Anda di halaman 1dari 92

Alergi dan Anafilaksis

dr. M Ikhsan Mokoagow, SpPD, M.Med.Sci

Pendahuluan
Umumnya sistem imun bersifat protektif
Mekanisme proteksi ini dapat berakibat pada

kerusakan jaringan dan bahkan dapat menyebabkan


kematian
Kapan?

Kerusakan hebat dapat terjadi ketika sistem imun


merespons secara berlebihan atau dalam bentuk
yang tidak tepat

Hypersensitivity (Allergy):
suatu respon abnormal terhadap antigen

Klasifikasi Coombs and Gell


Hypersensitivity Reactions:

Type I (Anaphylactic) Reactions

Type II (Cytotoxic) Reactions

Type III (Immune Complex) Reactions

Type IV (Cell-Mediated or Delayed) Reactions

Hipersensitivitas Tipe I

Tipe I - immediate (or atopic, or anaphylactic)


Reaksi alergi yang diprovokasi oleh pemaparan

ulang terhadap suatu antigen spesifik.


Paparan dapat berupa melalui:
Ingestion, inhalation, injeksi, kontak langsung
Reaksi ini diperantarai IgE antibodies dan

diakibatkan oleh adanya pelepasan cepat dari


histamine, tryptase, arachidonate dan substansi
(derivatives) oleh basophils dan sel mast.

Hypersensitivitas Tipe I
Respons terjadi secara cepat setelah
paparan

Reaksi terlokalisir (Localized )


Reaksi Sistemik

Umumnya dikenal sebagai Alergi


Antigen yang merangsang dinamakan
Alergen

Beberapa Contoh
Allergic asthma
Allergic conjunctivitis
Allergic rhinitis ("hay fever")
Anaphylaxis
Angioedema
Urticaria (hives)

Tanda dan Gejala


Reaksi lokal
o Umumnya ringan
o Lokasi reaksi tergantung portal of entry
o inhaled allergens mencapai paru asthma
o Beberapa makanan mengandung alergen
o Dapat menyebabkan diare atau tanda gejala
gastrointestinal lain

o Inflamasi kulit lokal dapat menimbulkan urticaria


(hives)

Urticaria

Mekanisme
Melibatkan produksi IgE, sebagai respons terhadap
antigen (allergen) tertentu.
Ig E memiliki afinitas yang sangat tinggi terhadap
reseptornya pada mast cells dan basophils.
Paparan berikutnya memicu pelepasan beragam
substansi aktif
Cross-linking of IgE Fc-receptor berperan penting
memicu degranulasi mast cell
Didahului peningkatan Ca++ influx
Ionophores akan meningkatkan Ca++ dalam sitoplasma
yang juga meningkatkan degranulasi

Fig 1

Figure 18.1a The mechanisms of a type I hypersensitivity reaction: sensitization


Allergen (antigen)
Antigen-presenting cell (APC)
phagocytizes and processes
antigen.

APC presents
epitope to Th2 cell.
Th2 cell
IL-4
B cell

IL-4 from Th2


cell stimulates selected
B cell clone.

B cells become plasma cells


that secrete IgE.
Plasma
cell
IgE against allergen

IgE stem binds to


mast cells, basophils,
and eosinophils.

IgE
Mast cell

Sensitization

Basophil

Eosinophil

Pencetus Sel Mast


Sel Mast dapat dipicu oleh stimuli lain:
-Exercise,
-Emotional stress
-Chemicals (e.g., photographic developing
medium, calcium ionophores, codeine, etc.),
-Anaphylotoxins (e.g., C4a, C3a, C5a, etc.).
Reaksi tersebut bukan merupakan suatu

reaksi hypersensitivity sekalipun


menyebabkan gejala yang serupa

Mediator yang dilepaskan Sel Mast


Histamine:

