The Immune System

and Disorders

Ketut Suryana

Div. of Allergy-Immunology, Dept. of Internal Medicine

Medical Faculty of Udayana University Sanglah General Hospital
Denpasar

Monday, Nov. 13, 2017

 INTRODUCTION
The Immune System
Skin
BARRIERS Mucous
membranes
Microbes If barriers
penetrated

Phagocytosis

INNATE Natural Killer cells

IMMUNITY
Inflammation
(Internal Defenses)
Fever
Cell-mediated
ADAPTIVE Immunity
If innate immunity
insufficient IMMUNITY Humoral Immunity
Immunity
Resistance to disease, specifically infectious diseases

The Immune system / Host defense mechanism

The collection of cells, tissues, and molecules that mediate
resistance to infections

The Immune response

The coordinated reaction of these cells and molecules to
infectious microbes, tumors, organ transplants

The physiologic function of the immune system

To prevent infections and to eradicate established
infections / to protect the body
Type of The Immune system
Innate / natural / native / non specific immunity

Adaptive / acquired / specific immunity

Innate and Adaptive Immunity

Abbas , 2012
Innate immunity
- The initial defense against infections / to block the entry
of various classes of microbes
(e.g; epithelial barriers, epithelial natural antibiotics)

- Eliminate microbes
(e.g; phagocytes, NK cells, & the complement system)

- Extracellular bacteria, fungi are combated by phagocytes,

complement, acute phase proteins

- Intracellular bacteria and viruses is mediated by phagocytes and

NK Cells with Cytokines
Components of innate immunity
Epithelial barriers
Phagocytes ; Neutrophils and monocytes / macrophages
Natural Killer Cells
The complement system
Cytokines of innate immunity
Other Plasma proteins.
Phagocytes recognize microbes by several
membrane receptors : Toll-like receptors (TLRs)
Epithelial barriers
Physical barrier to infection
The skin, mucous membranes of gastrointestinal tract,
respiratory tract
(the common portals of entry of various microbes

Killing of microbes, by :
Peptide antibiotics
Intraepithelial lymphocytes
(B lymphocytes / B-1 cells ,T lymphocytes)
Function of epithelia in innate immunity
Epithelia (physical barriers) : produce antimicrobial substance,
and harbor lymphocytes to kill microbes and infected cell.

(Abbas AK, 2012)

Phagocytes
(Neutrophils and Monocytes / macrophages)
Neutrophils ( PMNs ) and Monocytes
(MN phagocytes ) are recruited to site of infection
Recognize (by TLRs) and ingest microbes for intracellular killing.
Monocytes differentiate into macrophages that are found in
connective tissues.
PMNs and MN cells migrate extravascular to site of infection by
binding to endothelial adhesion molecules, in response to
chemoattractants.
Natural Killer Cells / NK Cells
A class of lymphocytes that respond to intracellular microbes
Killing infected cells and by producing the macrophage
activating cytokine (IFN).
The ability of NK Cells to protect against infections is enhanced
by secreted macrophage cytokine ( IL- 12 ).
NK Cells express receptors Fc for IgG antibodies.
Recognition of Infected Cells by NK cells

A.NK cells
kill host cells infected
(intracellular microbes)
thus eliminating
reservoirs of infection

B.NK cell respond to

IL-12 (produced by
macrophages) and
secrete IFN-,
which activates
the macrophages to kill
phagocytosed microbes.

(Abbas AK, 2012)

The multi step process of leukocyte migration
At sites of infection, macrophages that have encountered microbes produce cytokines
(TNF, IL-1)activate the endothelial cells of venulesproduce selectins,ligands for
integrins and chemokines. Selectins mediate rolling of leukocytes, integrins mediate
adhesion. Chemokines activate leukocytes and stimulate their migration to sites of
infections. CD31/PECAM-1 in transmigration. (Robbins & Cotran, 2010)
Cytokines of innate immunity
Microbes produce cytokines proinflammation (TNF, IL-1 ) and
chemokines in inflammatory site
stimulate inflammation (leukocyte recruitment)
activate NK Cells to produce IFN

(Abbas AK, 2012)

The major cytokines of innate immunity
TNF, IL-1, Chemokines, IL-12, IFN, IFN, IFN,
IL-10, IL-6, IL-15, IL-18.

(Abbas AK, 2012)

Plasma proteins of innate immunity
CRP (C-reactive protein)
- acute phase proteins that increase rapidly after infection.
- acute phase response is the protective response of CRP
- IL-6 stimulate the production of CRP by hepatocytes
- CRP binds to phosphorylcholine on microbes and coats it for
phagocytosis by macrophages which express
a receptor for CRP.
Toll-like Receptors ( TLRs )
TLRs / surface receptors are membrane proteins
Recognize a variety of microbe-derived molecules
Stimulate innate immune responses against the microbes.
TLRs contain of ;
Leucine-rich repeat motifs by characteristic cysteine-rich
motifs in their extracellular regions
TIR (Toll / IL-1 receptor) domain in their cytoplasmic regions
 Different TLRs are involved in responses to different
microbial products.

Different TLRs are involved in responses to different microbial products.

