lecture 9 Flashcards
(19 cards)
crohn’s disease symptoms
abdominal pain diarrhea nausea vomiting weight loss
can affect the entire gastrointestinal tract
has a discontinuous pattern throughout the gastrointestinal tract
(A defect in mucosal innate immunity)
ulcerative colitis symptoms
abdominal pain
rectal bleeding
bloody diarrhea
affects only the colon
starts at the rectum and progresses continuously through the colon
(A defect in mucosal innate immunity)
Revision of mucosal immune mechanisms
The surface of the gut is protected by both innate and adaptive immune mechanisms
A layer of mucus made by goblet cells and antimicrobial products produced by Paneth cells help protect against pathogens and keep commensal microorganisms under control
Antigens from food, pathogens and commensals can enter via the M cells and initiate adaptive responses including IgA production
In the absence of infection (inflammation) food and commensal organisms tend to generate a Treg response
In the absence of infection
Epithelial layers are the outermost layer - nearest to gut, close association to food and digestive enzymes
We have protective mechanisms for the gut and epithelial layers
Physical barriers are the mucosal layers, form a biofilm to trap foreign molecules
Enterocytes are epithelial cells - recognise infection
Goblet cells - specialised, produce mucus
? antibacterial peptides
Regulatory dampening down of the immune response. We have IgA released to make sure it neutralises the effect of the bacteria
We have dispersed peyer’s patches, role in immunosurveillance (check what is entering our immune system)
DIAGRAM IN L9 S3
in the presence of infection
Professional AG presenting cells (macrophages and dendritic cells) take up bacteria via phagocytosis and present AG.
V
Naïve T and B cells are activated within the GALT, -
B cells undergo class switching from IgM to IgA leave via the lymphatics, fully differentiate, then ‘home’ back to the lamina propria.
T cells become activated and differentiate, leave the GALT again home back to the lamina propria. The GALT can have CD4 helper cels (TH1, TH2, TH17; Treg and CD8 Tc
V
Depending on the activation signals will result in a specific inflammatory immune response.
TLRs, NOD1 and NOD2 activate NFkB
The epithelial cells play a major role in innate defences through the activity of PRRs, TLRs either on the apical surface or in vesicles which recognise PAMPS
NOD 1 and 2 are also PRRs found in the cytoplasm which recognise peptidoglycans released during infection.
Activation of TLRs or NODs activates the pathway NFkB leading to the generation of proinflammatory molecules via gene transcription
These chemokines and cytokines recruit and activate other innate immune cells
crohn’s disease
- causative agent
- modifying factors
- limital factors
causative agents: bacteria, virus and dietary
modifying factors: environmental and genetic
limital factors: lumial bacteria, digestive enzymes and bile acids
Crohn’s disease results from a breakdown in normal homeostatic mechanisms that occur in the gut
Innate and adaptive immunity normally cooperate to limit inflammation.
Mucus layer
Tight junctions between epithelial cells
Antimicrobial peptides from Paneth cells
Treg production which prevents effector T cell production and promotes IgA antibodies
Impaired homeostatic mechanisms lead to dysregulated TH1 and TH17 responses generating chronic inflammation.
what does crohn’s disease affect and what are the symptoms?
A regional enteritis which can affect any region of the gastrointestinal tract.
The symptoms are
- Abdominal pain
- Diarrhea
- Vomiting
- Weight loss
It is characterised as either an autoimmune or an immunodeficiency disease
Susceptibility is due to the interaction of both genetic and environmental components
how to analyse patient with crohn’s disease
Barium meal analysis of patient with Crohn’s showing narrowing of the bowel
The genetic component of susceptibility
The disease runs in families- siblings of sufferers are 30 times more likely to develop disease than the normal population
Genomic studies have associated the disease with a number of genetic loci- the first of which was NOD2
A frame shift mutation in NOD2 was found associated with the disease.
NOD2 deficiency leads to impaired activation of the NFkB pathway which leads to the impaired secretion of anti bacterial peptides called defensins
Environmental factors associated with Crohn’s
The increase in Crohn’s in the industrialised world indicates a clear environmental component
Dietary components are
Positive association with increased consumption of animal protein, milk protein and Omega6:Omega3
Negative association with vegetarian diet
Smoking has a strong positive association
Hormonal contraception (1960’s) is associated with dramatic increase in prevalence
Immunological characteristics
Originally thought to be T cell mediated autoimmune disorder.
More recently it is thought that impaired cytokine release by macrophages results in impaired innate immunity and sustained inflammatory response in the colon.
Th17 cells are thought to be important in disease.
Characterised by high levels of TNFα like many other autoimmune diseases.
Current available treatments
There is no cure for Crohn’s at the present time, all of the treatments are therefore based on alleviating the symptoms.
Most of the treatments are based on reduction of inflammation
Aminosalicylates
Corticosteroids
Immunosuppressants
Biologics like infliximab, certolizumab, natalizumab
In addition- dietary control and surgery
Biologics – monoclonal antibodies
DIAGRAM IN L9 S18-19
Infliximab-Remicade
A chimeric anti TNFα, which has a high affinity for TNFα but not TNFβ
DIAGRAM IN L9 S20
Mode of action of infliximab
A chimeric mouse/human anti TNFα monoclonal antibody.
Works by binding to TNFα and was originally thought to act by preventing TNFα binding to its receptor.
Actually causes programmed cell death of TNFα bearing activated T lymphocytes.
Elimination of these inflammatory T cells helps to reduce the symptoms of disease
infliximab in crohn’s disease
Three phenotypes of disease:
- Stricturing disease which causes a narrowing of the bowel
- Penetrating disease which causes abnormal connections of the bowel-fistula
- Inflammatory disease
Infliximab shown to be effective in closing fistula and maintaining closure in 2/3 of patients.
Infliximab also used to induce and maintain remission in inflammatory Crohn’s- giving remission of 30 weeks in up to 45% of patients.
These treatments reduce the need for steroid treatment to get inflammation under control.
Certolizumab- CimziaTM
This is a product for both RA and Crohn’s disease which consists of a pegylated Fab’ fragment of a humanised anti-TNFα antibody (CDP870).
The Fab’ retains all the biological specificity.
The pegylation (polyethylene glycol) provides extended half life in the serum to about 2 weeks.
Clinical Trial (PRECisE Program) illustrated that 65% of patients showed a clinical response after just 6 weeks.
Long term trials are still on-going.
Application for the licence was granted in 2008.
This is the first subcutaneous injection for the treatment of Crohn’s Disease and can be used through pregnancy since the drug does not cross the placenta
