The albumin-globulin ratio (AGR) is considered an important indicator reflecting an individual's immune function and nutritional status, and it is closely associated with various health conditions. However, despite its widely studied correlations in numerous health fields, the link between AGR and Overactive Bladder (OAB) is still not completely comprehended.

Data were sourced from the National Health and Nutrition Examination Survey (NHANES) database, selecting adult samples spanning from 2007 to 2018. Through comprehensive questionnaires and laboratory tests, we gathered data pertinent to OAB and the AGR. To explore the association between AGR levels and the likelihood of developing OAB, we utilized advanced statistical techniques, such as weighted multivariate logistic regression and restricted cubic spline (RCS) models. Furthermore, we carried out subgroup analyses to assess the uniformity of this association across various demographics.

After adjusting for relevant covariates, we discovered a marked negative correlation between AGR levels and the risk of OAB. As AGR increased, the incidence of OAB showed a declining trend (OR = 0.69; 95% CI 0.56-0.85). Furthermore, significant nonlinear dose-response relationship was observed between AGR levels and the risk of OAB (P < 0.001), and this association remained stable in stratified analyses.

Our results indicate that elevated AGR levels could be linked to a reduced risk of OAB. This observation highlights the potential role of AGR in assessing and preventing the occurrence of OAB.

Dysbiosis of the gut microbiota has been demonstrated in neurodevelopmental disorders but the underlying mechanisms that may explain these associations are poorly understood. Gut secretory immunoglobulin A (SIgA) binds pathogenic microbes, preventing mucosal penetration. Gut microbes also influence SIgA production and its binding characteristics through short-chain fatty acid (SCFA) metabolites, allowing them to regulate the immune response. Serum IgA deficiency has been noted in children with autism spectrum disorders (ASD). In this study, we aimed to determine whether SIgA level in infancy is associated with gut microbiota taxonomy and metabolites, and neurodevelopmental outcomes in preschool children.

For a subsample of 178 children from the Canadian CHILD Cohort Study, gut microbiota of fecal samples collected at 3-4 months and 12 months was profiled using 16S rRNA sequencing. Gut bacterial metabolites levels and SIgA level were measured by nuclear magnetic resonance (NMR) based metabolomics and SIgA enzyme-linked immunosorbent assay at 3-4 months, respectively. Bayley-III Scale of Infant Development was assessed at 12 and 24 months. We evaluated direct relationships in multiple linear regression models and putative causal relationships in statistical mediation models.

Propionate and butyrate levels at 3-4 months were associated with decreased Bayley cognitive score at 24 months (p-values: 0.01 and 0.02, respectively) in adjusted multiple linear regression models, but when we investigated an indirect relationship mediated by decreased SIgA level at 3-4 months, it did not reach statistical significance (p-values: 0.18 and 0.20, respectively). Lactate level at 3-4 months was associated with increased Bayley cognitive score at 24 months in adjusted multiple linear regression models (p-value: 0.01), but the statistical model mediated by increased SIgA level at 3-4 months did not reach statistical significance neither (p-value: 0.20).

Our study contributes to growing evidence that neurodevelopment is influenced by the infant gut microbiota and that it might involve SIgA level, but larger studies are required.

The human immune system is closely linked to microbiota such as a complex symbiotic relationship during the coevolution of vertebrates and microorganisms. The transfer of microorganisms from the mother's microbiota to the newborn begins before birth during gestation and is considered the initial phase of the intestinal microbiota (IM). The gut is an important site where microorganisms can establish colonies. The IM contains polymicrobial communities, which show complex interactions with diet and host immunity. The tendency towards dysbiosis of the intestinal microbiota is influenced by local but also extra-intestinal factors such as inflammatory processes, infections, or a septic state that can aggravate it. Pathogens could trigger an immune response, such as proinflammatory responses. In addition, changes in the host immune system also influence the intestinal community and structure with additional translocation of pathogenic and non-pathogenic bacteria. Finally, local intestinal inflammation has been found to be an important factor in the growth of pathogenic microorganisms, particularly in its role in sepsis. The aim of this article is to be able to detect the current knowledge of the mechanisms that can lead to dysbiosis of the intestinal microbiota and that can cause bacterial translocation with a risk of infection or septic state and vice versa.

IgA antibodies have an important role in clearing mucosal pathogens. In this study, we have examined the contribution of IgA to the immune control of the gastrointestinal bacterial pathogens Helicobacter pylori and Citrobacter rodentium. Both bacteria trigger a strong local IgA response that results in bacterial IgA coating in mice and in gastritis patients. Class switching to IgA depends on Peyer's patches, T-cells, eosinophils, and eosinophil-derived TGF-β in both models. In the case of H. pylori, IgA secretion and bacterial coating also depend on a functional bacterial type IV secretion system, which drives the generation of Th17 cells and the IL-17-dependent expression of the polymeric immunoglobulin receptor PIGR. IgA-/- mice are hypercolonized with C. rodentium in all examined tissues, suffer from more severe weight loss and develop more colitis. In contrast, H. pylori is controlled more efficiently in IgA-/- mice than their WT counterparts. The effects of IgA deficiency of the offspring can be compensated by maternal IgA delivered by WT foster mothers. We attribute the improved immune control observed in IgA-/- mice to IgA-mediated protection from complement killing, as H. pylori colonization is restored to wild type levels in a composite strain lacking both IgA and the central complement component C3. IgA antibodies can thus have protective or detrimental activities depending on the infectious agent.

We developed a 4-parameter clinical assay using Electric Field Induced Release and Measurement (EFIRM) technology to simultaneously assess SARS-CoV-2 RNA (vRNA), nucleocapsid antigen, host binding (BAb) and neutralizing antibody (NAb) levels from a drop of saliva with performance that equals or surpasses current EUA-approved tests. The vRNA and antigen assays achieved lower limit of detection (LOD) of 100 copies/reaction and 3.5 TCID₅₀/mL, respectively. The vRNA assay differentiated between acutely infected (n = 10) and infection-naïve patients (n = 33) with an AUC of 0.9818, sensitivity of 90%, and specificity of 100%. The antigen assay similarly differentiated these patient populations with an AUC of 1.000. The BAb assay detected BAbs with an LOD of 39 pg/mL and distinguished acutely infected (n = 35), vaccinated with prior infection (n = 13), and vaccinated infection-naïve patients (n = 13) from pre-pandemic (n = 81) with AUC of 0.9481, 1.000, and 0.9962, respectively. The NAb assay detected NAbs with a LOD of 31.6 Unit/mL and differentiated between COVID-19 recovered or vaccinated patients (n = 31) and pre-pandemic controls (n = 60) with an AUC 0.923, sensitivity of 87.10%, and specificity of 86.67%. Our combo assay represents a significant technological advancement to simultaneously address SARS-CoV-2 infection and immunity, and it lays the foundation for tackling potential future pandemics.

