Immunology Flashcards
What is a major source of pathogen in the GI tract?
Mucosal tissue
What does GALT stand for?
Gut Associated Lymphoid Tissue
What are the Immune structures of the GI tract?
Epithelial and mucus barrier
DCs (dendritic) and M cells
Innate cells and lymphocytes in the lamina propria
Organised. ALT Peyer’s patches
IgA secreting plasma cells
What is the purpose of Epithelial cells in the GI tract?
Form tight junctions to prevent entry into the lamina propria
Express PRRS (I.e. TLR), particularly on the basolateral surface
What is the purpose of Globet cells in the GI tract?
Produce highly glycosylated protein called muffins which generate the mucus barrier , preventing pathogen access to the epithelium.
Can be unregulated and modified by cytokine and bacterial infection
What is the purpose of Paneth cells?
Found at the base of the crypts and produce anti-microbial peptides.
In the small intestine, alpha-defending are produced as inactive precursors, cleaved by trypsin (also produced by Paneth cells).
Produce REGIII proteins that block bacterial colonisation, and can be bactericidal
What is the purpose of Microfold cells (M cells)?
Allow sampling of antigens from the lumen
What are the innate immune cells of the GI tract?
macrophages
What in the function of macrophages in the GI tract?
Highly phagocytic
Kill microbes
Secrete anti- inflammatory cytokines I.e. IL-10.
Do not produce inflammatory cytokines
Support regulatory T-cells in the GI tract
What are the adaptive immune cells of the GI tract?
Lymphocytes
Where are lymphocytes in the GI tract found.
Through the GI tract
In the lamina propria
As intraepithelial lymphocytes
What kind of function do adaptive cells perform?
Effector functions
What are the sites of immune activation and draining of lymph node?
Peyer’s patches
Isolated lymphoid follicles
What type of cell are Dendritic cells (DC)?
Antigen presenting cells (ADCs))
What is the function of antigen presenting cells (APCs) in the GI tract?
Sample antigens for presentation to T cells in GALT and mesenteric lymph
Some DCs extend dendritic processes between intestinal epithelial cells into the lumen.
True or false?
True
Wha is the function of Dendritic cells (DC) present in the lamina propria?
Sample anti gents that are derived from luminal contents and have gotten through the epithelial barrier
What does the epithelial layer of Oeyer’s patch contain?
Ordinary epithelial cells
M (microfold) cells
What is the function of M cells?
These cells are involved in continuous antigen sampling from the lumen, and deliver them via endocytosis to dendritic cells which then present to T cells.
Typical intestinal cells have villi while M cells have?
Irregular ruffled surfaces
Why ateM cells not protected as other epithelial cells?
M cells do not produce digestive enzymes or mucus and so are not protected from pathogens
Why a have some microbes have evolved to take advantage of M cells as a route of invasion through the mucosal barrier.
Because M cells do not produce digestive enzymes or mucus
Where are lymphocytes typically activated?
Secondary lymphoid organs are where lymphocytes interact with antigen and become activated.
What are encapsulated lymphoid tissue?
Lymph nodes- antigen from the tissues
Spleen- antigen from blood
What are the non-encapsulated lymphoid tissue?
Mucosa-associated lymphoid tissues(MALT) - antigen from mucosa
MALT represents the largest immune surface area and largest number of immune cells
True or false?
True
What is a distinctive feature of lymphocytes?
Recirculation between the blood, lymphoid organs and tissues
What is recirculation in lymphocytes?
Allows for low-frequency antigen-specific lymphocytes to sample antigens captured within the body
What controls cell migration ?
Specialised lymphocyte surface receptors inning to complementary receptors on the vessel walls of the tissue they enter
How do Dendritic cells with pathogen enter the lymph node?
Through lymphatic vessels.
What happens during circulation of lymphocytes?
DCs bearing antigen enter the lymph nodes through lymphatic vessels.
Naïve lymphocytes leave the blood and enter lymph nodes across the high endothelial venules (HEVs).
If the lymphocytes are activated, they return to the circulation via efferent lymphatics.
Effector cells preferentially leave the blood and enter peripheral tissues through venules at sites of inflammation.
Where in the Lymph node are T cells found?
Paracortex
Where are B cells found in the lymph node?
Found in the follicles within the cortex
Some follicles (secondary follicles) contain central areas called germinal centres.
Germinal centres (GC) develop in response to antigenic stimulation and are sites of B cell proliferation, somatic hypermutation and selection (more on this later), and class switch recombination.
What are Germinal Centres (GC)?
Some follicles (secondary follicles) contain central areas called germinal centres. Germinal centres (GC) develop in response to antigenic stimulation and are sites of B cell proliferation, somatic hypermutation and selection (more on this later), and class switch recombination.
