Disorders Caused by Immune Responses

Aminuddin Azis
SubBagian Alergi Imunologi
Bagian Ilmu Kesehatan THT-KL FKUH/RSUP Wahidin
Sudirohusodo
 IMMULOGIC SYSTEM
OF THE BODY

THE WORLD FULL OF MICROORGANISM

WHICH IS DANGEROUS TO OUR BODY
SINCE BIRTH OUR BODY COMPLETED WITH
THE IMMUNE SYSTEM

SOMETIMES THE SYSTEM DOES NOT WORK

 ADVANTAGE

THE IMMUNE SYSTEM

ALLERGY
AUTOIMUN
GRAFT REJECTION
ERYTHROBLASTOSIS
FOETALIS
PROTECTION
DISADVANTAGE
FROM
INFECTION
CONTROL
THE
PRAECANCER
NUTRITION CAUSES INFECTION
OF
ILLNES
OF
HUMAN
BEING

IMMUNOLOGIC
 Hypersensitivity:
1.TYPE 1 (Immediately Type )
2.TYPE 2 (Cytotoxic/ Cytolitic)
3.TYPE 3 (Imunecomplexs)
4.TYPE 4 (Delayed Type ))
1. Type I hypersensitivity
(Anaphylactic type)

Immediate hypersensitivity
reaction, resulting from release
of pharmacologically active
mediators.
TYPHE 1(ANAPHYLACTIC)

GENERAL

LOCAL(ATOPIC)
 SYSTEMIC ( General )

• Antigen enter the body

parenterally
• Foreign Serum (Horse
antitetanus-serum).
• Drug (eg Penicillin)
• The bite of an insect
 BEHAVIOUR OF ANAPHYLACTIC
REACTIONS

• DEGREE OF REACTION DEPENDS

ON LEVEL OF SENSITATION

• SCHOK DOSE CAN BE VERY

SMALL

• CAN CAUSES DEATH !

 SYMPTOMS OF SYSTEMIC
REACTION
• REACTIONS VERY QUICK
(MINUTES)
• DYSPNOE (BRONCHOSPASM,
LARYNGEAL OEDEMA)
• SKIN RASHES
• DIARHEA AND VOMITING
• FALL IN BLOOD PRESSURE
• OCCASIONALLY DEATH
 SYSTEMIC REACTION
PARENTRAL ADMINISTRATION 
WITHIN MINUTES  ITCHING
AND URTICARIA  RESPIRATORY
DIFFICULTY  VOMITING,
ABDOMINAL CRAMPS  DIARHEA
SYSTEMIC VASODILATATION
CIRCULATORY COLLAPSE 
DEATH
 LOCAL ANAPHYLACTIC

• ALSO CALLED ATOPIC ALLERGY

• 10% OF POPULATION
• ALLERGENS:
HAUSE DUST, ANIMAL HAIR,
FLOWER, FOOD: NUTS,FISH
STRAWBERRIES
• FAMILY HISTORY(50%)
• SERUM IgE MORE THAN NORMAL
 LOCAL REACTION
• SKIN  CONTACT ANTIGEN 
URTICARIA
• GASTROINTESTINAL  INGESTION
DIARHEA
• LUNG  INHALATION 
BRONCHOCONTRICTION
• NOSE  INHALATION  RHINITIS
• LOCAL REACTION  SYSTEMIC
 ITCHING
POLLEN OBSTRUCTION OF
ALLERGEN

THE NOSE
HOUSE
DUST SECRET FROM
MITES REACTION THE NOSE
SNEEZING
ANIMAL
DANDER

RHINITIS ALLERGICA
 Figure 19-1 Sequence of events in immediate hypersensitivity reactions. Immediate hypersensitivity
diseases are initiated by the introduction of an allergen, which stimulates TH2 reactions and IgE
production. IgE sensitizes mast cells by binding to FcεRI, and subsequent exposure to the allergen
activates the mast cells to secrete the mediators that are responsible for the pathologic reactions of
immediate hypersensitivity.
 MEDIATOR

