Disorders Caused by Immune Responses

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Subbagian Alergi Imunologi
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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

PROTECTION
FROM
INFECTION
CONTROL
THE
PRAECANCER

ALLERGY
AUTOIMUN
GRAFT REJECTION
ERYTHROBLASTOSIS
FOETALIS

DISADVANTAGE

ADVANTAGE

THE IMMUNE SYSTEM

NUTRITION

M
S
A
L
P
O
NE

CAUSES
OF
ILLNES
OF
HUMAN
BEING

INFECTION

DEG
ENER
ATI0N

GE
NE
TIC

IK
L
O
B
A
T
E
M

IMMUNOLOGIC

IMMUNOLOGIC
CELLS

IMMUNOLOGIC
ORGANS

T.LYMPHOCYTES
B.LYMPHOCYTES
MACROPHAGE
NATURAL KILLER
DENDRITIC
CELLS

THYMUS
BONE MARROW
GALT
MALT
BURSA FABRICUS
TONSIL
APPENDIX

IMMUNOLOGIC SYSTEM

ECXESS
REACTION

HYPERSENSITIVITY

ACCUMULATION OF IG

AMYLOIDOSIS

IMMUNITY RESPONSE

DEF.IMUN

AUTOIMUN

CAUSES OF HYPERSENSITIVITY DISEASES

-Autoimmunity
-Reactions against microbes
-Reactions against environmental antigen

Classification of Immunological Diseases (Hypersensitivity)

Type of
Hypersensitivity

Pathologic immune
mechanism

Mechanisms of tissue injury and

disease

Immediate
hypersensitivity :
Type I

IgE antibody

Mast cells and their mediators

(vasoactive amines, lipid mediators,
cytokines)

Antibody mediated :
Type II

IgM, IgG antibodies

against cell surface or
extracellular matrix
antigens

Opsonization and phagocytosis of cells

Complement and Fc receptormediated recruitment and activation of
leucocytes (neutrophils, macrophages)
Abnormalities in cellular functions, e.g.
hormone receptor signaling

Immune complex
mediated : Type III

Immune complex of
circulating antigens and
IgM or IgG antibodies

Complement and Fc receptormediated recruitment and activation of

leucocytes

Tcell mediated :
Type IV

1.CD4 Tcells (delayed

type hypersensitivity)
2.CD8 CTLs (Tcellmediated cytolysis)

1. Macrophage activation, cytokiunemediated inflammation

2. Direct target cell killing, cytokinemediated inflammation

For the better understanding of these inflammatory cascades

deleted type IV of hypersensitivity reactions have been reclassified into four main subtypes:
1.IVa with Th1 and monocyte directed and cytokines:
IFNgamma, IL-1, IL-2,
2.IVb with Th2 and eosinophils directed and cytokines: IL-5,
IL-4, IL-13,
3.IVc with T CD8+ directed and cytokines: perforin, granzyme
B, Fas Ligand,
4.IVd with T CD4+, CD8+ and neutrophil directed and
cytokines: IL8, GM-CSF.
Clinically delayed hypersensitivity eruptions are often an overlap of cytokine
pathways, with one preferential reaction dominating the final picture.
Type IVa and IVc play a role inthe mechanism of contact dermatitis, however type
IV b in chronic asthma, chronic allergic rhinitis and maculo-papular exanthema
with eosinophilia, type IV c in bullous reactions (i.e. Stevens-Johnsons Syndrome
or toxic epidermal necrolysis), so type IV d in pustular exanthema reactions (i.g.
AGEP - Acute Generalized Exanthematosus Pustule, Behcet disease).

1. Type I hypersensitivity
(Anaphylactic type)

Immediate hypersensitivity
reaction, resulting from release
of pharmacologically active
mediators.

Mechanisms of the late phase allergic

reaction
0

Early phase

24

Very late phase

Late phase

APC
Ag

MBP, ECP,
EDN, CLC etc

FceRI

Th2 B cells

IL-4

Eos
Histamin, PGD2,
LTs etc

Th0

TNF-
IL-4
IL-5
IL-8
GM-CSF
MIP-1
MCP-3

ICAM-1
VCAM-1
E-selection Eos

Epithelium

RANTES
MCP-4
Eotaxin

MBP, ECP,
EDN, CLC etc

IL-3
IL-4
IL-5
IL-6
IL-13
RANTES

Th2

RANTES
Ectaxin
IL-8
GM-CSF
Endothelium PAF

TNF-
IL-

IL-3
IL-4
IL-5
IL-8
GM-CSF

Mast cells

48 (h)

Baso
Histamin, LTC4

IL-4
IL-13
MIP-1
VCAM-1

RANTES
Eotaxin
IL-8
GM-CSF
PAF

Endothelium
Th2

Baso

Eos

Activation of mast
cells in type I
hypersensitivity and
release of their
mediators. ECF,
eosinophil
chemotactic factor;
NCF, neutrophil
chemotactic factor;
PAF, plateletactivating factor.
(From Robbins Basic
Pathology ,2003

Slide 7.9

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.