What is the site of B cell proliferation?
Germinal centres (GC)
What are the 2 stages of circulation. of lymphocytes?
- Recruitment to lymph node
2. Homing back to tissue
What is the Recruitment to lymph node?
Naïve T cell migrate into the lymph node involves the adhesion molecules L-selectin and LFA-1 and the chemokine receptor CCR7.
What does homing back to tissue involve?
Activated T cells change their expression of adhesion molecules and chemokine receptors. This promotes their recruitment back to the sites of infection.
Where does activation of GI Lymphocytes?
Activation can occur in the mesenteric lymph node or organised lymphoid tissue in the gut
Peyer’s patches are similar in structure to the lymph node.
True or false?
True
What is the region directly under the epithelial layer?
The sub epithelial dome SED, which is rich in Antigen presenting cells
Where are T cells present?
In T cell zones
Where are B cells present?
In B cell zones which include Germinal centres (GC)
What produces retinici acid?
Dendritic cells (DC)
What happens during the circulation of GÌ lymphocytes?
Cells that are activated by antigen in GALT are exposed to retinoic acid produced by the DC.
This induces the expression of CCR9 and the integrin α4β7.
These cells home back into the gut because the chemokine CCL25 (the ligand for CCR9) and the adhesion molecule MadCAM (the ligand for α4β7) are displayed on lamina propria venular endothelial cells.
What are the stages of circulation in GI lymphocytes?
1- T cells enter Peyer’s patches from blood vessels , directed by homing receptors CCR7 and L selectin
2- T cells in the Peyer’s patch encounter antigen transported across M cells and become activated by dendritic cells
3- Activated T cells drain via mesenteric lymph nodes to the thoracic duct and return to the gut via the bloodstream
4- Activated T cells expressing alpha4beta7 integrin and CCR9 home to the lamina propria and intestinal epithelium of the small intestine
What is the dominant form of adaptive in unity in the gut?
Hum oral - mediated by di Eric IgA molecules
What do tissue signals such as TGF-β do?
Promote B cell isotope switching to IgA
What is the structure of IgA?
Held as a diner by the J chain
Where are IgA found ?
I’m the lamina propria
How is IgA transported?
Via TRANSCYTOSIS:
It binds to the poly-Ig receptor and is transported across the epithelial cell
How is IgA released?
It is released via proteolytic cleavage of the receptor, which forms the secretory component and remains associated with IgA.
What is the function of IgA?
IgA does NOT activate complement.
It is a powerful neutralising antibody.
Mediates anti-viral activity and neutralisation of toxins
Secreted, Can bind and neutralise pathogens and toxins
Can bind and neutralise antigens internalised in endosomes
Can export toxins and pathogens from the lamina propria while being secreted
IgA can export toxins and pathogens from the lamina propria while being secreted
True or false?
True
What effector T cells are found in the GI tract?
Th17 cells
Th2 cells may play a role in response to intestinal helminth infections
Th1 cells are rare in the healthy GI tract.
What are the functions of Th17 cells?
Th17 cells play a role in maintaining mucosal epithelial barrier function due to production of IL-17 and IL-22 cytokines which act on intestinal epithelial cells.
These cytokines induce the expression of proteins important for barrier function, such as mucins and β-defensins.
Th17 cells are also capable of inducing acute inflammation to directly kill invading pathogens.
What group of cells are T regulatory cells (Treg cells) are from?
CD4+ T helpercells
What is the function of CD4+T helper cells?
Suppress immune responses and maintain self-tolerance
Which transcript or factor do Regulatory T cells express?
FoxP3
How are Regulatory T cells /Treg cells generated?
Natural Treg- They can be generated by self antigen recognition in the thymus
Inducible Treg- antigen recognition in peripheral lymphoid organs
What is the role of Treg cells in the GI tract?
Maintainance of tolerance towards luminal antigens
Most Treg cells I’m the GI tract are believed to be inducible, how is the differentiation induced?
Their differentiation is induced by local factors such as TGF-β and retinoic acid.
Natural Treg that migrate to the GI tract can expand in response to bacterial metabolites
True or false?
True
What is Oral Tolerance?
Oral tolerance is a term used to describe tolerance induced to antigens administered orally.
What is the function of Oral Tolerance?
To prevent inappropriate immune responses to food and commensal bacterial antigens.
What a
Happens during Oral Tolerance?
It involves multiple mechanisms including:
induction of Treg cells
Treg-mediated suppression
induction of hyporesponsiveness (anergy)
elimination of effector cells.
What happens during oral vaccination?
the antigen is introduced with concomitant activation of the innate immune system
What are the different types of immune disorders?