(Robbin & Cotran, 2010)
. Signaling by a prototypic TLR to bacterial LPS

Signaling by
a prototypic TLR,
TLR4In response to
bacterial LPS.
An Adapter protein links
the TLR
to a kinase,
which activates
transcription factors
such as NF-B and AP-
1, TIR, Toll / IL-1
receptor domain.

(Robbin & Cotran, 2010)

Role of Innate immunity in stimulating
Adaptive Immune Responses
A. Macrophage respond
to phagocytosed
microbes by
expressing
costimulators
(e.g. B7 proteins,
which are recognized
by the CD28 receptor
of T cells). Secreting
cytokines (e.g. IL-12).
Costimulators, IL-12,
with antigen
recognition active
the T cells.

(Abbas AK, 2012)

Adaptive Immunity
Two types of adaptive immunity :
Humoral immunity
Cell - mediated immunity
That are mediated by different cells and molecules.
Are designed to provide defense against extra and
Intracellular microbes.
Humoral and cell - mediated immunity

Adaptive
immunity

Cellular immunity
which is responsible
for defense against
intracellular
microbes.

Humoral immunity
which is responsible
for defense against
extracellular
microbes and their
toxins.

(Robbin & Cotran, 2010)

Properties of adaptive immune responses
Specificity for structurally distinct antigens
Memory of prior exposure to antigen
Phase of Adaptive immune response

Antigen recognition
Activation of lymphocytes
Effector phase (elimination
of antigen)
The response declines as
Antigen-stimulated
Lymphocytes die by
apoptosis.
Atigen-specific cells that
survive are responsible for
memory.

(Abbas AK, 2012)

Specificty, memory & self-limitation in adaptive immunity

Specificity ;
Antigens X and Y
Induce the production
of different antibodies
(antibody X and Y).

Memory ;
The secondary response
to antigen X is more rapid
and larger than
the primary response.

Self-limitation ;
Antibody levels decline
with time after each
Immunization.

(Abbas AK, 2012)

 Antigen
Is any substance that causes your immune
system to prompts the generation of antibodies
Antigens can be proteins, polysaccharides,
conjugates of lipids with : proteins (lipoproteins)
and polysaccharides (glycolipids)
An antigen may be a foreign substance from the
environment such as chemicals, bacteria,
viruses, or pollen.
An antigen may also be formed within the body,
as with bacterial toxins or tissue cells.
Origin of Antigens
Antigens can be classified in order of their class
Exogenous antigens
Endogenous antigens
Autoantigens
Exogenous antigens
Exogenous antigens are antigens that have entered the
body from the outside, for example by inhalation,
ingestion, or injection.
Exogenous antigens (inhaled, ingested, or injected) are
taken up by antigen-presenting cells (APCs)
Endogenous antigens
Endogenous antigens are antigens that have been
generated within cells as a result of normal cell
metabolism, or because of viral or intracellular bacterial
infection.
Autoantigens
An autoantigen is usually a normal protein or complex of
proteins (and sometimes DNA or RNA)
that is recognized by the immune system of
patients suffering from a specific autoimmune disease.

Due to mainly genetic and environmental factors

The immunological tolerance for antigen

has been lost in these patients.
 Antibodies
Antibodies are globular plasma proteins
(glycoprotein)

Produced by B-cell

Are antigen-specific

Bind and inactivate foreign particles

The basic functional unit of each antibody is

an immunoglobulin
 Y-shaped molecule

Each antibody
consists of four
polypeptides - two
heavy chains and
two light chains
connected by
disulfide bonds,
joined to form a "Y"
shaped molecule.
Function
Antibodies contribute to immunity in three ways:
they prevent pathogens from entering or damaging
cells by binding to them
they stimulate removal of pathogens by macrophages
and other cells by coating the pathogen
they trigger destruction of pathogens by stimulating
other immune responses such as the complement
pathway
The Complement system

A circulating and membrane associated proteins

(important in defense against microbes).
The activation of the complement system
initiated by three distinct pathways ;
Classical pathway
Alternative pathway
Mannose-binding Lectin pathway
Pathways of
complement activation.
Three distinct pathways of
complement system lead to
production of C3b (the early
steps).

C3b initiates the late steps of

complement activation,

Culminating in the production of

membrane attack complex
(MAC)

creates holes in plasma

membranes.

(Abbas AK, 2012)

Disorders of the Immune System /
Diseases of immunity
Hypersensitivity reactions
Autoimmune diseases
Immunologic deficiency syndromes
Hypersensitivity reactions
A reflection of excessive or abberant immune
responses
What is hypersensitivity?
Injurious consequences in the sensitized host,
following contact with specific antigen
Type of hypersensitivity reactions
(Gell & Coombs)

Type Type of immune Pathophysiology Clinical Typical chronology of

response symptoms reaction
I IgE Mast cell & basophil Anaphylactic Within 1-6 h after the
degranulation shock, last intake of the drug
Angioedema,
Urtica,
Bronchospasm

