GI mucosal immunology Flashcards by Isla Anderson

What does the upper GI tract consist of?

Oesophagus

Stomach

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What does the lower GI tract consist of?

Small intestine

Large intestine

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In basic terms, what are the 2 kinds of bacteria found in the GI tract?

Commensal bacteria

Pathogenic bacteria

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What are some examples of challenges of antigen processing in the GI tract

Develop self-tolerance

Develop exogenous tolerance

Develop an effective immune response

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What is self-tolerance?

Non-responsiveness of the immune system to self-antigens

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What is exogenous tolerance?

Non-responsiveness of the immune systemto newly encountered environmental antigens that are harmless

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What are examples of different facets to normal antigen processing in the GI tract?

Epithelial layer

Mucus layer

Innate immune response

Antigen presenting cells

Tolerance versus activated of adaptive immune response (T cell)

Soluble mediators of immunity

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How does the epithelial layer provide protection?

Specialised tight junctions that regulate permeability

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How does the mucus layer provide protection?

Physical barrier keeping microbes from host cells

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What are examples of antigen presenting cels?

Dendritic cells

Macrophages

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What are examples of soluble mediators of immunity?

Chemokines and cytokines

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What are the 2 different parts of the immune system?

Innate immune system

Adaptive immune system

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What kind of immune cells are innate?

Granulocyte (neutrophil, eosinophil, basophil)

Mast cell

Monocyte

Dendritic cell

Macrophage

Natural killer cell

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What kind of immune cells are adaptive?

CD4+ T cell (memory)

CD8+ T cell (memory)

B cell (memory), which become plasma cells that produce antibodies

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Where do all cells of the immune system originate from?

Haematopoitic stem cell which comes from bone marrow

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What are the 2 things that a haematopoietic stem cell can differentiate into?

Myeloid progenitor cell

Lymphoid progenitor cell

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What does myeloid progenitor cell differentiate into?

RBC

Platelet

All cells of innate immune system (except natural killer cells)

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What do lymphoid progenitor cells differentiate into?

All adaptive immune system cells

Natural killer cells

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Which immune system causes inflammation?

Innate immune system

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What is a key determinant of T cell differentiation?

The cytokine milieu

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How do cytokines vary in terms of inflammation?

Some are pro-inflammatory and some are anti-inflammatory

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What is a T cell called before it has differentiated into its subtype?

Naive T cell

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What are peyer’s patches?

Small masses of lymphatic tissue found throughout the ileum region of the small intestine

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What do peyer’s patches allow?

Sufficient sampling of particulate antigens and delivery to antigen presenting cells

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What is a macrophage?

Type of phagocyte which is responsible for detecting, engulfing and destroying pathogens and apoptotic cells

What is the first line of defence system in the gut?

macrophages

What are functions of macrophages?

Sampling of particulate antigens Phagocytic (ingests harmful pathogens or dying/dead cells) Secrete cytokines (such as IL-10 required for the survival of FoxP3 and Treg cells) Antigen presenting cells to modulate adaptive immune response

Where are dendritic cells found in the GI tract?

Lamina propria and peyer’s patches

Why are dendritic cells important for mucosal immune responses?

Efficient sampling of antigen Different dendritic cell subsets give rise to distinct T cell responses (such as tolerance vs immunity) Different subsets distinguished by cell markers) Present antigen to naive T cell

What to dendritic cells do after they have sampled gut bacteria and gut antigens?

Migrate to major lymph nodes

What do dendritic cells undergo maturation into?

Potent antigen presenting cells (APC)

What 3 signals determine T cell response from an antigen presenting cell?

MHC/peptide-TCR CD80-CD28 Cytokine

Which of MHC/peptide-TCR is on the antigen presenting cell and naive T cell?

MHC on antigen presenting cell Peptide-TCR on naive T cell

Which of CD80/CD28 is on antigen presenting cell and naive T cell?

CD80 on antigen presenting cell CD28 on naive T cell

What is the innate immune system based on?

Recognition of pathogens associated molecular patterns (PAMPS/MAMPS)

What T cell is required for clearance of intracellular pathogens?

Th1

What T cell is required for maintaining the immune homeostasis and tolerance?

Treg

What are 2 examples of what happens when the normal immune homeostasis goes wrong?

