ACQUIRED IMMUNITY

HUMORAL IMMUNITY
CELLULAR IMMUNITY

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 Th1 CTL

Intracell.pathogens

IgG

IgA
B
Ig
M
Th0 IgE

Worm

Th2 Dharmana E

Extracell. pathogens
 HLA ( Human Leucocyte Antigen )

DMB DMA DQB DRB

G
DQA DRA TNF B C E A H
F

Class I : HLA –A , B , C :
Presents in all nucleated cells
Class II : HLA- DR, DP , DQ :
T
Presents in APC (Antigen Presenting Cells)
Macrophage , B cells
Class III: C2, C4, Factor B, TNF Dharmana E
 HLA ( Human Leucocyte Antigen )

DMB DMA DQB DRB

G
DQA DRA TNF B C E A H
F

APC
CD4

T
Infected
cell
CD8 Dharmana E
Antigen : a substance that reacts with the products of a specific
immune response
Immunogen : a substance that induces a specific immune response
Epitope : that portion of an antigen that combines with the products
of a specific immune response

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 Foreignness
Chemical composition
Physical form
Genetic factors
Route
Dose
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 Th1 / Th2
concept

Induction of Th1 and Th2 subsets

IL-12 induced Th1 cell
development through STAT-4
dependent pathway
IL-4 favors the induction of Th2
cells through a STAT-6 dependent
pathway.
Il-12 is produced mainly by
activated macrophages and
dendritic cell I (DCI)
IL-4 is produced mainly by T cells
and by DCII

Abbas 2000 Dharmana E

Humoral immunity

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The components of protein serum

alpha1 alpha 2 beta gamma

Albumin Globulin
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 Antibody
production

B Plasma
cell

IL- 3,4,5,6, GM-CSF

M CD4

Antigen is presented by
macrophage and B cell to CD4 T cell
which in turn releases cytokines as
MHC II + Ag signal for B cell activation and
antibody production
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Antigen
 Antibody
production
IL- 4

IgE

IL- 5,
TGFb IgA

T B
IL- 4, 5

IgM

IL- 4,5,6,
IFNg
IgG E
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 Immunoglobulin

Fc
Fab

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Immunoglobulin classes

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 IgG IgA IgM IgD IgE

Subclasses 1,2,3,4 1,2

Complement
activation
++ - +++ - -
Opsonization ++++ + ? - +
Mast cell
sensitization
- - - - +
Transfer via + - - - -
placenta
Serum
concentration

Molecular 150 160- 900 180 190

weight 400

Allotype Gm(25) Am(2) Dharmana E

Some important properties of antibody :

• Agglutination : IgM, IgG

• Complement activation : IgM, IgG
• Mucosal protection : IgA , IgE
• Transfer via placenta : IgG
• Antitoxin : IgG, IgM
• Opsonization : IgG, IgM, IgE

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 CELLULAR IMMUNITY

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Th1-Th2 concept
The adaptive immune response to microbes residing
within the phagosome of phagocytes is mediated by T
lymphocytes, which recognize microbial antigens and
produce cytokines that activate the phagocytes and
stimulate inflammation

The adaptive immune response to microbes that infect in

the cytosol of various cell types including nonphagocytic
cells, is mediated by CD8 CTLs, which kill infected cells
and eliminate the reservoirs of infection.

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 CELLULAR MEDIATED
IMMUNITY

CD4

Intracellular
microbes

Macrophage

Macrophage presents the antigen in

IFN-gamma association with MHCII to CD4 T cell

CD4 Th1 Dharmana E

 CELLULAR MEDIATED
IMMUNITY

IFNg

CD4

IL-1
Intracellular
microbes
CD4 Th1 cell produces IFNg for
Macrophage macrophage activation

IFN-gamma

CD4 Th1 Dharmana E

 CELLULAR MEDIATED
IMMUNITY

IFNg

CD4

IL-1
Intracellular
microbes

Macrophage

IFN-gamma

CD4 Th1 Dharmana E

 CELLULAR MEDIATED
IMMUNITY

IFNg

IL-2 , IFN
CD4
CD8

IL-1
Intracellular
microbes
CD4 Th1 cell can also produce IL-
Macrophage 2, and along with IFNg contribute
the differentiation of CD8 T cell to
Cytotoxic T Lymphocyte (CTL) to
IFN-gamma kill tumor cells or virally infected
cells
CD4 Th1 Dharmana E
 CELLULAR MEDIATED
IMMUNITY