Oral candidiasis (OC), a prevalent opportunistic infection of the oral mucosa, presents a considerable health challenge, particularly in individuals with compromised immune responses, advanced age, and local predisposing conditions. A considerable part of the population carries Candida in the oral cavity, but only few develop OC. Therefore, the pathogenesis of OC may depend on factors other than the attributes of the fungus, such as host factors and other predisposing factors. Mucosal trauma and inflammation compromise epithelial integrity, fostering a conducive environment for fungal invasion. Molecular insights into the immunocompromised state reveal dysregulation in innate and adaptive immunity, creating a permissive environment for Candida proliferation. Detailed examination of Candida species (spp.) and their virulence factors uncovers a nuanced understanding beyond traditional C. albicans focus, which embrace diverse Candida spp. and their strategies, influencing adhesion, invasion, immune evasion, and biofilm formation. Understanding the pathophysiological microenvironments in OC is crucial for the development of targeted therapeutic interventions. This review aims to unravel the diverse pathophysiological microenvironments influencing OC development focusing on microbial, host, and predisposing factors, and considers Candida resistance to antifungal therapy. The comprehensive approach offers a refined perspective on OC, seeking briefly to identify potential therapeutic targets for future effective management.

SARS-CoV-2 infection induces a humoral immune response, producing virus-specific antibodies such as IgM, IgG, and IgA. IgA antibodies are present at mucosal sites, protecting against respiratory and other mucosal infections, including SARS-CoV-2, by neutralizing viruses or impeding attachment to epithelial cells. Since SARS-CoV-2 spreads through the nasopharynx, the specific IgAs of SARS-CoV-2 are produced quickly after infection, effectively contributing to virus neutralization. Dimeric IgA has been reported to be 10 to 15 times more potent than its equivalent IgG, suggesting that this isotype may be particularly interesting in developing new monoclonal antibodies and/or new vaccines efficiently neutralizing the virus at the mucosal sites. It is still unclear whether IgA antibodies in BAL might play a role in the disease course and if their presence may have a prognostic significance. However, a harmful effect on diseases with high IgA titers has been reported. This study evaluated mucosal-specific IgA and IgG profiles in BAL of patients with COVID-19 acute respiratory failure admitted to the ICU. We included 57 patients (41 males and 16 females), admitted to the ICU of the University of Foggia. We used a commercially available ELISA assay to evaluate the presence of SARS-CoV-2 IgG and IgA antibodies in plasma and BAL of the 57 hospitalized patients with severe COVID-19 respiratory failure. However, 40/57 BAL and plasma from infected patients were available for the ELISA test; the remaining specimens were unsuitable. IgG and IgA antibodies against SARS-CoV-2 were detectable in 37 (92.5%) and 40 (100%) plasma specimens, respectively. IgG antibodies were found in a single sample, while IgAs were detected in 19 of 40 BAL samples analyzed. Correlations between these parameters and patient outcomes reveal a signature associated with survival. Interestingly, a statistically significant inverse correlation was found between the mortality rate and the presence of IgA to SARS-CoV-2 in BAL specimens. None of the 19 patients with a positive IgA died, compared to 7 out of 12 patients with a negative IgA-BAL (p: <0.0004). Despite being limited in size, this study suggests a significant protective effect of mucosal immunity in COVID-19 patients, even in advanced disease stages, and a role of IgA in the defense against the virus, as well as the possible use of effective vaccines and therapeutic strategies based on IgA antibodies.

Background: Natural products are gaining attention for their potential benefits in gastrointestinal health. Plant-derived polysaccharides are essential for boosting intestinal immunity and maintaining gut homeostasis. This study investigated the effects of Korean red ginseng polysaccharides (KRG-P) on intestinal homeostasis including IgA and SCFA production and mucosal barrier integrity. Methods: Mice were orally administered KRG-P at doses of 50 mg/kg or 200 mg/kg for 10 days. Fecal IgA levels were measured on days 3, 5, and 11 and IgA from cultured Peyer's patch cells from KRG-P-treated mice were analyzed. Additionally, mRNA and protein expression levels of α-defensin, lysozyme, and E-cadherin in the small intestine were examined. Short-chain fatty acids (SCFAs) content in the cecum was also assessed. Results: KRG-P-treated groups showed a significant increase in fecal IgA levels on days 5 and 11, with no notable change on day 3. Cultured Peyer's patch cells from mice demonstrated heightened IgA production. Additionally, KRG-P administration upregulated α-defensin and lysozyme mRNA expression, along with elevated protein expression of E-cadherin, α-defensin, and lysozyme, in the small intestine. KRG-P treatment also led to increased cecal SCFA levels, including acetate, butyrate, and propionate. Conclusions: KRG-P may promote intestinal homeostasis and host defense mechanisms by activating immune cells in Peyer's patches, stimulating IgA production, enhancing antimicrobial peptide expression, and modulating gut microbiota metabolism through increased SCFA production.

