GI Immunity Flashcards
What are the components of the innate immune system in the GI tract?
- barrier and chemical mechanisms
- pattern recognition receptors (PRRs)
- cellular (phagocytes, NK cells)
How do the innate and adaptive immune systems communicate in the GI tract?
There is a high degree of communication and overlap between the 2 systems
What are pattern recognition receptors (PRRs)?
They are proteins expressed by macrophages, neutrophils and epithelial cells
What do PRRs detect?
They detect molecules that are typical for a particular type of pathogen
What are the 2 types of molecules that are detected by PRRs?
Pathogen-associated molecular patterns (PAMPs)
Damage-associated molecular patterns (DAMPs)
What are PAMPs and DAMPs associated with?
PAMPs are associated with microbial pathogens
DAMPs are associated with components of host cells that are released during cell damage/death
Where may PRRs be found within a cell?
They are either transmembrane (on cell surface)
or they are found intracellularly
What are examples of PRRs?
- Toll-like receptors
- NOD-like receptors
- Rigi-like receptors
- C-type lectins
- Scavenger receptors
What are the targets for antimicrobial peptides?
The fundamental differences between prokaryotic and eukaryotic cells
What type of organisms are killed by antimicrobial peptides?
Gram-negative and Gram-positive bacteria
What are examples of antimicrobial peptides?
- defensins
- probiotics
- granulysin
- histatin
- cathelin
What are the 5 main components of the GI innate immune system?
- pattern recognition receptors
- antimicrobial peptides
- cells
- complement components
- cytokines
What types of cytokines are produced and what is their main role?
Autocrine, paracrine and endocrine cytokines mediate host defence and inflammation
What is the role of cytokines, relating to the adaptive immune response?
They recruit, direct and regulate adaptive immune responses
This involves communication between different components of the immune system
What is the role of macrophages in the innate immune response?
- phagocytose and kill bacteria
- produce antimicrobial peptides
- produce inflammatory cytokines
What do macrophages in the innate immune system bind?
They bind lipopolysaccharides (LPS)
These are found in the outer membrane of Gram-negative bacteria
Where are plasmacytoid dendritic cells found?
In T cell zones of lymphoid organs and will circulate in the blood
What is the role of plasmacytoid dendritic cells?
They produce large amounts of interferon
This has anti-tumour and anti-viral activity
Where are myeloid dendritic cells found?
In T cell zones of lymphoid organs and will circulate in the blood
They are present in the interstices of the lung, heart and kidney
What is the role of myeloid dendritic cells?
They produce IL-12 and IL-10
What is the role of natural killer cells?
They kill foreign and host cells that have low levels of MHC-positive self-peptides
What is the role of NK-receptors on NK cells?
They can inhibit NK function in the presence of high expression of self-MHC
What are NK-T cells?
Lymphocytes which have both T cell and NK cell surface markers
what is the role of NK-T cells?
They recognise lipid antigens of intracellular bacteria through CD1 molecules
They then kill host cells infected by intracellular bacteria
What is the role of neutrophils in the innate immune system?
- phagocytose and kill bacteria
2. produce antimicrobial peptides
What is the role of eosinophils in the innate immune response?
They kill invading parasites
What is the role of mast cells and basophils in the innate immune response?
They release TNF, IL-6 and IFN in response to a variety of bacterial PAMPs
What is the role of epithelial cells in the innate immune response?
- produce antimicrobial peptides
2. tissue-specific epithelia produce mediators of local innate immunity
What is significant about the adaptive immune system being able to evolve?
It evolves in response to changing pathogen structures
Variable regions of pathogens mutate at a greater speed than humans
What is significant about the antigen receptor found on each lymphocyte?
It is unique to a particular pathogen
infection by the specific antigen leads to clonal expansion of the lymphocyte
What actions precede antigen presentation?
- antigens are internalised and broken down into peptides
- peptides associate with newly synthesises MHC II molecules
- peptides and MHC II molecules are brought to the cell surface
What happens if the presented peptides are foreign?
They are recognised by helper T cells
The helper T cells then produce cytokines to activate B cells and other T cells
When the T helper cell activates the B cell, which groups of molecules interact?
CD40L on the T helper cell interact with CD40 on the B cell
IL2, IL4 and IL5 are released by the T cell and detected by the interleukin receptor in the B cell
What do CD4+ helper T cells recognise?
Exogenous antigens presented by MHC II molecules
MHC II are on the surface of APCs - B cells, dendritic cells and macrophages
What do CD8+ cytotoxic T cells recognise?
Endogenous antigens presented by MHC I molecules
MHC I is present on the surface of ALL nucleated cells (platelets but not RBCs)
What are Th1 cells involved in?
Defence against intracellular pathogens
What are Th2 cells involved in?
Defence against parasitic worms, as well as allergy and asthma
What are Th17 cells involved in?
Defence against extracellular bacteria
Also have a role in autoimmunity and cancer
What are Treg cells involved in?
Immunosuppression
This is dampening down the immune response
Why is it important that the gut has a well developed immune system?