IFNg

CTL
IL-2 , IFN
CD4
CD8 CTL
CTL

IL-1
Intracellular
microbes CTL
CD4 Th1 cell can also produce IL-
Macrophage 2, and along with IFNg contribute
the differentiation of CD8 T cell to
Cytotoxic T Lymphocyte (CTL) to
IFN-gamma kill tumor cells or virally infected
cells
CD4 Th1 Dharmana E
 CELLULAR MEDIATED
IMMUNITY

CTL / CD8 killing activities

Antigen
expressed

Target
CD8 cell

Virus

Granzyme Perforine
MHC I + Antigen

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Tumor cell / virally infected cell /
transplant cell
 CELLULAR MEDIATED
IMMUNITY

CTL / CD8 killing activities

Virus released and dies

CD8

Virus

Granzyme Perforine

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Tumor cell / virally infected cell /
transplant cell
HIPERSENSITIVITY

Th1

TISSUE DAMAGE
CTL

IgG

IgA
B
Ig
Th0 M
IgE

Th2

INAPROPRIATE IMMUNE RESPONSE DUE TO :

EXESSIVE AMOUNT OF ANTIGEN
HEIGHTENED LEVEL OF IMMUNE RESPONSE Dharmana E
 CLASSIFICATION :
GELL & COOMBS :

1. TYPE I : ANAPHYLACTIC REACTIONS

2. TYPE II : CYTOTOXIC REACTIONS
3. TYPE III : IMMUNE COMPLEX-MEDIATED REACTIONS
4. TYPE IV : CELL-MEDIATED REACTIONS

Characteristic Type I Type II Type III TypeIV

Antibody IgE IgG,IgM IgG, IgM None
Antigens Exogenous Cell surface Soluble Tis/Org
Transferred by Antibody Antibody Antibody T-cells
Histology Basophils. Antibody Complement Monocytes
Eosinophils Complement Neutrophils Lymphocytes Dharmana E
 NK

Cytotoxic action

Mast-cell degranulation
Mediator release
Complement mediated lysis
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I II
 IL-4,5

Th2

Th0
Th1

IFN-g

IFN-g, IL-2

CTL
CTL

Immune-complex deposition Cell-mediated hypersensitivity

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III IV
CYTOTOXIC REACTIONS ( TYPE II )

ANTIBODY-DEPENDENT CYTOTOXIC HYPERSENSITIVITY

INVOLVE PRIMARILY ANTIBODY (IgG OR IgM) REACTING WITH

CELL BOUND ANTIGENS THAT LEADS TO DESTRUCTIVE
PROCESSES

Mechanisms of destructive processes :

1. Lysis via Complement activation
2. Phagocytosis of target cells
3. ADCC through natural killer cells (NK)

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 C3

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Fc receptor Complement C3 receptor
mediated lytic pathway mediated
CLINICAL
CLINICAL FEATURES
FEATURES ::

AlloimmuneReactions:
AlloimmuneReactions:
Red
Red blood
blood cells
cells lysis
lysis :: ABO
ABO blood
blood group
group
Platelet transfusion
transfusion :: HLA
HLA antigen
Rhesus
Rhesus Incompatibility
Incompatibility
Organ
Organ Transplantation
Transplantation

Autoimmune
Autoimmune Reactions
Reactions
Goodpasture’s
Goodpasture’s syndrome
syndrome
Granulocytopenia
Granulocytopenia
Autoimmune
Autoimmune hemolytic
hemolytic anemia
SLE
SLE Dharmana E

Idiophatic
Idiophatic thrombocytopenic
thrombocytopenic purpura
purpura
Positive and
negative selection
of T cells in the
thymus during the
SELF-TOLERANCE
process
 PERIIPHERAL TOLERANCE

