Mucosal vaccines can induce mucosal immunity, including antigen-specific secretory IgA production, to protect from invasion by pathogens and to neutralize toxins at mucosal surfaces. We established ...an effective antigen-delivering fusion protein, anti-GP2-SA, as a mucosal vaccine. The anti-GP2-SA consists of streptavidin (SA) fused to the antigen-binding fragment region from a mAb against glycoprotein 2 (GP2), an antigen-uptake receptor specifically expressed on M cells. Anti-GP2-SA targets antigen-sampling M cells in the follicle-associated epithelium covering Peyer's patches. Immunofluorescence showed that anti-GP2-SA specifically bound to M cells. Orally administered biotinylated ovalbumin peptide (bOVA) conjugated with anti-GP2-SA more efficiently induced OVA-specific fecal IgA secretion compared with bOVA alone or bOVA conjugated with SA. Furthermore, mice immunized by oral administration of the biotinylated Salmonella enterica serovar Typhimurium (S. Typhimurium) lysate conjugated with anti-GP2-SA were significantly better protected from subsequent infection by virulent S. Typhimurium than mice treated with the bacterial lysate alone or conjugated with SA. These results suggest that anti-GP2-SA-based M-cell-targeting vaccines are a novel strategy for inducing efficient mucosal immunity.
Innate lymphoid cells (ILCs) are a group of innate immune cells that possess overlapping features with T cells, although they lack antigen-specific receptors. ILCs consist of five subsets-ILC1, ILC2, ...ILC3, lymphoid tissue inducer (LTi-like) cells, and natural killer (NK) cells. They have significant functions in mediating various immune responses, protecting mucosal barrier integrity and maintaining tissue homeostasis in the lung, skin, intestines, and liver. ILCs react immediately to signals from internal and external sources. Emerging evidence has revealed that dietary micronutrients, such as various vitamins and minerals can significantly modulate immune responses through ILCs and subsequently affect human health. It has been demonstrated that micronutrients control the development and proliferation of different types of ILCs. They are also potent immunoregulators in several autoimmune diseases and play vital roles in resolving local inflammation. Here, we summarize the interplay between several essential micronutrients and ILCs to maintain epithelial barrier functions in various mucosal tissues and discuss their limitations and potentials for promoting human health.
Recent research has highlighted the importance of the gut microbiome in regulating aging, and probiotics are interventions that can promote gut health. In this study, we surveyed several novel lactic ...acid bacteria to examine their beneficial effect on organismal health and lifespan in C. elegans. We found that animals fed some lactic acid bacteria, including L. acidophilus 1244 and L. paracasei subsp. paracasei 2004, grew healthy. Supplementation with the lactic acid bacterial strains L. acidophilus 1244 or L. paracasei subsp. paracasei 2004 significantly improved health, including food consumption, motility, and resistance to oxidative stressor, hydrogen peroxide. Our RNA-seq analysis showed that supplementation with L. paracasei subsp. paracasei 2004 significantly increased the expression of daf-16, a C. elegans FoxO homolog, as well as genes related to the stress response. Furthermore, daf-16 deletion inhibited the longevity effect of L. paracasei subsp. paracasei 2004 supplementation. Our results suggest that L. paracasei subsp. paracasei 2004 improves health and lifespan in a DAF-16-dependent manner.
The mucosal immune system forms the largest part of the entire immune system, containing about three-quarters of all lymphocytes and producing grams of secretory IgA daily to protect the mucosal ...surface from pathogens. To evoke the mucosal immune response, antigens on the mucosal surface must be transported across the epithelial barrier into organized lymphoid structures such as Peyer's patches. This function, called antigen transcytosis, is mediated by specialized epithelial M cells. The molecular mechanisms promoting this antigen uptake, however, are largely unknown. Here we report that glycoprotein 2 (GP2), specifically expressed on the apical plasma membrane of M cells among enterocytes, serves as a transcytotic receptor for mucosal antigens. Recombinant GP2 protein selectively bound a subset of commensal and pathogenic enterobacteria, including Escherichia coli and Salmonella enterica serovar Typhimurium (S. Typhimurium), by recognizing FimH, a component of type I pili on the bacterial outer membrane. Consistently, these bacteria were colocalized with endogenous GP2 on the apical plasma membrane as well as in cytoplasmic vesicles in M cells. Moreover, deficiency of bacterial FimH or host GP2 led to defects in transcytosis of type-I-piliated bacteria through M cells, resulting in an attenuation of antigen-specific immune responses in Peyer's patches. GP2 is therefore a previously unrecognized transcytotic receptor on M cells for type-I-piliated bacteria and is a prerequisite for the mucosal immune response to these bacteria. Given that M cells are considered a promising target for oral vaccination against various infectious diseases, the GP2-dependent transcytotic pathway could provide a new target for the development of M-cell-targeted mucosal vaccines.