II IgG & complement IgG & complement- Cytopenia 5-15 days after start of
dependent cytotoxicity the elicting drug
III IgM or IgG and Deposition of immune Serum sickness, 7-8 days fro serum
complement or FcR complexes urticaria, sickness/urticaria
vasculitis 7-21 days after the
start of the elicting
drug for vasculities

Schrijevers R, Gilisseen L, Chiriac AM, Demoly P. Clin Trans Allergy, 2015.5;311-10

Schrijevers R, Gilisseen L, Chiriac AM, Demoly P. Clin Trans Allergy, 2015.5;311-10
Type of hypersensitivity reactions
(Gell & Coombs) (cont)
Type Type of immune Pathophysiology Clinical Typical chronology of
response symptoms reaction
IVa Th1 (IFN) Monocyte Eczema 1-21 dyas after the start
inflammation of the eliciting drug
IVb Th2 (IL-4 & IL-5) Eosinophilic MPE, DRESS 1 - several days after the
inflammation start of the eliciting drug
for MPE
2-6 weeks after the start
of the elicting drug for
DRESS
IVc Cytotoxic T-cells Keratinocyte death FDE, MPE, 1-2 days after the start of
(perforin, granzyme meiated by CD4 or SJS/TEN, the eliciting for fixed drug
B, FasL) CD8 Pustular, eruption
exanthema 4-28 days after the start
of the eliciting drug for
SJS/TEN
IVd T-cells (IL-8/CXCL8) Neutrophiic AGEP Typically 1-2 days after
inflammation the start of the eliciting
drug (but could be longer)
Schrijevers R, Gilisseen L, Chiriac AM, Demoly P. Clin Trans Allergy, 2015.5;311-10
1. Immediate Hypersensitivity (Type I)
Anaphylactic reaction (IgE mediated reaction)

Anaphylactic reaction / IgE mediated reaction

Anaphylactoid reaction (Non IgE mediated)
- Complement activation - Physical factors
- Substance for Histamine released - Idiopathic
- Arachidonic acid modulation
(Roitt I, 1997)
2. Antibody mediated (Type II) Hypersensitivity

(Abbas AK, 2004)

3. Immune Complex-Mediated (Type III) Hypersensitivity

(Robins & Cotran, 2005)

4. Cell-Mediated (Type IV) Hypersensitivity

Mechanism of T cell-mediated (type IV) hypersensitivity reactions.

A. In delayed type hypersensitivity reactions, CD4+ T cells (and sometimes CD8+ cells)
respond to tissue antigens by secreting cytokines that stimulate inflammation and
activates phagocytes, leading to tissue injury.
B. In some disease, CD8+ cytolytic T lymphocytes (CTLs) directly kill tissue cells.
APC, antigen-presenting cell. (Abbas AK, 2004)
Autoimmune diseases
Diseases caused by failure of self tolerance
and subsquent immune responses against
self or autologous antigens
Mechanisms of autoimmune diseases
Role of susceptibility genes

Susceptibility genes that

may interfere with self-
tolerance &
environmental triggers
( inflammation, other
inflammatory stimuli ) that
promote lymphocyte entry
into tissues, activation of
lymphocytes & tissue injury.

( Robbins & Cotran, 2005 )

Mechanisms of Autoimmunization
- Molecular mimicry - Cross reacting foreign Ags
(streptococcal infection Streptococcal M proteins)

- Polyclonal B cell activation

(Non-specific activation of multiple B cell clones)

- Breakdown of immunological homeostasis (tolerance)

Enhanced helper T-cell and decreased suppressor T-cell
functions
(Enhanced helper T-cell and decreased suppressor T-cell functions)

- Sequestered Ags
(Lens protein of the eye)
 IMMUNODEFICIENCY DISEASE
(IDD)
Results from a genetic or developmental defect
or acquired factors in the immune system,
and is a syndrome mostly characterized by
infection in clinic
 Primary immunodeficiency diseases
Secondary immunodeficiency diseases
1. Succeed some diseases SIDD
2. Iatrogenic SIDD
3. Acquired immunodeficiency syndrome (AIDS)
1. Succeed some diseases SIDD

- Infection virus infection decreased function of cellular

immunity, decreased function of the T cells
- Malignant tumors : decreased function of cellular immunity
decreased function of the T cells notablely
decreased function of the T and B cells
- Severe malnutrition : decreased function of the T cells
2. Iatrogenic SIDD
- Using immunosuppressive drugs, some antibiotic,
antineoplastic for a long time
- Damage by irradiation

3. Acquired Immnodeficiency Syndrome

(AIDS)
Reduce of CD4+ level
 Mechanisms of CD4 cells loss in HIV infection

Viral replication in infected cells is the major mechanism by which HIV causes lysis of CD4+
T cells (death of infected cells / cytopathic effect of the virus).
Apoptosis of uninfected CD4+ T cells by binding of soluble gp120 to the CD4 molecule,
followed by activation through the T-cell receptor by antigens, cross-linking of CD4
molecules & T-cell activation leads to abberant signaling & activation of death pathways.
CD8+ cytotoxic T lymphocytes may kill uninfected CD4+ T cells that are coated with gp120
released from infected cells.

( Robbins & Cotran, 2005 )