framework in which the acetylation of DOP and the secretion of small intestinal sIgA demonstrate a "piecewise correlation". This framework illustrates the influence of DOP acetylation on immunomodulatory activity and provides a theoretical basis for enhancing the added value of Dendrobium officinale resources.

Alcohol misuse is associated with disruption of the microbial homeostasis (dysbiosis) and microbial overgrowth in the gut, gut barrier disruption, and translocation of microbes into the systemic circulation. It also induces changes in regulatory mechanisms of the gut, which is the largest peripheral immune organ. The gut-liver axis is important for health and disease, and alterations in the intestinal immune system contribute to alcohol-associated liver disease (ALD). Understanding these changes might help discover new targets for drugs and therapeutic approaches.

A systematic literature search was conducted in PubMed, Medline, and Embase of manuscripts published between January 2000 and November 2023 using the terms ("alcohol" or "ethanol") AND ("immune" or "immunol") AND ("intestine," "colon," or "gut"). Eligible manuscripts included studies and reviews that discussed the effects of ethanol on immune cells in the intestine.

A total of 506 publications were found in the databases on November 20, 2023. After excluding duplicates and research not covering ALD (415 articles), 91 studies were reviewed. Also included were manuscripts covering specific immune cells in the context of ALD.

Balancing immune tolerance vs. initiating an immune response challenges the intestinal immune system. Alcohol induces disruption of the intestinal barrier, which is accompanied by a thicker mucus layer and reduced anti-microbial peptides. This leads to longer attachment of bacteria to epithelial cells and consequently greater translocation into the circulation. Bacterial translocation activates the immune system, reducing the activity of regulatory T cells and inducing T helper 17 response via a variety of pathways. The role of innate immune cells, especially Type 3 innate lymphoid cells, and of specific B- and T-cell subsets in ALD remains elusive. Gut dysbiosis, translocation of viable bacteria and bacterial products into the circulation, and changes in the intestinal barrier have been linked to immune deficiency and infections in patients with cirrhosis. Modifying the intestinal immune system could reduce intestinal inflammation and alcohol-induced liver injury. Understanding the underlying pathophysiology can help to detect new targets for drugs and design therapeutic strategies.

Obesity exacerbates susceptibility to infectious diseases. We investigated the effects of a high-fat diet (HFD) on intestinal immunity, particularly immunoglobulin (Ig)A-producing cells, B-cell activating factor (BAFF), and a proliferation-inducing ligand (APRIL) localization. Mice (4- to 20-weeks old) were fed HFD or standard chow diet, and their jejunum and ileum were fixed using the in vivo cryotechnique. Immunohistochemistry was performed for IgA, BAFF, and APRIL. In the HFD group, IgA+, IgA+CD22+ (p < 0.001), and IgA+CD138- (p = 0.007) cell counts were diminished in the middle sections of the lamina propria of jejunal villi, and BAFF levels were significantly reduced in jejunal villi. The HFD effects on IgA+ cell distribution seem to be confined to jejunal villi, hinting at localized vulnerabilities in intestinal immunity during obesity. Moreover, in the HFD group, IgA+ B-cell counts were reduced in the middle jejunum, indicating inhibition of the IgA+ B-cells through a T-cell-independent pathway.

Immunoglobulin A nephropathy (IgAN) is characterized by the production of galactose-deficient IgA1 (GdIgA1) antibodies. As the source of pathogenic antibodies, B cells are central to IgAN pathogenesis, but the B cell activation pathways as well as the potential B cell source of dysregulated IgA secretion remain unknown.

We carried out flow cytometry analysis of peripheral blood B cells in patients with IgAN and control subjects with a focus on IgA-expressing B cells to uncover the pathways of B cell activation in IgAN and how these could give rise to pathogenic GdIgA1 antibodies.

In addition to global changes in the B cell landscape-expansion of naïve and reduction in memory B cells-IgAN patients present with an increased frequency of IgA-expressing B cells that lack the classical memory marker CD27, but are CD21+. IgAN patients furthermore have an expanded population of IgA+ antibody-secreting cells, which correlate with serum IgA levels. Both IgA+ plasmabalsts and CD27- B cells co-express GdIgA1. Implicating dysregulation at mucosal surfaces as the driver of such B cell differentiation, we found a correlation between lipopolysaccharide in the serum and IgA+CD27- B cell frequency.