Some strains of lactic acid bacteria can regulate the host's intestinal immune system. Bacterial cells and membrane vesicles (MVs) of Limosilactobacillus antri JCM 15950T promote immunoglobulin A (IgA) production in murine Peyer's patch cells via toll-like receptor (TLR) 2. This study aimed to investigate the role of lipoteichoic acid (LTA), a ligand of TLR2, in the immunostimulatory activity of these bacterial cells and their MVs. LTA extracted from bacterial cells was purified through hydrophobic interaction chromatography and then divided into fractions LTA1 and LTA2 through anion-exchange chromatography. LTA1 induced greater interleukin (IL)-6 production from macrophage-like RAW264 cells than LTA2, and the induced IL-6 production was suppressed by TLR2 neutralization using an anti-TLR2 antibody. The LTAs in both fractions contained two hexose residues in the glycolipid anchor; however, LTA1 was particularly rich in triacyl LTA. The free hydroxy groups in the glycerol phosphate (GroP) repeating units were substituted by d-alanine (d-Ala) and α-glucose in LTA1, but only by α-glucose in LTA2. The dealanylation of LTA1 slightly suppressed IL-6 production in RAW264 cells, whereas deacylation almost completely suppressed IL-6 production. Furthermore, IL-6 production induced by dealanylated LTA1 was markedly higher than that induced by dealanylated LTA2. These results indicated that the critical moieties for the immunostimulatory activity of L. antri-derived LTA were the three fatty acid residues rather than the substitution with d-Ala in GroP. LTA was also detected in MVs, suggesting that the triacyl LTA, but not the diacyl LTA, translocated to the MVs and conferred immunostimulatory activity.

Some lactic acid bacteria activate the host intestinal immune system via toll-like receptor (TLR) 2. Lipoteichoic acid (LTA) is a TLR2 ligand; however, the moieties of LTA that determine its immunostimulatory activity remain unclear because of the wide diversity of LTA partial structures. We found that Limosilactobacillus antri JCM 15950T has three types of LTAs (triacyl, diacyl, and monoacyl LTAs). Specifically, structural analysis of the LTAs revealed that triacyl LTA plays a crucial role in immunostimulation and that the fatty acid residues are essential for the activity. The three acyl residues are characteristic of LTAs from many lactic acid bacteria, and our findings can explain the immunostimulatory mechanisms widely exhibited by lactic acid bacteria. Furthermore, the immunostimulatory activity of membrane vesicles released by L. antri JCM 15950T is due to the transferred LTA, demonstrating a novel mechanism of membrane vesicle-mediated immunostimulation.

Head and neck cancers (HNCs) are the seventh most common cancer worldwide, accounting for 4-5% of all malignancies. Salivary metabolites, which serve as key metabolic intermediates and cell-signalling molecules, are emerging as potential diagnostic biomarkers for HNC. While current research has largely concentrated on these metabolites as biomarkers, a critical gap remains in understanding their fluctuations before and after treatment, as well as their involvement in oral side effects. Recent studies emphasise the role of the oral microbiome and its metabolic activity in cancer progression and treatment efficacy by bacterial metabolites and virulence factors. Oral bacteria, such as P. gingivalis and F. nucleatum, contribute to a pro-inflammatory environment that promotes tumour growth. Additionally, F. nucleatum enhances its virulence through flagellar assembly and iron transport mechanisms, facilitating tumour invasion and survival. Moreover, alterations in the oral microbiome can influence chemotherapy efficacy and toxicity through the microbiota-host irinotecan axis, highlighting the complex interplay between microbial communities and therapeutic outcomes. Salivary metabolite profiles are influenced by factors such as gender, methods, and patient habits like smoking-a major risk factor for HNC. Radiotherapy (RT), a key treatment for HNC, often causes side effects such as xerostomia, oral mucositis, and swallowing difficulties which impact survivors' quality of life. Intensity-modulated radiotherapy (IMRT) aims to improve treatment outcomes and minimise side effects but can still lead to significant salivary gland dysfunction and associated complications. This review underscores the microbial and host interactions affecting salivary metabolites and their implications for cancer treatment and patient outcomes.

Multiple vaccine platforms have been employed to develop the nasal SARS-CoV-2 vaccines in preclinical studies, and the dominating pipelines are viral vectored as protein-based vaccines. Among them, several viral vectored-based vaccines have entered clinical development. Nevertheless, some unsatisfactory results were reported in these clinical studies. In the face of such urgent situations, it is imperative to rapidly develop the next-generation intranasal COVID-19 vaccine utilizing other technologies. Nanobased intranasal vaccines have emerged as an approach against respiratory infectious diseases. Harnessing the power of nanotechnology, these vaccines offer a noninvasive yet potent defense against pathogens, including the threat of COVID-19. The improvements made in vaccine mucosal delivery technologies based on nanoparticles, such as lipid nanoparticles, polymeric nanoparticles, inorganic nanoparticles etc., not only provide stability and controlled release but also enhance mucosal adhesion, effectively overcoming the limitations of conventional vaccines. Hence, in this review, we overview the evaluation of intranasal vaccine and highlight the current barriers. Next, the modern delivery systems based on nanoplatforms are summarized. The challenges in clinical application of nanoplatform based intranasal vaccine are finally discussed.

Despite the efficacy of immunotherapy in non-small cell lung cancer (NSCLC), the majority of the patients experience relapse with limited subsequent treatment options. Preclinical studies of various epithelial tumors, such as melanoma and NSCLC, have shown that harnessing the gut microbiome resulted in improvement of therapeutic responses to immunotherapy. Is this review, we summarize the role of microbiome, including lung and gut microbiome in the context of NSCLC, provide overview of the mechanisms of microbiome in efficacy and toxicity of chemotherapies and immunotherapies, and address current ongoing clinical trials for NSCLC including fecal microbiota transplantation (FMT) and live biotherapeutic products (LBPs).

Formation of granulation tissue is a fundamental phase in periodontal wound healing with subsequent maturation leading to regeneration or repair. However, persistently inflamed granulation tissue presents in osseous defects as a result of periodontitis and is routinely disrupted and discarded with non-surgical and surgical therapy to facilitate wound healing or improve chances of regeneration. Histological assessment suggests that granulation tissue from periodontitis-affected sites is effectively a chronic inflammatory tissue resulting from impaired wound healing due to persistence of bacterial dysbiotic bioflim. Nevertheless, the immunomodulatory potential and stem cell characteristics in granulation tissue have also raised speculation about the tissue's regenerative potential. This has led to the conception and recent implementation of surgical techniques which preserve granulation tissue with the intention of enhancing innate regenerative potential and improve clinical outcomes. As knowledge of fundamental cellular and molecular functions regulating periodontitis-affected granulation tissue is still scarce, this review aimed to provide a summary of current understanding of granulation tissue in the context of periodontal wound healing. This may provide new insights into clinical practice related to the management of granulation tissue and stimulate further investigation.