• PRIMARY MEDIATOR:
IN THE GRANULES OF MAST
CELL

• SECONDARY MEDIATOR:
LIPID MEDIATOR
CYTOKINES
 PRIMARY MEDIATOR
• BIOGENIC AMINES:
HISTAMINE:
CONTRACTION OF SMOOTH MUSCLEI
INCREASED NASAL SECRETION
GASTRIC JUICE INCREASE
ADENOSINE
INCREASED MEDIATOR OF MAST CELLS
INHIBIT AGREGATION OF PLATELET
• CHEMOTACTIC
• ENZYMES
 SECONDARY MEDIATOR

• LEUKOTRIENES
LEUK.C4 and D4
VASOAKTIF/SPASMOGENIC.
LEUK.B4
STRONG CHEMOTACTIC
FOR EOS,NEUT DAN
MONOCYTE
• PROSTAGLANDIN
PROST.D2
BRONCHOSPSM+ MUCUS
SECR.
 SECONDARY MEDIATOR

• PAF
PLATELET AGREGATION,
RELEASE HIST-->BRONCHOSPA
VASODELATATION
• CYTOKINES
TNF
IL1,IL3,IL4,IL5.IL6
 CYTOKINES INVOLVED IN TYPE 1

• IgE PRODUCTION
TH2 IL4,IL5,IL6
TH1  IFGAMMA
DOWN REGULATE.
• MAST CELL GROWTH
IL3,IL4
• EOS. GROWTH AND ACTIVATION
. IL5 FROM TH2
 TH1 IF GAMMA

DOWN REGULATE

MAST CELL

TH2 B CEll
IL 4,5 DAN 6
IL5 STIMULATE IL3 DAN IL 4
GROWTH
AND STIMULATE
ACTIVATION

EOS
 ANAPHYLACTOID

• CYTOKINES (IL8)
• CODEINE,MORPHINS
• MELLITIN (IN BEE VENOM)
• PHYSICAL STIMULI:
HEAT,COLD, SUNLIGHT
• STRES ? SEING MOTHER IN
LAW  ASTHMA
Figure 19-5 Biochemical events of mast cell activation. Cross-linking of bound IgE by antigen is thought to activate protein
tyrosine kinases (Syk and Lyn), which in turn cause activation of a MAP kinase cascade and a phosphatidylinositol-specific
phospholipase C (PI-PLCγ). PI-PLCγ catalyzes the release of IP3 and DAG from membrane PIP2. IP3
causes release of intracellular calcium from the endoplasmic reticulum. Calcium and DAG activate PKC, which
phosphorylates substrates such as myosin light chain protein and thereby leads to the degradation and release of
preformed mediators. Calcium and MAP kinases combine to activate the enzyme cytosolic phospholipase A2 (cPLA2),
which initiates the synthesis of lipid mediators.
Tissue reactions: variable in severity

Mildest may be only edema. Reaction

is triggered by mast cells, basophils.
If inflammatory cells are present,
many are eosinophils.
Clinical manifestation of immediate hypersensitivity
Clinical Syndrome
Allergic rhinitis, Sinusitis
(Hay fever)
Food allergies
Bronchial asthma
Anaphylaxis (may be
caused by drugs, bee
sting, food)
Clinical and Pathologic
Manifestation
Increased mucus secretion
;inflammation of upper airways,
sinuses
Increases peristalsis due to
contraction of intestinal muscle
Bronchial hyperresponsiveness
caused by smooth muscle contraction
;inflammation and tissue injury caused
by late phase reaction
Fall in blood pressure (shock) caused
by vascular dilatation; airway
obstruction due to laryngeal oedema
Syndrome Therapy Mechanism of action
Anaphylaxis Epinephrine Causes vascular smooth muscle
contraction; increases cardiac
output (to counter shock), inhibit
futher mast cell degranulation
Bronchial Corticosteroids Reduce inflammation
asthma Phosphodiesterase Relax bronchial smooth
inhibitor muscle
Most Desensitization Unknown; may inhibit IgE
allergic (repeated small production and increase other
dose allergen) Ig, may induce Tcell tolerance
disease
Anti IgE antibody Neutralize and eliminate IgE
Antihistamine Block action of histamine on
vessels and smooth muscle
Cromolyn Inhibits mast cell
degranulation
 2.HIPERSENSITIVITY TYPE 2
• COMPLEMENT- DEPENDENT
REACTIONS (REACTION DEPENDS
ON COMPLEMENT)
• ANTIBODY- DEPENDENT CELL
MEDIATED CYTOXICITY
• ANTIBODI MEDIATED CELLULAR
DYSFUNCTION
COMPLEMENT DEPENDENT REACTION

