Integrin CD11b provides a new marker of pre-germinal center IgA+ B cells in murine Peyer's patches.

Activated B cells can enter germinal centers (GCs) for affinity maturation to produce high-affinity antibodies. However, which activated B cells will enter GCs remains unknown. Here, we found a small population of CD11b+IgA+ B cells located outside of GCs in murine Peyer's patches (PPs). After injection of the CD11b+IgA+ PP B cells into a PP of a recipient mouse, they entered GCs forty hours later. They expressed GC surface markers and pre-GC B cell genes, suggesting that CD11b provides a novel surface marker of pre-GC IgA+ B cells in murine PPs. Furthermore, independently of dendritic cell activation, CD11b expression on B cells can be induced by bacterial antigens, such as pam3CSK4 and heat-killed Escherichia coli in vitro. In addition, mice orally administered with pam3CSK4 or heat-killed E. coli increased the number of PP GC B cells within two days, and enhanced the mucosal antigen-specific IgA response. Our results demonstrate that the induction of CD11b on B cells is a promising marker for selecting an effective mucosal vaccine adjuvant.

Decreased Taxon-Specific IgA Response in Relation to the Changes of Gut Microbiota Composition in the Elderly.

Gut microbiota is known to change with aging; however, the underlying mechanisms have not been well elucidated. Immunoglobulin A (IgA) is the dominant class of antibody secreted by the intestinal mucosa, and are thought to play a key role in the regulation of the gut microbiota. T cells regulate the magnitude and nature of microbiota-specific IgA responses. However, it is also known that T cells become senescent in elderly people. Therefore, we speculated that the age-related changes of IgA response against the gut microbiota might be one of the mechanisms causing the age-associated changes of gut microbiota composition. To prove our hypothesis, fecal samples from 40 healthy subjects (adult group: n = 20, an average of 35 years old; elderly group: n = 20, an average of 76 years old) were collected, and the gut microbiota composition and the response of IgA to gut microbiota were investigated. The relative abundance of Bifidobacteriaceae was significantly lower, whereas those of Clostridiaceae, Clostridiales;f__ and Enterobacteriaceae were significantly higher in the elderly group than in the adult group. There was no significant difference in the fecal IgA concentration between the adult and elderly groups. However, the taxon-specific IgA response to some bacterial taxa was different between the adult and elderly groups. To evaluate inter-group differences in the taxon-specific IgA response to each bacterial taxon, the IgA-indices were calculated, and the IgA-indices of Clostridiaceae and Enterobacteriaceae were found to be significantly lower in the elderly group than the adult group. In addition, Clostridiales;f__ and Enterobacteriaceae were significantly enriched in the IgA+ fraction in the adult group but not in the elderly group, whereas Clostridiaceae was significantly enriched in the IgA- fraction in the elderly group but not in the adult group. Some species assigned to Clostridiaceae or Enterobacteriaceae are known to be pathogenic bacteria. Our results suggest the possible contribution of decreased IgA response in the increased abundance of bacterial taxa with potential pathogenicity in the intestinal environment of the elderly. Our findings contribute to the understanding of the regulatory factor for the changes in the gut microbiota composition with aging.

Intestinal IgA as a modulator of the gut microbiota.

Accumulating evidence suggests that dysbiosis plays a role in the pathogenesis of intestinal diseases including inflammatory bowel disease (IBD) as well as extra-intestinal disorders. As a modulator of the intestinal microbiota, we isolated a mouse monoclonal IgA antibody (clone W27) with high affinities for multiple commensal bacteria, but not for beneficial bacteria such as Lactobacillus casei (L. casei). Via specific recognition of an epitope in serine hydroxymethyltransferase (SHMT), a bacterial metabolic enzyme, W27 IgA selectively inhibited the in vitro growth of bound bacteria, including Escherichia coli (E. coli), while having no effect on unbound beneficial bacteria such as L. casei. By modulating the gut microbiota in vivo, oral administration of W27 IgA effectively prevented development of colitis in several mouse models. Here we discuss how intestinal IgA modulates the gut microbiota through recognition of SHMT.

High-affinity monoclonal IgA regulates gut microbiota and prevents colitis in mice.

Immunoglobulin A (IgA) is the main antibody isotype secreted into the intestinal lumen. IgA plays a critical role in the defence against pathogens and in the maintenance of intestinal homeostasis. However, how secreted IgA regulates gut microbiota is not completely understood. In this study, we isolated monoclonal IgA antibodies from the small intestine of healthy mouse. As a candidate for an efficient gut microbiota modulator, we selected a W27 IgA, which binds to multiple bacteria, but not beneficial ones such as Lactobacillus casei. W27 could suppress the cell growth of Escherichia coli but not L. casei in vitro, indicating an ability to improve the intestinal environment. Indeed W27 oral treatment could modulate gut microbiota composition and have a therapeutic effect on both lymphoproliferative disease and colitis models in mice. Thus, W27 IgA oral treatment is a potential remedy for inflammatory bowel disease, acting through restoration of host-microbial symbiosis.

A novel germline mutation in a patient with nevoid basal cell carcinoma syndrome showing cystic lesion in the lung.

Nevoid basal cell carcinoma syndrome (NBCCS) manifests multiple defects involving the skin, endocrine and nervous systems, eyes and bones. Mutations in the patched homologue 1 (PTCH1) gene are the underlying causes of NBCCS, leading to aberrant cell proliferation through constitutive activation of the hedgehog signaling pathway. We identified a novel frameshift mutation (c.1207dupT) of PTCH1 in a NBCCS patient, which might explain multiple cystic lesions and neoplastic growth in the patient.