Mucosal Immune Defences Flashcards
Mucosal surfaces:
Mucosal surfaces (mucosae) are predominately out of sight Continually bathed in layer of thick fluid that they secrete = mucus
Mucus contains:
- glycoproteins
- proteoglycans
- peptides
- enzymes
Mucosal surfaces comprise epithelial cell layer lining:
- gastrointestinal tract
- respiratory tract
- urogenital tract
Also present in exocrine glands associated with:
- pancreas
- conjunctivae and lacrimal glands of eye
- salivary glands
- mammary glands of lactating breast
Mucosal Surface Functions:
Sites of communication – material and information passes between body and environment
Functions of gas exchange, food absorption, sensory activity and reproduction require surfaces to be dynamic, thin, permeable barriers. This renders the mucosal surface vulnerable to subversion and breach by pathogens.
Mucosal Defence:
Mucosal surfaces have a combined surface area of ~400 m^2 (about 200 times that of skin)
Covered largely by monolayer of epithelial cells
Very large numbers of antibody-producing cells (exceed those of spleen, lymph nodes and bone marrow combined)
Secretion of 5-15 g antibody onto mucosal surfaces/day
Defence of GI Tract:
Continuous contact with large populations of commensal microorganisms as well as large quantities of “foreign” material (food).
How to make immune responses that eliminate pathogenic microorganisms, limit the growth and location of commensals, but do not attack food?
GI tract has distinct secondary lymphoid tissues
Secondary lymphoid tissues and immune cells spread throughout gut and other mucosal tissues
Present in surface epithelium and in underlying connective tissues = lamina propria
Mesenteric lymph nodes defend gut = largest nodes in body arranged in a chain within gut connective tissue
Gut associated lymphoid tissues – GALT – has B and T cell zones like other secondary lymphoid tissues
Adaptive immune responses initiated locally in mucosa
Guarding entrance to gut are palatine tonsils, adenoids, and lingual tonsils = large aggregates of secondary lymphoid tissue covered by layer of squamous epithelium – form Waldeyer’s ring
Characteristic secondary lymphoid organs of intestine are Peyer’s patches
- Dome-like aggregates of lymphocytes of varying size
- 5-200 B cell follicles with germinal centres, T cell areas, and dendritic cells
Can also have “isolated lymphoid follicles”
Both types of lymphoid structure overlaid by specialized epithelial cells called microfold (M) cells
Microfold (M) Cells:
Characteristic ruffles or microfolds on surface
Absence of microvilli
Unlike enterocytes, M cells:
- do not secrete digestive enzymes or mucus,
- lack thick surface glycocalyx
- have weak system of lysosomes
M cells do:
- Take up intact microorganisms and particulate antigens from gut lumen
- Transport them to Peyer’s patch to initiate adaptive immune response
Antigen sampling in the gut:
Healthy gut epithelium actively monitors contents of the gut lumen
Enables appropriate adaptive immune responses to be made against invading pathogens
M cells of Peyer’s patch and isolated lymphoid follicles can uptake pathogens from lumen and transcytose them across epithelium into lymphoid tissue below – continuous sampling
Dendritic cells resident in lamina propria can also capture pathogens independently of M cells
Uptake and transport of antigens by M cells:
- M cell basal membrane is extensively folded to form a pocket
- Lymphocytes and dendritic cells lie in the pocket and transcytosed pathogen is delivered to them by the M cell
- Dendritic cells (DC) and B cells take up the microbes, process them, and present antigens to naïve T cells
- Ag-loaded DC either migrate from dome region to T cell areas of Peyer’s patch, or via draining lymph node to mesenteric lymph node
- There they stimulate Ag-specific naïve T cells to proliferate and differentiate
Dendritic cells in lamina propria outside organised lymphoid tissues capture pathogens:
In response to infection, Dendritic Cell mobility increases
Move to epithelial wall and extend processes between enterocytes
These capture microbes and antigens from gut lumen without disrupting integrity of epithelial barrier function
With cargo of antigens, Dendritic Cells move to T cell area of GALT or travel via draining lymph to T cell area of mesenteric lymph node
Lymphocytes activated in BLANKS return as BLANKS
Lymphocytes activated in mucosal tissues return as effector cells
Homing of effector T cells controlled by adhesion molecules and chemokines:
Gut-homing effector cells express integrin α4β7
- binds to mucosal vascular addressin MAdCAM-1 on endothelial cells of gut wall blood vessels
Chemokine CCL25 secreted by epithelium of small intestine binds to its receptor CCR9 on effector lymphocytes and guides them into gut tissue
T cells destined to become IEL express CCR9 and αEβ7 which binds to E-cadherin on epithelial cells -> intercalation into epithelium
Effector lymphocytes activated at one mucosal site recirculate through all mucosal sites
TRUE OR FALSE
TRUE
Naïve B cells activated in PP and mesenteric lymph nodes preferentially isotype switch to IgA
Directed by transforming growth factor β (TGFβ), a cytokine
Subsequently B cells leave the lymphoid tissue via lymph and blood, then return to the same lamina propria or to other mucosal sites (common mucosal immune system)
Differentiate into plasma cells and secrete dimeric IgA into subepithelial space
Human IgA
Important serum Ig (2-3 mg/ml)
Major antibody in seromucous secretions e.g. saliva, milk, colostrum gut tracheobronchial system urogenital tract
Class of antibody first encountered by many invading bacteria and viruses.
Classes:
IgA1
IgA2m(1)
IgA2m(2)
Serum IgA effector functions:
- Activation of complement via mannose binding lectin pathway
- FcαRI-mediated functions
IgA
- Exists in both monomeric and dimeric forms
- Serum IgA is chiefly monomeric, 9:1 IgA1:IgA2
- Secretory IgA is predominantly dimeric 40:60 IgA1:IgA2.
Has additional polypeptides: J chain and secretory component (SC)
SC derives from receptor mediating export to secretions - SC protects against harsh environment of secretions
Human Fc receptor is specific for BLANK
Human FC receptor is present on BLANKS
Human Fc receptor binds BLANK
Human Fc receptor is a very efficient trigger of:
Human Fc receptor is specific for human IgA Fc
Human Fc receptor is present on neutrophils, macrophages, monocytes, and eosinophils.
Human Fc receptor binds serum IgA1 and IgA2, and secretory IgA1 and IgA2
Human Fc receptor is a very efficient trigger of:
Phagocytosis
Superoxide generation
Enzyme release