ANTIBODY + ANTIGEN ----

>AKTIVATION COMPLEMENT ----
>MEMBRANE ATTACK COMPLEX
AND FIXATION ANTIBODY
WITH A COMPL C3B-->
OPSONIZATION.
 ADCC

ANTIBODY DEPENDENT CELL

MEDIATED CYTOXITY (ADCC)-->
NOT NEED PHAGOCYTOSIS.
LYSIS DONE BY
MONOCYT, EOS, NEUT WHICH
HAVE FC RECEPTOR.
 TYPE II REACTION

A. Complement dependent

MEMBRAN
ATTACK
COMPLEX
Target cell
Opsonic adherence
and phagocytosis
LYSIS
ADCC=ANTIBODY
DEPENDENT
CELL MEDIATED CYTOXITY

TARGET CELL

FC RECEPTOR

MACROPHAGE
 Figure 18-2 Effector mechanisms of antibody-mediated disease. A. Antibodies opsonize cells and may
activate complement, generating complement products that also opsonize cells, leading to phagocytosis
of the cells through phagocyte Fc receptors or C3 receptors. B. Antibodies recruit leukocytes by binding
to Fc receptors or by activating complement and thereby releasing by-products that are chemotactic for
leukocytes. C. Antibodies specific for cell surface receptors for hormones or neurotransmitters may
stimulate the activity of the receptors even in the absence of the hormone (left panel) or may inhibit
binding of the neurotransmitter to its receptor (right panel). TSH, thyroid-stimulating hormone.
 EXAMPLES OF TYPE II
• TRANSFUSION REACTION
• ERYTHROBLASTOSIS FOETALIS
• AHA (AUTOIMMUNE HEMOLYTIC
ANAEMIA)
• DRUG REACTION
• MYASTHENIA GRAVIS AND GRAVE
DISEASE
 Figure 18-2 Effector mechanisms of antibody-mediated disease. A. Antibodies opsonize cells and may
activate complement, generating complement products that also opsonize cells, leading to phagocytosis
of the cells through phagocyte Fc receptors or C3 receptors. B. Antibodies recruit leukocytes by binding
to Fc receptors or by activating complement and thereby releasing by-products that are chemotactic for
leukocytes. C. Antibodies specific for cell surface receptors for hormones or neurotransmitters may
stimulate the activity of the receptors even in the absence of the hormone (left panel) or may inhibit
binding of the neurotransmitter to its receptor (right panel). TSH, thyroid-stimulating hormone.
3. Type III Hypersensitivity
(Immune complex-mediated)
 TYPE III REACTION

INDUCTION BY ANTIGEN-ANTIBODY
COMPLEX WHICH CAUSES
DEXTRUCTION OF TISSUE AS
CONSEQUENCE OF ITS ABILITY TO
ACTIVATE MEDIATORS EXPECIALLY
COMPLEMENT.
TYPE III HYPERSENSITIVITY

