SKIN IMMUNITY
SKIN IMMUNITY
Joanna Narbutt, MD PhD
Joanna Narbutt, MD PhD
Department of Dermatology
Department of Dermatology
Medical University of Lodz
Medical University of Lodz
SKIN IMMUNITY
SKIN IMMUNITY
Joanna Narbutt, MD PhD
Joanna Narbutt, MD PhD
Department of Dermatology
Department of Dermatology
Medical University of Lodz
Medical University of Lodz
KEY FEATURES
KEY FEATURES
The major purpose of the immune
The major purpose of the immune
system is protection against harmful
system is protection against harmful
organisms
organisms
It is achieved by a rapid more
It is achieved by a rapid more
primitive reaction – innate immune
primitive reaction – innate immune
response
response
And by a higher developed specific
And by a higher developed specific
reaction – adaptive immune response
reaction – adaptive immune response
INNATE RESPONSE
INNATE RESPONSE
Skin barrier
Skin barrier
Complement
Complement
Antimicrobial peptides
Antimicrobial peptides
Cytokines
Cytokines
Macrophages
Macrophages
Neutrophils
Neutrophils
Eosinophils
Eosinophils
Basophils
Basophils
Mast cells
Mast cells
Natural killer cells
Natural killer cells
Toll-like receptors
Toll-like receptors
Skin – a major protective barrier
Skin – a major protective barrier
against the outside environment
against the outside environment
(microbial, chemical, physical insults)
(microbial, chemical, physical insults)
It has a well developed immune
It has a well developed immune
system – skin-associated lymphoid
system – skin-associated lymphoid
tissue (SALT)
tissue (SALT)
Innate and adaptive immunity are
Innate and adaptive immunity are
generated in the skin
generated in the skin
ADAPTIVE IMMUNE
ADAPTIVE IMMUNE
RESPON SE
RESPON SE
The characteristic features are:
The characteristic features are:
specificity and its improvement with
specificity and its improvement with
each successive encounter with the
each successive encounter with the
same antigen due to the accumulation
same antigen due to the accumulation
of immunological memory
of immunological memory
A crucial event during the generation
A crucial event during the generation
of an adaptive immune response is
of an adaptive immune response is
ANTIGEN PRESENTATION
ANTIGEN PRESENTATION
Antigen presentation
Antigen presentation
Antigen-presenting cells:
Antigen-presenting cells:
The most effective APCs are
The most effective APCs are
interdigitating dendritic cells located
interdigitating dendritic cells located
in the T cell areas of the spleen and
in the T cell areas of the spleen and
lymph nodes
lymph nodes
In the epidermis relevant APCs are
In the epidermis relevant APCs are
Langerhans cells
Langerhans cells
Langerhans cells
Langerhans cells
LCs are derived from bone marrow
LCs are derived from bone marrow
3-8% of keratinocytes in the epidermal
3-8% of keratinocytes in the epidermal
LCs are identified by electron microscopy or
LCs are identified by electron microscopy or
immunohistochemistry
immunohistochemistry
They have characteristic Birbeck granules
They have characteristic Birbeck granules
Histochemically human LC can be detected by
Histochemically human LC can be detected by
staining for
staining for
adenosine triphosphatase (ATPase), a
adenosine triphosphatase (ATPase), a
membrane bound enzyme
membrane bound enzyme
Molecules by antibodies: anti-CD45, anti-MHC
Molecules by antibodies: anti-CD45, anti-MHC
class II antigen, anti-CD1a, anti-Langerin
class II antigen, anti-CD1a, anti-Langerin
CD1a is the most useful marker for
CD1a is the most useful marker for
detecting human LCs since in the
detecting human LCs since in the
epidermis CD1a is exclusively expressed
epidermis CD1a is exclusively expressed
on LC both in normal and inflamed skin
on LC both in normal and inflamed skin
In humans the number of LCs is reduced
In humans the number of LCs is reduced
on the palms, soles, genitalia, buccal
on the palms, soles, genitalia, buccal
mucosa
mucosa
The density of LCs decreases with age,
The density of LCs decreases with age,
and is reduced in chronically UV-exposed
and is reduced in chronically UV-exposed
skin
skin
LCs are confined to the epidermis
LCs are confined to the epidermis
Other DCs are responsible for
Other DCs are responsible for
antigen presentation in
antigen presentation in
extracutaneous sites and organs
extracutaneous sites and organs
DCs are professional APCs which
DCs are professional APCs which
display an extraordinary capacity to
display an extraordinary capacity to
stimulate na
stimulate na
ï
ï
ve T cells and to initiate
ve T cells and to initiate
a primary immune response