We propose that dysregulated immunity in the mucosa may drive de novo B cell activation within germinal centres, giving rise to IgA+CD27- B cells and subsequently IgA-producing plasmablasts. These data integrate B cells into the paradigm of IgAN pathogenesis and allow further investigation of this pathway to uncover biomarkers and develop therapeutic interventions.

Adaptive immunity is critical in eliminating tumors, but cancer-intrinsic factors can subvert this function. Melanoma antigen-A4 (MAGE-A4), a cancer-testis antigen, is expressed in solid tumors and correlates with poor survival, but its role in tumorigenesis and antitumor immunity remains unclear. We found that expression of MAGE-A4 was highly associated with the loss of PTEN, a tumor suppressor, in human non-small cell lung cancers (NSCLC). Here, we show that constitutive expression of human MAGE-A4 with Pten loss in mouse airway epithelia results in metastatic adenocarcinoma. Tumors showed distinct enrichment in IgA+ CD138+ CXCR4+ plasma cells (PCs) and increased expression of CXCL12 in endothelial cells. Consistently, human NSCLC expressing MAGE-A4 showed increased CD138+ IgA+ PCs surrounding tumors. Abrogation of PCs decreased tumor burden, increased activated T cell infiltration, and reduced CD163+CD206+ macrophages in the MAGE-A4-induced lung tumors. These findings suggest MAGE-A4 promotes NSCLC tumorigenesis, in part, through the recruitment and retention of IgA+ PCs in the lungs.

The LIM-domain-only protein LMO2 interacts with LDB1 in context-dependent multiprotein complexes and plays key roles in erythropoiesis and T cell leukemogenesis, but whether they have any roles in B cells is unclear. Through a CRISPR/Cas9-based loss-of-function screening, we identified LMO2 and LDB1 as factors for class switch recombination (CSR) in murine B cells. LMO2 contributes to CSR at least in part by promoting end joining of DNA double-strand breaks (DSBs) and inhibiting end resection. Although LDB1 stabilizes LMO2 proteins, it is not required for end joining but functions as a positive regulator of AID transcription independent of LMO2, and this function of LDB1 requires its dimerization domain. Moreover, LDB1 directly binds to and promotes the looping of the AID promoter to upstream enhancers through dimerization. Our study revealed the mechanistically separated roles of LMO2 and LDB1 in different steps of CSR for antibody diversification.

Rheumatoid arthritis (RA) is a complex autoimmune disease characterized by chronic inflammation of the synovial tissue, where T cells play a central role in pathogenesis. Recent research has identified T peripheral helper (Tph) cells as critical mediators of local B cell activation in inflamed tissues. This review synthesizes the latest advancements in our understanding the of the role of T cells in RA, from initiation to established disease.

We explore recent advances regarding the genetic and epigenetic factors that predispose individuals to RA, the mechanisms of T cell activation and differentiation, and the interactions between T cells and other immune and stromal cells within the synovial microenvironment. The emergence of Tph cells as key drivers of RA pathobiology is highlighted, along with their potential as therapeutic targets. We also discuss the heterogeneity of T cell responses and their interplay with synovial cells, while addressing critical research gaps such as the drivers of T cell recruitment and the plasticity of synovial phenotypes. A deeper understanding of T cell dynamics in RA will provide valuable insights for developing targeted therapies to modulate T cell-mediated inflammation and improve patient outcomes.

The persistent emergence of COVID-19 variants and recurrent waves of infection worldwide underscores the urgent need for vaccines that effectively reduce viral transmission and prevent infections. Current intramuscular (IM) COVID-19 vaccines inadequately protect the upper respiratory mucosa. In response, we have developed a nonadjuvanted, IFN-armed SARS-CoV-2 fusion protein vaccine with IM priming and intranasal (IN) boost sequential immunization. Our study showed that this sequential vaccination strategy of the IM+IN significantly enhanced both upper respiratory and systemic antiviral immunity in a mouse model, characterized by the rapid increase in systemic and mucosal T and B cell responses, particularly the mucosal IgA antibody response. The IN boost triggered a swift secondary immune response, rapidly inducing antigen-specific IgA+ B cells. Further B cell receptor-seq (BCR-seq) analysis indicated that these IgA+ B cells primarily arose through direct class switching from preexisting IgG+ B cells in draining lymph nodes. Notably, our clinical studies revealed that the IN boost after IM vaccination elicited a robust systemic IgA antibody response in humans, as measured in serum. Thus, we believe that our cytokine-armed protein vaccine presents a promising strategy for inducing rapid and potent mucosal protection against respiratory viral infections.

