DISEASES of THE IMMUNE

SYSTEM
(I)

Dr. dr. Ni Wayan Winarti, Sp.PA

Anatomical Pathology Department
Faculty of Medicine Udayana University/Sanglah General Hospital
Immunity refers to protection against infections

The immune system is the collection of cells and

molecules that are responsible for defending the
body against the countless pathogens that
individuals encounter
THE NORMAL IMMUNE RESPONSE
• Innate immunity (also called natural, or native, immunity)
• Mediated by cells and proteins that are always present (hence the term
innate), poised to react against infectious pathogens
• Acts immediately in response to infection, provide the first line of defense
• Major reaction of innate immunity is inflammation

• Adaptive immunity (also called acquired, or specific, immunity)

• Normally silent
• Responds (or adapts) to the presence of infectious agents by generating
potent mechanisms for neutralizing and eliminating the pathogens
Innate Immunity
Innate Immunity
The major components of innate
immunity
• Epithelial barriers that block the entry of
microbes
• Phagocytic cells (mainly neutrophils and
macrophages)
• Dendritic cells (DCs)
• Natural killer (NK) cells and other innate
lymphoid cells
• Several plasma proteins, including the
proteins of the complement system
Innate Immunity
Recognition by receptors Reactions:
“Pattern recognition receptors” - Inflammation
- Anti viral production
- Stimulate adaptive immune response

The microbial structures recognized by these receptors

are called pathogen-associated molecular patterns

The substances released from injured and necrotic cells

are called damage-associated molecular patterns

Innate immunity uses about 100 different receptors to recognize

1000 molecular patterns.
Pattern recognition receptors

Four major classes of receptors:

• Plasma membrane receptors  extracellular

microbes
• Toll Like Receptors (TLRs) 1
• C-type lectin receptors 2

• Endosomal receptors  ingested microbes

• Toll Like Receptors (TLRs)

• Cytosolic receptors  cytoplasm

• NOD-like receptors (NLRs) 3
• RIG-like receptors for viral RNA 4
TLRs
• Present in plasma membranes and
endosomal vesicles
• Activate 2 transcription factors
1. NF-κB  synthesis and secretion of
cytokines and adhesion molecules
 recruitment and activation of
leukocytes
2. Interferon regulatory factors (IRFs)
 production of the antiviral
cytokines (type I interferons)
NLRs
• Present at cytosol
• Recognize a wide variety of
substances
• Activate inflammation via
inflammasome
Other Receptors for Microbial Products
• C-type lectin receptors (CLRs)
• expressed on the plasma membrane
• detect fungal glycans  elicit inflammatory reactions to fungi
• RIG-like receptors (RLRs)
• located in the cytosol
• detect nucleic acids of viruses  antiviral cytokines
• G protein–coupled receptors
• recognize short bacterial peptides containing N-formylmethionyl residues
• stimulate chemotactic responses of the cells
• Mannose receptors
• recognize microbial sugars and induce phagocytosis of the microbes
How do each of these cells work in innate immunity?
Epithelial barrier in innate immunity
• Intrinsic factors
• Factors that directly contribute to creating barrier to reduce uptake of Ag
from the lumen
• Ex: keratin, cilia, tight junction, desmosome
• Extrinsic factors
• The ability of the epithelium to secret a variety of factors into the lumen 
resistance to invasion by microorganism
• Ex. Mucus secreted by goblet cell/glandular cells, antimicrobial peptides a-
and b-defensins, lysozyme, secretory phospholipase A2 (SPA2), etc.
Phagocytic cells
MACROPHAGES NEUTROPHILS

Roles: Roles:
• Eliminate intracellular bacteria 
phagocytose ingested bacteria Phagocytose extracellular bacteria that
• Eliminate extracellular bacteria  opsonized by Ab or complement
phagocytose bacteria that opsonized by IgG or
C3b
• As antigen presenting cells (APCs)
communicate with adaptive immunity
Dendritic cells
• Under epithelia, interstitial tissue
• Role: Antigen presenting cells (APC)
• Have many receptors
• Express many MHC and can migrate to T cell population area
 recognized by T cells

• Note: Follicular dendritic cells express and activate B cells in germinal

center of lymphoid organ
 Natural Killer Cells
• Destroy irreversibly stressed and abnormal cells, such as virus-
infected cells and tumor cells
• A, Healthy cells express self class I MHC molecules 
recognized by inhibitory receptors  NK cells do not attack
normal cells
• B, In infected and stressed cells
• class I MHC expression is reduced  inhibitory receptors are not
engaged
• ligands for activating receptors are expressed  the infected cells are
killed.