a primary immune response
The role of keratinocytes in
The role of keratinocytes in
skin immune response
skin immune response
The major immunologic cells in the
The major immunologic cells in the
epidermis are LCs
epidermis are LCs
Keratinocytes also contribute to the
Keratinocytes also contribute to the
generation of a cutaneous immune
generation of a cutaneous immune
response
response
They can affect LCs by espression of
They can affect LCs by espression of
specific surface molecules and release
specific surface molecules and release
soluble mediators: cytokines,
soluble mediators: cytokines,
eicosanoids, neurohormones
eicosanoids, neurohormones
Inflammatory mediators:
Inflammatory mediators:
IL-1, IL-6, TNF-alpha, IL-8,
IL-1, IL-6, TNF-alpha, IL-8,
chemokines
chemokines
Antiinflammatory mediators:
Antiinflammatory mediators:
IL-10, TGF-beta
IL-10, TGF-beta
Immunomodulatory mediators:
Immunomodulatory mediators:
Il-7, IL-12, IL-15, IL-18, GM-csf, C-
Il-7, IL-12, IL-15, IL-18, GM-csf, C-
CSF, M-CSF
CSF, M-CSF
Cytokines not produced by
Cytokines not produced by
keratinocytes:
keratinocytes:
IL-2
IL-2
IL-4
IL-4
IFN-gamma
IFN-gamma
Prostaglandines (PGE2 has both
Prostaglandines (PGE2 has both
inflammatory and immunosuppressive
inflammatory and immunosuppressive
properties, induces cyclooxygenases
properties, induces cyclooxygenases
expression – carcinogenesis; erythema)
expression – carcinogenesis; erythema)
Leukotrienes (B4 is a neutrophil
Leukotrienes (B4 is a neutrophil
chemoattractant, mediates inflammation)
chemoattractant, mediates inflammation)
Substance P (inflammatory and
Substance P (inflammatory and
immunosuppressive properties)
immunosuppressive properties)
Pro-opiomelanocortin inflammatory and
Pro-opiomelanocortin inflammatory and
immunosuppressive properties)
immunosuppressive properties)
Melanocyte stimulating hormone (alpha-
Melanocyte stimulating hormone (alpha-
MSH) inflammatory and immunosuppressive
MSH) inflammatory and immunosuppressive
properties)
properties)
Keratinocytes can function as effector cells
Keratinocytes can function as effector cells
(presentation of antigen when enhanced
(presentation of antigen when enhanced
MHC class II expression) and as target cells
MHC class II expression) and as target cells
They express MHC class I molecule and
They express MHC class I molecule and
when they are infected (virus) can be
when they are infected (virus) can be
attacked by CD8+ T cells
attacked by CD8+ T cells
MHC class I-restricted T cell-mediated
MHC class I-restricted T cell-mediated
cytolysis is involved in lichen planus, fixed
cytolysis is involved in lichen planus, fixed
drug eruptions, cutaneous graft versus host
drug eruptions, cutaneous graft versus host
disease, herpes simplex infections
disease, herpes simplex infections
Regulatory T cells
Regulatory T cells
Chronic activation of CD4+ T cells in
Chronic activation of CD4+ T cells in
the presence of IL-10 induced CD4+
the presence of IL-10 induced CD4+
T cell clones with a low proliferative
T cell clones with a low proliferative
capacity which produced high levels
capacity which produced high levels
of IL-10, low levels of IL-2 and no IL-
of IL-10, low levels of IL-2 and no IL-
4
4
These antigens–specific T-cell clones
These antigens–specific T-cell clones
suppressed the proliferation of CD4+
suppressed the proliferation of CD4+
T cells in response to antigen
T cells in response to antigen
Changed expression of T regulatory
Changed expression of T regulatory
T cells CD4+ CD25+ in skin lesions
T cells CD4+ CD25+ in skin lesions
in psoriasis , AD
in psoriasis , AD
Changed levels of T regulatory T
Changed levels of T regulatory T
cells CD4+ CD25+ in serum of
cells CD4+ CD25+ in serum of
patients with autoimmune diseases
patients with autoimmune diseases
Antigen presentation
Antigen presentation
Antigen presentation to lymphocytes takes
Antigen presentation to lymphocytes takes
place in regional lymph nodes
place in regional lymph nodes
LCs actively take up an antigen and
LCs actively take up an antigen and
process it.
process it.
LCs become activated to leave the
LCs become activated to leave the
epidermis and to migrate to the draining
epidermis and to migrate to the draining
lymph nodes
lymph nodes
During migration LCs change their
During migration LCs change their
phenotype and start to resemble mature
phenotype and start to resemble mature
DCs.
DCs.
T cell receptor is able to recognize the
T cell receptor is able to recognize the
antigen bound to MHC molecules
antigen bound to MHC molecules
expressed on APCs.
expressed on APCs.
