Immunology of the Gut Flashcards
What are the implications of the large surface area of the GI tract?
exposure to a massive antigen load
What does the massive antigen load consist of?
- resident microbiota
- dietary antigens
- pathogen exposure
What is the impact of this large antigen load?
GI is in a state of ‘restrained activation’
What is a state of ‘restrained activation’
- tolerance (food and commensal bacteria) vs active immune response
- dual
What does immune homeostasis and development of a healthy immune system require?
the presence of bacterial microbiota
What are the 4 major phyla of bacteria?
- Bacteroidetes
- Firmicutes
- Actinobacteria
- Proteobacteria
What is the benefits of the gut microbiota?
provides traits that we can no evolve on our own
What factors stimulate bacterial growth/cell numbers?
- ingested nutrients
- secreted nutrients
What factors inhibit bacterial growth/cell numbers?
- chemical digestive factors
= bacterial lysis - peristalsis, contractions and defecation
= bacterial elimination
What chemical digestive factors are produced in the stomach?
- HCl
- Pepsin
- Gastric lipase
What chemical digestive factors are produced in the liver?
- Bile acids
What chemical digestive factors are produced in the pancreas?
- Trypsin
- Amylase
- Carboxypeptidase
What chemical digestive factors are produced in the small intestine?
- brush border enzymes
What chemical digestive factors are produced in the colon?
no host digestive factors
What is the general relationship between the toxicity of chemical digestive factors and the bacterial content?
the more toxic the digestive factors, the smaller the bacterial content
What is dysbiosis?
altered microbiota composition
What is the impact of symbionts on the host?
no effect, truly neutral
What is the impact of commensals on the host?
no effect, but benefit from being part of the host
What is the impact of pathobionts on the host?
no effect (normally) can cause dysregulated inflammation and disease
What are the important factors of immunological equilibrium in the gut?
- symbionts
- commensals
- pathobionts
What can cause dysbiosis?
- infection
- inflammation
- diet
- drugs/glutens
- hygiene
- genetics
What happens during dysbiosis?
production of bacterial metabolites and toxins
What are some examples of bacterial metabolites and toxins?
- TMAO
- SCFAs
- 4 - EPS
- bile acids
- AHR ligands
What is the effect of TMAO?
encourages the deposition of cholesterol in vessel walls leading to atherosclerosis
What is the effect of 4-EPS?
autism
What is the effect of SCFA’s?
decreased: IBD
increased: stress
What is the effect of AHR ligands?
- MS
- rheumatoid athritis
- asthms
What are the 2 primary physical types of barriers?
- Anatomical
- Chemical
What are the different types of anatomical barriers?
- epithelial barriers
- peristalsis
What are the different types of chemical barriers?
- enzymes
- acidic pH
What is involved in the epithelial barrier?
- mucus layer (goblet cells)
- epithelial monolayer, tight junctions
- paneth cells (in small intestines)
What is the role of Paneth Cells?
- bases of crypts of Lieberkuhn
- secrete antimicrobial peptides (defensins) and lysozyme
How do commensal bacteria act as barrier?
- occupy an ecological niche
- act as an ecological barrier
What is involved in the immunological barriers?
- MALT (Mucosa Associated Lymphoid Tissue)
- GALT (Gut Associated Lymphoid Tissue)
Where is MALT located?
- in submucosa below the epithelium
- as lymphoid mass containing lymphoid follicles
- follicles are surrounded by HEV postcapillary venules (easy passage of lymphocytes for a response)
What area is rich in immunological tissue?
oral cavity
- palatine tonsil lingual tonsils
- pharyngeal tonsils (adenoids)
What is the role of GALT?
responsible for both adaptive and innate immune response through generations of lymphoid cells and Abs
What type of response is mounted by GALT?
both adaptive and innate immune response
What are the non-organised forms of GALT?
- intra-epithelial lymphocytes (in between entry points) (eg: T cells and NK cells)
- Lamina propria lymphocytes
What are the organised forms of GALT?
- Peyer’s patches
- Caecal patches
- Isolated lymphoid follicles
- Mesenteric lymph nodes (encapsulated)
Where are Peyer’s patches found?
small intestine
Where are Caecal patches found?
large intestine
How are non-organised GALT released?
migrate to the tip of the microvilli prior to that as well as absorptive epithelial cells
What produces mucus secreting goblet cells?
- stem cells
- crypts
Where do Paneth cells migrate to?
the bottom of the crypt
How do you characterise Paneth cells?
- presence of dense granules that anti-microbial peptides
- appropriate lamina
Where are intraepithelial lymphocytes?
between entry sites
What is found in the mucosa of the microvilli?