Dilates and increases


permeability of blood vessels (swelling and
redness), increases mucus secretion
(runny nose), smooth muscle contraction
(bronchi).
Prostaglandins: Contraction of smooth
muscle of respiratory system and
increased mucus secretion.
Leukotrienes: Bronchial spasms

Mast Cells and the Allergic Response

Resting Mast Cell

IgE Cross-Linking by Allergen


(LinkIgE1)

LinkIgE1

From Figure 15-1, 7th Edition, p. 486

Sensitization of Mast Cells:


Isotype-Switching to IgE

Also Figure 15-2, 7th Edition, p. 490

Tanda dan Gejala


Reaksi Sistemik
Terjadi degranulasi sel Mast dalam jumlah
banyak pada saat yang bersamaan,
menyebabkan pelepasan histamin dan
mediator inflamasi dalam jumlah besar
Anafilaksis atau syok anafilaksis
Perasaan tercekik, sulit bernapas, pingsan,
nadi lemah cepat, hipotensi

Diagnosis
Type I (Immediate) Hypersensitivity

Detection of high levels


of IgE against specific
allergen
Alternatively, can
diagnose using skin
tests

Pencegahan
Identifikasi dan hindari allergen
Identifikasi alergen makanan dengan
mengeliminasi bahan makanan yang
dicurigai dari asupan harian

Terapi Reaksi Hypersensitivitas tipe I


Berikan obat yang mengatasi mediator inflamasi
Antihistamines

Tatalaksana asthma dengan corticosteroid dan


bronchodilator
Epinephrine mengatasi reaksi anafilaksis
Merelaksasi smooth muscle
Mengurangi permeabilitas vaskular
Asthma berat dan syok anafilaktik perlu terapi
kedaruratan

To Treat Type I Immediate Hypersensitivity


Based on the Underlying Mechanisms:

1. Block Effects of Primary Mediators on Target Cells


(e.g. respiratory smooth muscles or vascular
endothelium) : Antihistamines; Cortisone
2. Block Calcium Ion Influx: Cromolyn
3. Block the Effects of Calcium Ion Influx
a. Keep cyclic AMP (cAMP) from Falling Theophylline
b. Increase production of cAMP: Adrenaline

Hipersensitivitas Tipe II

Type II - antibody-dependent
Ab diproduksi oleh respons imun yang berikatan

dengan antigen pada permukaan sel pasien sendiri


Antigen dapat merupakan:
intrinsik
"self" antigen, innately part of the patient's cells

Ekstrinsik
diserap ke dalam sel melalui paparan terhadap antigen
asing, kemungkinan saat terjadi infeksi)

Type II (Cytotoxic) Reactions


Involve

activation of complement by IgG or


IgM binding to an antigenic cell.
Antigenic cell is lysed
Transfusion reactions
ABO Blood group system: Type O is universal
donor. Incompatible donor cells are lysed as they
enter bloodstream.
Rh Blood Group System: 85% of population is Rh
positive. Those who are Rh negative can be
sensitized to destroy Rh positive blood cells.

Hemolytic disease of newborn: Fetal cells are destroyed


by maternal anti-Rh antibodies that cross the placenta.

Figure 18.5 Events leading to hemolysis

Type A antigens on red


blood cells of patient
Donated red blood cells
with B antigen

Anti-B
antibody

Transfusion
Complement

Hemoglobin

Agglutination and
complement binding
Hemolysis

TYPEII
Antibodymediatedcytotoxicity
B
BEE
Drug reactions
TTH
HEER
E!!
Drug binds to RBC surface and antibody RE
against drug binds and causes lysis of RBCs
Immune system sees antibody bound to

"foreign antigen" on cell


ADCC

Figure 18.7 Events in the development of immune thrombocytopenic purpura

Drug
Platelet
Drug molecules bind to platelets,
forming drug-platelet complex.
Drug-platelet
complex

Complexes are antigenic,


triggering a humoral
immune response.

Antibodies bind to drug


molecules; complement
binds to antibodies.

Complement

Membrane attack
complexes of complement
lyse platelet, which leaks
cytoplasm.