Epithelial cells (ECs) provide the first line of defense against microbial threats and environmental challenges. They participate in the host's immune responses via the expression and secretion of various immune-related molecules such as cytokines and chemokines, as well as interaction with immune cells. A growing body of evidence suggests that the dysregulated function of ECs can be involved in the pathophysiology of a broad range of infectious, autoimmune, and inflammatory diseases, including inflammatory bowel disease (IBD), asthma, multiple sclerosis, and rheumatoid arthritis. To maintain a substantial immunoregulatory function of ECs, precise expression of different molecules and their regulatory effects are indispensable. MicroRNAs (miRNAs, miRs) are small non-coding RNAs that regulate gene expression commonly at post-transcriptional level through degradation of target messenger RNAs (mRNAs) or suppression of protein translation. MiRNAs implicate as critical regulators in many cellular processes, including apoptosis, growth, differentiation, and immune response. Due to the crucial roles of miRNAs in such a vast range of biological processes, they have become the spotlight of biological research for more than two decades, but we are still at the beginning stages of the use of miRNA-based therapies in the improvement of human health. Hence, in the present paper, attempts are made to provide a comprehensive overview with regard to the roles of miRNAs in the immunoregulatory functions of ECs. A better understanding of the molecular mechanisms through which immunoregulatory properties of ECs are manifested, could aid the development of efficient strategies to prevent and treat multiple human diseases.

Since May 2022, the global spread of monkeypox virus (MPXV) has presented a significant threat to public health. Despite this, there are limited preventive measures available. In this study, different computational tools were employed to design a multi-epitope vaccine targeting MPXV. Three key MPXV proteins, M1R, B6R, and F3L, were chosen for epitope selection, guided by bioinformatic analyses to identify immunodominant epitopes for T- and B-cell activation. To enhance immune stimulation and facilitate targeted delivery of the vaccine to specific cells, the selected epitopes were linked to novel carriers, including the extracellular domain of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a 12-mer Clec9a binding peptide (CBP-12), and a Toll-like receptor 2 (TLR2) peptide ligand. The designed vaccine construct exhibited strong antigenicity along with nonallergenic and nontoxic properties, with favorable physicochemical characteristics. The validated vaccine's tertiary structure underwent evaluation for interactions with CD80/86, Clec9a, and TLR2 through molecular docking and molecular dynamics simulation. The results ensured the vaccine's stability and high affinity for the aforementioned receptors. In silico immune simulations studies revealed robust innate and adaptive immune responses, including enhanced mucosal immunity essential for protection against MPXV. Ultimately, the DNA sequence of the vaccine construct was synthesized and successfully cloned into the pET-22b(+) vector. Our study, through integration of computational predictions, suggests the proposed vaccine's potential efficacy in safeguarding against MPXV; however, further in vitro and in vivo validations are imperative to assess real-world effectiveness and safety.

Immunoglobulin (Ig) A supports mucosal immune homeostasis and host-microbiota interactions. While commensal bacteria are known for their ability to promote IgA, the role of non-bacterial commensal microbes in the induction of IgA remains elusive. Here, we demonstrate that permanent colonization with the protozoan commensal Tritrichomonas musculis (T.mu) promotes T cell-dependent, IgA class-switch recombination, and intestinal accumulation of IgA-secreting plasma cells (PC). T.mu colonization specifically drives the expansion of T follicular helper cells and a unique ICOS+ non-Tfh cell population, accompanied by an increase in germinal center B cells. Blockade of ICOS:ICOSL co-stimulation or MHCII-expression on B cells is central for the induction of IgA following colonization by T.mu, implicating a previously underappreciated mode of IgA induction following protozoan commensal colonization. Finally, T.mu further improves the induction of IgA-secreting PC specific to orally ingested antigens and their peripheral dissemination, identifying T.mu as a "natural adjuvant" for IgA. Collectively, these findings propose a protozoa-driven mode of IgA induction to support intestinal immune homeostasis.

