Dr Alok Tripathi

lessfrustratedBiotechnology

Oct 23, 2013 (4 years and 17 days ago)

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Dr
Alok

Tripathi

Department of Biotechnology

aquaimmuno@yahoo.com

Hypersensitivities

• Immune responses to innocent antigens or
self antigens that lead to symptoms or tissue
damage

• Term “hypersensitivity” originally used to
denote acquired immune response, as was
“allergy”

• “Hypersensitivity” and Allergy” most
commonly refer to responses to innocent
antigens

• But autoimmune diseases are sometimes
subset of hypersensitivity


Atopy

is term used to describe condition of
general likelihood of responding with allergic
reaction

Classified by mechanism (Gel and Coombs 1963)

• Type I, Immediate:
IgE

antibody
triggering mast cells and eosinophils

• Type II, Antibody Mediated:
IgG

antibody reacting with cell surface or
matrix antigens

• Type III, Immune Complex
Mediated: antigen
-
antibody
complexes

• Type IV: T cell mediated

Type I: allergies.
IgE

and mast
cells

Usefulness of “Type I”
IgE

responses:

eliminating parasites, like
helminths

Propulsive smooth muscle
contraction,

mucus prevent infiltration
of epithelium by parasites

About 20% of people in US have some form of allergy


CD4 TH2 T cells
cytokine profile leads to
isotype

switching to
IgE

Sensitization
phase:


IgE
triggers Mast cell
degranulation

Effector

phase:

Sequence of events in Type I, “immediate
hypersensitivity”


Eosinophils & Basophiles contribute to the
chronic allergic reaction releasing similar
chemicals mediators to
IgE

binding to
Fc
e
eRI

(which is induced in eosinophils by
inflammation)


• Helper T cells (TH2) that secrete IL
-
4, IL
-
5, and
IL
-
13 are


responsible for inducing allergen specific
IgE

production


• Non
-
atopic individuals also have T cells that
recognize


allergens after sensitization, but in normal
individuals the


T cells are kept in check by
Tregs

(IL
-
10 and
TGFb
)


• Normal people activate TH1 helper T cells and
make
IgG



antibodies to same antigens


• Four distinct susceptibility genes
identified so far




G
-
protein coupled receptor expressed in
inflamed tissue

8% of children under 3, 4% of US
adults Leading cause of
anaphylaxis outside of hospitals,
30,K ER cases per year

May lead to
IgE

or cell mediated
responses, and be expressed any
of atopic sites (gut, skin, bronchi,
systemic)

Gut largest immunologic organ
for Food allergy


Systemic
antigen, like
bee sting

Systemic
response of
IgE

cross
linking
receptors on
connective
tissue mast
cells and
circulating
basophils



• Desensitization with protein or peptide
antigens, with or without adjuvant


• Anti
-
IgE

antibody




Xolair

approved in 03 for asthma, but not yet
tested for peanut allergy (Genentech)




TNX
-
901 very effective in clinical trials but
removed


from testing by biotech squabbling
(
Tanox
/Genentech


legal battle)





Peanut allergy treated with
treated with peptide
plusHeat

Killed
Listeria
, to induce TH1
response (in dogs, Frick 05)

• E.g.,
Ara

h 1,2, and 3
are peanut
proteins




Peptide
epitopes

recognized by
CD4 TCRs have been determined




Therapy with
Fel

d 1 peptides
increases TH1 T
cellsrather

then T
reg

T cells (Alexander 05)

Fel

d 1 is
component
of cat
dander

generation of
IgG

antibodies
that prevent

allergic antigen
from reaching
IgE

coated
mast cells

Desensitization may also be due to

Hygiene hypothesis

• Asthma and allergies increasing
dramatically in recent years in
developed countries

• Exposure to pathogens (larger
families, day care, farms) lowers
incidence of allergies

• Suggested that TH1 responses limit
TH2responses, but TH1 and TH2
are not solely antagonistic, and basis
of hygiene effects are
notyet

clear