Reciprocal regulation of lymphoid tissue development in the large intestine by IL-25 and IL-23.

Isolated lymphoid follicles (ILFs) develop after birth in the small and large intestines (SI and LI) and represent a dynamic response of the gut immune system to the microbiota. Despite their similarities, ILF development in the SI and LI differs on a number of levels. We show that unlike ILF in the SI, the microbiota inhibits ILF development in the colon as conventionalization of germ-free mice reduced colonic ILFs. From this, we identified a novel mechanism regulating colonic ILF development through the action of interleukin (IL)-25 on IL-23 and its ability to modulate T regulatory cell (Treg) differentiation. Colonic ILF develop in the absence of a number of factors required for the development of their SI counterparts and can be specifically suppressed by factors other than IL-25. However, IL-23 is the only factor identified that specifically promotes colonic ILFs without affecting SI-ILF development. Both IL-23 and ILFs are associated with inflammatory bowel disease, suggesting that disruption to this pathway may have an important role in the breakdown of microbiota-immune homeostasis.

Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium.

The transcytosis of antigens across the gut epithelium by microfold cells (M cells) is important for the induction of efficient immune responses to some mucosal antigens in Peyer's patches. Recently, substantial progress has been made in our understanding of the factors that influence the development and function of M cells. This review highlights these important advances, with particular emphasis on: the host genes which control the functional maturation of M cells; how this knowledge has led to the rapid advance in our understanding of M-cell biology in the steady state and during aging; molecules expressed on M cells which appear to be used as "immunosurveillance" receptors to sample pathogenic microorganisms in the gut; how certain pathogens appear to exploit M cells to infect the host; and finally how this knowledge has been used to specifically target antigens to M cells to attempt to improve the efficacy of mucosal vaccines.

The functional maturation of M cells is dramatically reduced in the Peyer's patches of aged mice.

The transcytosis of antigens across the follicle-associated epithelium (FAE) of Peyer's patches by microfold cells (M cells) is important for the induction of efficient immune responses to mucosal antigens. The mucosal immune response is compromised by ageing, but effects on M cells were unknown. We show that M-cell density in the FAE of aged mice was dramatically reduced. As a consequence, aged Peyer's patches were significantly deficient in their ability to transcytose particulate lumenal antigen across the FAE. Ageing specifically impaired the expression of Spi-B and the downstream functional maturation of M cells. Ageing also dramatically impaired C-C motif chemokine ligand 20 expression by the FAE. As a consequence, fewer B cells were attracted towards the FAE, potentially reducing their ability to promote M-cell maturation. Our study demonstrates that ageing dramatically impedes the functional maturation of M cells, revealing an important ageing-related defect in the mucosal immune system's ability to sample lumenal antigens.

The Escherichia coli heat-labile enterotoxin B subunit protects from allergic airway disease development by inducing CD4+ regulatory T cells.

The B subunit of E. coli heat-labile enterotoxin (EtxB) protects against the development of T helper type 1 (Th1)-mediated autoimmune pathologies in mice. Protection was transferable with splenic CD4(+) T cells and was less effective following CD25 depletion; implying a T regulatory cell (Treg)-mediated process. We hypothesized that if this were the case, then EtxB would also control a Th2-mediated disorder. We tested the effect of EtxB treatment on asthma development in ovalbumin (OVA)-sensitized mice. EtxB treatment diminished eosinophilia in bronchoalveolar lavage samples, reduced OVA-specific immunoglobulin E and interleukin 4 production locally and systemically, and reduced airway hyper-reactivity. EtxB induced a dose-dependent increase in Foxp3(+)CD4(+) T cells, and adoptive transfer of splenic CD4(+) T cells partially suppressed lung pathology. Importantly, EtxB treatment increased OVA-specific CD4(+)Foxp3(+) T cells in the lung and systemically. These data demonstrate that EtxB modulates the differentiation of allergen-specific T cells causing inducible Treg induction and preventing disease.

M cell-depletion blocks oral prion disease pathogenesis.

Many prion diseases are orally acquired. Our data show that after oral exposure, early prion replication upon follicular dendritic cells (FDC) in Peyer's patches is obligatory for the efficient spread of disease to the brain (termed neuroinvasion). For prions to replicate on FDC within Peyer's patches after ingestion of a contaminated meal, they must first cross the gut epithelium. However, the mechanism through which prions are conveyed into Peyer's patches is uncertain. Within the follicle-associated epithelium overlying Peyer's patches are microfold cells (M cells), unique epithelial cells specialized for the transcytosis of particles. We show that following M cell-depletion, early prion accumulation upon FDC in Peyer's patches is blocked. Furthermore, in the absence of M cells at the time of oral exposure, neuroinvasion and disease development are likewise blocked. These data suggest M cells are important sites of prion uptake from the gut lumen into Peyer's patches.