Immunity against respiratory pathogens is often short-term, and, consequently, there is an unmet need for the effective prevention of such infections. One such infectious disease is coronavirus disease 19 (COVID-19), which is caused by the novel Beta coronavirus SARS-CoV-2 that emerged around the end of 2019. The World Health Organization declared the illness a pandemic on 11 March 2020, and since then it has killed or sickened millions of people globally. The development of COVID-19 systemic vaccines, which impressively led to a significant reduction in disease severity, hospitalization, and mortality, contained the pandemic's expansion. However, these vaccines have not been able to stop the virus from spreading because of the restricted development of mucosal immunity. As a result, breakthrough infections have frequently occurred, and new strains of the virus have been emerging. Furthermore, SARS-CoV-2 will likely continue to circulate and, like the influenza virus, co-exist with humans. The upper respiratory tract and nasal cavity are the primary sites of SARS-CoV-2 infection and, thus, a mucosal/nasal vaccination to induce a mucosal response and stop the virus' transmission is warranted. In this review, we present the status of the systemic vaccines, both the approved mucosal vaccines and those under evaluation in clinical trials. Furthermore, we present our approach of a B-cell peptide-based vaccination applied by a prime-boost schedule to elicit both systemic and mucosal immunity.

The early microbial colonization of human mucosal surfaces is essential for the development of the host immune system. Already during pregnancy, the unborn child is prepared for the postnatal influx of commensals and pathogens via maternal antibodies, and after birth this protection is continued with antibodies in breast milk. During this critical window of time, which extends from pregnancy to the first year of life, each encounter with a microorganism can influence children's immune response and can have a lifelong impact on their life. For example, there are numerous links between the development of allergies and an altered gut microbiome. However, the exact mechanisms behind microbial influences, also extending to how viruses influence host-microbe interactions, are incompletely understood. In this review, we address the impact of infants' first microbial encounters, how the immune system develops to interact with gut microbiota, and summarize how an altered immune response could be implied in allergies.

Secretory (S) IgA is the predominant mucosal Ab that protects host epithelial barriers and promotes microbial homeostasis. SIgA production occurs when plasma cells assemble two copies of monomeric IgA and one joining chain (JC) to form dimeric (d) IgA, which is bound by the polymeric Ig receptor (pIgR) on the basolateral surface of epithelial cells and transcytosed to the apical surface. There, pIgR is proteolytically cleaved, releasing SIgA, a complex of the dIgA and the pIgR ectodomain, called the secretory component (SC). The pIgR's five Ig-like domains (D1-D5) undergo a conformational change upon binding dIgA, ultimately contacting four IgA H chains and the JC in SIgA. In this study, we report structure-based mutational analysis combined with surface plasmon resonance binding assays that identify key residues in mouse SC D1 and D3 that mediate SC binding to dIgA. Residues in D1 CDR3 are likely to initiate binding, whereas residues that stabilize the D1-D3 interface are likely to promote the conformational change and stabilize the final SIgA structure. Additionally, we find that the JC's three C-terminal residues play a limited role in dIgA assembly but a significant role in pIgR/SC binding to dIgA. Together, these results inform models for the intricate mechanisms underlying IgA transport across epithelia and functions in the mucosa.

The SARS-COV-2 virus is a deadly agent of inflammatory respiratory disease. Since 2020, studies have focused on developing new therapies based on galactose-rich IgA antibodies. Clinical surveys have also revealed that galactose-deficient IgA1 polymerizes in serum, producing IgA nephropathy, which is a common cause of kidney failure in young adults. Here we show that IgA1-IgA2 dimers are efficiently and economically purified in solution via conjugated nonionic surfactant micellar aggregates. Quantitative capture at pH 7 and extraction at pH 6.5 can avoid antibody exposure to acidic, potentially denaturing conditions. Brij-O20 aggregates lead to the highest process yields (88-91%) and purity (94%). Recovered IgA dimers preserve their native secondary structure and do not self-associate. Increasing the reaction volume has little impact on yield or purity. By introducing an efficient, inexpensive IgA purification protocol, we assist pharmaceutical firms and research laboratories in developing new IgA-based therapies as well as in increasing our understanding of IgA1 polymerization.

Colorectal cancer (CRC) ranks among the top causes of mortality globally. Gut inflammation is one crucial risk factor that augments CRC development since patients suffering from inflammatory bowel disease have an increased incidence of CRC. The role of immunoglobulin (Ig)A in maintaining gut homeostasis and preventing inflammation has been well established. Our earlier work demonstrated that the marginal zone and B1 cell-specific protein (MZB1) promotes gut IgA secretion and its absence results in pronounced dextran sulfate sodium salt (DSS)-induced colitis. In the present study, we explored the role of MZB1 in CRC development using the azoxymethane (AOM)/DSS-induced CRC model. We observed an increase in both the number and size of the tumor nodules in Mzb1-/- mice compared with Mzb1+/+ mice. The increase in CRC development and progression in Mzb1-/- mice was associated with reduced intestinal IgA levels, altered gut flora, and more severe gut and systemic inflammation. Oral administration of the monoclonal IgA, W27, alleviated both the gut inflammation and AOM/DSS-induced CRC. Notably, cohousing Mzb1+/+ and Mzb1-/- mice from the 10th day after birth led to similar CRC development. Our findings underscore the pivotal role of MZB1-mediated IgA secretion in suppressing the onset and progression of CRC triggered by gut inflammation. Moreover, our study highlights the profound impact of microbiota composition, modulated by gut IgA levels, on gut inflammation. Nonetheless, establishing a direct correlation between the severity of colitis and subsequent CRC development and the presence or absence of a particular microbiota is challenging.

Secretory (S) Immunoglobulin (Ig) A is the predominant mucosal antibody that protects host epithelial barriers and promotes microbial homeostasis. SIgA production occurs when plasma cells assemble two copies of monomeric IgA and one joining-chain (JC) to form dimeric (d) IgA, which is bound by the polymeric Ig receptor (pIgR) on the basolateral surface of epithelial cells and transcytosed to the apical surface. There, pIgR is proteolytically cleaved, releasing SIgA, a complex of the dIgA and the pIgR ectodomain, called secretory component (SC). The pIgR's five Ig-like domains (D1-D5) undergo a conformational change upon binding dIgA, ultimately contacting four IgA heavy chains and the JC in SIgA. Here we report structure-based mutational analysis combined with surface plasmon resonance binding assays that identify key residues in mouse SC D1 and D3 that mediate SC binding to dIgA. Residues in D1 CDR3 are likely to initiate binding whereas residues that stabilize the D1-D3 interface are likely to promote the conformation change and stabilize the final SIgA structure. Additionally, we find that the JC's three C-terminal residues play a limited role in dIgA assembly but a significant role in pIgR/SC binding to dIgA. Together results inform new models for the intricate mechanisms underlying IgA transport across epithelia and functions in the mucosa.

