No description available.

No description available.

No description available.

Flagellin is a highly immunogenic, bacterial protein considered to be abundant in the intestinal lumen. It has been reported to be an immunodominant antigen in patients with inflammatory bowel disease (IBD). In the work presented in this thesis several complementary murine models of IBD were employed to elucidate the role of innate immune sensing of flagellin in the development of intestinal inflammation. Pattern recognition receptors (PRRs) enable mammals to discriminate self from non-self through the recognition of microbial signatures, such as bacterial flagellin. Flagellin is detected by at least two distinct PRRs, NOD-like receptor 4 (NLRC4) and Toll-like receptor 5 (TLR5). Our experiments revealed that NLRC4 promoted protective effects during acute intestinal inflammation mediated by infection with Citrobacter rodentium, a close relative of enteropathogenic E. coli. Following infection with C. rodentium, Nlrc4^-/- mice developed more severe weight loss, increased bacterial colonisation levels and exacerbated intestinal inflammation compared to WT counterparts. Bone marrow chimera experiments revealed that NLRC4 expression in non-hematopoietic cells provided protection and intestinal epithelial cells expressed high NLRC4 mRNA levels. These results suggest that NLRC4 inflammasome activation in the intestinal epithelium provides potent, protective effects during infection with a mucosal pathogen. In contrast, TLR5 was shown to promote protective effects during chronic, T-cell mediated intestinal inflammation driven by adoptive transfer of naïve CD4+ T-cells into lymphopenic Rag^-/- hosts. The absence of TLR5 in Rag^-/- recipients resulted in accelerated and exacerbated IBD. Furthermore, chronic T-cell dependent colitis driven by Helicobacter hepaticus, a flagellated, enteric bacterium, was more severe in mice deficient in TLR5. Finally, construction of a H.hepaticus Type 6 secretion system deletion mutant revealed delayed pathogenicity in an innate model of intestinal inflammation, most likely due to reduced initial colonisation of mutant H.hepaticus.

No description available.

The importance of gut associated lymphoid tissues has been extensively reported in higher vertebrates, but less is known in lower vertebrates. In mammals immunoglobulin (Ig)A is the primary Ig of mucosal immunity. But no IgA has been identified in cold-blooded animals. In higher vertebrates, antigen must stimulate the lymphoid tissues in the intestines to elicit an IgA response, and cytokines from CD4 positive helper T cells are required for B cell switch. It is not known if this is the case in lower vertebrates, or if T cell help evolved before or after class switch recombination between functional antibody isotypes. My study will fill in these gaps in our knowledge by comparing oral antigen inoculation relative to intraperitoneal antigen inoculation in frogs (Xenopus sp.). Oral immunization is a novel approach to eliciting immune responses in Xenopus. I propose that IgX will increase with oral inoculation compared to intraperitoneal injection. This would be the first demonstration of class switch upon oral immunization to a mucosal isotype in the first vertebrates that employs higher vertebrate Ig heavy chain switch mechanism, which would shed light on the most fundamental aspects of our humoral adaptive immune system. Using a total Ig ELISA protocol, measuring total relative levels of IgM, there was no difference between the first three groups of orally immunized frogs compared to intraperitoneally immunized frogs. However, a response to serum IgX was seen in the first group. On the other hand, the refined Ag-specific ELISA protocol did present a significant increase in serum IgM response in frogs immunized systemically over orally immunized animals, but not an overall IgX response. Phylogenetic analysis suggests that, contrary to initial reports, IgA evolved from IgX. With consideration of entire constant region and individual constant domain analyses as well as synteny and function, we suggest new hypotheses of vertebrate antibody evolution to be tested as immunogenetic coverage of more species continues to expand.

Tübingen, Univ., Diss., 2005.

Universiẗat, Diss., 2003--Giessen.

Background Endoscopic ultrasound-guided fine-needle aspiration and biopsy (EUS-FNA/FNB) has been traditionally used for making a tissue diagnosis. Several newer techniques are emerging as a viable alternative to EUS-FNA/FNB, including mucosal incision-assisted biopsy (MIAB), with a view to increasing the diagnostic yield for upper gastrointestinal (GI) subepithelial tumors (SETs). We conducted a systematic review and meta-analysis to describe the overall diagnostic yield of MIAB for upper GI SETs. Methods Multiple electronic databases (MEDLINE, EMBASE and Google Scholar) and conference abstracts were comprehensively searched. The primary outcome of our meta-analysis was the overall diagnostic yield of the MIAB. The secondary outcome was to study complications in terms of perforation and clinically significant bleeding. The meta-analysis was performed using a DerSimonian and Laird random-effect model. Results Seven studies were included in the final meta-analysis, reporting a total of 159 patients (male 86, female 73) with a mean age of 58 years. The overall pooled diagnostic yield of MIAB was 89% (95% confidence interval [CI] 82.65-93.51, I2=0.00). Histologically, GI stromal tumor was the reported diagnosis in 38.62% (95%CI 22.29-56.24, I2=77.51%) of tumors, followed by leiomyoma 25% (95%CI 18.02-32.62, I2=4.42%). The overall rate of clinically significant bleeding following the procedure was 5.03% (95%CI 0.36-12.86, I2=57.43%) and no perforations were reported. Conclusions MIAB is a safe and effective technique for the diagnosis of upper GI SETs and can be considered as a viable alternative to EUS-FNA/FNB. MIAB can be performed during routine endoscopy and no advanced equipment is required.

Streptococcus pneumoniae (Spn) is the most common etiology of bacterial pneumonia, which is one of the leading causes of death in children and the elderly worldwide. During non-lethal infections with Spn, immune cells accumulate in the lungs and protect against reinfection with more lethal strains, this protection is termed heterotypic immunity. Lymphocyte populations such as resident memory T cells and resident memory B cells are known to be crucial for heterotypic immunity, but their diversity remains understudied. Here, we aimed to elucidate resident lymphocyte heterogeneity in the lungs after recovery from pneumococcal pneumonia, and their contributions to heterotypic immune protection. We developed a comprehensive immunophenotyping panel for full-spectrum flow cytometry (FSFC) to identify novel subsets of lymphocytes and combined it with an unbiased analysis approach. With this tool we discovered that murine lungs were enriched for unexpected subsets of resident lymphocytes, and we defined CD73 as a potential lymphocyte residence marker. We discovered a novel subset of CD4+ T cells defined by the phenotype CD11a+CD69+GL7+, which corresponded to a significant proportion of lung CD4+ TRM cells. Initial analyses demonstrated GL7+ T cells resembled CD4+ TRM cells. Functional studies revealed that unlike GL7- TRM subsets that were mostly RORT+, GL7+ TRM cells were also Gata-3+ and/or T-bet+ could secrete type 2 or type 1 cytokines, suggesting they were poised to be TH2 or TH1-like in function. This study emphasizes the use of a multiparameter panel for FSFC as tool to identify novel lymphocyte subsets. We conclude that the environment of pneumonia-recovered lungs contains heterogeneous subsets of resident lymphocytes, including GL7+ TRM cells. We propose these subsets may contribute to lung immunity in unique ways and may be important players in serotype-independent protection to pneumococcal pneumonia. / 2024-01-23T00:00:00Z