CD4+ T cells recognize antigens in
CD4+ T cells recognize antigens in
association with MHC class II
association with MHC class II
molecules
molecules
CD8+ T cells recognize antigens in
CD8+ T cells recognize antigens in
association with MHC class I
association with MHC class I
molecules
molecules
If the antigen is produced endogenously
If the antigen is produced endogenously
within the cell (e.g. viral or tumor
within the cell (e.g. viral or tumor
proteins) it is complexed with MHC class I
proteins) it is complexed with MHC class I
molecules through intracellular
molecules through intracellular
processing pathways
processing pathways
After processing peptides (8-12 amino
After processing peptides (8-12 amino
acid residues) are loaded onto MHC class
acid residues) are loaded onto MHC class
I molecules, they are transported to the
I molecules, they are transported to the
cell surface
cell surface
Many cells can serve as APCs for MHC
Many cells can serve as APCs for MHC
class I restricted antigen presentation
class I restricted antigen presentation
MHC-class II-dependent antigen presentation
MHC-class II-dependent antigen presentation
is critically dependent on DCs (LCs,
is critically dependent on DCs (LCs,
monocytes/macropahges, lymphocytes B)
monocytes/macropahges, lymphocytes B)
MHC class II-associated antigen presentation
MHC class II-associated antigen presentation
targets preliminary exogenous antigens
targets preliminary exogenous antigens
Exogenous antigenes are taken up via macro-
Exogenous antigenes are taken up via macro-
or micropinocytosis or via receptor-mediated
or micropinocytosis or via receptor-mediated
endocytosis
endocytosis
The peptide fragments enter specialized
The peptide fragments enter specialized
endosomal compartments containing MHC
endosomal compartments containing MHC
class II molecules
class II molecules
The complex peptide-MHC class II
The complex peptide-MHC class II
molecule is transported and
molecule is transported and
expressed on the cell surface
expressed on the cell surface
It allows antigen recognition by T
It allows antigen recognition by T
cells carrying appropriate TCR (T
cells carrying appropriate TCR (T
cell receptor)
cell receptor)
TCR-MHC class II complex/peptide
TCR-MHC class II complex/peptide
is not sufficient to activate T cells
is not sufficient to activate T cells
Specific activation requires the
Specific activation requires the
involvement of co-stimulatory
involvement of co-stimulatory
signals
signals
Only in the presence of these co-
Only in the presence of these co-
stimulatory signals T cells undrgo
stimulatory signals T cells undrgo
antigen-specific clonal expansion
antigen-specific clonal expansion
The first signal is the interaction of the
The first signal is the interaction of the
TCR with peptide-MHC class II
TCR with peptide-MHC class II
complex presented by APC – it
complex presented by APC – it
determines the specificity of the
determines the specificity of the
immune response
immune response
The second signal – involves surface
The second signal – involves surface
molecules and cytokines which
molecules and cytokines which
promote the clonal expansion of
promote the clonal expansion of
specific T cells and their differentiation
specific T cells and their differentiation
into effector and memory cells
into effector and memory cells
Without these co-stimuli signalling
Without these co-stimuli signalling
by the antigen receptors alone will
by the antigen receptors alone will
either cause anergy (nonreactivity)
either cause anergy (nonreactivity)
or apoptotic cell death
or apoptotic cell death
Cytokines, preferentially
Cytokines, preferentially
inflammatory mediators like IL-1, IL-
inflammatory mediators like IL-1, IL-
6 and TNF-alpha also provide co-
6 and TNF-alpha also provide co-
stimulatory signals by themselves
stimulatory signals by themselves
and in addition upregulate co-
and in addition upregulate co-
stimulatory molecules
stimulatory molecules
If a T cell recognizes specific peptide
If a T cell recognizes specific peptide
in association with the appropriate
in association with the appropriate
MHC molecules and additionally
MHC molecules and additionally
become activated by co-stimulatory
become activated by co-stimulatory
signals, division and clonal expansion
signals, division and clonal expansion
take place.
take place.
Some of the activated T cells remain
Some of the activated T cells remain
in the lymph nodes functioning as
in the lymph nodes functioning as
central memory cells
central memory cells
Development of TH1 or TH2 immune response
Development of TH1 or TH2 immune response
depends on the presence of certain cytokines
depends on the presence of certain cytokines
Cytotoxic (CD8+) and helper (CD4+) T cells
Cytotoxic (CD8+) and helper (CD4+) T cells
are effector cells
are effector cells
They play an important role in in immune
They play an important role in in immune
responses by recognizing foreign antigens and
responses by recognizing foreign antigens and
by activating other components of the cell-
by activating other components of the cell-
mediated immune response to eliminate
mediated immune response to eliminate
pathogens.
pathogens.