T T
Sequestered Antigens

Treg

T
T
T

Activation No Activation
CTLA - 4 IFN-g

PAMP IL-12, IL-18 Th1

CYTOKINES
TLR

CD 28
Naïve T
CTLA-4
B7

TCR

MHC II
MAC Th2
IL-4
IL-4
 PAMP

CYTOKINES
TLR

CD 28
Naïve T
CTLA-4
B7
APOPTOSIS
TCR

MHC II
MAC
 IFN-g

PAMP IL-12, IL-18 Th1

CYTOKINES
TLR

CD 28
Naïve T
CTLA-4
B7

TCR

MHC II
MAC Th2
IL-4
IL-4
 Possible mechanisms of autoimmunity in AITD

“Self reactive” clones

Failure of clonal deletion
Thyroid

Mutation / polymorphism
of TCR, CTLA-4, TLR,
cytokine (IL-4) genes,

Inheritance of specific HLA-DR3 , DQA1*0501 : Grave’s disease

HLA or other genes that HLA-DR4, DR5 : Hashimoto thyroiditis
influence the disease HLA-DRB1*07 : protective for GD
susceptibility
 Possible mechanisms of autoimmunity in AITD

Virus, Heatshock
Cross reacting Antigens proteins,
Microchimerism
Thyroid

Release of sequestered
Antigens

Molecular mimicry
Viral / bacterial infection Activation of CTL
Transfusion Reactions
Occur when a recipient has antibodies that react against donor erythrocytes
Antibodies to ABO antigens usually IgM and cause agglutination, complement
activation and intravascular hemolysis.
Other blood group induces IgG. The IgG sensitized cells are usually taken up by
phagocytic cells in the liver or spleen, although severe reaction may cause
erythrocytes destruction by complement activation. These transfusion reaction may
occur in unsensitized individuals and develop over days or weeks after the transfusion
as antibodies against the foreign antigens are produced.

Five major blood group system involved in transfusion reaction

ABO A, B or O
Kell K or k
Duffy Fya, Fyb or Fy
Rhesus C or c; D or d; E or e
MN M or N
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Hemolytic Disease of the Newborn (HDNB)

HDNB occurs when the mother has been previously sensitized to the infant’s erythrocytes
and makes IgG antibodies. These antibodies cross the placenta and react with the fetal
erythrocytes, causing cells destruction.
Rhesus D (RhD) is the most commonly involved antigen
The risk of HDNB due to Rh incompatibility will be reduced if the father is of different ABO
group to mother. Why ? ABO is more immunogenic than Rh antigens. The cells will be
destroyed before the Rh antigens sensitize the mother !

Hyperacute graft rejection

Occurs when preformed cytotoxic antibodies present in recipient’s blood. Te most severe
reactions in this type of rejection are due to ABOand HLA antigens.
Tissue matching is very important for donor selection.

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Autoimmune haemolytic anaemias
Arise spontaneously as autoimmune diseases, or may be indirect as reactions to
drugs
AIHA can be devided into 3 types, depending upon whether they are due to :
Warm autoantibodies (react with antigens at 37 c)
Frequently found against Rhesus system antigens, The cause is unknown but
some are associated with other autoimmune diseases. The anaemia to be a result
of accelerated clearance of the sensitized erythrocytes by spleen macrophages as
well as complement-mediated lysis.
Cold-reactive autoantibodies
The antibodies are primarily IgM and fix complement strongly. In most cases
specific for Ii blood group. Some cases may follow infection with Mycoplasma
pneumoniae due to cross reacting antigens. Cells destruction occurs in the
peripheral circulation (particularly in winter) due to complement-mediated lysis.
Drug induced reaction to blood components
May occurs in three different ways:
The drug bind to red blood cells and antibodies are produced against the drug :
sedormid, penicillin, quinin, sulphoamide
Immune complex consists of drug-antibody absorbed on to the erythrocytes
The drug is absorbed on to cell membrane , induces an autoantibodies against cell
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membrane.
COMPLEMENT

COMPLEMENT

COMPLEMENT

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REACTIONS AGAINST TISSUE ANTIGENS

Good pasture’s syndromes

Antibodies to collagen type IV, a major group component of basement membrane.
The antibody usually IgG fixing complement

Pemphigus
Autoantibodies against desmoglein 1 and 3 (component of desmosomes) which
form the junction between epidermal cells. The antibody is IgG4 against a different
part of the molecule.
Strongly associated with HLA-DR4 (DRB1*0402)

Myasthenia gravis
Autoantibody against Acetylecholine receptors located at the motor endplate where
the neuron contact the muscle.