Autoimmunity
Allergy
Inflammatory disorders
Immunodeficiency
What is Autoimmunity?
An inappropriate reaction to self- failure of self tolerance
What is Allergy?
A type of inappropriate response to innocuous non-self
Define inflammatory disorder?
Poorly regulated inflammation (I.e. chronic)
What is Immunodeficiency?
Absent or ineffective immune responses
What are Hypersensitivity Reactions?
Inappropriate or excessive immune responses can lead to tissue damage.
Types I-III involve antibodies, while Type IV is cell mediated immune responses
It is common for more than one type of hypersensitivity reaction to be involved in mediating tissue damage
What are the 4 types of hypersensitivity reactions?
Type I: Allergic (immediate)
Type II: Cytotoxic
Type III: Complex-mediated
Type IV: Cell-mediated (delayed-type)
What mediates type I hypersensitivity?
IgE and mast cells
I.e. hay fever, asthma
What mediates type II hypersensitivity?
IgM (IGM)
Complement
Phagocytes
ADCC
I.e. haemolytic anaemia, rejection of blood transfusion
What mediates Hypersensitivity type III?
Soluble Ag-Ab (IgG)
Complexes
Polymorphism
Complement
What mediates hypersensitivity type IV?
Immune cells
I.e. TB granuloma
What is the reaction that occurs in hypersensitivity type I ?
Engagement of IgE antibodies bound to mast cells leads to degranulation – allergic response.
What is the reaction that occurs in hypersensitivity type II?
IgG antibodies to cell surface or extracellular matrix - associated antigens.
Promotes destruction via phagocytosis, complement activation, or antibody-dependant cell cytotoxicity (ADCC).
Antibody binding can also block function.
What type of reaction occurs with hypersensitivity type III?
Antibody recognition of soluble antigen leads to deposition of Ab-Ag complexes in tissues or serum.
Activation of complement or recruitment of neutrophils that release lytic molecules.
What reaction Halle s with hypersensitivity type IV?
Cell mediated. Damage mediated through inflammation, or through direct cytotoxicity
What is Coeliac disease?
Autoimmune disease of the GI tract triggered by dietary gluten
What is Inflammatory Bowel Disease(IBD) ?
Inflammatory Bowel Disease (IBD) is a group of inflammatory disorders, characterised by excessive inflammatory response (to commensal microbes) and includes ulcerative colitis and Crohn’s disease
What triggers Coeliac Disease (CD)?
Gluten
What is Coeliac diseases strongly associated with?
HLA Class II proteins.
What is the Pathogenesis of Coeliac Disease?
Gluten-derived peptides (e.g. gliadin) reach the sub-epithelial region.
•Transglutaminase (TG) deamidation of glutamines generates potent immunostimulatory epitopes
•These are presented via HLA-DQ2/DQ8 on APC to CD4 T cells
•CD4 T cells produce high levels of pro-inflammatory cytokines, thus inducing a Th1 response that results in mucosal remodelling and villous atrophy.
•In addition, TG-gliadin complexes that bind to TG-specific B cells, are endocytosed and processed. Gliadin-DQ2/DQ8 complexes are then presented by the TG-specific B cells to gliadin-specific T cells, a process that leads to the production of anti-TG antibodies (autoantibodies).
What are the 2types of Inflammatory Bowel Disease?
Ulcerative colitis – confined to the colon, mucosal layer only
Crohn’s disease – any part of GI Tract, transmural inflammation
What is the clinical characteristic of Inflammatory Bowel disease?
recurrent inflammation of intestinal segments with diverse clinical manifestations.
Symptoms of ulcerative colitis
bloody diarrhoea
abdominal pain with fever
weight loss
Symptoms of Crohn’s disease?
fever
abdominal pain
diarrhoea (often without blood)
fatigability.
What are the main T helper cells in the GÌ tract? And their function?
Th17 and Treg and together they maintain a balance between inflammatory responses and tolerance.
What is the role of TGF-β present in the GI tract environment?
Helps to promote differentiation of Th17 and Treg cells but also to inhibit Th1 and Th2 effector cell differentiation.
What is the pathogenesis of IBD?
Exaggerated response to commensal micro flora with a Th1 profile in Crohn’s disease and a Th2 profile in ulcerative colitis and Th17 cells found in both conditions.
What are the risk factors for IBD?
genetic predisposition
environmental factors
commensal microbiota
host barrier function.
What are the genetic risk factors in Crohn’s disease?
NOD2 (a PRR), NFκB signalling pathway protein
autophagy clearance of intracellular bacteria
What is the genetic risk factor for Ulcerative colitis?
HLA-B*27 (MHC class I)
