Basic Immunology from

the Dermatologic point of

view

Cont.

INNATE IMMUNITY
Rapid responses to a
broad range of microbes

ADAPTIVE IMMUNITY
Slower responses to
specific microbes

External defenses -1ST Line

Internal defenses - 2nd Line

Invading
microbes
(pathogens)

Skin
Phagocytic cells
Humoral response
Mucous membranes Antimicrobial peptides (antibodies)
Secretions
Inflammatory response
Cell-mediated response
Natural killer cells
(cytotoxic
lymphocytes)

Adaptive Immunity

Adaptive immunity

The innate immune system effectively prevent

free growth of bacteria within the body.
however, many pathogens have evolved
mechanisms allowing them to bypass the innate
immune system and generates a threshold level
of antigen which triggers the adaptive immune
system .

Functions of the
adaptive immune
system

1. The RECOGNITION of specific non-self antigens in

the presence of self, during the process of
ANTIGEN PRESENTATION.
2. The generation of TAILORED RESPONSES to
eliminate specific pathogens.
3. The development of IMMUNOLOGIC MEMORY in
which each pathogen is remembered by a
signature antibody. These memory cells can be
called upon to quickly eliminate a pathogen on
subsequent infections due to enhancement with
each successive antigen encounter owing to the
accumulation of memory .

Adaptive immune
system

The lymphocytes of the adaptive immune

system are:
T cells mature in the thymus
B cells mature in the bone marrow
The process starts by antigen presentation.

Adaptive immune
system

It has two separate but overlapping arms:

I.

Humoral, or antibody-mediated (B
Cell) immunity
II. Cellular, or cell-mediated (T Cell)
immunity

Antigens

1. Foreign substances
Mainly proteins, often microorganisms and their
toxins

2. Human cells that have been transformed

May be tumor cells, or cells infected with viruses

3. Human tissue
Organ transplants, tissue grafts, incompatible
blood types during a transfusion

4. Autoimmune diseases
Tissue from the persons own body becomes an
antigen

Antigen presenting
cells (APCs)

With the exception of non-nucleated cells all cells are

capable of presenting antigen and of activating the
adaptive response.
depending on how and where the antigen first encounters
cells of the immune system.
Some cells are specially equipped to present antigen, and
to prime naive T cells and are termed professional (APC).
Dendritic cells: Langerhans cells (LCs) are key APCs.
B-cells
Macrophages
Neutrophils

Dendritic cells (DC)

Defined as professional APCs that display an

extraordinary capacity to stimulate naive T
cells and initiate a primary immune response.

LNGERHANS CELLS

Dendritic Cells of the epidermis.

Derived from the bone marrow
EXPRESSES:
1. Birbeck granules
2. Langerin
3. MHC class II.
4. CD1, useful marker for LCs, since within the epidermis
(normal or inflamed) it is exclusively expressed on LCs.
5. S100 ptn
6. Vimentin
7. FcRI
Derived from the bone marrow from CD34 precursor cells.

LNGERHANS CELLS

LCs cannot be identified in routinely fixed and stained

histologic sections; their recognition requires electron
microscopy or histochemical analysis.

Numbers of LCs are reduced in following:

1. The palms and soles, genitalia and buccal mucosa.
2. With age.
3. Chronically UV-exposed skin.

Langerhans cells can be visualized by staining using

an antibody against MHC class II molecules. Note the
dendritic shape of Langerhans cells.

Electron microscopic picture of a Langerhans cell.

Arrows indicate The Birbeck granules, rod-shaped
organelles specific for Langerhans cells. They are
said to resemble tennis rackets

LC: Antigen
presentation

Resident Langerhans cell engulfs the

exogenous antigen or express the
endogenous one
Starts emigration to the lymph nodes to meet
the T cells.
During this trip it develops some changes to
become similar to mature Dendritic cell.

Changes of LCs
during migration

:
a) Molecules involved in antigen uptake as Birbeck granules,
Fc receptors
b) Molecules mediating the attachment to neighboring
keratinocytes ( E-Cadherins).
:
c) Expression of receptors involved in tissue homing at the
lymph nodes as CD44.
d) Surface molecules necessary for antigen presentation and
T cell priming as MHC class I, MHC class II, CD40, CD54,
CD58, CD80, CD86.
e) Type IV collagenase enable their penetration through the
basement membrane.
f) Their dendricity becomes more pronounced.

Ag Presentation to
T-Cells

APC to B cells and T cells is not the same.

T cells only identify the antigen when
processed into peptides bound to specific
surface molecules on APC.
B cells can identify the whole antigen by
antibodies on their surface

Ag Presentation to
T-Cells

T-cells identify the processed antigen bound to

MHC on the surface of Dendritic cells.
T helper CD4 T cells identify antigens bound
to MHC II while;
Cytotoxic CD8 T cells identify antigen T cells
bound to MHC I
Exogenous and endogenous antigen
presentation.