Several novel vaccine platforms aim at mucosal immunity in the respiratory tract to block SARS-CoV-2 transmission. Standardized methods for mucosal sample collection and quantification of mucosal antibodies are therefore urgently needed for harmonized comparisons and interpretations across mucosal vaccine trials and real-world data.

Using commercial electrochemiluminescence antibody panels, we compared SARS-CoV-2 spike-specific IgA and IgG in paired saliva, nasal secretions, and serum from 1048 healthcare workers with and without prior infection.

Spike-specific IgA correlated well in nasal secretions and saliva (r>0.65, p<0.0001), but the levels were more than three-fold higher in nasal secretions as compared to in saliva (p<0.01). Correlations between the total population of spike-specific IgA and spike-specific secretory IgA (SIgA) were significantly stronger (p<0.0001) in nasal secretions (r=0.96, p<0.0001) as opposed to in saliva (r=0.77, p<0.0001), and spike-specific IgA correlated stronger (p<0.0001) between serum and saliva (r=0.73, p<0.001) as opposed to between serum and nasal secretions (r=0.54, p<0.001), suggesting transudation of monomeric spike specific IgA from the circulation to saliva. Notably, spike-specific SIgA had a markedly higher SARS-CoV-2 variant cross-binding capacity as compared to the total population of spike specific IgA and IgG in both nasal secretions, saliva and serum, (all p<0.0001), which emphasizes the importance of taking potential serum derived monomeric IgA into consideration when investigating mucosal immune responses.

Taken together, although spike-specific IgA can be reliably measured in both nasal secretions and saliva, our findings imply an advantage of higher levels and likely also a larger proportion of SIgA in nasal secretions as compared to in saliva. We further corroborate the superior variant cross-binding capacity of SIgA in mucosal secretions, highlighting the potential protective benefits of a vaccine targeting the upper respiratory tract.

The incidence of prematurity has been increasing since the twenty-first century. Premature neonates are extremely vulnerable and require a rich supply of nutrients, including carbohydrates, proteins, docosahexaenoic acid (DHA), arachidonic acid (ARA) and others. Typical breast milk serves as the primary source for infants under six months old to provide these nutrients. However, depending on the individual needs of preterm infants, a more diverse and intricate range of nutrients may be necessary. This paper provides a comprehensive review of the current research progress on the physical and chemical properties, biological activity, function, and structure of breast milk, as well as explores the relationship between the main components of milk globular membrane and infant growth. Additionally, compare the nutritional composition of milk from different mammals and newborn milk powder, providing a comprehensive understanding of the differences in milk composition and detailed reference for meeting daily nutritional needs during lactation.

Clostridium botulinum Loch Maree expresses an extremely potent botulinum neurotoxin subtype, A3 causing botulism and several gastrointestinal disorders in mammals. Several recombinant vaccines have been developed for human botulism and no vaccine is currently available for the treatment of diseases caused by other virulence factors. Hence, we designed, constructed, and characterized a multi-epitope vaccine from new virulence proteins identified from this organism using an immunoinformatics approach. The vaccine construct used in this study was designed from 6B cell linear epitopes, 12 cytotoxic T cell lymphocyte epitopes, and 15 helper T cell lymphocyte epitopes, with a defensin adjuvant and adjusting linker sequences. A molecular modeling approach was used to model, refine, and validate the 3D structure of the vaccine construct. Molecular docking studies were performed to determine the stability of the molecular interactions between the vaccine construct and human toll-like receptor 7. The in silico molecular cloning was used to clone a codon-optimized synthetic vaccine gene in pCYB1 vector and expressed in Escherichia coli. The results of this study identified six new virulence proteins: peptidoglycan hydrolase, SCP-like extracellular protein, N-acetylmuramoyl-l-alanine amidase, putative membrane protein, drug/metabolite exporter, and bacillolysin. The top B-cell, cytotoxic T-cell lymphocyte, and helper T-lymphocyte epitopes were predicted from these virulence proteins with greater accuracy and reliability. HLA-A*02:01 and HLA-A*03:01 were identified as HLA-A-binding alleles for cytotoxic T-cell lymphocyte epitopes. DRB1*0110 and DRB1*0115 are the dominant alleles that bind to helper T-cell lymphocyte epitopes. The synthetic gene construct was highly expressed in a heterologous host and produced considerable amounts of antigenic protein. The multi-epitope vaccine is more conservative in the sequence-structure-function link, immunogenic with less allergenicity, and possibly provokes cellular and humoral immunity. The present study suggests that the designed multi-epitope vaccine is a promising prophylactic candidate for the virulence and intoxication caused by subtype A3 strains.

The novel coronavirus disease (COVID-19) and its infamous "Variants" of the etiological agent termed Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) has proven to be a global health concern. The three antibodies, IgA, IgM, and IgG, perform their dedicated role as main workhorses of the host adaptive immune system in virus neutralization. Immunoglobulin-A (IgA), also known as "Mucosal Immunoglobulin", has been under keen interest throughout the viral infection cycle. Its importance lies because IgA is predominant mucosal antibody and SARS family viruses primarily infect the mucosal surfaces of human respiratory tract. Therefore, IgA can be considered a diagnostic and prognostic marker and an active infection biomarker for SARS CoV-2 infection. Along with molecular analyses, serological tests, including IgA detection tests, are gaining ground in application as an early detectable marker and as a minimally invasive detection strategy. In the current review, it was emphasized the role of IgA response in diagnosis, host defense strategies, treatment, and prevention of SARS-CoV-2 infection. The data analysis was performed through almost 100 published peer-reviewed research reports and comprehended the importance of IgA in antiviral immunity against SARS-CoV-2 and other related respiratory viruses. Taken together, it is concluded that secretory IgA- Abs can serve as a promising detection tool for respiratory viral diagnosis and treatment parallel to IgG-based therapeutics and diagnostics. Vaccine candidates that target and trigger mucosal immune response may also be employed in future dimensions of research against other respiratory viruses.

