Basic immunology from the dermatologic point of view (adaptive immunity)
Basic Immunology from the
Dermatologic point of view
External defenses -1ST Line
Rapid responses to a
broad range of microbes
Slower responses to
Internal defenses - 2nd Line
Natural killer cells Cell-mediated response
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 .
1. The RECOGNITION of specific “non-self” antigens in the
presence of “self”, during the process of ANTIGEN
2. The generation of TAILORED RESPONSES to eliminate
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” .
Functions of the adaptive
The lymphocytes of the adaptive immune system
• 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)
II. Cellular, or cell-mediated (T Cell) immunity
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 person’s own body becomes an
With the exception of non-nucleated cells all cells are capable
of presenting antigen and of activating the adaptive
- 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.
Defined as professional APCs that display an
extraordinary capacity to stimulate naive T cells and
initiate a primary immune response.
Dendritic cells (DC)
Dendritic Cells of the epidermis.
Derived from the bone marrow
1. Birbeck granules
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
Derived from the bone marrow from CD34 precursor 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
Resident Langerhans cell engulfs the exogenous
antigen or express the endogenous one
Starts emigration to the lymph nodes to meet the T
During this trip it develops some changes to become
similar to mature Dendritic cell.
LC: Antigen presentation
a) Molecules involved in antigen uptake as Birbeck
granules, Fc receptors
b) Molecules mediating the attachment to neighboring
keratinocytes ( E-Cadherins).
a) Expression of receptors involved in tissue homing at
the lymph nodes as CD44.
b) Surface molecules necessary for antigen presentation
and T cell priming as MHC class I, MHC class II,
CD40, CD54, CD58, CD80, CD86.
c) Type IV collagenase enable their penetration through
the basement membrane.
d) Their dendricity becomes more pronounced.
Changes of LCs during
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
B cells can identify the whole antigen by antibodies
on their surface
Ag Presentation to
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.
Ag Presentation to
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
MHC class II is present on antigen presenting cells.
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
TYPES OF AP to T-
T cells undergo thymic education through positive and negative selection.
They are taught the difference between self and non-self molecules in
their school to achieve Immunologic tolerance.
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
Those who fail have affinity to self antigens receive
signals for apoptosis (negative selection) thus no auto
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
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.
Types of T cells
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 α/β type while only 10% are of the γ/δ type in body
Do not follow the classic way of antigen recognition .
May play a role in innate immunity.
Increase in the skin in leprosy and lieshmaniasis.
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.
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
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
Development of a productive T-cell immune response
requires exposure of these cells to at least two types of
The first signal is the interaction of the TCR with
peptide–MHC 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.
B7 FAMILY e.g. B7-1 (CD80) and B7-2 (CD86)
induced by cytokines (TNF, IL-1) or by various TLR
Cytokines, especially inflammatory mediators
like IL-1, IL-6 and TNF-α, 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.
After proper antigen presentation
and costimulation T cell
becomes activated division
Memory T cells develop
In the dermis.
CD4 OR CD8.
memory phenotype CD45RO+/CD45RA-
Skin homing receptor CLA(cutaneous
lymphocyte associated antigen).
Criteria of Skin 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
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.
Memory T cells
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
Effector T cell function
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
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
T helper response
Th1 cells Th 2 cells
Differentiation from Th0
a) IL-2: stimulates both
Th and Tc
b) IFN GAMMA:
macrophages and NK
cells and IL-12.
a) IL-4: Stimulates B cells
to produce IgE and
stimulates further Th 2
response and inhibits
b) IL-5: promotes
c) IL-10: inhibits Th1
Th1 cells versus Th2
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.
Transforming growth factor B .
Helps IgA production.
Suppresses both Th1 and Th2 responses.
CD4 + T cells.
Secretes large amounts of IL-10.
Suppressor effect on both immune
Produced by immature inactive dendritic
Important for TOLERANCE towards self
antigens and regulating inflammation.
Regulatory T cells (Tregs)
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
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-α and IFN-γ, which are released as
long as TCR stimulation continues. These mediators can
affect distant cells as well as the target cell
Cytotoxic T cells (CD8+ T
B cells function to protect the host by producing
antibodies that identify unique antigen and neutralize
B Cells are the major cells involved in the creation of
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
The B lymphocyte (B cells)
T cell B cell
in the context of an
Activation signals Th1 Th2
B cell Vs. T cell
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 re-infects the host; while the host
experiences few, if any, symptoms.
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
Antibody levels then decline.
Secondary immune response – re-exposure to the
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.
Antibodies (or immunoglobulin, Ig), are large Y-
shaped 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(
μ), IgG(γ ), IgA(α ), IgD( δ), or IgE(ε ).
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
Four subclasses (IgG1, IgG2, IgG3, IgG4) are
defined by the amino acid sequences of their
Most of the autoimmune dermatoses caused by
autoantibodies are mediated by IgG, most often
Crosses the placenta and confers passive immunity.
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
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.
IgE monomer is the classic anaphylactic antibody that
mediates most immediate allergic and anaphylactic
Mast cells and basophils express high-affinity receptors
for the Fc portion of IgE (FcεRI). Antigens, anti-IgE
antibodies or other substances that crosslink at least two
IgE molecules bound on mast cells induce the release of
Also LCs, dermal DCs and peripheral blood DCs as well
as monocytes from atopic individuals can bind monomeric
IgE via the high-affinity FcεRI.
The second IgE receptor, FcεRII exhibits weaker binding
affinity and is expressed on macrophages, eosinophils,
platelets, and particular subtypes of T and B cells.
The function of IgD still remains mysterious. Recent
evidence suggests that IgD participates in respiratory
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).
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.
When a specific antigen binds to mast cell-bound IgE,
the FcεRI becomes activated, which leads to
degranulation and release of preformed mediators,
5. Leukotrienes (B4, C4, D4 and E4),
6. Platelet activating factor
i. vascular permeability
iii. induction of an inflammatory response
Type I Hypersensitivity
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
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 Sub acute
Immune complexes are formed 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
Type IV Hypersensitivity
Cell-mediated 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.
The body produces auto-antibodies and sensitized TC cells
that destroy its own tissues
systemic lupus erythematosus (SLE)
Dr Samia Esmat Professor of Dermatology Cairo
Bolognia: Dermatology, 2nd &3rd ed.
Immense Immunology Insight
Immunity and the immune system Dr. Angelo Smith