GI Immunology Flashcards
What are the major components of the innate immune system?
- Cells (macrophages, dendritic etc)
- Complement components
- Cyotkines
- Antimicrobial peptides
- PRR (Patter Recognition Receptors)
What do PRRs recognise?
Pathogen associated molecular patterns (PAMPs) but also Danger associated molecular patterns (DAMPs)
What are the 2 groups of PRRs?
- Cell surface (transmembrane) and intracellular receptors - TLRs, NLRs, RLRs and CLRs
- Fluid-phase soluble molecules
What are NK-T cells?
Lymphocytes with both T cell and NK surface markers that recognise lipid antigens of intracellular bacteria such as M. tuberculosis by CD1 molecules and kill host cells infected with intracellular bacteria.
Job of NK cells?
Kill foreign and host cells that have low levels of MHC+ self peptides. Express NK receptors that inhibit NK function in the presence of high expression of self-MHC
What is the adaptive immune response?
Evolution in response to changing pathogen structures
Adaptive immune system utilises existing systems to generate DIVERSITY of antigen receptors
What is the central feature of the adaptive immune system?
- Unique antigen receptor found on each lymphocyte
- In response to infection this lymphocyte undergoes CLONAL expansion
Is the adaptive immune system specific?
High degree of specificity
What receptors are involved in the adaptive immune system?
- B cell antigen receptors (immunoglobulin)
- T cell antigen receptor
Describe the method of antigen presenting
- Antigens are internalised
- Broken down to peptides
- Peptides associate with newly synthesised Class 2 molecules and brought to cell surface
- If peptides are foreign, they are recognised by T helper cells that are then activated
- T helper cells produce cytokines needed by B cells, T cells etc
What do T cells recognise?
T-cells recognise epitopes
presented via MHC molecules by professional Antigen Presenting Cells (APCs)
What is humoral immunity?
Antibody-related
What are the different types of T cells?
- Killer or cytotoxic T cells
- T helper cells
- Suppressor T cells
What are T helper cells also known as?
CD4+
What are killer T cells also known as?
CD8+
What is function of killer T cells?
Kill pathogens
What is the function of T helper cells?
- Secrete cytokines which control immune response
- Active B cells and T cells
(Are target of HIV)
What is function of suppressor T cells?
Dampen down immune response
Where is the major site of contact in the body for foreign antigens?
The gut
What is the first line of defence in the gut?
Mucosal surface - separate the external environment from the internal sterile environment and therefore represent the first line of defence
What different responses may various antigens require?
- Ignorance/tolerance (active suppression)
- Robust protective immune response
Gut immune system is capable of both of these things
What are the innate defences of the gut immune system?
- Commensal bacterial flora
- Epithelial barrier
- Biochemical factors produced by epithelial cells
What are the specific defences of the gut immune system?
Lymphoid tissue associated with mucosal surfaces [Gut associated lymphoid tissue; GALT]
What is ‘commensal’?
Living together in non-harmful coexistence
What is the optimum gut flora balance?
Beneficial bacteria should predominate and present a barrier to invading organisms
What can upset gut flora balance?
Age, illness, antibiotics etc
What is breast milk a source of?
Prebiotics
How are prebiotics able to reach the bowel unmodified?
Resist host digestion and absorption in stomach and SI
What happens to prebiotics when it reaches the bowel?
- Fermented by microflora in GI tract
- Might selectively stimulate the activity of potentially beneficial bacteria
What are the benefits of gut microflora?
Resistance to colonisation by pathogens Stimulate local immunity Oral tolerance Nutrition Epithelial cell turnover Intestinal motility
What is colonisation resistance?
Is the ability of normal gut flora to impede growth of pathogens
What can antibiotics cause?
Treatment with antibiotics causes massive death of the commensal bacteria that normally colonise the colon. This allows pathogenic bacteria, e.g. C. difficile, to proliferate and occupy an ecological niche that is usually occupied by the harmless commensals.
What are the hazards of gut microflora?
Disease of GI tract (IBS, ulcers)
Extraintestinal disease
Autoimmunity
Allergy
What is the function of the epithelial barrier?
- Prevents penetration by microorganisms
- Intestinal mucosal barrier is a single cell layer
How is the epithelial barrier self renewing?