The gut is the major site of contact in the body for foreign antigens
What is the first line of defence against pathogens in the gut?
The GI tract mucosal surface
This separates the external environment from the internal sterile environment
What 3 categories of antigens does the gut mucosal barrier encounter?
- harmless antigens e.g. in food
- commensal bacterial flora
- pathogenic organisms that have developed effective methods for colonisation and invasion
What is the difference in immune response required for harmless antigens and pathogenic antigens?
Harmless antigens require active suppression through the development of tolerance
Pathogenic organisms require a protective immune response
Why is the gut immune system functionally and anatomically different from the systemic IS?
Why is this significant?
The gut immune system is capable of mounting a robust response against pathogenic antigens
It also is capable of maintaining a required tolerance against non-pathogenic antigens
What are the 3 main components of the gut immune system?
- innate defences
- specific defences
- microfold cells
What are the main innate defences of the gut immune system?
- commensal bacterial flora
- epithelial barriers
- biochemical factors produced by epithelial cells
What are the main specific defences of the gut immune system?
Lymphoid tissue associated with mucosal surfaces
This is gut-associated lymphoid tissue - GALT
Where are microfold (M cells) located?
Within Peyer’s patches
What is the role of the microfold (M) cells?
They sample antigen from the lumen of the small intestine and deliver it to antigen-presenting cells and lymphocytes via transcytosis
Where are the M cells located with respect to the antigen-presenting cells and lymphocytes?
The M cells are in the Peyer’s patches touching the gut lumen
The lymphocytes and APCs are located in a pocket-like structure on the basolateral side
How do M cells differ from enterocytes?
They lack microvilli on their apical surface
Instead, they have broader microfolds
They are also less abundant than enterocytes
What are enterocytes?
Simple columnar epithelial cells found in the small intestine
Approximately how many, and how many species of, bacteria live in the GI tract?
10^14 bacteria
There are 300 - 1000 species of bacteria in the gut, but most are commensals
How may some of the bacteria in the gut be capable of causing harm?
Some are capable of causing disease through infection or increasing risk of cancer
What is the optimum “gut flora balance”?
The beneficial bacteria should predominate and provide a barrier to invading organisms
What are the most common ‘beneficial’ gut bacteria?
Gram-positive lactobacilli
Bifidobacteria
How does the composition of GI flora vary?
It differs among individuals
It also differs during life within the same individual
What are factors that can upset the balance of GI flora?
- climate
- increased age
- medication - especially antibiotics
- illness and stress
- infection
- socioeconomic circumstances and lifestyle
How does intestinal bacterial composition change upon birth?
Foetuses are sterile in the womb
From birth, infants are exposed to microbes that originate from the mother and the surrounding environment
Why does an infant’s gut flora closely mimic the mother’s gut flora?
the infant tends to acquire flora swallowed from vaginal fluid at birth
Vaginal flora and intestinal flora are similar
At what age is colonic microflora considered adult-like?
2 years
What happens to the bacterial groups in the faeces after the climax microflora has been reached?
The major bacterial groups in the faeces of adults remain relatively constant over time
How do the types of bacteria in the elderly vary to younger adults?
The elderly harbour fewer bifidobacteria
They have higher levels of enterobacteria and Clostridium difficile
What a prebiotic and what is its role?
It is a non-digestible food ingredient
It will encourage a specific type of bacteria to grow over another
Why is a prebiotic beneficial to the host?
It selectively stimulates the growth and/or activity of one or a limited number of bacteria in the colon
This improves health
What must happen to the prebiotic before it can perform its role?
It is fermented by microflora colonising the GI tract in the large bowel
Where are prebiotics found?
Found naturally in breast milk and some foods (e.g. onions and bananas)
What is the pathway that leads from breast milk to the maturation of the mucosal immune system?
- breast milk
- inulin-type fructans (prebiotic)
- colonic fermentation
- acidic pH
- lactobacillus, bifidobacteria (probiotics)
- stimulation of intestinal host defences
- maturation of mucosal immune system
why does inulin pass through most of the digestive tract intact?
What happens to it in the colon?
It is indigestible by ptyalin and amylase (which digest starch)
In the colon it is fermented to release carbon dioxide, hydrogen and/or methane
what are probiotics?
dietary supplements containing potentially beneficial bacteria or yeasts
What are the 2 most common probiotic bacteria?
Lactobacillus and bifidobacteria
They are lactic acid producing Gram-positive bacteria
Why do people take probiotics?
Normal intestinal microflora play a role in enhancing resistance to colonisation by exogenous, potentially pathogenic organisms
What are the 6 main benefits of gut microflora?
- resistance to colonisation by pathogens
- stimulation of local immunity
- oral tolerance
- nutrition
- epithelial cell turnover
- intestinal motility
What is symbiosis?
The development of a poor immune response in the absence of commensals
Oral tolerance cannot be induced
What is meant by ‘nutrition’ being an essential benefit of gut microflora?
Intestinal flora has a high rate of metabolic activity
They complete for nutrients that are vital to the survival of pathogens
What is the problem with antibiotics and commensal bacteria?