They also play an essential role in activating B
They also play an essential role in activating B
cells
cells
CD8+ Tc cells are crucial to antiviral and
CD8+ Tc cells are crucial to antiviral and
antitumor responses
antitumor responses
Allergic contact
Allergic contact
hypersensitivity (CHS)
hypersensitivity (CHS)
CHS is highly relevant for
CHS is highly relevant for
dermatologists
dermatologists
It is pathogenic basis for allergic
It is pathogenic basis for allergic
contact dermatitis
contact dermatitis
Induction of CHS
Induction of CHS
Most of the contact allergens are low-
Most of the contact allergens are low-
molecular weight chemicals
molecular weight chemicals
After penetrating into the skin they couple
After penetrating into the skin they couple
with host proteins to act as full antigens =
with host proteins to act as full antigens =
haptens
haptens
LCs take up the hapten, process it and
LCs take up the hapten, process it and
migrate towards the regional lymph nodes
migrate towards the regional lymph nodes
There the antigen is presented to na
There the antigen is presented to na
ï
ï
ve T
ve T
cells
cells
During the emigration LCs convert from
During the emigration LCs convert from
a resting to activated functional state
a resting to activated functional state
This process is initiated by
This process is initiated by
keratinocytes which secrete
keratinocytes which secrete
inflammatory cytokines (Il-1beta, IL-6,
inflammatory cytokines (Il-1beta, IL-6,
IL-12, TNF-alpha, chemokines)
IL-12, TNF-alpha, chemokines)
enhanced cell surface molecule
enhanced cell surface molecule
expression (MHC class I and II
expression (MHC class I and II
molecules, adhesion molecules – ICAM,
molecules, adhesion molecules – ICAM,
co-stimulatory molecules)
co-stimulatory molecules)
Presentation of the hapten in the regional
Presentation of the hapten in the regional
lymph nodes causes activation of the na
lymph nodes causes activation of the na
ï
ï
ve T
ve T
cells carrying the appropriate TCR and finally
cells carrying the appropriate TCR and finally
results in generation of effector cells (mainly T
results in generation of effector cells (mainly T
CD8+; also T CD4+ cells)
CD8+; also T CD4+ cells)
Simultaneously regulatory T cells are
Simultaneously regulatory T cells are
generated
generated
Balance between effector and regulatory T
Balance between effector and regulatory T
cells depends on the dose of antigen applied –
cells depends on the dose of antigen applied –
extremely low doses of antigen results not in
extremely low doses of antigen results not in
sensitisation but tolerance, mediated by CD8+
sensitisation but tolerance, mediated by CD8+
regulatory cells of the Tc2type
regulatory cells of the Tc2type
Elicitation of CHS
Elicitation of CHS
T cells that heve been primed in regional
T cells that heve been primed in regional
lymph nodes express the skin homing
lymph nodes express the skin homing
antigen CLA (cutaneous lymphocyte
antigen CLA (cutaneous lymphocyte
antigen) – they have capacity to enter the
antigen) – they have capacity to enter the
skin
skin
These T cells become activated when they
These T cells become activated when they
encounter the hapten presented by APCs
encounter the hapten presented by APCs
in the skin (LCs, other DCs,
in the skin (LCs, other DCs,
keratinocytes, dermal mast cells,
keratinocytes, dermal mast cells,
macrophages)
macrophages)
The earliest findings are:
The earliest findings are:
Mast cell degranulation
Mast cell degranulation
Vasodilatation
Vasodilatation
Influx of neutrophils and
Influx of neutrophils and
mononuclear T cells
mononuclear T cells
Histologically: spongiosis, thickness
Histologically: spongiosis, thickness
of the epidermis, intraepidermal
of the epidermis, intraepidermal
vesicles
vesicles
Clinically: contact dermatitis
Clinically: contact dermatitis
Effects of UVR on the
Effects of UVR on the
immune system
immune system
Evidence that UVR (especially UVb
Evidence that UVR (especially UVb
290-320 nm; also UVa 320-400 nm)
290-320 nm; also UVa 320-400 nm)
suppresses the skin immune system;
suppresses the skin immune system;
Suppression of elicitation of CHS in the
Suppression of elicitation of CHS in the
humans previously irradiated with UVR
humans previously irradiated with UVR
Reactivation of infections (herpes
Reactivation of infections (herpes
simplex, herpes zoster) after solar
simplex, herpes zoster) after solar
exposure, especially in chronically
exposure, especially in chronically
immunosuppressed individuals
immunosuppressed individuals
UVR suppresses the immune system in a
UVR suppresses the immune system in a
local as well in a systemic fashion
local as well in a systemic fashion
Immunosuppression is a direct
Immunosuppression is a direct
consequence of nuclear DNA damage
consequence of nuclear DNA damage
caused by UVR, cis-urocanic acid
caused by UVR, cis-urocanic acid
generation
generation
Beneficial therapeutic effects of
Beneficial therapeutic effects of
phototherapy may be attributed to the
phototherapy may be attributed to the
immunosuppressive effects of UV radiation
immunosuppressive effects of UV radiation