- macrophage
- IgA B cells
- DC
- I cell
Where are Peyer’s patches?
- submucosa small intestine
- mainly in the distal ileum
What are Peyer’s patches?
aggregated lymphoid follicles covered with follicle associated epithelium (FAE)
What are characteristics of Peyer’s patches?
- no goblet cells
- no secretory IgA
- lack microvilli
What are the causes of infectious diarrhoea?
- Clostridium difficile
- Klebsiella oxytoca
- Clostridium perfringens
- Salmonella spp
(can cause bloody diarrhoea)
What are the causes of non-infectious diarrhoea?
- antibiotics side effect
- post-infectious IBS
- IBD
- Microscopic colitis
- Ischaemic colitis
- Coeliac disease
- Haemorrhoids
How do you manage C. difficile?
- Infection control (side room)
- Discontinue inciting antibiotic agents
- Management of fluids, nutrition and diarrhoea
What would classify a non-severe infection?
- WCC < 15
- Creatinine < 150
What would classify a severe infection?
- WCC > 15
- Creatinine > 150
What fulminant colitis?
- hypotension
- shock
- ileus
- toxic megacolon
How do you treat non-severe C. difficile infections?
- ABx with oral vancomycin/fidaxomicin/metronidazole
- role of Faecal Microbiota Transplantation (FMT)
How do you treat severe/fulminant colitis C. difficile infections?
- ABx
- supportive care
- close monitoring
- early surgical consultation
What is the first line treatment of fulminant colitis and toxic megacolon?
- Medical therapy with antibiotics and supportive management
- IV fluid resuscitation and inotropic support
What are the indications for surgery?
- Colonic perforation
- Necrosis/Full-thickness ischaemia
- Intra-abdominal hypertension
- Abdominal compartment syndrome
- Clinical signs of peritonitis
- Worsening abdominal exams
- End-organ failure
What is pseudomembranous colitis?
- manifestation of severe colonic disease
- characteristic yellow-white plaques that form pseudomembranes on the mucosa
What tends to cause pseudomembranous colitis?
C. difficile
How do you confirm pseudomembranous colitis?
- endoscopy
- biopsy
What does chronic inflammation with no granulomas on a colonoscopy indicate?
Ulcerative colitis
What do Peyer’s patches consist of?
- dome area filled with dendritic cells
- B cell follicles
- interfollicular T cells
What does the development of the naive T and B cells require?
exposure to bacterial microbiota
How does antigen uptake to Peyer’s patches occur?
via M (microfold) cells in FAE - express IgA receptors facilitating the transfer of IgA-bacteria complexes into the Peyer's patches.
What can trans-epithelial dendritic cells do?
- open up tight junction proteins and send the dendrites outside into the lumen of the intestinal tract to directly sample bacteria
- mesenteric lymph nodes
What happens in the B cell adaptive response?
- mature naive B cells express IgM in Peyer’s patches
- on antigen presentation switch to IgA
- T cells and epithelial cells influence B cell maturation via cytokine production
- B cells mature to become IgA secreting plasma cells
- in lamina propria
How is secretory IgA produced?
- plasma cell produces IgA
- taken into enterocyte vesicle
- enzymatic cleavage
- leading to secretory IgA in the lumen
What does secretory IgA do?
- bind luminal antigen
- prevents adhesion and invasion
(secreted by 90% of gut B cells)
What happens in lymphocyte homing and circulation?
- lymphocytes from Peyer’s patch move into the mesenteric lymphnode
- in the lymphnode they proliferate
- return to circulation via the thoracic duct into the systemic venous system
- can either enter the peripheral immune system or return to the intestinal mucosa via vessels in the lamine propria
What is part of the peripheral immune system?
- skin
- tonsils
- BALT (Bronchus Associated Lymphoid Tissue)
Why do enterocytes and goblet cells have a rapid turnover?
- first line of defense and may be directly affected by toxicity
- may have impacts on function, metabolic rate …
- shorten the effect of lesions
What happens if enterocyte and goblet cell turnover is interrupted?
severe intestinal dysfunction
What is the mechanism behind cholera infections?
- Vibrio cholerae serogroups 01 and 0139
- bacteria reaches small intestine, contact with epithelium triggers the release of cholera enterotoxin
- internalised via retrograde endocytosis
- increased adenylate cyclase acitvity
- increased cAMP
- secretion of salts and water follows by CFTR
How is cholera transmitted?
- faecal-oral route (contaminated water and food)
What are the main symptoms of cholera?