The human gut includes plasma cells (PCs) expressing immunoglobulin A1 (IgA1) or IgA2, two structurally distinct IgA subclasses with elusive regulation, function, and reactivity. We show here that intestinal IgA1+ and IgA2+ PCs co-emerged early in life, comparably accumulated somatic mutations, and were enriched within short-lived CD19+ and long-lived CD19- PC subsets, respectively. IgA2+ PCs were extensively clonally related to IgA1+ PCs and a subset of them presumably emerged from IgA1+ precursors. Of note, secretory IgA1 (SIgA1) and SIgA2 dually coated a large fraction of mucus-embedded bacteria, including Akkermansia muciniphila. Disruption of homeostasis by inflammatory bowel disease (IBD) was associated with an increase in actively proliferating IgA1+ plasmablasts, a depletion in long-lived IgA2+ PCs, and increased SIgA1+SIgA2+ gut microbiota. Such increase featured enhanced IgA1 reactivity to pathobionts, including Escherichia coli, combined with depletion of beneficial A. muciniphila. Thus, gut IgA1 and IgA2 emerge from clonally related PCs and show unique changes in both frequency and reactivity in IBD.

The Rehmannia glutinosa polysaccharides (RGP) have various benefits such as enhancing immune cell activity, decreasing oxidative stress and delaying or inhibiting tumor occurrence. Although much research has been directed at understanding the role of RGP, its influence on gut immunity is largely understudied. Here, we aimed to dissect the immune-regulating effects of RGP in the mice intestines. In vivo experiments involving the oral administration of RGP to mice at dosages of 100, 200, and 400 mg/kg over seven consecutive days revealed that RGP therapy significantly increased the percentages of CD3+ T lymphocytes and CD19+ B lymphocytes in intestines and improved the integrity of the mucosal barrier. Moreover, RGP modified the gut microbiota composition by enhancing the abundance of beneficial bacteria like Lactobacillus and Akkermansia. Fecal microbiota transplantation (FMT) experiments further revealed that RGP modulated the host's intestinal immunological function by altering the gut microbiota composition. These findings indicate that RGP may control the immunological function of the intestines.

Human milk oligosaccharides could prevent pathogenic bacterial infections in neonates; however, direct in vivo anti-infection evidence was still lacking. Here, we systematically evaluated the effects of 2'-fucosyllactose (2'-FL) and 3'-sialyllactose (3'-SL) on the structural development and functional maturation in neonates and their defense against enteroaggregative Escherichia coli infection. It was found that supplementation with 2'-FL and 3'-SL improved the resistance of weaned mice to enteroaggregative E. coli. The mechanism related to the promotion of 2'-FL and 3'-SL in the maturation of intestinal mucosal immunity by promoting stem cell differentiation, mucus layer integrity, and tight junction formation. 2'-FL and 3'-SL significantly increased the ratio of Th1 and Treg cells in the lamina propria, contents of short-chain fatty acids, as well as the serum content of IgA. This study lays a theoretical basis for the application of 2'-FL and 3'-SL in infant formula, as well as the development of intestinal health products.

Immunoglobulin (Ig) G isotypes in the sera of healthy mice and humans react to commensal bacteria. We previously reported that BALB/c mice with normal gut microbiota possessed abundant B cells that produced IgG2b reactive to commensal bacteria in cecal patches (CePs), indicating a potential source of a systemic pool of commensal bacteria-reactive IgG2b. Mice housed under germ-free conditions demonstrate the importance of the gut microbiota in driving cecal IgG2b responses. However, it is unclear whether the constitutive presence of the gut microbiota and specific bacterial taxa are important for IgG2b responses in adult mice. In this study, we showed that elimination of the gut microbiota by mixed antibiotic treatment in adult mice decreased the abundance of IgG2b+ B cells, follicular helper T (Tfh) cells in CePs, and the serum levels of commensal bacteria-reactive IgG2b. Reduced IgG2b responses have also been observed in mice with an altered gut microbiota following treatment with ampicillin or vancomycin. Changes in the diversity and composition of the cecal microbiota, particularly a decrease in Lachnospiraceae, Muribaculaceae, Ruminococcaceae, and Bacteroidaceae abundance at the family level, were observed in these mice. In addition, depletion of CD4+ T cells by the injection of neutralizing antibodies in adult mice reduced IgG2b responses. Our results suggest that specific gut bacteria susceptible to ampicillin and vancomycin play roles in providing an abundance of Tfh cells to help the generation of IgG2b+ B cells in CePs in adult mice, which may contribute to the supply of systemic commensal bacteria-reactive IgG2b.

