Lecture 16 - Allergies Flashcards
6 types of allergic disease
- eczema
- allergic rhinitis
- asthma
- food allergy
- venom allergy
- drug allergy
difference btwn allergic rhinitis and asthma
allergic rhinitis occurs in upper airway, asthma occurs in lower airway
frequency of allergic disease
1/3 of ppl have 1 or more atopic disease
2 most prevalent respiratory allergies:
- allergic rhinitis
- asthma
what is the name of the immune response that occurs in allergy?
Type 2 response
when does an antigen become an allergen?
once it activates type 2 response
describe what happens in type 2 response for allergy
- IgE is produced and binds mast cell
- when IgE binds antigen, mast cell is activated and degranulates
- degranulation releases histamine, leukotrienes, IL4/IL13
is IgE alone sufficient to induce allergy?
no!!
where do allergic mediators act?
locally and systemically
symptoms induced by inflammatory mediators
- skin rash/itch
- sneezing
- itchy eyes
- coughing
- reactive airways
- increased intestinal motility
- edema
are IgE and mast cells required for asthma?
helps response, but not required to induce symptoms
2 factors that cause allergies to develop
- genetic
- environment
describe a baby’s immune system when it is born
exposed to many new microbes –> immune system must be fully regulatory so it can be calm
what happens to a baby’s immune system without FOXP3?
No Treg –> immune system cannot be calm, it goes crazy
how does atopic dermatitis develop on baby and how can this lead to food allergy?
once born, baby no longer moisturized in womb so it has a little atopic dermatitis with T2 activation
then food Ag touches skin where there’s atopic dermatitis –> T2 already activated so will develop T2 response against Ag
where in the body is T2 more common when you’re older?
T2 response in airways occurs later –> airways less exposed to Ag when young
what type of environment is best to develop tolerance?
complex Ag environment can help induce tolerance
what cells mainly mediate asthma? which cells are less involved?
mainly Th2, less mast cells (IgE)
what can asthma lead to?
fibrosis in the lungs
why is fibrosis in the lungs bad?
decreased elasticity = bad for lungs
besides genetics and environment, what is an example of something that can drive T2 response?
ex. viruses
describe how allergy becomes systemic
allergic sensitization may occur in 1 organ, but immune response can trigger a systemic inflammatory response
4 key cytokines
- TSLP
- IL4
- IL13
- IL5
2 less important cytokines
- IL33
- IL25
what 2 types of cells produce the key T2 cytokines
- DCs
- epithelial cells
what 2 types of cells are stimulated by T2 cytokines?
- TH2
- ILC2
where are ILC2?
airways
role of Th2 cells
cause B cells to class switch and form IgE plasma cells that produce allergen-specific IgE for binding to mast cells and basophils
difference btwn ppl who are allergic vs non-allergic
allergic: inflammatory T2 response
non-allergic: still takes Ag and presents it, then induces regulatory response
Th cells in non-allergic vs allergic
non-allergic: ANERGIC
allergic: Th2
Tfh cells in non-allergic vs allergic
allergic: Tfh13 (make IL13)
Treg cells in non-allergic vs allergic
non-allergic: has FOXP3 and also TGFbeta on surface that is inducible for peripheral tolerance
allergic: less TGFbeta
Ab in non-allergic vs allergic
non-allergic: IgG
allergic: IgE
role of innate immune system in non-allergic vs allergic
non-allergic: mainly regulatory
allergic: mainly pro-inflammatory
what happens if you block T2 with treatment? why?
T1 becomes more prominent and inflammation still occurs –> bc all responses always induced, just magnitude matters
what’s a better idea than just blocking a response?