- severe dehydration
- water diarrhoea
- vomiting
- nausea
- abdominal pain
What does CFTR stand for
Cystic fibrosis transmembrane conductance regulator
How do you diagnose cholera?
- bacterial culture from stool sample on selective agar (GS)
- rapid dipstick tests
How do you treat cholera?
- oral rehydration
How do you vaccinate against cholera?
- Dukoral
- oral
- inactivated
What are the possible viral causes of infectious diarrhoea/gastroenteritis?
- Rotavirus (children)
- Norovirus
What are the possible bacterial causes of infectious diarrhoea/gastroenteritis?
- Campylobacter jejuni
- E. coli
- Salmonella
- Shigella
- C. difficile
- Cholera
What are the possible protozoal parasitic causes of infectious diarrhoea/gastroenteritis?
- Giardia lamblia
- Entamoeba histolytica
What are rotaviruses?
- RNA virus
- replicates in enterocytes
- 5 types (A-E)
How common are rotaviruses?
most common cause of diarrhoea in children and infants
How do you treat rotaviruses?
- oral rehydration therapy
- vaccination (live, attenuated against type A)
What is Norovirus?
- RNA virus
- incubation: 24-48hours
How are Noroviruses transmitted?
- faecal-oral transmission
- may shed for up to 2 weeks
- outbreaks in closed communities common
What are the symptoms of Norovirus?
- acute gastroenteritis
- recovery in 1-3 days
How do you diagnose Norovirus?
Sample PCR
What are the causes of food poisoning?
Campylobacter
- Campylobacter jejuni
- Campylobacter coli
How is Campylobacter transmitted?
- undercooked meat
- untreated water
- un-pasturised milk
- low infective dose
How do you treat for Campylobacter?
- not usually required
- Azithromycin is standard ABx
- Resistance to fluoroquinolones is problematic
What are the pathotypes of E. coli?
gram negative bacteria
- Enterotoxic E. coli
- Enterohaemorrhagic/Shiga toxin-producing E. coli
- Enteroinvasive E. coli
- Enteropathogenic E. coli
- Enteroaggregative E. coli
- Diffusely adherent E. coli
What symptoms is Enterotoxic E. coli associated with?
- cholera like toxin
- water diarrhoea
What symptoms is Enterohaemorrhagic/Shiga toxin-producing E. coli associated with?
5-10% loss kidney function
haemolytic uraemic syndrome
What symptoms is Enteroinvasive E. coli associated with?
- shigella like illness
- bloody diarrhoea
How does Clostridium difficile infect the body?
- always present in the gut
- dysbiosis - intermediate dysbiotic state
- pathogen induced disturbance and toxin induction
How do you manage Clostridium difficile?
- isolation
- stop ABx
- Metronidazole (can also trigger infection)
- Vancomycin
- reccurence rate 15-35%, increasingly more difficult to treat
- faecal microbiota transplant
What symptoms would indicate a C. difficile infection?
- raised WCC and CRP
- new onset diarrhoea
- generalised tenderness
- signs of dehydration (AKI and dry mucous membranes)
How do you diagnose a C. difficile infection?
- stool sample for C. difficile toxin
- stool cultures
- Imaging (AXR)
What would cause dilation of the large intestine (transverse) secondary to a C. difficile infection?
toxic megacolon
What clinical features suggest toxic megacolon?
- dilation of bowel
- septic features of the patient
What investigations would you do for suspected IBD?
- Stool culture for C. diff infections
- Stool culture (calprotectin)
- Endoscopy
What are the management options for UC?
- steroids
- 5 ASA
- immune suppressants (azathioprine and methotreaxate)
- biologic therapy
- diet
- FMT
- ABx,PBx
What would classify UC as mild?
- 4 BM/day
- no systemic toxicity
- normal ESR/CRP
- mild symptoms
What would classify UC as moderate?
- more than 4BM/day
- mild anaemia
- mild symptoms
- minimal systemic toxicity
- nutrition maintained
- no weight loss
What would classify UC as severe?
- more than 6 BM/day
- severe symptoms
- systemic toxicity
- significant anaemia
- increased ESR/CRP
- weight loss
What can azathioprine cause?
reactivation of diseases like:
- Hep B/C
- HIV
- TB
What must be tested when prescribing azathioprine to prevent toxicity?
thiopurine methotransferase (TPMT)
What is the last line medical treatment for presistant UC?
Infliximab with Azathioprine
What are the side effects of Infliximab?
- demyelinating disease
- autoimmunity
- congestive heart failure
- hepatoxicity
- malignancy
- infection/bone marrow suppression
- infusion reactions