Nanomaterials (NMs) are increasingly used in medical treatments, electronics, and food additives. However, nanosafety-the possible adverse effects of NMs on human health-is an area of active research. This review provides an overview of the influence of biomolecular coronas on NM transformation following various exposure routes. We discuss potential exposure pathways, including inhalation and ingestion, describing the physiology of exposure routes and emphasising the relevance of coronas in these environments. Additionally, we review other routes to NM exposure, such as synovial fluid, blood (translocation and injection), dermal and ocular exposure, as well as the dose and medium impact on NM interactions. We emphasize the need for an in-depth characterisation of coronas in different biological media, highlighting the need and opportunity to study lung and gastric fluids to understand NM behaviour and potential toxicity. Future research aims to predict better in vivo outcomes and address the complexities of NM interactions with biological systems.

Immunoglobulin A (IgA) is the most abundantly produced antibody in humans. IgA is a unique class of immunoglobulin due to its multiple molecular forms, and a defining difference between the two subclasses: IgA1 has a long hinge-region that is heavily O-glycosylated, whereas the IgA2 hinge-region is shorter but resistant to bacterial proteases prevalent at mucosal sites. IgA is essential for immune homeostasis and education. Mucosal IgA plays a crucial role in maintaining the integrity of the mucosal barrier by immune exclusion of pathobionts while facilitating colonization with certain commensals; a large part of the gut microbiota is coated with IgA. In the circulation, monomeric IgA that has not been engaged by antigen plays a discrete role in dampening inflammatory responses. Protective and harmful roles of IgA have been studied over several decades, but a new understanding of the complex role of this immunoglobulin in health and disease has been provided by recent studies. Here, we discuss the physiological and pathological roles of IgA with a special focus on the gut, kidneys, and autoimmunity. We also discuss new IgA-based therapeutic approaches.

Nasal vaccines are a promising strategy for enhancing mucosal immune responses and preventing diseases at mucosal sites by stimulating the secretion of secretory IgA, which is crucial for early pathogen neutralization. However, designing effective nasal vaccines is challenging due to the complex immunological mechanisms in the nasal mucosa, which must balance protection and tolerance against constant exposure to inhaled pathogens. The nasal route also presents unique formulation and delivery hurdles, such as the mucous layer hindering antigen penetration and immune cell access.

This review focuses on cutting-edge approaches to enhance nasal vaccine delivery, particularly those targeting C-type lectin receptors (CLRs) like the mannose receptor and macrophage galactose-type lectin (MGL) receptor. It elucidates the roles of these receptors in antigen recognition and uptake by antigen-presenting cells (APCs), providing insights into optimizing vaccine delivery.

While a comprehensive examination of targeted glycoconjugate vaccine development is outside the scope of this study, we provide key examples of glycan-based ligands, such as lactobionic acid and mannose, which can selectively target CLRs in the nasal mucosa.

With the rise of new viral infections, this review aims to facilitate the design of innovative vaccines and equip researchers, clinicians, and vaccine developers with the knowledge to enhance immune defenses against respiratory pathogens, ultimately protecting public health.