Figure 18.6 Events in the development of hemolytic disease of the newborn-overview

TYPEII

Rhfactorincompatibility
B
BEE
TTH
HEER
REE!!

Examples

Autoimmune haemolytic anaemia


Immune thrombocytopenia
Transfusion reactions
Hashimoto's thyroiditis
Graves' disease
Myasthenia gravis
Hemolytic disease of the newborn

Hipersensitivitas Tipe III

Type III - immune complex


In type III hypersensitivity:
soluble immune complexes (aggregations of

antigens and IgG and IgM antibodies) form in the


blood and are deposited in various tissues
(typically the skin, kidney and joints)

This may trigger an immune response

according to the classical pathway of


complement activation.
The reaction takes hours to days to develop

known also as

immune complex

disease
occurs when immune complex (Ag-Ab)

are not removed from circulation


These complexes are deposited in
various tissues and organs such as:
Kidneys
Joints
Lung
Skin

MECHANISM
Step 1
Large quantities of
soluble antigenantibody complexes
form in the blood and
are not completely
removed by
macrophages.

Step 2

These antigenantibody complexes


lodge in the capillaries
between the
endothelial cells and
the basement
membrane.

Step 3

These antigen-antibody
complexes activate the
classical complement
pathway leading to
vasodilatation.

Step 4

The complement proteins and antigen-antibody complexes


attract leukocytes to the area.

Step 5
The leukocytes
discharge their killing
agents and promote
massive
inflammation. This
can lead to tissue
death and
hemorrhage.

Figure 18.8 The mechanism of type III (immune-complex mediated) hypersensitivity-overview


Antigens combine with
antibodies to form
antigen-antibody complexes.
Antigen
Antibody (IgG)
Antigen-antibody complex

Phagocytes remove most


of the complexes, but
some lodge in the walls
of blood vessels.

There the complexes


activate complement.
Inactive complement
Active complement

Antigen-antibody complexes
and activated complement
attract and activate
neutrophils, which release
inflammatory chemicals.
Neutrophil
Inflammatory chemicals

Inflammatory chemicals
damage underlying
blood vessel wall.

Systemic Lupus Erythmatosus

The disease is characterized by the presence of

autoantibodies , which form immune complexes


with autoantigens and are deposited within the
kidney glomeruli
The resulting type III hypersensitivity is

responsible for the glomerulonephritis


(Inflammation of blood capillary vessels in the
glomeruli)

TYPEIII
Immune Complex Disease
B
BEE
TTH
HEER
REE!!

Serumsicknessfromlargeamountsofantigen

suchasinjectionofforeignserum.

Serumsicknessisusuallytransientimmunecomplexdisease

withremovalofantigensource.

Serum Sickness

A disease caused by the injection of large doses of a protein


antigen into the blood and characterized by the deposition of
antigen-antibody complexes in blood vessel walls, especially in
the kidneys and joints.

Serum Sickness
Systemicimmunecomplexdisease

Largeamountsofantigen
suchasinjectionofforeign
serum.

Days after Antigen Injection

Serum sickness

TYPEIII
Immune Complex Disease
Localizeddisease

B
BEE
TTH
HEER
REE!!

Depositedinjointscausinglocalinflammation=

arthritis.
Depositedinkidneys=glomerulonephritis.

Immune Complex Mediated Hypersensitivity

Examples:
Immune complex glomerulonephritis
Rheumatoid arthritis
Serum sickness
Subacute bacterial endocarditis
Symptoms of malaria
Systemic lupus erythematosus
Arthus reaction

Hipersensitivitas Tipe IV

Type IV (Cell-Mediated) Reactions


Involve

reactions by TD memory cells.

First contact sensitizes person.


Subsequent contacts elicit a reaction.

Reactions

are delayed by one or more days


(delayed type hypersensitivity).

Delay is due to migration of macrophages and T


cells to site of foreign antigens.