MHC

The MHC complex is divided into three

subgroups called MHC class I, MHC class II and
MHC class III.
MHC class I is present on all nucleated cells
(except RBCs).
MHC class II is present on antigen presenting
cells.

TYPES OF AP to Tcells

1. Exogenous antigens:
are engulfed by the APC, processed and
presented in association with MHC II.
2. Endogenous antigens:
(VIRUS AND TUMOURS) are processed and
presented in association with MHC I

lymphocytes

T cells undergo thymic education through positive and negative

selection. They are taught the difference between self and nonself molecules in their school to achieve Immunologic tolerance.

T cells

T cells develop and mature in the Thymus after migration

of the stem cells from the bone marrow.
At the thymus only T cells that can recognize foreign
and not self antigen in the MHC complex get a
survival signal (positive selection) and pass to the
circulation and lymph nodes.
Those who fail have affinity to self antigens receive
signals for apoptosis (negative selection) thus no
auto attack.
Positive and negative selection allow the survival of just
those T cells that recognize foreign (but not self)
peptides in the context of self MHC molecules and thus
are useful for immune defense without causing auto-attack

Types of T cells

1. Immature T cells:
Express both CD4 and CD8 molecules.
2. Mature T cells:
Later with the development of the T-cell
receptor (TCR), they either express:
a)CD4 and become T helper cell that binds
antigens in MHCII
b)CD8 molecule and becomes T cytotoxic
cell that binds antigens on MHCI.

The T-CELL
RECEPTOR (TCR)

It is the part responsible for recognition of

the specific antigen and the further T cell
response.
TCR are transmembrane molecules that are
mainly of the / type while only 10% are of
the / type in body and skin.

/ T-cells

Do not follow the classic way of antigen

recognition .
May play a role in innate immunity.
Increase in the skin in leprosy and
lieshmaniasis.

TCR

Can recognize a huge number of antigens

encoded by more than 400 genes that are
modified and rearranged to cover an endless
number of antigens by recombination
activation genes
when defective ----combined immune
deficiency.

TCR SIGNALLING

CD3 is an important part of TCR

responsible for transmission of the
signal to the cell that encodes for the
cytokine needed to stimulate the
required response for that particular
antigen.

Costimulatory
molecules

Signaling through the TCR complex alone does not

suffice to activate T cells. The presence of
costimulatory signals is needed for T cells to
undergo antigen-specific clonal expansion.
Development of a productive T-cell immune response
requires exposure of these cells to at least two types
of stimuli.
The first signal is the interaction of the TCR with
peptideMHC complexes presented by APCs,
which determines the specificity of the immune
response.
The second signal involves surface molecules and
cytokines, which determine the clonal expansion
of specific T cells and their differentiation into
effector and memory cells.

Costimulatory
molecules

B7 FAMILY e.g. B7-1 (CD80) and B7-2 (CD86)

induced by cytokines (TNF, IL-1) or by various TLR
ligands
Cytokines, especially inflammatory mediators
like IL-1, IL-6 and TNF-, also provide
costimulatory signals by themselves and, in
addition, upregulate costimulatory molecules.
Are very important for completion of the T-cell
response other wise ANERGY (non-reactivity)
and failure of T-cell stimulation occurs.

CLONAL
EXPANSION

After proper antigen

presentation and costimulation
T cell becomes activated
division occurs.
Memory T cells develop

Criteria of Skin T
cells

Majority are:
In the dermis.
CD4 OR CD8.
/ TCR.
memory phenotype CD45RO+/CD45RA Skin homing receptor CLA(cutaneous
lymphocyte associated antigen).

Memory T cells

1. CENTRAL MEMORY T CELLS [TCM]:

express lymph node homing receptors and thus stay
in the lymph nodes. CD45RO+CD45RA- CCR7+
Have no effector function. They stimulate dendritic
cells to produce IL-12 upon secondary stimulation
and differentiate into CCR7- cells.
2. EFFECTOR MEMORY T CELLS [TEM]:
CD45RO+CD45RA- CCR7- develop receptors to
migrate to the inflamed tissues (e.g. CLA in the
skin). express receptors for migration to inflamed
tissues and have immediate effector function.

Effector T cell
function

After recognition of the antigen

CD4: T helper cells (Th):
activate the immune system to combat the
antigen including both T and B cells.
CD8: T cytotoxic cells (Tc):
Antiviral and anti-tumor responses

T helper response

According to the type of antigen recognized by

the Th cells they secrete different cytokine
patterns that will further stimulate different
parts of the immune system.
Pre-activated precursor Th cells (Th0) secretes
a wide variety if cytokines which then
develops into: Th1 or Th2 with more restricted
type of cytokine secretion.