Immunoglobulin (Ig) M is the first antibody isotype to appear during evolution, ontogeny and immune responses. IgM not only serves as the first line of host defense against infections but also plays ...an important role in immune regulation and immunological tolerance. For many years, IgM is thought to function by binding to antigen and activating complement system. With the discovery of the IgM Fc receptor (FcμR), it is now clear that IgM can also elicit its function through FcμR. In this review, we will describe the molecular characteristics of FcμR, its role in B cell development, maturation and activation, humoral immune responses, host defense, and immunological tolerance. We will also discuss the functional relationship between IgM-complement and IgM-FcμR pathways in regulating immunity and tolerance. Finally, we will discuss the potential involvement of FcμR in human diseases.
Earlier gas measurements of firn air (atmosphere in open pore channels) at polar sites have revealed the occurrence of gas fractionation phenomena during bubble close-off, in addition to well-known ...thermal and gravitational gas separation. Nevertheless, because of difficulties posed by measurement, little is known about the distribution of air constituents in already closed pores (bubbles) in firn. Herein, we describe the application of high-sensitivity pure rotational Raman spectroscopy, combined with sample immersion in the fluorocarbon-based inert fluid for removing the optical disturbance by diffused reflection. That application efficiently elicits information about nitrogen and oxygen composition ratios (N2/O2 or O2/N2) for each air bubble in firn. The developed methodology presents important implications for elucidating how gas records are formed and modified in the course of pore close-off in polar firn.
Fc receptors specifically bind to the Fc region of Igs to mediate the unique functions to each class of Igs. To identify a novel Fc receptor for IgM, we searched expressed sequence tag database for ...molecules containing Ig domains with homology to those of known Fc receptors for IgM, Fcα/μR and polymeric Ig receptor. As a result, we identified TOSO/Fas apoptotic inhibitory molecule 3 (FAIM3) as a possible Fc receptor for IgM. HeLa cells transfected with a TOSO/FAIM3-expression vector bound to IgM but not IgG and were able to internalize IgM-conjugated beads but not IgG-conjugated beads, suggesting that TOSO/FAIM3 is indeed a receptor for IgM (FcμR). FcμR protein was expressed predominantly on B-lineage cells; expression of the Fcmr transcripts was observed from the pre-B-cell stage and maintained thereafter during B-cell development. These results identify TOSO/FAIM3 as a receptor for IgM and suggest that FcμR may serve as an uptake receptor for IgM-opsonized antigens by B cells.
Nasopharynx-associated lymphoid tissue (NALT) is one of the major constituents of the mucosa-associated lymphoid tissue (MALT), and has the ability to induce antigen-specific immune responses. ...However, the molecular mechanisms responsible for antigen uptake from the nasal cavity into the NALT remain largely unknown. Immunohistochemical analysis showed that CCL9 and CCL20 were co-localized with glycoprotein 2 (GP2) in the epithelium covering NALT, suggesting the existence of M cells in NALT. In analogy with the reduced number of Peyer's patch M cells in CCR6-deficient mice, the number of NALT M cells was drastically decreased in CCR6-deficient mice compared with the wild-type mice. Translocation of nasally administered Salmonella enterica serovar Typhimurium into NALT via NALT M cells was impaired in CCR6-deficient mice, whereas S. Typhimurium demonstrated consistent co-localization with NALT M cells in wild-type mice. When wild-type mice were nasally administered with an attenuated vaccine strain of S. Typhimurium, the mice were protected from a subsequent challenge with wild-type S. Typhimurium. Antigen-specific fecal and nasal IgA was detected after nasal immunization with the attenuated vaccine strain of S. Typhimurium only in wild-type mice but not in CCR6-deficient mice. Taken together, these observations demonstrate that NALT M cells are important as a first line of defense against infection by enabling activation of the common mucosal immune system (CMIS).
Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing pancreatic β-cells are destroyed. Intestinal helminths can cause asymptomatic chronic and immunosuppressive infections and ...suppress disease in rodent models of T1D. However, the underlying regulatory mechanisms for this protection are unclear. Here, we report that CD8
regulatory T (Treg) cells prevent the onset of streptozotocin -induced diabetes by a rodent intestinal nematode. Trehalose derived from nematodes affects the intestinal microbiota and increases the abundance of Ruminococcus spp., resulting in the induction of CD8
Treg cells. Furthermore, trehalose has therapeutic effects on both streptozotocin-induced diabetes and in the NOD mouse model of T1D. In addition, compared with healthy volunteers, patients with T1D have fewer CD8
Treg cells, and the abundance of intestinal Ruminococcus positively correlates with the number of CD8
Treg cells in humans.
Increases in adhesive and invasive commensal bacteria, such as Escherichia coli, and subsequent disruption of the epithelial barrier is implicated in the pathogenesis of inflammatory bowel disease ...(IBD). However, the protective systems against such barrier disruption are not fully understood. Here, we show that secretion of luminal glycoprotein 2 (GP2) from pancreatic acinar cells is induced in a TNF-dependent manner in mice with chemically induced colitis. Fecal GP2 concentration is also increased in Crohn's diease patients. Furthermore, pancreas-specific GP2-deficient colitis mice have more severe intestinal inflammation and a larger mucosal E. coli population than do intact mice, indicating that digestive-tract GP2 binds commensal E. coli, preventing epithelial attachment and penetration. Thus, the pancreas-intestinal barrier axis and pancreatic GP2 are important as a first line of defense against adhesive and invasive commensal bacteria during intestinal inflammation.
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