Allergic incidents of crustacean aquatic products occur frequently, and tropomyosin (TM) is the main allergen. Therefore, it is worthwhile to develop technologies to efficiently reduce the allergenicity of TM. In this study, ultrasound-assisted cold plasma (UCP) treatment was used to regulate shrimp allergy. The remarkable changes in TM structure were substantiated by alteration in secondary structure, reduction in sulfhydryl content, change in surface hydrophobicity, and disparity in surface morphology. The IgE and IgG binding ability of TM significantly decreased by 52.40% and 46.51% due to UCP treatment. In the Balb/c mouse model, mice in the UCP group showed most prominent mitigation of allergic symptoms, proved by lower allergy score, changes in levels of TM-specific antibodies, and restoration of Th1/Th2 cytokine imbalance. Using a proteomics approach, 439 differentially expressed proteins (DEPs) in the TM group (vs phosphate-buffered saline group) and 170 DEPs in the UCP group (vs TM group) were determined. Subsequent analysis demonstrated that Col6a5, Col6a6, and Epx were potential biomarkers of TM allergy. Moreover, Col6a5, Col6a6, Dcn, and Kng1 might be the target proteins of UCP treatment, while PI3K/Akt/mTOR might be the regulated signaling pathway. These findings proved that UCP treatment has great potential in reducing TM allergenicity and provide new insights into the development of hypoallergenic shrimp products.

Maintaining intracellular redox balance is essential for the survival, antibody secretion, and mucosal immune homeostasis of immunoglobulin A (IgA) antibody-secreting cells (ASCs). However, the relationship between mitochondrial metabolic enzymes and the redox balance in ASCs has yet to be comprehensively studied. Our study unveils the pivotal role of mitochondrial enzyme PCK2 in regulating ASCs' redox balance and intestinal homeostasis. We discover that PCK2 loss, whether globally or in B cells, exacerbates dextran sodium sulphate (DSS)-induced colitis due to increased IgA ASC cell death and diminished antibody production. Mechanistically, the absence of PCK2 diverts glutamine into the TCA cycle, leading to heightened TCA flux and excessive mitochondrial reactive oxygen species (mtROS) production. In addition, PCK2 loss reduces glutamine availability for glutathione (GSH) synthesis, resulting in a decrease of total glutathione level. The elevated mtROS and reduced GSH expose ASCs to overwhelming oxidative stress, culminating in cell apoptosis. Crucially, we found that the mitochondria-targeted antioxidant Mitoquinone (Mito-Q) can mitigate the detrimental effects of PCK2 deficiency in IgA ASCs, thereby alleviating colitis in mice. Our findings highlight PCK2 as a key player in IgA ASC survival and provide a potential new target for colitis treatment.

Enzyme-linked immunosorbent assays (ELISAs) have been used to measure anti-human-papillomavirus (HPV) immunoglobulin IgG. The goal of this study was to evaluate the reproducibility of ELISAs measuring different HPV immunoglobulin isotypes, IgG1, 2, 3, and 4, IgA, and IgM, against HPV16.

Seventy-two serum samples collected from participants in the Costa Rica HPV Vaccine Trial (CVT) and immunized with bivalent HPV vaccine (2vHPV) were used for reproducibility assessment. IgG2 and IgG4 levels were too low to be detected. Levels of IgG1, IgG3, IgA, and IgM were measured, and the data were used to calculate intraclass correlation coefficients (ICCs) and coefficients of variation (CVs).

CVs were assessed between technicians (12.8-22.7%) and across days (6.2-30.6%). The overall CVs ranged from 7.7-31.1%. IgM ELISA showed higher CVs (15.8-31.1%) than IgG1, IgG3, and IgA (6.2-22.7%). All ICC values were >98.7%. IgG3 was detected in all samples, while IgG1 and IgA had >86.3% detectability and IgM had 62.1% detectability. Pearson correlational analyses between different antibodies all showed significant correlations (p ≤ 0.001), except when comparing IgGs or IgA to IgM (p = 0.29-0.53).

Our data showed that these ELISAs are reproducible and detect isotype antibodies to HPV16 L1 across a range of concentrations in 2vHPV-vaccinated participants.

Breast milk is a vital source of nutrients, prebiotics, probiotics, and protective factors, including antibodies, immune cells and antimicrobial proteins. Using bacterial lipopolysaccharide arrays, we investigated the reactivity and specificity of breast milk antibodies towards microbial antigens, comparing samples from rural Kenya and urban Switzerland. Results showed considerable variability in antibody reactivity both within and between these locations. Kenyan breast milk demonstrated broad reactivity to bacterial lipopolysaccharides, likely due to increased microbial exposure. Antibodies primarily recognized the O-antigens of lipopolysaccharides and showed strong binding to specific carbohydrate motifs. Notably, antibodies against specific Escherichia coli O-antigens showed cross-reactivity with parasitic pathogens like Leishmania major and Plasmodium falciparum, thus showing that antibodies reacting against lipopolysaccharide O-antigens can recognize a wide range of antigens beyond bacteria. The observed diversity in antigen recognition highlights the significance of breast milk in safeguarding infants from infections, particularly those prevalent in specific geographic regions. The findings also offer insights for potential immunobiotic strategies to augment natural antibody-mediated defense against diverse pathogens.