Reactions

are frequently displayed on the skin:


itching, redness, swelling, pain.

Tuberculosis skin test


Poison ivy
Metals
Latex in gloves and condoms (3% of health care workers)

Type IV Hypersensitivity
Type IV hypersensitivity is often called

delayed type as the reaction takes two to


three days to develop.
Unlike the other types, it is not antibody

mediated but rather is a type of cellmediated response.

Type IV hypersensitivity is also known as cell

mediated or delayed type hypersensitivity.


The classical example of this hypersensitivity is

tuberculin (Montoux) reaction


Reaction peaks 48 hours after the injection of

antigen (PPD or old tuberculin). The lesion is


characterized by induration and erythema

Some clinical examples:


Contact dermatitis (poison ivy rash, for example)
Temporal arteritis
Symptoms of leprosy
Symptoms of tuberculosis
Transplant rejection

Type IV hypersensitivity is involved in the

pathogenesis of many autoimmune and infectious


diseases:
Tuberculosis
Leprosy
Blastomycosis
Histoplasmosis
Toxoplasmosis
Leishmaniasis
Granulomas due to infections and foreign antigens.

Another form of delayed hypersensitivity is

contact dermatitis (poison ivy, chemicals,


heavy metals, etc.) in which the lesions are
more papular
Type IV hypersensitivity can be classified into

three categories depending on the time of


onset and clinical and histological
presentation

Allergic Contact Dermatitis Response to


Poison Ivy Hapten

Type

Reaction
Fig
5

contact

tuberculin

granuloma

time

48-72 hr

48-72 hr

21-28
days

Clinical
appearance

Histology

Antigen and site

eczema

lymphocytes, followed
by macrophages;
edema of epidermis

epidermal ( organic
chemicals, poison
heavy metals, etc.)

local induratio

lymphocytes,
monocytes,
macrophages

intradermal (tuberculin
lepromin, etc.)

hardening

macrophages, epitheloid
and giant cells,
fibrosis

persistent antigen or
foreign body prese
(tuberculosis, lepro
etc.)

Mechanism:
The mechanism includes T lymphocytes and

monocytes and/or macrophages.

Cytotoxic T cells (Tc) cause direct damage

whereas helper T (TH1) cells secrete cytokines


which activate cytotoxic T cells, recruit and
activate monocytes and macrophages, which
cause the bulk of the damage

The delayed hypersensitivity lesions mainly

contain monocytes and a few T cells.

Delayedtypehypersensitivity
Th1cellsandmacrophages

B
BEE
DTH response is from:
TTH
HEER
Th1 cells release cytokines to activate macrophages
REE!!
causing inflammation and tissue damage.
Continued macrophage activation can cause chronic
inflammation resulting in tissue lesions, scarring, and
granuloma formation.
Delayed is relative because DTH response arise 24-72

hours after exposure rather than within minutes.

StagesofTypeIVDTH
B
BEE
TTH
HEER
REE!!

Sensitizationstage
MemoryTh1cellsagainstDTHantigens
aregeneratedbydendriticcellsduringthe
sensitizationstage.
TheseTh1cellscanactivatemacrophages
andtriggerinflammatoryresponse.

StagesofTypeIVDTH
Effectorstage

B
SecondarycontactyieldswhatwecallDTH.
BEE
TTH
HEER
REE!!
Th1memorycellsareactivatedandproduce

cytokines.

IFN,TNFandTNFwhichcausetissue
destruction,inflammation.
IL2thatactivatesTcellsandCTLs.
Chemokinesformacrophagerecruitment.
IL3,GMCSFforincreasedmonocyte/macrophage

StagesofTypeIVDTH
Effectorstage

B
BEE
TTH
Secondaryexposuretoantigen
HEER
REE!!
Inflamedareabecomesredandfluidfilledcan

formlesion.

Fromtissuedamagethereisactivationofclotting
cascadesandtissuerepair.

Continuedexposuretoantigencancausechronic

inflammationandresultingranulomaformation.

