This is a small summary for the course advanced immunology from the master biomedical sciences at the UvA. It includes all the information you need for one of the 9 Janeway tests during this course. Look out for the bundle, because that's a lot cheaper!
Inflammation & allergy – René Lutter
Antigens not associated with infectious agents (pollen, food) sometimes elicit adaptive immune
responses → disease (allergy). Hypersensitivity reactions due to immunological responses were
divided in 4 types historically:
• Type 1: IgE antibodies → mast cell activation.
• Type 2/3: Antigen specific IgG antibodies → complement or FcR bearing effector cells.
• Type 4: Driven by cellular factors → lymphocytes & myeloid cells.
Most normal and pathologic host immune responses involve humoral and cellular responses. Most
allergic reactions occur because an individual is sensitized to innocuous antigen (allergen) by
producing IgE antibodies against it. Result of unwanted type 2 response. IgE binding triggers
activation of mast cells and basophils. Some allergies are driven by IgG antibodies/cellular immune
responses.
Most of population does not develop allergic reactions, but half of population shows a response to at
least one substance in environment. A predisposition to become IgE sensitized to allergens is called
atopy → higher chance (40-60%) for child to become allergic (instead of 10%).
IgE is defence against extracellular parasitic organisms (helminths/protozoa) → prevalent in
developing nations. Burden allergic diseases Western world is high, Afrika and Middle east lower but
changing due to modernization.
Immediate hypersensitivity reactions: Allergic reactions caused by activation of mast cells and
basophils by multivalent antigen bridging IgE bound to their cell surfaces. IgE is located in tissues →
tightly bound to mast cells (high affinity IgE receptor). Antigen binding to IgE crosslinks IgE receptor
→ release chemical mediators from mast cells → allergic disease.
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To develop allergy, individual must be exposed to antigen under condition that result in IgE
production. Symptoms occur at second exposure of this antigen (so after antibodies formed). Most
common symptoms occur in nose (rhinitis), eyes (conjunctivitis), lower airways and lungs (asthma),
food allergy, systemic reactions.
• Systemic reactions: Spread antigen through body via circulation, can be limited to organ like
skin. They can lower blood pressure life threatening if targeting vascular system. Can cause
anaphylaxis.
Atopic individuals often develop sensitization to many different antigens → multiple different
symptoms. Kids with eczema (food allergens) often develop asthma/rhinitis (atopic march).
Non-atopic individuals develop sensitization to one specific antigen like bee venom of penicillin, can
develop any time of life.
• Not all sensitizations will lead to symptomatic allergic response (even in atopic individuals).
Signals leading to IgE response (type 2 immune reaction): Signals that favour differentiation naive T
cells into Th2 & signals that are Th2 cytokines and co-stimulatory ligands → B cells switch to IgE. If a
T cell will respond to antigen presented by DC depends on:
• Cytokines (before and during response, IL5/9/13 → Th2, IL12 & IFNgamma → Th1).
• Intrinsic properties antigen.
, • Antigen dose.
• Route of presentation.
Immune defences against parasites are found under the skin and in mucosal tissues (airways and
gut) because this is their place of entry. Cells at this site are specialised at secreting cytokines for
type 2 response. DCs take up antigens → lymph nodes → CD4 naive T cells become Th2 cells →
IL4/5/13 → more Th2 → class switching B cells to IgE production.
➔ IL-33 from mast cells and damaged epithelial cells → amplification Th2
response. Can also act directly on Th2 cells by IL-33 receptors.
Normally, allergic responses against common antigens are avoided because DCs that
encounter antigen in absence of danger signals (microbial infection) induce CD4 T
cells to Tregs → tolerance.
IL-4/13 first signal to switch to IgE, they act on Jak1/3 → phosphorylation/activation
STAT6. Second signal is the co-stimulatory interaction between CD40L (T cell) and
CD40 (B cell).
Murine mast cells and basophils also produce signals that drive IgE production.
They express FCepsilonRI when they are activated by crosslinking FCepsilonRI with
IgE → express CD40L and secrete IL-4.
➔ Human basophils can induce class switching and IgE production (like Th2 cells).
Class switching happens in lymph nodes that drain site of antigen entry or in inducible lymphoid
follicles (mucosal & other tissues at sites of persistent inflammation) → mast cells and basophils can
amplify B cell response close to site of allergic reaction.
➔ Therapies: Block this amplification.
IgE response can be amplified by capture of IgE by FCepsilon receptors on DCs. Langerhans cells of
the skin (DCs) express FCepsilonRI in an inflammatory setting → IgE can bind to these. DC can take
up the antigen (very effectively) → presented to naive T cells → Th2 response.
Eosinophils also have IgE receptors (controversial). May act as APC to T cells (not lymph nodes).
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Once mast cells are activated (cross linking
IgE with FCepsilonRI receptor) they secrete
pharmacological mediators like histamine
from granules and they synthesise
prostaglandins, leukotrienes and platelet
activating factor (PAF, plasma membrane).
They also release cytokines and
chemokines.
The consequences of IgE mediated mast
cell activation depends on the dose of
antigen and route of entry (swollen eyes,
rhinitis to anaphylaxis). The immediate
response of mast cells is often followed by
a more sustained inflammation (Th2, eosinophils, basophils).
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