Inflammatory bowel disease (IBD) Coeliac disease

What is inflammatory bowel disease?

Chronic, relapsing, remitting inflammation of the GI tract

What are the 2 main examples of IBD?

Crohn’s disease Ulcerative colitis

What is the difference between Crohn’s disease and ulcerative colitis?

Differ in type and location of inflammation

examples of T helper cells

Th1, Th2, Th17

examples of T regulatory cells

Th3, Tr1, Treg

what is the innate immune system?

A universal and evoluntionarily conserved system of host defence Induced upon infection with microbes (eg.Intracellular pathogens) Based on recognition of pathogen associated molecular patterns (PAMPS/MAMPS) Main players include Macrophages, monocytes, neutrophils and Dendritic cells General inflammatory response displayed by all cells Plays a fundamental role in the induction and regulation of the adaptive immune response

Adaptive Immune system?

Induced upon infection by specialized pathogens Based on recognition of specific antigens presented by professional antigen presenting cells (eg. Dendritic cells) Carried out by effector cells mainly, T and B cells.

what do gut dendritic cells exist as?

several defined phenotypes which have distinguishable cell markers and functions

what do DC subsets and macrophage have an important role in?

driving T cell differentiation eg. Th1 or Tregs

what are required for are required for clearance of intracellular pathogens?

Th1 cells

what are required for maintaining immune homeostasis and tolerance

Tregs (Tregs, Tr1, Th3)

what cells contribute to mucosal tolerance.

B cells through differentiation in plasma cells and IgA

What is inflammatory bowel disease?

Chronic, relapsing, remitting inflammation of the GI tract

What are the 2 main examples of IBD?

Crohn’s disease Ulcerative colitis

What is the difference between Crohn’s disease and ulcerative colitis?

Differ in type and location of inflammation

What does the pathogenesis of IBD involve?

Genome Microbiome Environment Other unknown factors

What is the innate immune systems involvement in IBD?

Dysfunctional innate receptor handling of bacteria Breakdown of immune tolerance ILCs

What is the adaptive immune systems involvement in IBD?

Traditionally Th1 versus Th2 paradigm, many other lymphocyte populations are important (such as Th17, regulatory T cells, B cells)

What are different treatment strategies for IBD?

Target lymphocytes directly Target single cytokines Target migration of immune cells to GI mucosa Target multiple cytokines Target cytokine intracellular signalling pathways Modulation of microbiota

What does anti-TNF biologics involve?

Inhibition of a single cytokine

What is used to target migration of immune cells to GI mucosa?

Vedolizumab

What are integrins?

Transmembrane proteins used to lymphocyte trafficking and cell adhesion

What drug is used for multi-cytokine blockage?

Ustekinumab

What does multi-cytokine blockage (Ustekinumab) target?

Towards p40 subunit of IL-12 and IL-23

What does IL-12 control?

Proinflammatory Th1 cytotoxic T cell response

What does IL-23 control?

Pro-inflammatory Th17 axis

What drug is used for multi-cytokine blockage through inhibition of intracellular signalling?

Tofacitnib

How does multi-cytokine blockage through inhibition of intracellular signalling with Tofacitnib work?

Pan JAK inhibitor (JAK1 and JAK3)

What interleukins are inhibited by Tofacitnib?

IL2 IL6 IL7 IL9 IL12 IL15 IL21 IL23 IFN

What do initial studies suggest about faecal transmission (FMT) and IBD?

Is likely effective in ulcerative colitis

What is coeliac disease?

Common digestive condition where the small intestine becomes inflamed and unable to absorb nutrients

What does coeliac disease cause intolerance to?

Dietary gluten in wheat and similar proteins

What are symptoms of coeliac disease?

Malabsorption causing failure to thrive as a child Iron deficiency anaemia Fatigue GI symptoms such as loose stool, abdominal pain or asymptomatic

What causes genetic susceptibility to coeliac disease?

HLA-DQ2/8 on antigen presenting cell

What does HLA stand for?

Human leukocyte antigen

What does human leukocyte antigen (HLA) allow?

Immune cells to identify self and non-self antigens

What are consequences of coeliac disease for the gut?

Loss of villi (loss of absorptive capacity) Increase in intra-epithelial lymphocytes