Figure 19-3 Mast cell activation. Antigen binding to IgE cross-links FcεRI molecules on mast cells,
which induces the release of mediators that cause the hypersensitivity reaction (A, B). Other stimuli,
including the complement fragment C5a, can also activate mast cells. A light photomicrograph of a
resting mast cell with abundant purple-staining cytoplasmic granules is shown in C. These granules are
also seen in the electron micrograph of a resting mast cell shown in E. In contrast, the depleted granules
of an activated mast cell are shown in the light photomicrograph (D) and electron micrograph (F).

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.

Figure 19-6 Biologic effects of mediators of immediate hypersensitivity. Mast cells and basophil mediators include biogenic
amines and enzymes stored preformed in granules as well as cytokines and lipid mediators, which are largely newly
synthesized on cell activation. The biogenic amines and lipid mediators induce vascular leakage, bronchoconstriction, and
intestinal hypermotility, all components of the immediate response. Cytokines and lipid mediators contribute to
inflammation, which is part of the late-phase reaction. Enzymes probably contribute to tissue damage. Activated
eosinophils release preformed cationic proteins as well as enzymes that are toxic to parasites and host cells. Some
eosinophil granule enzymes probably contribute to tissue damage in chronic allergic diseases.

Figure 19-10 Mediators and treatment of asthma. Mast cell-derived leukotrienes and PAF are thought to be the major
mediators of acute bronchoconstriction. Therapy is targeted both at reducing mast cell activation with inhibitors such as
cromolyn and at countering mediator actions on bronchial smooth muscle by bronchodilators such as epinephrine and
theophylline. These drugs also inhibit mast cell activation. Mast cell-derived cytokines are thought to be the major
mediators of sustained airway inflammation, which is an example of a late-phase reaction, and corticosteroid therapy is
used to inhibit cytokine synthesis. Cytokines are also produced by TH2 cells (not shown).

(2) 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

Clinical and Pathologic

Manifestation

Allergic rhinitis, Sinusitis

(Hay fever)

Increased mucus secretion

;inflammation of upper airways,
sinuses

Food allergies

Increases peristalsis due to

contraction of intestinal muscle

Bronchial asthma

Bronchial hyperresponsiveness
caused by smooth muscle
contraction ;inflammation and tissue
injury caused by late phase reaction

Anaphylaxis (may be
caused by drugs, bee
sting, food)

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
asthma

Corticosteroids
Reduce inflammation
Phosphodiesterase Relax bronchial smooth
inhibitor
muscle

Most
allergic
disease

Desensitization
(repeated small
dose allergen)
Anti IgE antibody
Antihistamine
Cromolyn

Unknown; may inhibit IgE

production and increase other
Ig, may induce Tcell tolerance
Neutralize and eliminate IgE
Block action of histamine on
vessels and smooth muscle
Inhibits mast cell
degranulation

2. Type II Hypersensitivity
Cytolytic or cytotoxic reactions

Mechanism:
(1)Complement-dependent reactions
Transfusion reactions
Erythroblastosis fetal
Autoimmune hemolytic anemia
Certain drug reactions

Figure 18-1 Types of antibody-mediated diseases. Antibodies may bind specifically to tissue antigens (A),
or they may be deposited as immune complexes that are formed in the circulation (B). In both cases, the
deposited antibodies induce inflammation, leading to tissue injury.

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.

Figure 18-3 Pathologic features of antibody-mediated glomerulonephritis. A. Glomerulonephritis induced

by an antibody against the glomerular basement membrane (Goodpasture's syndrome): the light
micrograph shows glomerular inflammation and severe damage, and immunofluorescence shows
smooth (linear) deposits of antibody along the basement membrane. B. Glomerulonephritis induced by
the deposition of immune complexes (SLE): the light micrograph shows neutrophilic inflammation, and
the immunofluorescence and electron micrograph show coarse (granular) deposits of antigen-antibody
complexes along the basement membrane. (Immunofluorescence micrographs are courtesy of Dr. Jean
Olson, Department of Pathology, University of California San Francisco, and the electron micrograph is

Figure 18-4 Sequence of immunological responses in experimental acute serum sickness. Injection of
bovine serum albumin into a rabbit leads to the production of specific antibody and the formation of
immune complexes. These complexes are deposited in multiple tissues, activate complement (leading to
a fall in serum complement levels), and cause inflammatory lesions, which resolve as the complexes and
the remaining antigen are removed. (Adapted from Cochrane CG. Immune complex-mediated tissue
injury. In Cohen S, PA Ward, and RT McCluskey [eds]. Mechanisms of Immunopathology. Werbel & Peck,
New York, 1979, pp 29-48. Copyright 1979, Wiley-Liss, Inc.)

Antibody-dependent cell-mediated
cytotoxicity (ADCC).
May be relevant to:
- Graft rejection
- The destruction of targets too large to
- be phagocytosed, such as parasites or
tumor cells.

