Aantekeningen Food Allergies and Intolerances – Immunology
Lecture 1 – General aspects of the immune system
Innate immune system – immune system which is rapidly activated (within minutes or hours) and constitutes
the first barrier of defence of the organism. It involves physical barriers (e.g. epithelium), neutrophils,
phagocytic cells, dendritic cells and NK cells.
Adaptive immune system – immune system which is mainly mediated by B-lymphocytes and T-lymphocytes,
but also dendritic cells and macrophages. It is characterized by its specificity (capacity to distinguish specific
antigens) and its memory (capacity to respond more intensively to repeated exposures to the same pathogen).
Innate immune recognition:
- Pathogen Associated Molecular Patterns (PAMPs) – molecules with conserved motifs that are associated
with pathogen infection that serve as ligands for host pattern recognition molecules and activate the innate
immune responses
- Pattern Recognition Receptors (PRRs) – receptors which
recognize PAMPS, for example the toll-like receptor (TLR)
Example PAMPs and PRRs:
- Gram- bacteria have LPS in their membrane. TLR4 is able to
recognize/bind LPS, so with one receptor, all gram- bacteria
can be recognized.
- Gram+ bacteria have LTA in their membrane. TLR2 is able to
recognize/bind LTA, so with one receptor, all gram+ bacteria
can be recognized.
Cytokine networks – proteins mediating interactions between immune cells (soluble, rapidly made,
immediately absorbed by the cell):
- Paracrine (short-distance communication through the release of chemical messengers)
- Autocrine (cell signals to itself, releasing a ligand that binds to receptors on its own surface or receptors
inside the cell)
- Endocrine (long-distance communication, acting as peptide hormones) activity
Two different sets of cytokines:
1. Pro-inflammatory cytokines – from the innate immune system, enhancing cellular immune responses
Examples: TNF-α, IL-1a, IL-1B, IL-6, IL-8
2. Anti-inflammatory cytokines – from the adaptive immune system, favouring antibody responses:
Examples: IL-1ra, TNF-β, IL-10, IL-4, IL-13
Sepsis – serious condition resulting from the presence of living bacteria in the bloodstream (generally gram-),
resulting in an extreme response by the body, producing many pro-inflammatory cytokines, potentially leading
to the malfunctioning of various organs, shock and death (multiple organ failure).
Phases of the immune response:
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,Start of immune response: beneath the epithelial layer in the airways and GI-tract, a network of dendritic cells
is found, which are the first immune cells that get into contact with any antigen. The dendritic cell is the cell
that connects the innate immune system to the adaptive immune system:
Adaptive immune recognition: antigens are taken up by antigen-presenting cells like dendritic cells and
macrophages. Cells take up these proteins, cut them up into small peptides. Some of these small peptides can
be displayed on MHC II molecules and showed to T-cells, thereby activating the T-cells. Most important class
are the helper T-cells. Cytotoxic T-cells important in anti-virus and anti-tumour defence but not so much in
allergic responses. Helper T-cells help cytotoxic T-cells to become killer cells and help B-cells to produce
antibodies.
T-cell subsets – different T-cells can be activated that release different types of cytokines than those that are
produced in the innate immune response:
- Th2 – typical in allergies that produce IL-4 and IL-13. IL-4 and IL-13 will on their turn instruct B-cells to make
IgE antibodies (inducing allergic reactions).
- Th1 – produce IFN-γ to make sure T1 and T2 are in equilibrium.
- Treg – important in the immune system. They control the immune response and makes sure the immune
response is nicely regulated (compare to orchestra conductor). Treg cells produce particularly IL-10
(preventing allergic reactions) in the GI-tract. In the lungs and airways, mainly TGFβ is produced, doing the
same thing.
Balanced and unbalanced immune system:
- Equal amount of Th1 and Th2 -> homeostasis
- More Th1 than Th2 cells -> autoimmune disorders
- More Th2 than Th1 cells -> asthma and allergies
- More Th17 than Treg cells -> autoimmune disorders and
inflammatory bowel disease
B-cells and antibody production:
Primary and secondary immune response:
- Primary antibody response (allergic sensitisation) – mainly IgM production. After 30 days, no antibodies
present anymore but memory B cells present
- Secondary antibody response (allergic reaction) – much faster response, level of response much higher and
only IgG produced which even binds better to the antigen than initially
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,Lecture 2 – Gut mucosal immune system
Mucosal immune system – immune system of relevance in airways and gut, so important for allergies. Slimy
mucus is produced by goblet cells. Bacteria get stuck in this mucus and are unable to come into contact with
epithelial cells. With age, this mucus layer becomes thinner.