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Anti-glomerular basement membrane
(Immunofluorescence Test)

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Dharmana E
 IMMUNE COMPLEX MEDIATED REACTION (TYPE III)

INITIATED BY ANTIGEN-ANTIBODY (IMMUNE COMPLEX) THAT

EITHER ARE FORMED LOCALLY AT THE SITE OF TISSUE
DAMAGE OR DEPOSITED FROM THE CIRCULATION

MECHANISMS OF TISSUE DAMAGE:

1. Complement acivation
2. Attraction of PMN which release tissue-damaging mediators
3. Platelet aggregation causing microthrombi and vasoactive amine
release

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 CLINICAL FEATURES

ARTHUS REACTION: local IC formation :

Rheumatoid arthritis, Pigeon fancier’s disease,
farmer’s lung disease.

SERUM SICKNESS: soluble IC : systemic:

glomerulonephritis, vasculitis, chorioiditis,

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Back
IMMUNOPATHOLOGY

Immune complex

Platelet
Immune-complex
Complement
Proteolytic enzymes ,
Inflammatory mediators, Dharmana E
Macrophage etc

PMN Back
IMMUNOPATHOLOGY

Immune complex

Platelet

Complement
Proteolytic enzymes ,
Inflammatory mediators, Immune-complex
Dharmana E
Macrophage etc

PMN Back
IMMUNOPATHOLOGY

Immune complex

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 CELL-MEDIATED REACTIONS (TYPE IV)
DELAYED HYPERSENSITIVITY AND CELL-MEDIATED
CYTOTOXICITY (TYPE IV)

Pathogenic mechanisms:
Effector cells :
CD4+Th1 cells that activate macrophages and other cells through
cytokines secretion

CD8+ ( T cytotoxic cells ) which are directly cytotoxic to target cells by

releasing perforin / granzyme.

Eosinophils mediated cells destruction

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 CELL-MEDIATED (TYPE IV) REACTIONS : DELAYED
HYPERSENSITIVITY AND CELL-MEDIATED CYTOXOXICITY

CELLS / MEDIATORS INVOLVED IN TYPE IV REACTIONS ;

LYMPHOCYTES ( TH1 CD4+ )

MACROPHAGES

CTL (T CYTOTOXIC CD8)

CYTOKINES (IFN-g, IL-2 also TNF, IL-1,6 and 8)

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Back
 IL-4,5

Th2

Th0
Th1

IFN-g

IFN-g, IL-2

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CTL
CTL
Back
 CLINICAL FEATURES :

INFECTIONS
BACTERIAL ( TUBERCULOSIS, LEPROSY)
FUNGAL ( BLASTOMYCOSIS AND HISTOPLASMOSIS)
VIRAL ( HERPES AND MUMPS )
PROTOZOAN ( LEISHMANIASIS )
WORMS ( SCHISTOSOMIASIS, TRICHINELLOSIS )
TUMORS
CONTACT DERMATITIS
GRAFT REJECTION
LATE PHASE OF ALLERGIC RHINITIS / ASTHMA
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 IFN-g Th1

Th1

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Granuloma

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 IMUNOPATOLOGI
Reaksi alergi
IgE (Type I)

Mast Cell
Histamin, Serotonin, Lekotrien,
Prostaglandin, TNF , etc…….

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 Reaksi alergi Rinitis
IgE
Asma
Mast Cell
Histamin, Serotonin, Lekotrien,
Prostaglandin, TNF , etc…….
Urtika

Diare

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 Molecular events of histamine release
Allergens

Ca2+ IgE

cAMP

Phosphodiesterase

AMP
Adenylate
cyclase

cAMP

Histamine
Histamine Dharmana E

Histamine
Histamine Receptor
Receptor Dharmana E Targert organs
Back
 Mosmann 1986

Th1 Th2
IFN-g

IL- 4

IL-4
IFN- IL-5
g
IL-6
IL-2
IL-10

Cellular dominant Humoral dominant

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 Peripheral Blood Mononuclear Cells