TypeIVDTH
Contactdermatitis
B
BEE
TTH
TheresponsetopoisonoakisaclassicTypeIV.
HEER
REE!!
Smallmoleculesactashaptensandcomplexwithskin
proteinstobetakenupbyAPCsandpresentedtoTh1
cellstogetsensitization.
DuringsecondaryexposureTh1memorycellsbecome
activatedtocauseDTH.

Contactdermatitis
B
BEE
TTH
HEER
REE!!

Delayedtypehypersensitivity
(DTH)
B
DTH is a type of immune
BEE
TTH
response classified
by
HEER
RE
Th1 and macrophage E!!
activation that results in
tissue damage.
DTH can be the result of
Chronic infection or
Exposure to some antigens.

Granuloma Formation from DTH


Mediated by Chronic Inflammation
B
BEE
TTH
HEER
REE!!

DrugreactionscanbeanyType
ofHypersensitivity
B
BEE
TTH
HEER
REE!!

The hypersensitivity reactions

Figure 12-2

Allergens
B
BEE
TTH
HEER
REE!!
Allergensarenonparasiteantigensthatcan

stimulateatypeIhypersensitivityresponse.

AllergensbindtoIgEandtrigger

degranulationofchemicalmediators.

Allergens
Example: Der P1

B
BEE
TTH
HEER
Der P1 is an enzyme
allergen
R
EE!!
from the fecal pellets
of the dust mite.

Dermatophagoides
pteronyssinus
(common dust mite)

Der P1 Allergen

B
BEE
TTH
HEER
REE!!

Allergen is easily aerosolized and inhaled


Der P1 breaks down components of tight junctions
which helps it to cross mucosa.

Atopy
B
BEE
Atopyisthetermforthegenetictraittohavea
TTH
HEER
predispositionforlocalizedanaphylaxis.REE!!

AtopicindividualshavehigherlevelsofIgE

andeosinophils.

Genetic Predisposition
TypeIhypersensitivity
B
BEE
TTH
Candidatepolymorphicgenesinclude:
HEER
REE!!
IL4Receptor.
IL4cytokine(promoterregion)
FcRI.HighaffinityIgEreceptor
ClassIIMHC
(presentpeptides
promotingTh2response)
Inflammationgenes.

Mechanismsofallergicresponse

Sensitization
Th2/Bcellinteraction

Busse and Lemanske NEJM Feb 2001. 344:350

IL-4
B
BEE
IL-4R T
TH
HEER
REE!!
CD40
Drive B cell
Activation and IgE
isotype switch.

Some Definitions and Concepts


"Hypersensitivity" - Suggests Heightened Response
Includes in-appropriate or mis-regulated response
"Allergy: Generally refers to Type I Immediate Hypersensitivity;
But also hear Types II and III "Allergy
Atopic Allergy (Atopic Individual):
Genetic misregulation of IgE production or response
"Immediate"Within minutes (Type I)
or hours (Types II and III)
"Delayed" Takes two or more days
"Phylaxis" Protection
"Anaphylaxis" - Opposite of Protection; Damaging
Link to American College of Allergy, Asthma & Immunology
http://www.acaai.org

Positive
Wheal and
Flare
Reaction

Non-IgE Antibody-related Initiators of


Type I Hypersensitivity
Complement Activation Products:
C3a, C4a, C5a
"Anaphylotoxins"
Various Drugs: ACTH, Codeine,
Morphine, Penicillin
NonIgE

Anafilaksis

Anafilaksis adalah reaksi alergi berat


bersifat sistemik melibatkan multiorgan

Kulit, jalan napas, sistem vaskular, dan GIT tract

Kasus berat dapat menyebabakan obstruksi


jalan napas total, kolaps kardiovaskular, dan
kematian
Reaksi Anaphylactoid (pseudoanaphylactic )
Gejala klinis serupa tapi bukan diperantarai
sistem imun
Tatalaksana serupa