PS:
• NK cell express CD16 (receptor for IgG)  killed IgG coat Antigen
• NK cell may produce IFN gamma to activate macrophage
Complement
• a series of >20 proteins,
circulating in the blood and
tissue fluid
• Normally inactive
• In response to
microorganisms 
sequentially activated in an
enzyme cascade
• 3 pathways
In summary, reactions of Innate Immunity are:
• Inflammation
Cytokines, products of complement activation, & other mediators that
produced during innate immune reactions  vascular and cellular
components of inflammation
• Anti-viral defense
Type I interferons  activate enzymes that degrade viral nucleic acids and
inhibit viral replication
• Stimulate adaptive immune response
Antigen Presenting cells (macrophages, DCs)
Adaptive Immunity
• The adaptive immune system consists of lymphocytes and
their products, including antibodies
• Can recognize a vast array of foreign substances
• Two types
• Humoral immunity
• Cell-mediated (or cellular) immunity
Humoral immunity
• Against extracellular pathogens
• Mediated by soluble proteins called antibodies (produced by B
cells)

Cell-mediated (or cellular) immunity

• Against intracellular pathogens
• Mediated by T cells
 Cytotoxic T Lymphocytes (CTL)  killing the infected cell
 T helper (Th) cell  produce cytokine  inflammation
 Four steps of adaptive immune responses

1. Antigen recognition

2. Activation of specific naive lymphocytes to proliferate and

differentiate into effector and memory cells

3. Elimination of the antigen

4. Decline of the response

1. Antigen recognition
Different receptors:
LYMPHOCYTES
� T Cell Receptor (TCR) complex
- CTL : CD8
- Th : CD4
Signal 2: CD28 bind to B7
protein of APC (co-stimulator)
• CD80 = B7.1
• CD86 = B7.2

� B Cell Antigen receptor

T and B cells have similar
morphology
• IgM/D
• CD21
Signal 2 : complement as co-
stimulator, CD21 as receptor
• T cells recognize antigen if only the antigen presented via MHC
(in human, MHC are called Human Leukocyte Antigens (HLA)  clustered in
chromosome 6)
• Class I MHC molecules
• Display peptides that are derived from proteins, such as viral and tumor
antigens, that are located in the cytoplasm and usually produced in the cell
• Recognized by CD8+ T lymphocytes (CTLs)
• Class II MHC molecules
• Present antigens that are internalized into vesicles, and are typically
derived from extracellular microbes and soluble proteins.
• Recognized by CD4+ T lymphocytes (Th)

CTL (CD 8+ T cell)  MHC class I

Th (CD 4+ T cell)  MHC class II
Four steps of adaptive immune responses
1. Antigen recognition
2. Activation of specific naive lymphocytes to proliferate and
differentiate into effector and memory cells
3. Elimination of the antigen
4. Decline of the response

Lymphocytes that have not encountered the antigen for which they
are specific are said to be naive cells
Lymphocytes that are activated by recognition of antigens and other
signals will differentiate into effector cells, which perform the
function of eliminating microbes
Lymphocytes in a state of heightened awareness and are able to
react rapidly and strongly to combat the microbe in case it returns
are named memory cells
3a. Elimination of Ag by HUMORAL
IMMUNITY
3b. Elimination of Ag by CELLULAR
IMMUNITY

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Cytokines: Messenger Molecules of the
Immune System
• Many cellular interactions and functions of immune cells are
mediated by secreted proteins called cytokines
• Molecularly defined cytokines are called interleukins, because they
mediate communications between leukocytes
• The majority of these cytokines act on the cells that produce them
(autocrine actions) or on neighboring cells (paracrine) and rarely at a
distance (endocrine)
Cytokines: Messenger Molecules of the
Immune System
• Cytokines in innate immune responses
• Include TNF, IL-1, IL-12, type I IFNs, IFN-γ, and chemokines
• Major sources : macrophages, dendritic cells, and NK cells
• Produced rapidly after encounter with microbes and other stimuli
• Function to induce inflammation and inhibit virus replication
Cytokines: Messenger Molecules of the
Immune System
• Cytokines in adaptive immune responses
• Produced by CD4+ T lymphocytes
• Function to promote lymphocyte proliferation and differentiation and to
activate effector cells
• Pro-inflammatory : IL-2, IL-4, IL-5, IL-17, and IFN-γ
• Anti inflammatory : TGF-β and IL-10
Cytokines: Messenger Molecules of the
Immune System
Some cytokines stimulate hematopoiesis  called Colony-stimulating
Factors (CSFs)
- Functions : to increase leukocyte numbers during immune and
inflammatory responses, and to replace leukocytes that are
consumed during such responses
- Produced by marrow stromal cells, T lymphocytes, macrophages, and
other cells
- Examples : GM-CSF, and IL-7
Subset of T Helper Cells
4. Decline of immune response
• After eliminating pathogens  effector cells undergo apoptosis
• Memory cells survive for years
Disorder associated with immune response
• Hypersensitivity
• Autoimmune disease
• Immunodeficiency
• Transplant rejection
 HYPERSENSITIVITY:
IMMUNOLOGICALLY
MEDIATED TISSUE INJURY
Hypersensitivity  excessive or harmful/injurious immune reactions

• Can be elicited by
• Exogenous environmental antigens (microbial and nonmicrobial)  allergy
• Endogenous self antigens  autoimmune disease

• Hypersensitivity usually results from an imbalance between the effector

and the control mechanisms
The mechanisms of tissue injury in hypersensitivity reactions are
the same as the effector mechanisms of defense against
infectious pathogens, but poorly controlled, excessive, or
misdirected