Antibiotics cause massive death of commensal bacteria in the colon
This allows pathogenic bacteria to proliferate and colonise the colon
How do the commensal bacteria usually act as a physical barrier to prevent colonisation of pathogens?
The pathogens must be able to attach themselves to enterocytes before they can cause an infection
What % of intestinal microflora are potentially pathogenic?
What conditions are commonly caused by gut microflora?
15%
Irritable bowel syndrome and ulcers
Ulcers are caused by Helicobacter pylori
What is eubiosis?
A state of balance within the microbial population in the GI tract
what is dysbiosis?
A state of imbalance within the microbial population of the GI tract
The greater the imbalance, the greater the symptoms of GI tract disease
What extraintestinal diseases can be caused by gut microflora?
- septicaemia
- autoimmunity
- reactive arthritis
- allergy
What is the purpose of the intestinal mucosal barrier?
It is a single layer of cells that prevents penetration by microorganisms
What is meant by the epithelial barrier being a “self-renewing system”?
It undergoes continuous renewal from stem cells located near the base of the crypts of Lieberkhun
What will stem cells at the base of the crypts of Lieberkhun differentiate into?
- enterocytes
- goblet cells
- enteroendocrine cells
- paneth cells
what is the role of goblet cells?
They produce mucins to provide for mucous layers that resist microbial access
what are the roles of the mucus layer?
- it traps pathogens and the cilia waft them away
2. it prevents excessive proliferation of healthy bacteria
How do enterocytes remove pathogens?
They have cilial action that creates a current to remove microbes that are poorly adhered
What antimicrobial chemicals are produced by enterocytes?
- antimicrobial peptides
- lysozyme
- lactoferrin
- defensins
- cathelicidins
What is the problem with secretory IgA as a defence mechanism of the epithelial barrier?
It is of limited specificity to bind to microbes
What is ‘organised mucosal-associated lymphoid tissue’?
What is its role?
It is known as mucosal follicles
They are involved in the induction of immune responses (specific defence)
Where are mucosal follicles found?
- there are single follicles present along the length of the GI tract
- most follicles are aggregated in Peyer’s patches in the lower part of the SI and appendix
What are Peyer’s patches?
They act as the lymph nodes of the gut
What are ‘diffuse mucosal-associated comprising widespread lymphocytes’?
Intraepithelial lymphocytes that are interspersed between epithelial cells
Most of them are T cells (90%)
What is the role of leucocytes in the lamina propria?
They act as effector sites for immune responses
This includes lymphocytes, macrophages, mast cells and neutrophils
Within the GALT, what cells are found within Peyer’s patches?
- M cells
- antigen-presenting cells
- follicles containing B and T lymphocytes
Why are Peyer’s patches open to the gut environment?
It allows them to recognise any pathogens which may be present
M cells on the surface provide continuous surveillance
What is the first stage in induction of a specific immune response through a Peyer’s patch?
M cells take up antigens from the gut lumen
They pass the antigens to dendritic cells (APCs)
Dendritic cells present the antigen to T-cells
What happens after the dendritic cells have presented the antigen to the T cells?
The T-cells activate B cells
B cells migrate to mesenteric lymph nodes and differentiate into plasma cells
Plasma cells in the tissues secrete IgA
Where does T-cell priming occur?
In the mesenteric lymph nodes (MLNs)
How are T-cells involved in the induction of tolerance?
They induce tolerance by active suppression/clonal anergy
what are the 2 types of intestinal lymphocytes?
- intraepithelial lymphocytes (IEL)
2. lamina propria lymphocytes (LPL)
Where are intraepithelial lymphocytes located?
What do they mostly consist of?
Located between intestinal epithelial cells
Consist mainly of CD8+ cytotoxic T cells
What do intraepithelial lymphocytes produce?
- IL-2
- IFN gamma
- CCL5 (chemokine)
- perforin and granzyme
what are the functions of intraepithelial lymphocytes?
- epithelial homeostasis
- mucosal barrier function
- reactivity with stress-induced epithelial cell antigens
Where are lamina propria lymphocytes located?
What do they mostly consist of?
In the loose connective tissue that lies under the epithelium
Consist mainly of CD4+ helper T cells
what are the functions of the lamina propria lymphocytes?
- Th1 cells provides defence against intracellular pathogens
- Th2 provide antibody-mediated response to allergens and parasites
- Th17 cells provide defence against mucosal pathogens
Where is IgA synthesised?
Where is it transported to?
Synthesised by plasma cells in the lamina propria
Transported across the epithelium to be secreted in colostrum, maternal milk, salvia and tears
What is the role of IgA?
Ir prevents attachment of bacteria or toxins to the epithelia
What are the other functions of IgA?
- neutralises viruses and toxins
2. enhances non-specific defence mechanisms through lactoperoxidase and lactoferrin
What is a main property of IgA?
It is relatively resistant to proteolysis
What does IgA inhibit?
- bacterial adhesion
- macromolecule absorption
- inflammatory effects of other antibodies