Th1 cells versus Th2

cells
Th1
cells
Th 2 cells

Differentiation from
Th0 mediated by

Secretes

Mediates

IL-12

a) IL-2: stimulates
both Th and Tc
proliferation.
b) IFN GAMMA:
activates
macrophages and
NK cells and IL-12.

CELL MEDIATED
RESPONSE

IL-4
a) IL-4: Stimulates B
cells to produce IgE
and stimulates
further Th 2
response and
inhibits Th1
response.
b) IL-5: promotes
eosinophil growth.
c) IL-10: inhibits Th1
response
HUMORAL IMMUNITY

Th1/Th2 decision

1. Depends mainly upon the type of antigen

presented.
2. The cytokines it stimulates.
3. The Dendritic cells.
4. the toll like receptor.
5. Dose of antigen.
6. Genetic background of the host.
7. The APC and its cytokines.
8. The co-stimulatory molecules.

Th3 cells

Transforming growth factor B .

Helps IgA production.
Suppresses both Th1 and Th2
responses.

Regulatory T cells
(Tregs)

CD4 + T cells.
Secretes large amounts of IL-10.
Suppressor effect on both immune
responses.
Produced by immature inactive
dendritic cells.
Important for TOLERANCE towards self
antigens and regulating inflammation.

Function of regulatory T cells

Cytotoxic T cells

(CD8+ T

cells)
Direct killing of the organism or the abnormal or infected cells.

TC1 and TC2 in cytokine patterns (functional roles still remain to

be determined. Even).
Viral and anti-tumor activities.
Cytotoxic T cells with CD8 surface protein are called CD8+ T cells.
Three different pathways of killing:
a) Perforin which forms pores in the target cell's plasma
membrane this causes ions and water to flow into the target
cell, making it expand and eventually lyse then Granzyme
that can enter target cells via the perforin-formed pore and
induce apoptosis.
b) Tc cells activate the death receptor Fas on the target cell by
expressing the cognate death ligand FasL. The activated Fas
also triggers apoptosis.
c) Cytokines, including TNF- and IFN-, which are released as
long as TCR stimulation continues. These mediators can
affect distant cells as well as the target cell

The B lymphocyte (B
cells)

B cells function to protect the host by

producing antibodies that identify unique
antigen and neutralize specific pathogens.
B Cells are the major cells involved in the
creation of humoral immunity.
Like the T cell receptor, B cells express a
unique B cell receptor (BCR), in this case, an
immobilized antibody molecule. The BCR
recognizes and binds to only one particular
antigen.
Differentiates into an effector cell, known as a
PLASMA CELL

B-cell
response

B cell Vs. T cell

ACTIVATION

Antigens
reorganization
Activation signals

T cell

B cell

Processed form

Native form

in the context of an
MHC

Th1

Th2

Plasma cells

Short lived cells (2-3 days) which secrete

antibodies that bind to antigens, making them
easier targets for phagocytes, and trigger the
complement cascade.
About 10% of plasma cells will survive to
become long-lived antigen specific memory B
cells primed to produce specific antibodies and
respond quickly if the same pathogen reinfects the host; while the host experiences
few, if any, symptoms.

Immunological Memory

Primary immune response cellular

differentiation and proliferation, which occurs
on the first exposure to a specific antigen
Lag period: 3 to 6 days after antigen challenge.
Peak levels of plasma antibody are achieved in
10 days.
Antibody levels then decline.

Immunological Memory

Secondary immune response re-exposure

to the same antigen
Sensitized memory cells respond within hours.
Antibody levels peak in 2 to 3 days at much
higher levels than in the primary response.
Antibodies bind with greater affinity, and their
levels in the blood can remain high for weeks to
months.

Primary and Secondary Humoral Responses

Antibodies

Antibodies (or immunoglobulin, Ig), are large Yshaped proteins used by the immune system to
identify and neutralize foreign objects.
In mammals there are five types of antibody: IgA,
IgD, IgE, IgG, and IgM, differing in biological
properties, each has evolved to handle different
kinds of antigens.
Heavy chains: The heavy chains of a given
antibody molecule determine the class of that
antibody: IgM( ), IgG( ), IgA( ), IgD( ), or IgE( ).

Immunoglobulin G

IgG is monomer Ig & the most abundant

immunoglobulin, accounting for approximately

75% of the total amount of serum immunoglobulin.
The major immunoglobulin of the secondary
immune response.
Four subclasses (IgG1, IgG2, IgG3, IgG4) are
defined by the amino acid sequences of their
constant region.
Most of the autoimmune dermatoses caused by
autoantibodies are mediated by IgG, most often
IgG4.
Crosses the placenta and confers passive
immunity.