• SYSTEMIC
SYSTEMIC IMMUNE COMPLEX
DISEASE
• LOCAL.
LOCAL IMMUNE COMPLEX
DISEASE (ARTHUS REACTION))
 TYPE OF REACTION

• ANTIGEN : EXOGEN-ENDOGEN
• LOCAL OR SYSTEMIC
• THREE PHASES:
1.FORMATION AG-AB
COMPLEX IN THE CIRCULATION
2.DEPOSITION AG-AB COMPLEX
3.INFLAMMATORY REACTION
• DEPOSITION AG-AB COMPLEX: KIDNEY,
JOINT, SKIN, HEART, BLOOD VESSEL.
Schematic illustration of the three sequential phases in the induction of systemic
type Ⅲ (immune complex) hypersensitivity. (From Robbins Basic Pathology ,2003）
 Schematic representation of the pathogenesis of immune complex-mediated
tissue injury. The morphologic consequences are depicted as boxed areas. .
(From Robbins Basic Pathology ,2003）
Slide 7.14
Examples of Human Immune Complex-Mediated Diseases

Diseases Antigen Involved Clinicopathologic

manifestations
Systemic Lupus DNA, nucleoproteins, Nephritis, arthritis,
Erythematosus otrhers vasculitis
Polyarteritis Hepatitis B virus Vasculitis
nodosa surface antigen
Poststreptococcal Streptococcal cell wall Nephritis
glomerulonephritis antigens may be
“planted” in glomerular
basement membrane
Serum sickness Various proteins Arthritis, vasculitis,
nephritis
 4. Type IV Hypersensitivity
(Cell-Mediated )

Delayed hypersensitivity reaction

(1) Tissue reaction: Consist of
parenchymal destruction associated with
perivascular lymphocytic and macrophage
reaction.
(2) Diseases:

① Chronic active hepatitis

② Viral exanthem
③ Contact dermatitis
④ Graft rejection
⑤ Inflammatory bowel
disease.
Figure 18-5 Mechanisms of T cell-mediated diseases. A. In delayed-type hypersensitivity reactions, CD4+
T cells (and sometimes CD8+ cells) respond to tissue antigens by secreting cytokines that stimulate
inflammation and activate phagocytes, leading to tissue injury. APC, antigen-presenting cell. B. In some
diseases, CD8+ CTLs directly kill tissue cells.
 Schematic illustration of
the events that give rise
to the formation of
granuloma in type Ⅳ
hypersensitivity
reactions. Note the role
played by T cell-derived
cytokines. . (From Robbins
Basic Pathology ,2003）

Slide 7.18
 Example of T Cell-Mediated Immunological Diseases
Disease Specificity of Human disease Animal models
pathogenic T cells
Type I (Insulin Islet cell antigens Yes, specificity of T NOD mouse, BB rat,
Dependent) DM (insulin, glutamic acid cells not established transgenic mouse
decarboxylase, others models
Rheumatoid arthritis Unknown antigen in joint Yes;specificity T cells Collagen induced
synovium and role of antibody arthritis, others
not established
Multiple sclerosis, Myelin basic protein, Yes; T cell recognize EAE induced by
experimental proteolipid protein myelin antigens immunization with CNS
autoimmune myelin antigens; TCR
encephalomyelitis transgenic models
Inflammatory bowel Unknown Yes Colitis induced by
disease (Crohn’s depletion of regulatory T
ulcerative colitis) cells, knockout of IL-10
Peripheral neuritis P2 protein of peripheral Guillain-Barre Induced by immunization
nerve myelin syndrome with peripheral nerve
myelin antigens
Autoimmune Myocardial proteins Yes (post viral Induced by immunization
myocarditis myocarditis); with myosin or infection
specificity of T cells by Coxsackie virus
not established
 SUMMARY
MECHANISM
TYPE OF
MECHANISM DESTRUCTION
HYPERSENSITIVITY
OF TISSUE

MEDIATOR
TYPE 1 IgE MAST CELLS

OPSONISASI
TYPE 2 IgM,IgG FAGOSITOSIS
ACTIVATION OF M,L

IgM ,IgG ACTIVATION OF

TYPE 3 COMPLEX IMUN LEUCOCYTE

ACTIVATION OF M
CD4
TYPE 4 CD8
DIRECT KILLING
OF CELL