Host-microbe interaction in the gut: On the epithelium, a lot of stuff is produced to
keep the epithelium clean and kill the microbes and make sure there is no interaction
with the TLRs that would induce inflammation. Paneth cells, situated in the lower
base of the crypts, produce anti-microbial proteins (AMPs)
4 different ways in which the gut takes up digested materials (proteins):
1. Epithelial cells – take up single amino acids and dipeptides directly
2. M cells – right on top of clusters of immune cells, called Peyer’s patches. These M
cells are able to take up large particles, e.g. aggregates of proteins or bacterial cell
wall fragments
3. CD103 dendritic cells – specific dendritic cells with an extension that can squeeze
between two epithelial cells and directly grasp antigens from the gut lumen
4. Tight junctions – complexes of different proteins between epithelial cells that are
connected at so-called kissing points. Only water and very small molecules
(peptides <600 Da) can pass through these tight junctions via paracellular transport, but most molecules
pass the cells through transcellular transport. The tight junctions therefore ensure the gut barrier function.
First immune response in new-borns: baby’s get some microbes from the mother’s faeces and their gut gets
colonized by bacteria. The baby’s immune system is immediately challenged and learns how to react on foreign
particles. Most microbes are anaerobic and will die in the baby’s gut, because it is still filled with oxygen. These
bacterial fragments can easily leak between the baby’s epithelial cells. This will teach the immune system what
to react to and what not.
Help in immune response from the mother through breast feeding: opposed to cow’s milk, human breast milk
contains human milk oligosaccharides (HMO’s) which allow bifidobacteria to grow. Bifidobacteria are
facultative anaerobic bacteria that can stand a little oxygen. They will consume the HMO’s in order to grow and
multiply and absorb the oxygen, making the baby’s gut anaerobic, just like in adults. When the mother is unable
to breastfeed, no bifidogenic flora will develop in the baby’s gut. This will result in different gut flora. Long time
health status is determined by this gut flora and can be modulated by dietary intervention in the first three
years of life.
Babies born through a caesarean section: baby’s get a lot of bacteria from e.g. skin and upper airways, instead
of gut microbiota. It takes about 3 years before this difference is gone.
Children and elderly are more susceptible to infections: as the immune system tries hard to prevent
inflammation in elderly and young children, these age groups are more susceptible to infectious diseases. In
adults, the opposite is the case, which is why many auto-immune diseases develop around the age of 20-25:
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, Food modulates immunity at four distinct levels in the gut:
1. Microbiota composition and metabolites: outgrowth & adhesion pathogens
2. Interaction with epithelia: cytokine production and barrier function
3. Local activation of immune cells: local effects (e.g. belly ache due to celiac disease)
4. Migration of immune cells or uptake in blood: systemic/distant effects (e.g. red spots in skin and breathing
problems due to shrimp)
Decision between immune activation and immune tolerance is made by dendritic cells:
- Immature DC’s ensure immune tolerance (antigen uptake and processing)
- Mature DC’s are the start of an immune reaction (antigen presentation, costimulation and T-cell activation)
Dysbiosis – microbiota in the gut is disturbed (e.g. normally dominating species underrepresented and normally
outcompeted species increasing to fill the void) due to:
- Genetics (mutations in certain genes)
- Lifestyle (diet, stress)
- Early colonization (birth in hospitals, altered exposure to microbes)
- Medical practices (vaccination use, antibiotic, hygiene)
Lecture 3 – Food allergy: mechanisms and implications
Basic concepts hypersensitivities:
Hypersensitivity – undesirable effects against (non-harmful) foreign stimuli
Allergy – immune mediated hypersensitivity
Intolerance – non-immune mediated hypersensitivity (e.g. enzyme deficiency)
Hyperreactivity – excessive irritability (by physical stimuli such as smoke and dust)
Immunopathology of allergy & intolerance:
- Acute complaints: direct IgE-mediated food allergy (within 20 minutes)
- Chronic complaints: not IgE-mediated (e.g. gluten intolerance)
Basics of allergic reaction:
1. Sensitisation: exposure with allergen on epithelium in the nose, lungs
or GI tract. This allergen crosses the barrier (metabolized or eaten up
directly) and ends up in the lamina propria. Antigen presenting cell
presents fragments of the allergen and activates Th2 cell, which produces
IL-4 cytokines which will instruct B-cells to produce IgE antibodies, which
bind to mast cells
2. Allergic reaction: next time antigens are coming in they can bind
directly to the IgE antibodies on the mast cells. As a result, the mast cells
will release mediators such as histamine, inducing allergic symptoms.
Clinical symptoms in patients at allergen exposure:
- Skin: atopic dermatitis (10-12%)
- Gut: food allergy (20%)
- Nose: rhinitis, hay fever (10-20%)
- Lungs: asthma (2,5-10%)
Based on the clinical symptoms, the type of allergy is hard to determine, as symptoms can be different for the
same underlying allergy
Oral allergy syndrome (OAS) – no primary allergy but cross-reactive with weak symptoms, like swelling lips
Allergic asthma – airways are extreme sensitive to certain allergens, causing trouble with breathing due to
excessive mucus production that clog up the airways
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