PMI02-2006 Flashcards
What is the surface area of the gut and the skin?
Gut = 400m^2
Skin = 2m^2
What is the main route of entry for infectious microbes?
Mucosal surfaces
Compare systemic and mucosal environments.
Systemic = contained, sterile and rarely encounters unidentified antigens
Mucosa = Exposed, non-sterile and encounters unidentified antigens continuously
What is the importance of mucosal immunity?
Protection against pathogens
Prevention of hypersensitivity to foods/commensals
Immunopathology
Vaccine development (administered via mucosa)
Lymphocyte development
What is included under the term “mucosal surfaces/tissues”?
GI tract
Uro-genital tract and kidneys
Eyes, nasal and oral cavity, lungs (respiratory tract)
Exocrine glands (lacrimal, salivary, mammary)
What non-immunological barriers are present at mucosal surfaces?
Natural barriers (eg stomach acid)
Mucin
Peristalsis
Proteolysis/enzymes
Tight junctions
What immunological barriers are present at mucosal surfaces?
Secretory IgA/IgM
Intraepithelial lymphocytes
Phagocytes
What are the two types of regional secondary mucosal immune tissues?
Inductive and effector sites
What are inductive sites?
Where the immune response is induced and regulated
What are effector sites?
Where the immune response has an impact
What does MALT stand for?
Mucosal associated lymphoid tissue
Inductive and effector sites
What is meant by the common mucosal immune system?
All the different mucosal surfaces of the body are part of one “common” system connected by the lymphatic and circulatory systems
Exposure at one inductive site will give rise to responses in many effector sites
What are the inductive and effector sites of the GALT?
Inductive = Peyer’s patches, isolated lymphoid follicles, mesenteric lymph nodes
Effector = lamina propria
Describe Peyer’s patches.
Sub-epithelial follicles located throughout the small intestine (~200 in humans)
50% B cells, 30% T cells, 8% macrophages
(Very few plasma cells)
Connected to lymphatic system via efferent lymph vessels only (via mesenteric lymph nodes)
B cells here give rise to IgA-producing plasma cells which can move to all mucosal sites in the body
Describe isolated lymphoid follicles.
Induced by products of commensal gut microbes (so are not present before birth)
Mainly B cells, some T cells and dendritic cells
More numerous than Peyer’s patches
What are M cells associated with?
Peyer’s patches
Isolated lymphoid follicles
What does the M in M cells mean?
Microfold
Describe M cells.
Unique epithelial cell subset existing within the main epithelial layer above Peyer’s patches and isolated lymphoid follicles
Specialised in uptake and transepithelial transport of particulate antigens (large and bulky)
No brush border but instead have surface folds
Large basal invagination to allow dendritic and T/B cells to engage and rapidly contact antigens
Describe how T cell activation occurs at M cells.
- M cell takes up antigen by endocytosis or phagocytosis
- Antigen is transported across M cell in vesicles and released at basal surface
- Antigen is bound by dendritic cells which activate T cells
Give an example of an antigen that will be transported across an M cell.
Toxins of Cholera, Salmonella, Campylobacter, Yersinia, Shigella, E.coli
Latex particles
Horseradish peroxidase
Ferritin
Poliovirus, HIV
Fungi
What occurs at Peyer’s patches?
T/B cells become fully activated (also in mesenteric lymph nodes)
T/B cells switch expression from L-selectin and CCR7 to α4β7 integrin and CCR9 so they home more readily
B cells class switch to IgA
What cells are specific to the mucosal immune system?
(Epithelial cells)
M cells
Intraepithelial lymphocytes
γδ T cells
What type of T cell is most common in the lamina propria?
CD4+ T cells (2x the amount of CD8+)
What does α4β7 integrin recognise?
MadCAM
What does each type of Th cell in the lamina propria do and what do they secrete?
Th1 = activate macrophages via IFNγ
Th2 = induce B cell class switching to IgA via IL-5
Th17 = maintain epithelial barrier via IL-22, activate neutrophils via IL-17
Describe intraepithelial lymphocytes.
T cells, majority are CD8αα (homodimer)
Up to 70% may be γδ T cells (especially in germ-free animals)
Express αEβ7 integrin which recognises E-cadherin on enterocytes
Unresponsive to TCR stimulation
Many are extrathymically derived
What does αEβ7 integrin recognise?
E-cadherin
What is immune cell migration to epithelial cell surfaces dependent on?
Chemokines
Give an example of a chemokine released by epithelial cells.
CCL25
CCL20
What chemokine receptor binds CCL25?