A systematic search was carried out through search platforms and specialized databases, such as Academic Google, PubMed, and Scopus, using thesauri: breast feeding, obesity, immunology, and human milk in English and Spanish, and those articles published from January 2000 to December 2021, in both languages. Only those reports that included quantitative data on immunological components in the milk of normal-weight and overweight women were considered. The PRISMA 2020 guides were used, and a total of 306 articles were reviewed, of which a total of 33 were included, according to the basic inclusion criteria. It was observed that in obese mothers, there is an increase in certain immune cells, such as B lymphocytes, cytotoxic T lymphocytes, and NK cells, and cytokines, such as IL-6 and IFN-γ; other alterations included the bacterial population and proteins with antibacterial action. Also, a decrease in growth factors such as TGF-β and IFG-1 was documented in overweight women. Immunoglobulin concentrations did not show substantial changes. This brief review shows that maternal overweight is associated with changes in the biochemical and immunological parameters of milk.

In recent years, dysbiosis, abnormalities in the gut microbiota, has been reported to be associated with the development of many diseases, and improving the gut microbiota is important for health maintenance. It has been shown that the host recognizes and regulates intestinal bacteria by means of IgA antibodies secreted into the gut, but the precise nature of the commensal gut bacteria recognized by each IgA antibody is unclear. We have cloned monoclonal IgA antibodies from mouse intestinal IgA-producing cells and are searching for bacterial molecules recognized by each IgA clone. Although the interaction of IgA antibodies with intestinal bacteria is still largely unknown and requires further basic research, we discuss the potential use of orally ingestible IgA antibodies as agents to improve intestinal microbiota.

Immunoglobulin (Ig) has been widely acknowledged to be produced solely by B-lineage cells. However, growing evidence has demonstrated the expression of Ig in an array of cancer cells, as well as normal cells including epithelial cells, epidermal cells, mesangial cells, monocytes, and neutrophils. Ig has even been found to be expressed in non-B cells at immune-privileged sites such as neurons and spermatogenic cells. Despite these non-B cell-derived Igs (non-B-Igs) sharing the same symmetric structures with conventional Igs (B-Igs), further studies have revealed unique characteristics of non-B-Ig, such as restricted variable region and aberrant glycosylation. Moreover, non-B-Ig exhibits properties of promoting malignant behaviours of cancer cells, therefore it could be utilised in the clinic as a potential therapeutic biomarker or target. The elucidation of the generation and regulation of non-B-Ig will certainly broaden our understanding of immunology.

We developed a 4-parameter clinical assay using Electric Field Induced Release and Measurement (EFIRM) technology to simultaneously assess SARS-CoV-2 RNA (vRNA), nucleocapsid antigen, host binding (BAb) and neutralizing antibody (NAb) levels from a drop of saliva with performance that equals or surpasses current EUA-approved tests. The vRNA and antigen assays achieved lower limit of detection (LOD) of 100 copies/reaction and 3.5 TCID₅₀/mL, respectively. The vRNA assay differentiated between acutely infected (n=10) and infection-naïve patients (n=33) with an AUC of 0.9818, sensitivity of 90%, and specificity of 100%. The antigen assay similarly differentiated these patient populations with an AUC of 1.000. The BAb assay detected BAbs with an LOD of 39 pg/mL and distinguished acutely infected (n=35), vaccinated with prior infection (n=13), and vaccinated infection-naïve patients (n=13) from control (n=81) with AUC of 0.9481, 1.000, and 0.9962, respectively. The NAb assay detected NAbs with an LOD of 31.6 Unit/mL and differentiated between COVID-19 recovered or vaccinated patients (n=31) and pre-pandemic controls (n=60) with an AUC 0.923, sensitivity of 87.10%, and specificity of 86.67%. Our multiparameter assay represents a significant technological advancement to simultaneously address SARS-CoV-2 infection and immunity, and it lays the foundation for tackling potential future pandemics.

Cancer vaccines, a burgeoning strategy in cancer treatment, are exploring innovative administration routes to enhance patient and medical staff experiences, as well as immunological outcomes. Among these, oral administration has surfaced as a particularly noteworthy approach, which is attributed to its capacity to ignite both humoral and cellular immune responses at systemic and mucosal tiers, thereby potentially bolstering vaccine efficacy comprehensively and durably. Notwithstanding this, the deployment of vaccines through the oral route in a clinical context is impeded by multifaceted challenges, predominantly stemming from the intricacy of orchestrating effective oral immunogenicity and necessitating strategic navigation through gastrointestinal barriers. Based on the immunogenicity of the gastrointestinal tract, this review critically analyses the challenges and recent advances and provides insights into the future development of oral cancer vaccines.

The first 1000 days of life is a critical period that contributes significantly to the programming of an individual's future health. Among the many changes that occur during this period early in life, there is growing evidence that the establishment of healthy gut microbiota plays an important role in the prevention of both short- and long-term health problems. Numerous publications suggest that the quality of the gut microbiota colonisation depends on several dietary factors, including breastfeeding. In this respect, a relationship between breastfeeding and the risk of inflammatory bowel disease (IBD) has been suggested. IBDs are chronic intestinal diseases, and perinatal factors may be partly responsible for their onset. We review the existence of links between breastfeeding and IBD based on experimental and clinical studies. Overall, despite encouraging experimental data in rodents, the association between breastfeeding and the development of IBD remains controversial in humans, partly due to the considerable heterogeneity between clinical studies. The duration of exclusive breastfeeding is probably decisive for its lasting effect on IBD. Thus, specific improvements in our knowledge could support dietary interventions targeting the gut microbiome, such as the early use of prebiotics, probiotics or postbiotics, in order to prevent the disease.

The evolution of adaptive immunity in Camelidae resulted in the concurrent expression of classic heterotetrameric and unconventional homodimeric heavy chain-only IgG antibodies. Heavy chain-only IgG bears a single variable domain and lacks the constant heavy (CH) γ1 domain required for pairing with the light chain. It has not been reported whether this distinctive feature of IgG is also observed in the IgA isotype.