Self-renewing system undergoing continuous renewal from stem cells located near the base of the crypts of Lieberkhun
What can stem cells of the GI tract differentiate into?
Enterocytes [E]
Goblet cells [G]
Enteroendocrine cells [E]
Paneth cells [P]
How are goblet cells involved in defence?
Produce mucins to provide for mucus layers that resist microbial access
How are enterocytes involved in defence?
- Mechanical action – cilia action creates current to remove microbes that are poorly adhered
- Produce antimicrobial peptides (defensins, cethelicidins)
- Produce antimicrobial proteins (lysozyme, lactoferrin)
How is secretory IgA involved in defence?
May be of limited specificity to bind to microbes
What does the correct function of the immune system of the gut require?
- Tolerance vs commensal microbial flora and food antigens
2. Protective immunity vs pathogens
What can the lymphoid elements of the mucosal tissues be divided into?
- The organised mucosa associated
lymphoid tissue - The diffuse mucosa associated lymphoid tissue
What is the organised mucosa associated
lymphoid tissue responsible for?
The induction of the immune response
What does the organised mucosa associated lymphoid tissue consist of?
Mucosal follicles
How are the mucosa follicles of the organised mucosa associated lymphoid tissue arranged?
- Aggregated follicles in Peyers Patches [lower part of small intestine; Ileum], appendix.
- Single follicles in along length of GI tract
What does the diffuse mucosa associated lymphoid tissue consist of?
Widespread leukocytes scattered throughout the epithelium and the lamina propria of the mucosa
What is the diffuse mucosa associated lymphoid tissue responsible for?
Effector sites for immune response
What is GALT?
Gut-associated lymphoid tissue (GALT) is a component of the mucosa-associated lymphoid tissue (MALT) which works in the immune system to protect the body from invasion in the gut.
What are peyer’s patches?
Groupings of lymphoid follicles in the mucus membrane that lines your small intestine
Specialised sites of initiation of immune responses
What are M cells? Where are they found?
Found in Peyer’s patches
Microfold cells - specialised
What is the job of M cells?
Transport antigens from the lumen to cells of the immune system, thereby initiating an immune response or tolerance
Pass antigens to professional APCs [dendritic cells]
Describe the induction of the specific immune response involving peyer’s patches
M-cells pass antigens to professional APCs [dendritic cells]
Dendritic cells present antigens to T-cells and B-cells are activated
B-cells migrate to mesenteric lymph nodes
Differentiated plasma cells migrate to tissues
Plasma cells secrete IgA
Where does T cell priming occur?
MLNs
What do inductive response leads to?
Oral tolerance
What are the main cell type involved in the induction of tolerance by active suppression/clonal anergy?
T cells
What are the 2 main types of intestinal lymphocytes?
- Intraepithelial lymphocytes (IEL)
2. Lamina Propria lymphocytes (LPL)
Where are intraepithelial lymphocytes (IEL) found?
Between intestinal epithelial cells
What are intraepithelial lymphocytes?
Mostly CD8+ (cytotoxic T cells)
What do intraepithelial lymphocytes produce?
Produce IL-2, IFN-g, CCL5 [a chemokine]
What is the function of IELs?
- Epithelial homeostasis
- Mucosal barrier function
- Reactivity with stress-induced epithelial cell Antigens
Where are LPLs found?
Found in loose connective tissue, the lamina propria, that lies under the epithelium – together make up the mucosa
What are LPLs?
Mostly CD4+ (helper T cells):
- Th1 cells: cell-mediated responses (intracellular pathogens)
- Th2 cells: antibody-mediated responses (allergens, parasites)
- Th17 cells: cell-mediated responses (mucosal pathogens, irritable bowel syndrome)
Where is IgA synthesised?
Synthesised by plasma cells in lamina propria then transported across epithelium
Where is IgA secreted?
In colostrum, maternal milk, saliva and tears
What is function of IgA?
- Prevents attachment of bacteria or toxins to epithelia
- Protects against infectious agents
What are the properties of IgA?
- Relatively resistant to proteolysis
- Neutralises viruses and toxins
- Enhances non-specific defence mechanisms (Lactoperoxidase, Lactoferrin)
Inhibits - Bacterial adhesion
- Macromolecule absorption
- Inflammatory effects of other Igs