Cytokines

IFN-g IL-12

TYPE 1 TYPE 2
IL- 4 Il-10 IL-4
IFN-g
IL-5
IL-2 IL-6
IL-12
IL-10
IL-13

Cellular dominant Humoral dominant

Dharmana E Domination of Type II cytokines induces allergic reactions

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Dharmana E
Abbas 2000 Dharmana E

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 SKIN TEST

ALERGEN
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 Mast cell

PREFORMED NEWLY SYNTHESIZED

Histamine : vasodilation, increase Lipoxygenase pathway :
permeability, bronchoconstriction Leukotriene C4 , D4 ( SRSA) , Leukotriene B4 :
Vasoactive, bronchoconstriction, chemotaxis
ECF : Eosinophil chemotaxis
NCF : Neutrophil chemotaxis
Cyclo-oxygenase pathway :
Prostaglandin , tromboxane :
PAF : Mediator release Affect bronchial muscle, platelet aggregation ,
vasodilation
IL-3,4,5,6,
TNF : Ig E production, eosinophil
maturation, acute phase response

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 Mast cell activation
and granule release

Gastrointestinal Airways Blood vessels

Increased fluid Decreased diameter, Increased blood flow,
secretion, Increased increased mucus increased permeability
peristalsis secretion

Expulsion of Expulsion of airway Increased of :

gastrointestinal content content ( coughing,
Fluid, cells and
(diarrhea, vomiting) phlegm ) Dharmana E
protein , effector
respone in tissues
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 PREFORMED :
MBP, ECP Toxic to helminths, bacteria, host cells
Eosinophil peroxidase
Lysosomal hydrolase Tissue damage, remodelling
Lysophospholipase

EOSINOPHIL NEWLY SYNTHESIZED

Leukotriene C4, D4, E4 Incr. Permeability, bronchoconstriction
mucus secretion
Lipoxin Promote inflammation

IL-3, 5, GM-CSF Eosinophil production and activation

IL-8, 10, RANTES
Eotaxin, MIP-1alpha Chemotaxis of leukocytes

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 Membrane
Phospholipid

Phospholipase

ARACHIDONIC ACID

cyclooxygenase lipoxygenase

Prostaglandin endoperoxide 5-H PETE

Leukotriene A4
Thromboxane
synthetase gluthathione

Thromboxane A2 Prostaglandines Leukotriene Leukotriene 5-HETE

C4, D4 , E4 B4

Vasoconstriction, Vasoactive agents SRS-A , Bronchial Leucocyte activation

Pletelet smooth muscle Dharmana E
aggregation Dharmana E contraction
 Early phase ( 0 –1 ) Late phase ( 6-8 ) Very late phase (24-48)

MBP, ECP,
Macr EDN etc.
B
Il-3, Il-4
IL-5, IL-8
GMCSF
Mast cell
Eos
Th2 MBP, ECP,
IL-3, IL-4 EDN etc.
IL-5, IL-6
IL-13
TNF
IL-4 Th2 RANTES
IL-5
IL-8
Histamine, GM-CSF
Leukotriene, MIP-1 IL-4, IL-13
Prostaglandin MIP-1
MCP-3
etc
RANTES Bas
Eotaxin,
GM-CSF

Adhesion
molecules

Dharmana E
 Early phase ( 0 –1 ) Late phase ( 6-8 ) Very late phase (24-48)

MBP, ECP,
Macr EDN etc.
B
Il-3, Il-4
IL-5, IL-8
GMCSF
Mast cell
Eos
Th2 MBP, ECP,
IL-3, IL-4 EDN etc.
IL-5, IL-6
IL-13
TNF
IL-4 Th2 RANTES
IL-5
IL-8
Histamine, GM-CSF
Leukotriene, MIP-1 IL-4, IL-13
Prostaglandin MIP-1
MCP-3
etc
RANTES Bas
Eotaxin,
GM-CSF

Adhesion
molecules

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 Early phase ( 0 –1 ) Late phase ( 6-8 ) Very late phase (24-48)