REDIRECT the immune system
5 methods of allergic disease treatment
- allergen avoidance
- symptom management
- targeted immune blockade
- immunotherapy
- prevention
5 drugs for symptom management
- antihistamines
- corticosteroids
- antileukotrienes
- bronchodilators
- epinephrine
what does Remibrutiniib do?
blocks BTK involved in mast cell degranulation –> no degranulation = no mast cell effect
why might Remibrutiniib be better than antihistamines?
antihistamines only block His receptor but mast cell can still degranulate and anaphylaxis can still occur
why might Remibrutiniib not be good?
BTK is involved in B cell maturation so would be bad idea to block this!
issues with current targeted blockade treatments
only treat symptoms –> T2 still there and not redirected to regulatory –> don’t cure allergy
what proportion of allergies improve/resolve over time?
1/5
what 2 things happen with allergy as you age?
- allergy response becomes more severe
- threshold of allergen is lower
why is it good to expose baby to complex Ag environment when they are young?
so their immune system can receive inputs to strengthen regulation –> need some inflammation to train immune system to have anti-inflammation
describe immunomodulation
plasticity of T cell subsets: Th2 <–> Treg
principle of immunotherapy for allergy
start with very low dose allergen and gradually build up so patients can start to tolerate their allergens
how did immunotherapy for allergy start?
isolate bee venom to induce desensitization
2 forms of immunotherapy for environmental allergens
- allergy shots
- sublingual
describe the general idea of food immunotherapy
start with low amounts and gain tolerance
describe food immunotherapy in adults
success rate?
can work but must eat specific amount of that food everyday to induce desensitization –> if you stop, will regain allergy
30%
why can you regain allergy if you stop food immunotherapy in adult?
immune system is already developed in adults so baseline can’t be changed
food immunotherapy success rate in kids under 2?
why does food immunotherapy work better in kids under 2?
95%
immune response / baseline is not fixed
how does food immunotherapy work?
given amount of Ag below allergy threshold to “tickle” immune system –> induce regulatory response and lose inflammatory response
what % of people will outgrow their food allergy?
20%
what happens to IgE in ppl who naturally resolve their allergy?
IgE levels decrease
how are immunotherapy-treated ppl different from ppl with tolerance / natural resolution?
immunotherapy-treated ppl still have some aspects of allergy response
effect of immunotherapy on B cells
reduced drive for new B cells to make IgE –> but don’t know how long the existing B cells exist so it makes it hard when disease already exists
4 limitations of immunotherapy
- risk of anaphylaxis
- therapy is YEARS
- no info on duration of non-responsiveness
- less successful in adults
overall, what is the goal of immunotherapy
to immunomodulate the immune system
what response is increased in immnotherapy?
REGULATORY
what happens to cytokines with immunotherapy?
INCREASE in tolerant cytokines (TGFbeta and IL10)
DECREASE in T2 cytokines (IL4, IL13)
4 modifiable environmental risk factors
- allergens, irritants in the home
- food introduction protocols
- supplements (vitamins, probiotics)
- infections, antibiotics
mucosal contact = tolerizing or sensitizing?
mucosal = TOLERIZING
skin contact = tolerizing or sensitizing?
skin = SENSITIZING
what do ppl think asthma results from?
failure to tolerize mucosal immune system in early life
(bc non-allergic ppl have tolerant immune response when contact allergen)
epidemiological evidence of urban vs. farm life affecting allergy?
exposure to farms, stables, and farm milk in early life and long-term is protective
epidemiological evidence of birth order affecting allergy?
higher birth order is protective
epidemiological evidence of daycare affecting allergy?
daycare gives best protection for asthma if <6 months old
epidemiological evidence of pets affecting allergy?
exposure to pets is protective
epidemiological evidence of cockroach allergen affecting allergy?
cockroach allergen is sensitizing which increase risk of asthma
epidemiological evidence of early food introduction affecting allergy?
early introduction of complex antigenic foods reduces risk of food allergy
how are oral vs skin exposures to food antigens different?
ORAL = reduced risk of allergy (mucosa is tolerizing)
SKIN = increased risk of allergy (skin is sensitizing)