Immunoglobulin A nephropathy (IgAN) is the most prevalent primary glomerular disease worldwide and it remains a leading cause of kidney failure. Clinical manifestations of IgA are exacerbated by infections, and emerging data suggest that aberrant mucosal immune responses are important contributors to the immunopathogenesis of this disease. However, the exact stimuli, location and mechanism of nephritis-inducing IgA production remains unclear. In this focused review we explore recent developments in our understanding of the contribution of the mucosal immune system and mucosal-derived IgA-producing cells to the development of IgAN.

Mucosal barrier tissues and their mucosal associated lymphoid tissues (MALT) are attractive targets for vaccines and immunotherapies due to their roles in both priming and regulating adaptive immune responses. The upper and lower respiratory mucosae, in particular, possess unique properties: a vast surface area responsible for frontline protection against inhaled pathogens but also simultaneous tight regulation of homeostasis against a continuous backdrop of non-pathogenic antigen exposure. Within the upper and lower respiratory tract, the nasal and bronchial associated lymphoid tissues (NALT and BALT, respectively) are key sites where antigen-specific immune responses are orchestrated against inhaled antigens, serving as critical training grounds for adaptive immunity. Many infectious diseases are transmitted via respiratory mucosal sites, highlighting the need for vaccines that can activate resident frontline immune protection in these tissues to block infection. While traditional parenteral vaccines that are injected tend to elicit weak immunity in mucosal tissues, mucosal vaccines (i.e., that are administered intranasally) are capable of eliciting both systemic and mucosal immunity in tandem by initiating immune responses in the MALT. In contrast, administering antigen to mucosal tissues in the absence of adjuvant or costimulatory signals can instead induce antigen-specific tolerance by exploiting regulatory mechanisms inherent to MALT, holding potential for mucosal immunotherapies to treat autoimmunity. Yet despite being well motivated by mucosal biology, development of both mucosal subunit vaccines and immunotherapies has historically been plagued by poor drug delivery across mucosal barriers, resulting in weak efficacy, short-lived responses, and to-date a lack of clinical translation. Development of engineering strategies that can overcome barriers to mucosal delivery are thus critical for translation of mucosal subunit vaccines and immunotherapies. This review covers engineering strategies to enhance mucosal uptake via active targeting and passive transport mechanisms, with a parallel focus on mechanisms of immune activation and regulation in the respiratory mucosa. By combining engineering strategies for enhanced mucosal delivery with a better understanding of immune mechanisms in the NALT and BALT, we hope to illustrate the potential of these mucosal sites as targets for immunomodulation.

IgA nephropathy is a mesangioproliferative glomerular disease with significant morbidity and mortality. Most patients with IgA nephropathy develop kidney failure in their lifetime, reducing their life expectancy by a decade. Since its first description in 1968, it has been established that kidneys of IgA nephropathy patients are injured as "innocent bystanders" by nephritogenic IgA1-containing immune complexes. Results from clinical, biochemical, immunologic, and genetic studies suggest a multistep pathogenetic mechanism. In genetically predisposed individuals, this process results in formation of circulating immune complexes due to the binding of IgG/IgA autoantibodies to the polymeric IgA1 molecules with incomplete O-glycosylation. This event is followed by the addition of other proteins, such as complement C3, resulting in the formation of nephritogenic immune complexes. These complexes are not effectively removed from the circulation, and some of them pass through the fenestration of glomerular endothelial cells to enter the mesangial space and activate mesangial cells. It is thought that the process is initiated by soluble immune complexes and that their accumulation results in the formation of immunodeposits that further amplify glomerular injury. Here we summarize current understanding of the pathogenesis of IgA nephropathy and discuss experimental model systems that can inform development of new therapeutic strategies and targets.