Hoque, Syed Samiul

2019-02-15T14:29:33Z

2019-02-15T14:29:33Z

2000

Gastrointestinal infections are a major cause of mortality and morbidity especially in the developing world. It is nearly a century since it was first observed that antibodies were present in the gut and it is now clear that secreted antibodies in the gut mucosa are crucial for host defence against pathogens. In addition, they may be important in the interaction of the host with commensal bacteria and oral vaccines.

The development of a new clinical technique, whole gut lavage, has facilitated the collection of large amounts of gut fluid containing antibodies for the study of immune responses in the Gl tract in health and disease.

The aims and related hypotheses of this thesis were: a) To develop an antibody test that could be used as a tool to examine the gut humoral immune response to bacteria of the gut flora. In order to develop the antibody test, various antigens were prepared from the bacterial cell wall and their biological potentials were examined with human and murine cell lines. These tests could be combined with studies of other facets of gut immunity for which methods were already available, in order to explore active immunity and tolerance in the mucosal and systemic compartments. b) To examine and compare humoral immunity in the gut and serum of immunologically normal people from Edinburgh and Dhaka, in order to establish and test the following hypotheses: 1. In view of the probable higher antigenic load from a potentially contaminated environment, there would be evidence of gut damage and inflammation in the healthy people of Dhaka, and thus high levels of IgA, compared to people in Edinburgh. 2. In the developing country, the drive for production of high levels of humoral responses to bacteria would have the additional effect that antibodies to other gut antigens, such as foods, would be absent or of low titre.

By studying patients with chronic colitis (inflammatory bowel disease), it might be possible to investigate how chronic gut inflammation affects specific antibodies and to identify the sources of gut antibodies, ie. serum- derived or locally produced. Prompted by the case of a patient with hypereosinophilic syndrome, high gut IgA concentrations and ulcerative colitis, the stimuli for eosinophil migration into the gut and eosinophil activation were examined and possible interaction with the regulation of humoral immunity investigated.

My literature review concentrates on a monograph on The gut as an immune organ' and illustrates the important features of intestinal immunoglobulins and antibodies. In the first chapter a section on bacterial structure and antigens has been included and the current knowledge on the regulation of eosinophil migration has been discussed. There is a small section on an appraisal of the whole gut lavage procedure that has been used in this thesis. Chapter 2 includes characteristics of patients and healthy volunteers, laboratory methods and technical development. A pilot study to confirm technical competence and reproducibility of methods is presented in chapter 3. Chapter 4 describes various gut damage and immune parameters in people from Edinburgh and Dhaka. Despite higher antigenic load, no evidence of gut damage, but high IgA, was found in the Dhaka groups. Results of anti-endotoxin and antibacterial antibodies, including those to various core types of E.coli LPS are presented in chapter 5. A section on the purity of the antigens and their biological potential by producing nitric oxide, inducing various cytokines in murine and human cell line have been presented. For the first time it has been found that IgA antibodies against various core types of LPS of E.coli are present in the gut, and their potential in the therapy of sepsis syndrome and for oral vaccine development has been discussed. Chapter 6 describes the of humoral immunity, role of gut bacteria, and cytokines controlling local and systemic immunity and pathogenicity in chronic inflammatory bowel disease. Evidence has been presented in chapter 7 to support the view that the source of IgG antibody detected in the gut of patients with active IBD is locally produced and not serum derived.

The drive for production of a high humoral response to bacteria may be responsible for absent or low titre antibodies to other gut antigens, such as food. The antigen-driven bystander suppression or recently described Th1/Th2 paradigm is the purported mechanism for these results. The implications of these results in therapeutics and strategies for oral vaccine against infectious disease have been discussed in chapter 8. The stimuli of eosinophil migration in to the gut and their role in the mucosal inflammation of IBD have been discussed in chapter 9. For the first time it has been shown that the eosinophil specific chemoattractant, eotaxin, is secreted into the gut lumen; this may help in our understanding of the diseases related to eosinophil accumulation.

The final chapter is an overview with some speculation on the relationship of the findings to future developments.

http://hdl.handle.net/1842/34671

The University of Edinburgh

Annexe Thesis Digitisation Project 2019 Block 22

Already catalogued

Geographical and disease influences on intestinal antibodies in man

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy