Mucosal Immunity Flashcards
what are the physiological functions of mucosal tissues
gas exchange, food absorption, sensory activities, reproduction
what makes the mucosal tissues highly vulnerable
fragile and permeable
give an example of a non pathogenic antigen
dietary protein
what does trans and para cellular mean
para- travelling in tight gap between
trans- travelling through cells
describe how the mucosal tissues of the body are unified
an immune response in one can be common in all sites
what are the mucosal tissues of the body
GI tract, resp tract, uro-genital tract, mammary glands, kidney
what is the role of the primary lymphoid tissue
regulate and monitor antigen passage
how do immune cells evoke a response in the lymph nodes
dendritic cells come to the lymph nodes with antigens and look for T cells that will recognise antigens- if found = immune response, proliferation, differentiation and production of antibodies
describe the anatomical features (3) of the gut mucosal immune system
intimate relationship between mucosal epthelia and lymphoid tissue
organised lymphoid tissue structures unique to mucosal sites
specialised antigen uptake mechanisms to maximise sampling
what are the effector mechanisms of the gut mucosal immune system
activates/ memory T cells
natural effector/ regulatory T cells responsible for down regulating immune response aswell
what are effectors and roles of the immmunoregulatory environment within the gut mucosal immune system
inhibitory macrophages and tolerising dendritic cells
active down regulation of immune response
what is peyers patch
specialised lymph node (secondary lymph tissue) that sits in the epithelium of the gut, site of antigen sampling of gut contents
where are lymphoid tissues found in the gut
scattered throughout lamina propria of intestine and in organised lymphoid tissues- peyers patch
what covers the peyers patch
an epithelial layer containing specialised cells called M cells which have characteristic membrane ruffles
describe the structure and role of M cells
M for microvilli which cover the surface to increase SA
antigen sampling- acts as a gateway to peyers patch. beneath M cell in dendritic cell that processes and presents antigen to T cells which leave patch and move to mesentery lymph nodes
how do M cells sample the gut contents and transport the antigens to the T cells
M cells take up antigen by endocytosis and phagocytosis
antigen is transported across the M cell in vesicles and released at the basal surface
antigen is bound by dendritic cells which activate T cells
how can dendritic cells sample the gut contents
can extend processes across the epithelial layer
what is the main site of antigen sampling
lamina propria
what are to distinct compartments of the mucosal immune system
the epithelium and the lamina propria
what are the immune cells of the lamina propria
CD4 T cells, dendritic, macrophage, mast, DC, IgA, plasma cell
what are the immune cells of the epithelial layer
CD8 T cells, dendritic cells
describe the pathway of T cells to and from the peyers patch
enter via bloodstream, activated, drain via mesenteric lymph nodes to the thoracic duct, return to gut via blood stream, travel to lamina propria to carry out effector function
how does the T cell leave the small intestine
gut homing effector T cells bind to MAdCAM-1 on endothelium
gut epithelial cells express chemokines specific for gut homing T cells which allow the movement into the lamina propria
where can lymphocytes primed in the gut migrate to
other mucosal sites
what is the most common imunoglobulin in the intestine
IgA (mucosa) 80%
IgM 15%
IgG 5 %
reverse of systemic immune response
what does a dimeric immunoglobulin mean
two molecules joined together by a J (joining) chain
what path do immunoglobins take in the intestine immune response
binds to receptor on basolateral face of epithelial cell ( in lamina propria)
endocytosis and transcytosis to the apical face of cell
released into lumen
what is the role of the IgA that is released into the lumen
bind to and neutralise pathogens and toxins
is then internalised by endosomes
exports toxins and pathogens form the lamina propria
how can people with IgA deficiency be a-symptomatic
as IgM can replace IgA as is also a polymeric Ig can used same polymeric Ig receptor on epithelial cells
what is the most common intraepithelial lymphoctye
90% T cells (80% of these T cells CD8+)
why dont intraepithelial lymphocytes have normal function
as they have resticited antigen receptor repertoire and are anchored to the epithelial lining by an intergrin
what is the role of intraepithelial lymphoctyes
virus infects mucosal epithelium cell
infected cell displays viral peptide to CD8 IEL via MHC class I
activated IEL kills infected epithelial cell by perforin/granzyme and Fas-dependent pathways
when do epithelial cells undergo stress
as a result of an infection, damage, toxic peptides
what happens to stressed epithelial cells
stress receptors
killed by activated IEL via the perforin/granzyme pathway
protect cells around stressed one
what happens to the epithelium when cells start to get killed
flattened epithelium as cells cannot be produced from the crypts as fast as they are being killed
what is oral tolerance
Default response to oral administration of protein state of specific peripheral unresponsiveness
body has discriminated between pathogen and innocuous agent
what immune responses are mediated the most and why
T cell and IgE responses as these are the ones that cause damage do the host
what do commensal organism help with
regulate local hyporesponsiveness
what are the mechanisms of mucosal hyporesponsiveness
Anergy or deletion of antigen specific T cells- no costimulation
(anery = absence of the normal immune response to a particular antigen or allergen)
Generation of regulatory T cells- weak costimulation
both induce B cells to make IgA which is protective not inflammatory
