Infection and immunology of the gut Flashcards
What is meant by restrained activation
tolerant to food antigens and commensal bacteria but reactive to pathogens
Describe the importance of the microbiota
roles in nutrition, digestion, development- essential in our development.
What should the G.I tract remain tolerant to
Food antigens
Commensal bacteria
What should the G.I tract be immunoreactive to
Immunoreactivity
Pathogens
Describe the G.I tract antigen load
§ There is a massive anti-gen load in the gut:
o 10^14 resident bacteria.
o Dietary antigens.
o Exposure to external pathogens.
§ The gut immune system remains in a state of restrained activation – tolerance vs. active immunity to antigens.
§ The Bacteroidetes are the most prevalent bacteria in the gut – especially in the colon (from terminal ileum).
o 4 major phyla: Bacteroidetes, Firmicutes, Actinobacteria and Proteobacteria.
Surface area of GI tract 400m2.
Describe the epithelium of the G.I tract
The epithelium of the digestive tract is, by definition, an external environment, because it is possible for bacteria to reach there without needing to cross a membrane.
The gut has a huge internal surface area which facilitates its role of absorption
The enormous resident population of bacteria in our gut is ten times as many cells in our body, having 100 times as many genes as the human genome!
What is essential for the development of a healthy immune system
Immune homeostasis of gut & development of healthy immune system requires presence of bacterial microbiota.
Describe the presence of microbiota in different parts of the G.I tract
Loads in the mouth is because we put lots of dirty things into it, including food, fluid, cutlery, air etc.
Into the stomach, the low pH kills lots of bacterial populations (except H. pylori).
The number is kept low in the duodenum, jejunum and proximal ileum because of paneth cells and Peyer’s patches (discussed in detail later).
Beyond the ileocaecal valve the number of microorganisms increases markedly.
List the immunological defects seen in germ-free mice
development of small intestine development of mesenteric lymph nodes CD8 and CD4 T cells CD4 and CD25 T cells production of secretory IgA Expression of REG3 gamma and angiogenin 4 (Paneth cells) levels of ATP (intestine) Expression of MHC 2 Expression of TLR 9 Levels of IL-25
Describe the enormity of our microbiota
1014 gut bacteria and 1013 cells in body - Most densely populated “ecosystem” on Earth.
4 major phyla of bacteria (Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria), also viruses & fungi.
Provide traits we have not had to evolve on our own - Genes in gut flora 100 times our own genome.
How can the host increase the numbers of bacteria in the microbiota
Ingested and secreted nutrients encourage bacterial growth
However chemical digestive factors and peristaltic contractions and defecation leads to decreased cell numbers
Describe the chemical protections of each part of the G.I tract
Stomach- HCL (pH 1.4) gastric lipase, pepsin
Liver- Bile acids
pancreas- trypsin, amylase, carboxypeptidase
S.I - brush border enzymes
Colon- no host digestive factors
What is meant by dysbiosis
Altered microbiota composition
Describe the symbiotic relationship we have with the microbiota
They take nutrients from us but provide us with benefits
What can cause dysbiosis
Infection or inflammation Diet Xenobiotics Hygiene genetics
Describe the physical barriers of mucosal defence
a tight epithelial wall, glycocalyx, mucous and unstirred layer. Also, persitalsis to keep things moving along the GI tract.
Anatomical (epithelial barrier, peristalsis)
Describe the chemical barriers of mucosa
Chemical (Enzymes, acidic pH)
bactericidal enzymes from paneth cells, and acid from stomach.
Describe bacterial protection in mucosal defence
commensal bacteria maintain immune system priming and may attack foreign species.
Commensal bacteria: occupy “ecological niche”- provide competition for attachment to the epithelial wall
Describe the role of immune system in mucosal defence
Mucosa-associated lymphoid tissue (MALT) rich in T cells & B cells, whose components can be further categorized into GALT (Gut-associated lymphoid tissue), BALT (Bronchus-associated lymphoid tissue) etc.
Describe the role of the epithelial barrier in mucosal defence
Mucus layer - Goblet cells Epithelial monolayer - Tight junctions Paneth Cells (small intestine) Bases of crypts of Lieberkühn. Secrete Antimicrobial peptides (defensins) and lysozyme.
What can the metabolites and toxins of bacteria cause
Systemic disease
Describe MALT
Found in the submucosa below the epithelium, as lymphoid mass containing lymphoid follicles
Follicles are surrounded by HEV postcapillary venules, allowing easy passage of lymphocytes
The oral cavity is rich in immunological tissue. (LINGUAL, PALATINE AND PHARYNGEAL TONSILS)
What is the role of GALT
Responsible for both adaptive & innate immune responses through generation of lymphoid cells & Abs.
Also cell-mediated responses
Describe unorganised GALT
Intra-epithelial lymphocytes – Make up one-fifth of intestinal epithelium, e.g., T cells, NK cells
Lamina propria lymphocytes
Summarise the categories of GALT
GALT can be split into two categories depending on organisation. There are organised sites of lymphoid tissue such as Peyer’s patches in the small intestine and lymphocytes in mesenteria lymph nodules (i.e. where the lymph from the villi drain). And, there are disorganised sites which include lymphocytes in the lamina propria (mainly IgA-secreting B-cells) and lymphocytes in the interstitial space below the basolateral membrane of the epithelium (called intra-epithelial cells).
Additionally, although not technically GALT, there are Kuppfer cells in the liver which can phagocytose bacteria.
What are Peyer’s patches and where are they found
Peyer’s patches consists of aggregated lymphoid follicles covered with follicle associated epithelium (FAE).
They are found in the small intestine, having highest concentration in the distal ileum.
Describe follicle associated epithelium
FAE - no goblet cells, no secretory IgA, lack microvilli
What is the function of Payer’s patches and what is essential in their development
They function as “immune sensors” since they are capable of monitoring local bacteria, and provide protection against pathogenic bacteria.
Their development requires exposure to bacterial flora (i.e. they are barely present in animal models that are born and reared in sterile environments). Humans have about 50 by the last trimester of gestation, and hit the maximum of about 250 by their teenage years.
Peyer’s patches are rich in B cells, T cells, macrophages and dendritic cells.
Describe the roles of M cells
Antigen uptake via M (microfold) cells within FAE.
M cells expressIgA receptors, facilitating transfer of IgA-bacteria complexinto the peyer’s patches.
Summarise the roles of M cells
FAE contains specialized enterocytes or M cells. The main function of M cells is to perform transcytosis of luminal bacteria, antigens and proteins.
M cells express IgA receptors, facilitating transfer of IgA-bacteria compex into the peyer’s patches.
Antigen uptake is a combined effort by specialised M-cells and dendritic cells. These antigens are then presented to the lymphocytes for assessment and potential immunological response. Activated cells develop gut homing markers (see lymphocyte circulation) and migrate to mesenteric lymph nodes for proliferation.
Describe the role of dendritic cells in antigen sampling
§ Dendritic cells sample antigen using dendrites.
§ DCs take up antigen and process, then present to:
o Naïve T-cells in Peyer’s patch.
o Transport to mesenteric lymph nodes.
Describe the activation of B cells in the B cell adaptive response
Mature naïve B-cells express IgM in PPs
Upon antigen presentation class switch to IgA
T-cells & epithelial cells influence B cell maturation via cytokine production.
B cells further mature to become IgA secreting plasma cells.
Populate lamina propria