• Hypersensitivity diseases is often associated with the inheritance of

particular susceptibility genes
Classification
• Type I : Immediate hypersensitivity
• Type II : Antibody-mediated disease
• Type III : Immune complex-mediated disease
• Type IV : T cell-mediated disease / delayed hypersensitivity
Immediate (type I) hypersensitivity
• Initiated by the introduction of an allergen, which stimulates Th2 responses
and IgE production in genetically susceptible individuals.
• IgE binds to Fc receptors (FcεRI) on mast cells  secretion of mast cells
mediators  pathologic manifestations
• Mast cell degranulation  vasoactive amine
• Cleaving membrane phospholipids
• Release of cytokine and chemokines recruit inflammatory cells, mainly eosinophils
IL-4
IL-5
IL-13
Phases of immediate hypersensitivity reactions.
(A) Kinetics of the immediate and late-phase reactions.
• The immediate vascular and smooth muscle reaction to allergen develops within minutes after challenge (allergen exposure in
a previously sensitized individual)
• The late-phase reaction develops 2 to 24 hours later.
(B) The immediate reaction is characterized by vasodilation, congestion, and edema
(C) The late-phase reaction is characterized by an inflammatory infiltrate rich in eosinophils, neutrophils, T cells
Immediate hypersensitivity reaction may occur as a systemic disorder
or as a local reaction
Antibody-Mediated Diseases (Type II
Hypersensitivity)
• Caused by antibodies directed against target antigens on the surface
of cells or other tissue components
• The antigens may be normal molecules intrinsic to cell membranes or
in the extracellular matrix, or they may be adsorbed exogenous
antigens (e.g., a drug metabolite)
Mechanisms of antibody-mediated injury
(A) Ab (IgG) opsonize cells  recognized by
macrophages  phagocytosis
(B) Ab bind to Ag  complement activation 
Inflammation
(C) Ab disturb the normal function of receptors
Examples:
• Ab to the acetylcholine (ACh) receptor impair
neuromuscular transmission in myasthenia gravis
• Ab against the thyroid-stimulating hormone (TSH)
receptor activate thyroid cells in Graves disease
Examples of Antibody-Mediated Diseases (Type II Hypersensitivity)
Immune Complex–Mediated Diseases (Type
III Hypersensitivity)
• Antigen–antibody (immune) complexes that are formed in the
circulation may deposit in blood vessels, leading to complement
activation and acute inflammation
• Less frequently, the complexes may be formed at sites where antigen
has been “planted” previously (called in situ immune complexes)
• The antigens that form immune complexes may be
• exogenous, such as a foreign protein that is injected or produced by an
infectious microbe
• endogenous, if the individual produces antibody against self antigens
(autoimmunity)
The sequential phases in the
induction of systemic immune
complex–mediated diseases (type
III hypersensitivity)
Examples of Immune Complex–Mediated Diseases
T Cell–Mediated Diseases (Type IV
Hypersensitivity)
• Several autoimmune disorders, as well as pathologic reactions to
environmental chemicals and persistent microbes, are now known to
be caused by T cells
• Two types
(1) cytokine-mediated inflammation, in which the cytokines are produced
mainly by CD4+ T cells
(2) direct cell cytotoxicity, mediated by CD8+ T cells
Mechanisms of T-cell–mediated (type
IV) hypersensitivity reactions
(A) Th1 cells respond to tissue antigens by
secreting cytokines  inflammation and
phagocytosis (mainly macrophages)
Th17  mainly neutrophils
(B) CTLs directly kill tissue cells expressing
intracellular antigens
CD4+ T Cell–Mediated Inflammation
Th1
APCs Th0 • IFN-γ  activate macrophages to
phagocytose and kill microorganisms
IL-2, IL-12 IL-1, IL-6, IL-23 • TNF, IL-1, and chemokines 
inflammation
Th1 Th17 • IL-12  amplifies Th1 response

IFN-γ
IL-17, IL-22, chemokines Th17
TNF, IL-1, chemokines • IL-17, IL-22, chemokines, and several
IL-21
IL-12 other cytokines  recruit neutrophils
and monocytes  inflammation
• IL-21  amplifies Th17 response
Delayed hypersensitivity reaction
in the skin ex. tuberculin test,
contact dermatitis
• (A) Perivascular accumulation
(“cuffing”) of mononuclear
inflammatory cells (lymphocytes
and macrophages), with
associated dermal edema and
fibrin deposition
• (B) IHC  CD4 (+)
• Persistent or nondegradable antigens 
granulomatous inflammation
(A) A section of a lymph node shows several
granulomas:
• Epithelioid cells
• Lymphocytes
• Multinucleate giant cells
(B) The events that give rise to the formation of
granulomas in type IV hypersensitivity reactions,
illustrating the role of TH1 cytokines
CD8+ T Cell–Mediated Cytotoxicity
• Involved in:
• Type 1 diabetes
• Graft rejection
• Virus-infected
• Tumor
• Mechanism of T cell–mediated killing of targets involves perforins and
granzymes  trigger apoptosis
• Note: CD8+ T cells also produce cytokines, notably IFN-γ  inflammatory
reactions
T Cell–Mediated Diseases
Terima Kasih