what causes crohns disease
inappropriate responses to commensal organisms
how do commensal bacteria regulate hyporesponsiveness
block gene transcription and inhibit dendritic cell maturation leading to CD4 T cells differentiating into TH3 or Treg cells
how do pathogens not cause hyporesponsiveness
active gene transcription and activate dendritic cells meaning CD4 T cells differentiate into TH1 and TH2 cells
what is the mucosal response to infection
innate mechanisms eliminate most intestinal infections rapidly
activation through ligation of pattern recognition receptors (e.g. on dendritic cells)
intracellular sensors in epithelial cells (PRR) activate the NFkB
Gene transcription and production of cytokines, chemokines and defensins
activation of underlying immune response
what is the outcome of intestinal pathogens determined by
the microorganism and the host immune response:
CD4 T cells activated and can differentiate into TH1 (host damage) or TH2 cells (protective)
what are the effector functions of TH2
TH2 usually protective, induces cytokines:
-(IL 13) increases the production of mucous and induces epithelial cell repair
-(IL 5) recruits and activate eosinophils
-(IL 3 and 9) drive mast cell recruitment
drive B cells to produce IgE
what are TH1 cell effector functions
activate macrophages
activate B cells to produce IgG2a
what is the main antibody for parasites
IgE
how does the HIV virus dysregulate mucosal immunity
destroys memory cells:
HIV infects dendritic cells, uses dendritic cell activation to move itself to lymph nodes where it infected T cells, activating them, using them to move back to mucosal sites and infect all CD4 cells in mucosal site, enters blood stream and causes widespread dissemination
what is the most common mucosal disorder associates with primary immuno deficiency
selective IgA deficiency
what is CVID and describe it
common variable immune deficiency
- recurrent sinopulmonary and GI bacterial infections, presents in adulthood
- failure to differentiate Ig secreting cells do low immunoglobulins
- can cause irrversible damage e.g bronchiectasis
what is XLA, describe it
x linked agammaglobulinaemia
- sinopulmonary and GI infection
- no B cells
- presents in boys at 7-8 months as IgA from breast milk stopped
what is CGD, describe it
chronic granulomatuos disease
- staphylococcus aureus/inflammatory granulomas infections (pneumonia, liver abscess, liver perianal and skin abscess)
- failure of phagocyte respiratory burst (how neutrophils kill pathogens)
what is SCID, define it
severe combined immunodeficiency
- T and B cell defects
- present in early life with fungal and viral infections
what is a food allergy reaction caused by
Type I hypersensitivity reaction initiated by crosslinking of allergen specific IgE on the surface of mast cells with the specific allergen.
Memory response- immune system must be primed
why do food allergens affect the body in a similar way to venoms or IV drugs
as venoms and drugs in bloodstream, cause a response in epithelium mast cells
food passes as unprocessed proteins through into bloodstream from gut
how are mast cells involved in an allergic reaction
IgE binds to FC receptor on mast cells activating them. Activated mast cells provide contact and secreted signals to B cells to stimulate IgE production
cause
-release of histamine
-cause rhinitis and asthma due to contraction of bronchial smooth muscle and increased mucous secretion
-causes contraction of intestinal smooth muscle causes vomiting
what is coeliac disease
gluten sensitivity enteropathy- genetically linked auto-immune disorder causing damage to the small intestine leading to malnutrition
how is coeliac cured/ treated
incurable, treated via avoidance of gluten
is coeliac disease an allergy
no- as not mediated by IgE, instead mediated by T cells and IEL
what is thought to cause coeliac
genetic susceptibility, trigger unknown
what is the immune pathway of coeliac disease
Gamma interferon from Gluten specific T cell activate epithelial cells which produce IL-15 which induces proliferation and activation of IEL
Both T cells and IEL can then kill epithelial cells
what component of the immune system leads to the damage of the intestinal epithelium
cytokines released by activated lymphocytes
what happens when a coeliac stops eating gluten
the damaged, lymphocyte infiltrated enterocytes are replaced by normal columnar ones, assuring normal transport from the body into the lumen, gut returns to normal
how is coeliac disease diagnosed
biopsy, serology for IgA anti- TTG
what is anti tTG antibody
produced by B cells, helped by T cells, in response to gluten tTg complex (in coeliac disease)
what part of the GI tract does crohns afffect
any part- from mouth to anus- commonly distal ileum and colon
what is crohns disease characterised by
focal and discontinuous inflammation with deep and eroding fissures +/- granulomas
what mediates crohns disease
TH1, CD4+ T cells, gamma interferon, IL-12, TNF alpha (really inflammatory) - T cell mediated
what is thought to cause crohns disease
multiple genetic deficiency and immunologic mechanisms (multifactoral)
what is crohns a form of
inflammatory bowl disease
what is ulcerative colitis
form of inflammatory bowl disease
what part of GI tract is affected by UC
restricted to rectum and colon- starts in colon and moves proximally and contiguously (can develop extra intestinal manifestations- arthritis, uveitis and skin lesions)
what is UC characterised by
distortion of the crypts with infiltration of monocytes/ neutrophils and plasma cells
inflammation and ulceration in the surface mucosa
what cant you make without IgA
antibodies
in both crohns and UC what is produced in large amount
the inflammatory cytokines IL-1, IL-6 and TNF alpha
what are the pharmacological treatements for crohns and UC
Non specific anti-inflammatory and immunosuppressive drugs steroids/azathioprine/cyclosporin/methotrexate
anti-TNF alpha