MBP, ECP,
Macr EDN etc.
B
Il-3, Il-4
IL-5, IL-8
GMCSF
Mast cell
Eos
Th2 MBP, ECP,
IL-3, IL-4 EDN etc.
IL-5, IL-6
IL-13
TNF
IL-4 Th2 RANTES
IL-5
IL-8
Histamine, GM-CSF
Leukotriene, MIP-1 IL-4, IL-13
Prostaglandin MIP-1
MCP-3
etc
RANTES Bas
Eotaxin,
GM-CSF

Adhesion
molecules

Dharmana E

Adapted from : Immunopathology of Allergic Rhinitis (Ebisawa M.et.al)

CYTOTOXIC REACTIONS ( TYPE II )
ANTIBODY-DEPENDENT CYTOTOXIC HYPERSENSITIVITY

INVOLVE PRIMARILY ANTIBODY (IgG OR IgM) REACTING WITH

CELL BOUND ANTIGENS THAT LEADS TO DESTRUCTIVE
PROCESSES

NK C

Mechanisms of destructive processes :

1. Lysis via Complement activation
2. Phagocytosis of target cells
Dharmana E
3. ADCC through natural killer cells (NK)
CLINICAL FEATURES :
AlloimmuneReactions:
Red blood cells lysis : ABO blood group
Platelet transfusion : HLA antigen
Rhesus Incompatibility
Organ Transplantation
Autoimmune Reactions
Goodpasture’s syndrome
Granulocytopenia
Autoimmune hemolytic anemia
SLE
Idiophatic thrombocytopenic purpura

Dharmana E
IMMUNE COMPLEX MEDIATED REACTION (TYPE III)
INITIATED BY ANTIGEN-ANTIBODY (IMMUNE COMPLEX) THAT
EITHER ARE FORMED LOCALLY AT THE SITE OF TISSUE
DAMAGE OR DEPOSITED FROM THE CIRCULATION

MECHANISMS OF TISSUE DAMAGE:

1. Complement activation
2. Attraction of PMN which release tissue-damaging mediators
3. Platelet aggregation causing microthrombi and vaso active amine
release

Dharmana E
 CLINICAL FEATURES

ARTHUS REACTION: local IC formation :

Rheumatoid arthritis, Pigeon fancier’s disease,
farmer’s lung disease.

SERUM SICKNESS: soluble IC : systemic:

glomerulonephritis, vasculitis, chorioiditis,

Dharmana E
IMMUNOPATHOLOGY

Immune complex

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IMMUNOPATHOLOGY

Immune complex

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 CELL-MEDIATED REACTIONS (TYPE IV)
DELAYED HYPERSENSITIVITY AND CELL-MEDIATED
CYTOTOXICITY (TYPE IV)

Pathogenic mechanisms:
Effector cells :
CD4+Th1 cells that activate macrophages and other cells through
cytokines secretion

CD8+ ( T cytotoxic cells ) which are directly cytotoxic to target cells by

releasing perforin / granzyme.

Eosinophils mediated cells destruction

Dharmana E
 CELL-MEDIATED (TYPE IV) REACTIONS : DELAYED
HYPERSENSITIVITY AND CELL-MEDIATED CYTOXOXICITY

CELLS / MEDIATORS INVOLVED IN TYPE IV REACTIONS ;

LYMPHOCYTES ( TH1 CD4+ )

MACROPHAGES

CTL (T CYTOTOXIC CD8)

CYTOKINES (IFN-g, IL-2 also TNF, IL-1,6 and 8)

Dharmana E
 IL-4,5

Th1

Th2

IFN-g

IFN-g, IL-2

Dharmana E
CTL
CTL
 CLINICAL FEATURES :

INFECTIONS
BACTERIAL ( TUBERCULOSIS, LEPROSY)
FUNGAL ( BLASTOMYCOSIS AND HISTOPLASMOSIS)
VIRAL ( HERPES AND MUMPS )
PROTOZOAN ( LEISHMANIASIS )
WORMS ( SCHISTOSOMIASIS, TRICHINELLOSIS )
TUMORS
CONTACT DERMATITIS
GRAFT REJECTION
LATE PHASE OF ALLERGIC RHINITIS / ASTHMA
Dharmana E
Dharmana E
Imunopatologi
Granuloma

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Dharmana E
Dharmana E