Mucosal administration of the B subunit of E. coli heat-labile enterotoxin promotes the development of Foxp3-expressing regulatory T cells.

Understanding the processes by which certain mucosal pathogens and their products induce regulatory T cells (Tregs) is important in determining mechanisms of pathogenicity and may point toward their use in treating immunological disorders. Accordingly, we have studied the events that follow mucosal administration of the B subunit of E. coli heat-labile enterotoxin (EtxB). EtxB modulates the response to co-administered antigens and can prevent autoimmune disease. Our data show that EtxB translocates across the nasal epithelium, modulating the expression of interleukin-10 (IL-10) and transforming growth factor-ß(1) (TGF-ß(1)). The modulated microenvironment drives an increase in Forkhead box P3 (Foxp3)-positive T cells, predominantly in the CD4(+)CD25(-) subset. Adoptive transfer experiments showed that enhanced Foxp3 expression was particularly evident in recently activated T cells by concomitant unrelated antigen challenge, and was both TGF-ß(1) and IL-10 dependent. This ability to alter T-cell differentiation pathways following mucosal delivery explains how EtxB may modify mucosal immune environments and prevent unwanted pathologies.

Mucosal mast cells and nematode infection: strain-specific differences in mast cell precursor frequency revisited.

Mucosal mast cells (MMC) play an important role in the immune response against selected species of intestinal nematode. The kinetics with which different strains of inbred mice resolve infection with Trichinella spiralis correlates with their ability to mount MMC responses in the intestinal mucosa. Homologues of MMC that express and constitutively secrete abundant amounts of the granule chymase, mouse mast cell protease-1 (mMCP-1), can be generated in vitro from bone marrow cultures supplemented with interleukins-3 and -9, stem cell factor and transforming growth factor-beta1. Using the enhanced growth characteristics of these MMC homologues, a novel limiting dilution assay for mast cell precursor (MCp) frequency has been developed. The assay is highly specific, in that cultures containing mast cells are identified with mMCP-1 specific antibody, and almost three-fold more sensitive than previously published systems. MCp frequencies were compared in BALB/c and C57/BL10 strains of mice that, respectively, respond rapidly and slowly to infection with T. spiralis. MCp frequency (1/378 bone marrow cells) was significantly greater in BALB/c than C57/BL10 mice (frequency: 1/751). Similarly the rate of growth of MMC homologues and the production of mMCP-1 was significantly greater in BALB/c than in C57/BL10 bone marrow cultures.

Urologic experience in 48 heart transplant recipients.

BACKGROUND: Urologic experience in heart transplant recipients as a population group has not been reported. METHODS: We reviewed the charts of 48 consecutive heart transplant recipients who were evaluated and treated in our outpatient urologic clinic. Patients were treated for various urologic conditions by both medical and surgical means. RESULTS: No major complications were encountered. CONCLUSIONS: Heart transplant recipients may be treated with minimal morbidity; thus, their urologic complaints should be addressed and treated with confidence.

Large transitional cell carcinoma of the proximal third of the ureter in a young man.

We report an unusual case of a 37-year-old black man found to have a large transitional cell carcinoma of the proximal third of the ureter. This case is of interest because of the relatively young age of the patient, the upper third ureteral origin of the tumor, and the volume of the tumor burden.

Nuclear precursor molecules of the two beta-globin mRNAs in Friend erythroleukemia cells.

Processing of the beta major and beta minor globin pre-mRNAs has been compared in murine erythroleukemia cells induced to synthesize hemoglobin by dimethyl sulfoxide or hemin treatment, using both the Northern blot technique and S1 nuclease mapping with 3' and 5' end-labeled probes. The small intervening sequence of both beta-globin pre-mRNAs was removed in one step, although minor amounts of incompletely spliced RNA were detected. During the processing of the large intervening sequence of beta major globin pre-mRNA two internal splice sites were clearly detected. On the contrary, the beta minor globin pre-mRNA did not show any internal splice sites. A model of processing of the mouse adult beta major globin pre-mRNA is proposed.