(3)Antibody-mediated cellular dysfunction

Myasthenia gravis: muscle weakness
Graves disease: hyperthyroidism

Schematic illustration of three different mechanisms of antibody-mediated

injury in type hypersensitivity. A, Complement-dependent reactions that
lead to lysis of cells or render them susceptible to phagocytosis.
(From Robbins Basic Pathology ,2003
Slide 7.10

Antibody-dependent cell-mediated cytotoxicity (ADCC). IgG-coated target

cells are killed by cells that bear Fc receptors for IgG (e.g., NK cells,
macrophages). . (From Robbins Basic Pathology ,2003
Slide 7.11

Antireceptor antibodies disturb the normal function of receptors. In this

example, acetylcholine receptor antibodies impair neuromuscular
transmission in myasthenia gravis. (From Robbins Basic Pathology ,2003
Slide 7.12

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)
(1) Reaction types
Arthus reaction
serum sickness
Collagen diseases

(2) Toxic complex diseases:

Acute glomerulonephritis
Systemic lupus erythematosus
Necrotizing angiitides
Rheumatoid arthritis
Progressive systemic sclerosis
Dermatomyositis etc.

Schematic illustration of the three sequential phases in the induction of systemic

type (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

4. Type IV Hypersensitivity
(Cell-Mediated )
Delayed hypersensitivity reaction
(1) Tissue reaction:
reaction Consist of
parenchymal destruction
associated with perivascular
lymphocytic and macrophage
reaction.

(2) Diseases:
Chronic active hepatitis
Viral exanthem
Contact dermatitis
Graft rejection
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.

Figure 18-6 Postulated mechanisms of autoimmunity. In this proposed model of an organ-specific T cellmediated autoimmune disease, various genetic loci may confer susceptibility to autoimmunity, in part by
influencing the maintenance of self-tolerance. Environmental triggers, such as infections and other
inflammatory stimuli, promote the influx of lymphocytes into tissues and the activation of self-reactive T
cells, resulting in tissue injury.

Delayed hypersensitivity in the skin. Immunoperoxidase staining

reveals a predominantly perivascular cellular infiltrate that marks
positively with anti-CD4 antibodies. ( Dr. Louis Picker) .
(From Robbins Basic Pathology ,2003
Slide 7.16

Schematic illustration of
the events that give rise
to the formation of
granuloma in type
hypersensitivity
reactions. Note the role
played by T cell-derived
cytokines. . (From Robbins
Basic Pathology ,2003

Slide 7.18

Examples of Human Immune Complex-Mediated Diseases

Diseases

Antigen Involved

Clinicopathologic
manifestations

Systemic Lupus
Erythematosus

DNA, nucleoproteins,
otrhers

Nephritis, arthritis,
vasculitis

Polyarteritis
nodosa

Hepatitis B virus
surface antigen

Vasculitis

Poststreptococcal
glomerulonephritis

Streptococcal cell wall Nephritis

antigens may be
planted in glomerular
basement membrane

Serum sickness

Various proteins

Arthritis, vasculitis,
nephritis

Example of T Cell-Mediated Immunological Diseases

Disease

Specificity of
Human disease
pathogenic T cells

Animal models

Type I (Insulin
Dependent) DM

Islet cell antigens

(insulin, glutamic acid
decarboxylase, others

Yes, specificity of T
cells not established

NOD mouse, BB rat,

transgenic mouse
models

Rheumatoid arthritis

Unknown antigen in joint

synovium

Yes;specificity T cells
and role of antibody
not established

Collagen induced
arthritis, others

Multiple sclerosis,
experimental
autoimmune
encephalomyelitis

Myelin basic protein,

proteolipid protein

Yes; T cell recognize

myelin antigens

EAE induced by
immunization with CNS
myelin antigens; TCR
transgenic models

Inflammatory bowel
disease (Crohns
ulcerative colitis)

Unknown

Yes

Colitis induced by
depletion of regulatory T
cells, knockout of IL-10

Peripheral neuritis

P2 protein of peripheral
nerve myelin

Guillain-Barre
syndrome

Induced by immunization
with peripheral nerve
myelin antigens

Autoimmune
myocarditis

Myocardial proteins

Yes (post viral

myocarditis);
specificity of T cells
not established

Induced by immunization
with myosin or infection
by Coxsackie virus

THERAPEUTIC APPROACHES FOR

IMMUNOLOGIC DISEASES
- Antiinflammatory Agents
- Depletion of Cells and Antibodies
- Anticytokine Therapies
- Agents That Inhibit Cell-Cell Interaction in
Human Responses
- Intravenous IgG

1. Diseases caused by immune responses called hypersensitivity

diseases
2. Hypersensitivity disease classified according to the mechanism
of tissue injury
3. Immediate hypersensitivity (type I, commonly called allergy) is
caused by the production of IgE antibody against environmental
Ag or drugs (allergens) sensitization and degranulation of mast
cell
4. The clinical manifestation and pathology are due to the action of
mediators secreted by mast cells
5. Ab against cell and tissue Ag may cause tissue injury
6. Ab may bind to circulating Ag to form immune complex which
deposit in vessels and cause tissue injury
7. Tcell mediated diseases caused by CD4 Tcell mediated delayed
hypersensitivity or by killing of host cells by CD8 CTLs