Gene-specific primers were used to generate an IgA heavy chain cDNA library derived from RNA extracted from the dromedary's third eyelid where isolated lymphoid follicles and plasma cells abound at inductive and effector sites, respectively.

Majority of the cDNA clones revealed hallmarks of heavy chain-only antibodies, i.e. camelid-specific amino acid substitutions in framework region 1 and 2, broad length distribution of complementarity determining region 3, and the absence of the CHα1 domain. In a few clones, however, the cDNA of the canonical IgA heavy chain was amplified which included the CHα1 domain, analogous to CHγ1 domain in IgG1 subclass. Moreover, we noticed a short, proline-rich hinge, and, at the N-terminal end of the CHα3 domain, a unique, camelid-specific pentapeptide of undetermined function, designated as the inter-α region. Immunoblots using rabbit anti-camel IgA antibodies raised against CHα2 and CHα3 domains as well as the inter-α region revealed the expression of a ~52 kDa and a ~60 kDa IgA species, corresponding to unconventional and canonical IgA heavy chain, respectively, in the third eyelid, trachea, small and large intestine. In contrast, the leporine anti-CHα1 antibody detected canonical, but not unconventional IgA heavy chain, in all the examined tissues, milk, and serum, in addition to another hitherto unexplored species of ~45 kDa in milk and serum. Immunohistology using anti-CHα domain antibodies confirmed the expression of both variants of IgA heavy chains in plasma cells in the third eyelid's lacrimal gland, conjunctiva, tracheal and intestinal mucosa.

We found that in the dromedary, the IgA isotype has expanded the immunoglobulin repertoire by co-expressing unconventional and canonical IgA heavy chains, comparable to the IgG class, thus underscoring the crucial role of heavy chain-only antibodies not only in circulation but also at the mucosal frontiers.

Animal ecology and evolution have long been known to shape host physiology, but more recently, the gut microbiome has been identified as a mediator between animal ecology and evolution and health. The gut microbiome has been shown to differ between wild and domestic animals, but the role of these differences for domestic animal evolution remains unknown. Gut microbiome responses to new animal genotypes and local environmental change during domestication may promote specific host phenotypes that are adaptive (or not) to the domestic environment. Because the gut microbiome supports host immune function, understanding the effects of animal ecology and evolution on the gut microbiome and immune phenotypes is critical. We investigated how domestication affects the gut microbiome and host immune state in multiple pig populations across five domestication contexts representing domestication status and current living conditions: free-ranging wild, captive wild, free-ranging domestic, captive domestic in research or industrial settings. We observed that domestication context explained much of the variation in gut microbiome composition, pathogen abundances and immune markers, yet the main differences in the repertoire of metabolic genes found in the gut microbiome were between the wild and domestic genetic lineages. We also documented population-level effects within domestication contexts, demonstrating that fine scale environmental variation also shaped host and microbe features. Our findings highlight that understanding which gut microbiome and immune traits respond to host genetic lineage and/or scales of local ecology could inform targeted interventions that manipulate the gut microbiome to achieve beneficial health outcomes.

Secretory (S) Immunoglobin (Ig) A is the predominant mucosal antibody, which mediates host interactions with commensal and pathogenic microbes, including Clostridioides difficile. SIgA adopts a polymeric IgA structure that is bound by secretory component (SC). Despite significance, how SIgA supports diverse effector mechanisms is poorly characterized and SIgA-based therapies nonexistent. We engineered chimeric (c) SIgAs, in which we replaced SC domain D2 with a single domain antibody or a monomeric fluorescent protein, allowing us to investigate and enhance SIgA effector mechanisms. cSIgAs exhibited increased neutralization potency against C. difficile toxins, promoted bacterial clumping and cell rupture, and decreased cytotoxicity. cSIgA also allowed us to visualize and/or quantify C. difficile morphological changes and clumping events. Results reveal mechanisms by which SIgA combats C. difficile infection, demonstrate that cSIgA design can modulate these mechanisms, and demonstrate cSIgA's adaptability to modifications that might target a broad range of antigens and effector mechanisms.

We report the case of a 31-year-old male who presented with repeated episodes of nephritic-nephrotic syndrome in concomitance with infection. IgA was diagnosed and was initially responsive to treatment with immunosuppressors but further disease flare did not respond to treatment. Based on three consecutive renal biopsies over 8 years, a pattern switch from endocapillary proliferative IgA nephropathy to membranous proliferative glomerulonephritis with monoclonal IgAκ deposits was observed. Bortezomib-dexamethasone combination therapy finally led to a favorable renal response. This case provides new insights into the pathophysiological mechanisms of proliferative glomerulonephritis with monoclonal immunoglobin deposits (PGNMID), highlighting the importance of repeat renal biopsies and routine evaluation of monoclonal immunoglobin deposits in proliferative glomerulonephritis with refractory nephrotic syndrome.

Respiratory mucosal host defense relies on the production of secretory IgA (sIgA) antibodies, but we currently lack a fundamental understanding of how sIgA is induced by contact with microbes and how such immune responses may vary between humans. Defense of the nasal mucosal barrier through sIgA is critical to protect from infection and to maintain homeostasis of the microbiome, which influences respiratory disorders and hosts opportunistic pathogens.

We applied IgA-seq analysis to nasal microbiota samples from male and female healthy volunteers, to identify which bacterial genera and species are targeted by sIgA on the level of the individual host. Furthermore, we used nasal sIgA from the same individuals in sIgA deposition experiments to validate the IgA-seq outcomes.

We observed that the amount of sIgA secreted into the nasal mucosa by the host varied substantially and was negatively correlated with the bacterial density, suggesting that nasal sIgA limits the overall bacterial capacity to colonize. The interaction between mucosal sIgA antibodies and the nasal microbiota was highly individual with no obvious differences between potentially invasive and non-invasive bacterial species. Importantly, we could show that for the clinically relevant opportunistic pathogen and frequent nasal resident Staphylococcus aureus, sIgA reactivity was in part the result of epitope-independent interaction of sIgA with the antibody-binding protein SpA through binding of sIgA Fab regions. This study thereby offers a first comprehensive insight into the targeting of the nasal microbiota by sIgA antibodies. It thereby helps to better understand the shaping and homeostasis of the nasal microbiome by the host and may guide the development of effective mucosal vaccines against bacterial pathogens. Video Abstract.

