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