Immunoglobulin M

The largest immunoglobulin.

IgM molecules are pentamers that (in addition
to light and heavy chains) contain one J chain.
IgM is the major immunoglobulin produced in
the primary immune response.
Upon binding to its antigen, IgM induces
agglutination and activates the classical
complement pathway.

Immunoglobulin A

IgA is the predominant immunoglobulin present in

mucosal surfaces prevent attachment of pathogens
to epithelial cell surfaces.
IgA can activate the complement system via the
alternative (but not the classical) pathway.
Two subclasses of IgA exist, IgA1 and IgA2. IgA
molecules can be joined by a J chain; this dimer form
is mostly found in secretions, while in the serum, IgA
circulates primarily as a monomer.
IgA molecules can be involved in the pathogenesis of
bullous autoimmune diseases.

Immunoglobulin E

IgE monomer is the classic anaphylactic antibody that

mediates most immediate allergic and anaphylactic
reactions.
Mast cells and basophils express high-affinity receptors
for the Fc portion of IgE (FcRI). Antigens, anti-IgE
antibodies or other substances that crosslink at least
two IgE molecules bound on mast cells induce the
release of mediators.
Also LCs, dermal DCs and peripheral blood DCs as well
as monocytes from atopic individuals can bind
monomeric IgE via the high-affinity FcRI.
The second IgE receptor, FcRII exhibits weaker binding
affinity and is expressed on macrophages, eosinophils,
platelets, and particular subtypes of T and B cells.

Immunoglobulin D

The function of IgD still remains mysterious.

Recent evidence suggests that IgD participates
in respiratory immune defense.
It binds to basophils and mast cells,
stimulating their production of antimicrobial
factors.
IgD may also exert proinflammatory functions,
as illustrated by the
hyperimmunoglobulinemia D with periodic
fever syndrome (HIDS).

Mechanisms of Antibody
Action

Functions of
antibodies

INNATE IMMUNITY ADAPTIVE IMMUNITY

PAMP

Trigger

(Pathogenassociated molecular
pattern)

Specific antigens

Action

Min to hours

Days to weeks

PRR (Pattern

Receptors

recognition receptor)

Memory
Communication

No

Effectors

TCR, BCR

as TLR

Yes
Cytokines

Complement
Antigen presentation
Phagocytosis

Complement
Antigen presentation
Antibodies
Cytotoxicity

Hypersensitivity

Hypersensitivity
An allergic reaction.
An exaggerated response.
Tissue destruction occurs as a
result of the immune response.
Four main types.

Type I Hypersensitivity
Immediate (Anaphylactic
type)

The reaction occurs within minutes after

exposure to an antigen.
Plasma cells produce IgE.
IgE causes mast cells to release histamine,
causing increased dilation and permeability
of blood vessels and constricting smooth
muscle in bronchioles of the lungs.
The reaction may range from hay fever to
asthma and life-threatening anaphylaxis.

Type I Hypersensitivity
When a specific antigen binds to mast cellbound IgE, the FcRI becomes activated,
which leads to degranulation and release of
preformed mediators, including:
1. Histamine
2. Bradykinin
3. Serotonin.
4. Prostaglandins
5. Leukotrienes (B4, C4, D4 and E4),
6. Platelet activating factor
They enhance
i. vascular permeability
ii. bronchoconstriction
iii. induction of an inflammatory
response

Acute Allergic Response

Type II
Hypersensitivity
Cytotoxic type (Sub acute
type)

Antibody combines with an antigen bound

to the surface of tissue cells, usually a
circulating RBC.
Activated complement components, IgG
and IgM antibodies in blood, participate in
this type of hypersensitivity reaction.
This destroys the tissue that has the
antigens on the surface of its cells (e.g., Rh
incompatibility).

Type III
Hypersensitivity

Immune
complex type (serum sickness,
SLE)
(Also
a Subare
acute
Immune
complexes
formedtype)
between
microorganisms and antibody in circulating
blood.
These complexes leave the blood and are
deposited in body tissues, where they cause
an acute inflammatory response.
Tissue
destruction
occurs
following
phagocytosis by neutrophils.

Type IV
Hypersensitivity Cellmediated
type
(delayed)
T lymphocytes
that previously have
been introduced to an antigen cause
damage to tissue cells or recruit
other cells.
Responsible for the rejection of
tissue grafts and transplanted
organs
Allergic contact dermatitis.

Autoimmune Diseases

The body produces auto-antibodies and sensitized

TC cells that destroy its own tissues
Examples include:
systemic lupus erythematosus (SLE)
Pemphigus

References

Dr Samia Esmat Professor of Dermatology

Cairo University
Bolognia: Dermatology, 2nd &3rd ed.
Immense Immunology Insight
Immunity and the immune system Dr. Angelo
Smith WHPL