Previous work has shown that Secretory-IgA (SIgA) binding to the intestinal microbiota is variable and may regulate host inflammatory bowel responses. Nevertheless, the impact of the SIgA functional binding to the microbiota remains largely unknown in preterm infants whose immature epithelial barriers make them particularly susceptible to inflammation. Here, we investigated SIgA binding to intestinal microbiota isolated from stools of preterm infants <33 weeks gestation with various levels of intestinal permeability. We found that SIgA binding to intestinal microbiota attenuates inflammatory reactions in preterm infants. We also observed a significant correlation between SIgA affinity to the microbiota and the infant's intestinal barrier maturation. Still, SIgA affinity was not associated with developing host defenses, such as the production of mucus and inflammatory calprotectin protein, but it depended on the microbiota shifts as the intestinal barrier matures. In conclusion, we reported an association between the SIgA functional binding to the microbiota and the maturity of the preterm infant's intestinal barrier, indicating that the pattern of SIgA coating is altered as the intestinal barrier matures.

The mucosal barrier constitutes a huge surface area, close to 40 m2 in humans, located mostly in the respiratory, gastrointestinal and urogenital tracts and ocular cavities. It plays a crucial role in tissue interactions with the microbiome, dietary antigens and other environmental materials. Effective vaccinations to achieve highly protective mucosal immunity are evolving strategies to counteract several serious diseases including tuberculosis, diphtheria, influenzae B, severe acute respiratory syndrome, Human Papilloma Virus infection and Acquired Immune Deficiency Syndrome. Interestingly, one of the reasons behind the rapid spread of severe acute respiratory syndrome coronavirus 2 variants has been the weakness of local immunization at the level of the respiratory mucosa. Mucosal vaccines can outperform parenteral vaccination as they specifically elicit protective mucosal immune responses blocking infection and transmission. In this scenario, chitosan-based nanovaccines are promising adjuvants-carrier systems that rely on the ability of chitosan to cross tight junctions and enhance particle uptake due to chitosan-specific mucoadhesive properties. Indeed, chitosan not only improves the adhesion of antigens to the mucosa promoting their absorption but also shows intrinsic immunostimulant abilities. Furthermore, by finely tuning the colloidal properties of chitosan, it can provide sustained antigen release to strongly activate the humoral defense. In the present review, we agnostically discuss the potential reasons why chitosan-based vaccine carriers, that efficiently elicit strong immune responses in experimental setups and in some pre-clinical/clinical studies, are still poorly considered for therapeutic formulations.

Specific IgA antibody has been shown to play an important role in resistance to gastrointestinal nematode (GIN) infections in sheep, particularly in Teladorsagia circumcincta parasitosis. In some breeds, negative associations have been shown between IgA levels and worm burden in experimentally infected sheep. In the present study, we have studied the relationship between IgA levels in naturally infected sheep (582 ewes in total; 193 younger than one year old and 389 older than one year old) and fecal egg count (FEC) in the Assaf, Castellana, and Churra breeds. ELISA assays were performed to measure IgA levels against the somatic antigen of T. circumcincta third larval stage (L₃) and a 203-amino-acid fragment of the protein disulfide isomerase from the same GIN species. A multilevel random intercept model was developed to predict the infection risk according to age or breed. Spearman's correlation rank was used for statistical analysis. The prediction model showed that breed was not an influential factor in this study, although the Assaf breed could be considered slightly more susceptible than the others. In addition, age affected the infection risk, with the young ewes more susceptible to infection than the adult groups, except for the Castellana breed, whose risk of infection was similar at all ages. The most significant positive association was found between FEC and IgA measured in the nasal secretions of young ewes using both antigens (Rho = 0.5; p = 0.00); the correlation of FEC with IgA in serum was moderately significant (Rho = 0.306; p = 0.00). Comparing both antigens, the protein disulfide isomerase antigen was less reactive than the somatic antigen from L₃. In conclusion, under natural conditions, specific IgA against GIN was positively associated with FEC in sheep, with nasal secretions from young animals being the sample where this association is stronger, which, therefore, could be used as a marker of infection in further studies.

Their ability to induce the production of IgA, especially in the intestine, is one of the health benefits of soluble dietary fibers (SDFs), but the mechanism involved is unclear.

This study was designed to identify the relationship between the induction of IgA by SDFs and the cecal short-chain fatty acids (SCFAs) content, and to evaluate the importance of T cell-independent IgA production for SDF-induced IgA production.

We compared the SDFs fructooligosaccharides (FO), indigestible glucan (IG), and polydextrose (PD). Male BALB/cAJcl mice or T cell-deficient BALB/cAJcl-nu/nu (nude) mice were fed diets supplemented with one SDF (3% w/w) for 10 weeks and we measured IgA content in their feces, plasma, lung, and submandibular gland.

In BALB/cAJcl mice, the consumption of all three SDF diets induced fecal IgA production, but the response was stronger in the IG and PD groups than in the FO group. The IgA concentration of the plasma and lung were also higher in the FO and PD groups, and these groups showed significantly higher cecal acetic and n-butyric acid content. In contrast, in nude mice, the induction of IgA production was identified only in fecal samples of mice fed the three SDF diets, even though there were significant increases in cecal SCFAs content.

The induction of IgA production by SDFs is occurred T cell-independently in the intestine, but that in the plasma, lung, and submandibular gland is T cell-dependent. SCFAs generated in the large intestine might influence the systemic immune system, but there is no clear relationship between the generation of SCFAs and intestinal IgA production in response to SDF consumption.

Mucus is a viscoelastic gel that acts as a protective barrier for epithelial surfaces. The mucosal vehicles and adjuvants need to pass through the mucus layer to make drugs and vaccine delivery by mucosal routes possible. The mucoadhesion of polymer particle adjuvants significantly increases the contact time between vaccine formulations and the mucosa; then, the particles can penetrate the mucus layer and epithelium to reach mucosa-associated lymphoid tissues. This review presents the key findings that have aided in understanding mucoadhesion and mucopenetration while exploring the influence of physicochemical characteristics on mucus-polymer interactions. We describe polymer-based particles designed with mucoadhesive or mucopenetrating properties and discuss the impact of mucoadhesive polymers on local and systemic immune responses after mucosal immunization. In future research, more attention paid to the design and development of mucosal adjuvants could lead to more effective vaccines.