CCR9
What chemokine receptor binds CCL20?
CCR6
Describe the process of homing/migration to epithelial tissues by immune cells.
- Chemoattraction - chemokines recruit lymphocytes and induce adhesion molecule expression on lymphocytes and endothelial cells
- Rolling adhesion - lymphocytes bind loosely to endothelial cells and rolls along (L-selectin and MadCAM-1)
- Tight adhesion - interaction between L-selectin and MadCAM-1 leads to α4β7 integrin expression which binds strongly to MadCAM-1 to stop rolling
- Further “inside-out” signalling causes expression of ICAM-1/2 and LFA-1 which help stop rolling
- Diapedesis - junctions between endothelial cells become loose and lymphocyte penetrates into tissues/extravasates
What adhesion molecules are expressed during the chemoattraction stage of homing?
L-selectin = T cell
MadCAM-1 = endothelial cell
What adhesion molecules are expressed to arrest rolling during homing?
α4β7 integrin on lymphocyte (to bind MadCAM-1)
ICAM-1/2 (endothelial cells)
LFA-1/αLβ2 (lymphocytes)
What is class switching of B cells to IgA mediated by?
TGF-β
IL-5
Describe secretory IgA synthesis.
- Similar production of monomeric IgA as IgG
- Cell also produces J chain which associates with IgA molecules to form a dimer which is secreted from plasma cells
- Dimer binds to secretory chain receptor (polymeric IgA receptor) on basal membrane of epithelial cell
- Endocytosis and disulfide bonds form with IgA and secretory component
- Released at apical surface after cleavage (IgA-secretory component complex)
What do both IgA and IgG do?
Neutralise viruses, enzymes and toxins
Inhibit adherence
Agglutinate
Why do the mechanisms of defence by IgG and IgA differ?
Environment
IgG in serum so lots of complement and phagocytes present
IgA on mucosa so diluted complement and few phagocytes
What functions does IgA have?
Immune exclusion - prevent microbe entering body
Intracellular neutralisation of pathogens during synthesis/transcytosis - also allows prevention of virus secretion
Associate with non-specific factors (lysozyme, lactoferrin, peroxidase) to target them at microbes/toxins
What are the mucosal functions of Treg cells?
Maintain an environment that:
- doesn’t respond to commensals
- doesn’t respond to food/ingested antigens
- does respond to pathogens
What two substances are essential in Treg cell regulation of responses in mucosal immunity? What do they control?
TGF-β
Retinoic acid
Control:
- mucosal homing
- dendritic cell activation
- induction of Treg cells
What are the functions of intraepithelial lymphocytes?
Protect and maintain epithelial barrier to protect against infection
Act via MHC class I—CD8 interaction to cause apoptosis of virally infected cells by Fas-Fas ligand or perforin granzyme action
What is meant by mucosal tolerance?
State of immune non-responsiveness to antigens induced by feeding/exposure at mucosal inductive sites
How was mucosal tolerance discovered?
Group of mice fed ovalbumin over 7 days
These mice did not develop an immune response to ovalbumin injected but control group developed strong responses
What are necessary features for mucosal tolerance?
Normal immune function
Symbiosis (absence of commensals leads to poor immune function so mucosal tolerance won’t be maintained)
What are the general properties of mucosal tolerance? (8)
Antigen specific
Often partial (only part of immune response inhibited)
Incomplete (only reduced levels rather complete abolishment of one component)
Wanes with time
Tolerance can be local or systemic - common immune system
Adjuvant addition = better the immunogen, better the tolerance induced
Dose and route dependent
Less impact on already immunised animals (as easier to abrogate a response than reduce an already established one)
What happens when mucosal tolerance is not maintained?
Immune responses to food/food intolerance (eg coeliac disease)
Immune responses to commensals => inflammatory bowel diseases (eg Crohn’s disease, ulcerative colitis)
What are the two proposed mechanisms in mucosal tolerance?
Vitamin A/retinoic acid and TGF-β from epithelial cells driving dendritic cell activity
Induction of anergy
How do TGF-β and retinoic acid contribute to mucosal tolerance?
Causes dendritic cells to drive T cell differentiation from naive CD4+ to an inducible Treg phenotype as well as maturation of natural Tregs
Dendritic cells and Tregs go on to activate a general suppressive response in other Th cells responding to the same antigen
Describe induction of anergy.
Some epithelial cells in the gut and lungs normally express MHC class II but no co-stimulatory molecules
When these cells present antigens to T cells, there is no secondary activating signal via CD28 leading to anergy of responsive T cells => non-responsive T cells
