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بسم الله الرحمن الرحيم. Epidermis as an immune organ. By Doaa Hegab Ass. Lecturer of Dermatology & Venereology. Cutaneous immune responses involve the coordinated actions of epidermal and dermal cells along with the network of cytokines.

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epidermis as an immune organ

Epidermis as an immune organ

By

Doaa Hegab

Ass. Lecturer of Dermatology & Venereology

slide3
Cutaneous immune responses involve the coordinated actions of epidermal and dermal cells along with the network of cytokines.
epidermis serves as an immunological organ through
Epidermis serves as an immunological organ through:
  • Keratinocytes

(Immune-Competent epithelial Cells)

  • Langerhans cells

(Epidermal Antigen-Presenting Cells)

  • Epidermal T cells

(Dendritic Epidernal T Cells-Specialized Resident Epithelial T Cells)+ (Epidermotropic T Lymphocytes-Circulating T Cells That Home to the Epidermis)

  • Melanocytes

(Epidermal Pigment Cells With Immune Properties)

slide7

Role of keratinocytes

ʘ Keratinocytes play a role in innate immune responses in the skin

ʘ Keratinocytes may play a role in initiating adaptive immune responses in the skin by releasing cytokines and expressing cellular adhesion molecules to facilitate the movement of immunecompetent cells.

  • Immunomodulatory role
  • Inducer of immune reaction
  • Target of immune reaction
role of keratinocytes in the pathogenesis of skin diseases
Role of keratinocytes in the pathogenesis of skin diseases
  • Eczema
  • Psoriasis
  • Pemphigus
  • Erythema multiforme
  • GVHD
slide9

Immunomodulatory role of keratinocytes

Immunomodulatory and inflammatory role of keratinocyte is played through its

Secretory function

  • Cytokine, chemokine secretion
  • Neuropeptide secretion
  • AMP (Defensins and cathelicidins)
  • Eicosanoid secretion
  • Free radicals
slide10

Secretory function

  • Cytokine secretion
    • Autocrine function
    • Paracrine function
    • Endocrine function
slide11

Secretory function

  • Cytokine secretion

Exposure to noxious stimuli

(hypoxia, trauma, radiation, Haptens, microbes, toxins)

Production and release of many cytokines

slide12

Initiation of inflammation

  • IL-1, TNFα, IL-6 and chemokines
  • Modulation of LC function
  • IL-1, GMCSF, TNFα And IL-10
  • T cell activation
  • IL-15

Cytokines action

  • Regulation of growth of different epithelial and mesenchymal cells
  • TNFαand β, PDGF, BFGF,KGF, NGF and VEGF
slide13

Chemokine secretion

  • keratinocytes produce the chemokines CCL17, CCL20, and CCL27 that are major recruitment signals for systemic, immunocytes expressing CCR4, CCR6, and CCR27, respectively.

CCL27

CCL20

CCL17

CCR4

CCR6

CCR27

slide14

Secretory function

Bacteria, viruses, fungi, parasites

Keratinocytes

AMP

Defensins(1-4)

cathelicidins

Attack cell membrane

Damage numerous intracellular structures

slide16

Secretory function

  • Neuropeptide secretion
    • Neuropeptides
    • Neurohormones
slide17

Secretory function

Neuropeptides

CGRP

SP

Somatostatin

LC function

slide18

Secretory function

Neurohormones

(Pro Opio Melano Cortin)

Keratinocytes

(Stimulated by UVR, IL-1, Tumour promoters)

POMC

αMSH

Release of IL-10 with anti-inflammatory & immunosuppressive effect

slide19

Secretory function

  • Eicosanoids secretion
    • PGE2: pro-inflammatory and immunosupressive effect
    • LTB4: neutrophil chemotaxis
slide20

Secretory function

  • Free radicals

Superoxide (O2)

Hydrogen peroxide (H2O2)

Nitric oxide (NO)

Hydroxy radical (HO)

Host defense via pro-inflammatory & immunomodulatory function

Solar damage

photoaging

slide21

Keratinocytes as inducers of immune response & as immunologic target cells

  • MHC I expression
  • MHC IIexpression
slide22

MHC I expression by keratinocytes

Target for CD8 (cytotoxic T cells)

Keratinocyte destruction

  • Secretory products of CD8 cells
  • Perforin
  • Lymphotoxin αand β
  • TNF
  • Granzyme
  • Binding to cell surface death receptors:
  • CD95 (FAS, Apo1)
  • TNFR
slide23
Clinical application:

MHC I/CD8 mediated cell death occurs in:

  • LP
  • GVHD
  • Other lichenoid dermatitis (drug reactions)
  • HS
  • CD
  • EM
  • TEN
slide24

MHC II expression by keratinocytes

Infiltrating T cells IFNɣ

Keratinocytes

MHC II

Tolerance to subsequent stimulation.

MHC II bearing keratinocytes provide signals that specifically inhibit cell-mediated immune responses in the skin

* Binding & killing by MHC II restricted T cells (CD4)

*Activate memory and effector T cells.

slide25
In normal, non-inflamed epidermis, keratinocytes have only class I MHC antigens on their surface and do not express class II MHC antigens (HLA-DP, -DQ, and -DR).
  • In inflamed skin, however, infiltrating T lymphocytes secrete IFNɣ , which is capable of activating keratinocytes to transiently express class II MHC antigens (DR).
slide26

ICAM-1 (CD54) expression by keratinocytes

Infiltrating T cells IFNɣ & TNFα

Keratinocytes

ICAM-1

LFA-1-ICAM-1 conjugate formation with T cells.

Recruiting and moving immune cells to the point of antigenic stimulation or skin injury.

-Allergic contact hypersenstivity -Psoriasis

-LP -MF

slide27

Pattern Recognition receptors

  • Toll like receptors
  • Nucleoside Oligomerization Domain receptors (NOD R)
slide28

Trauma or infection

Toll like receptors on keratinocytes & LC

IL12

IL12

LC

B cells Ab

Th1 response

LC

Infl.cytokines

AMP

Ag presentation to naïve T cells

Autoimmunity

Innate immunity

Adaptive immunity

slide29

Trauma or infection

Apoptosis

NOD R

AMP

caspaces

IL1 & IL18

Auto inflamation &autoimmunity

Ps Vitiligo SLE RA

Apoptosis

slide32
LC probably make important contributions to innate immunity, combining the expression of myriad microbial sensors with potent phagocytic and macropinocytotic capacity.
  • Indeed, LC might be regarded as epidermal “trash collectors”, clearing the tissue of moieties ranging from toxins through microbes to apoptotic keratinocytes.
slide33
Cytokines and other factors produced by LC and/or other myeloid-lineage cells contribute to the growth and survival of epithelial cells, that presumably reinforces the integrity of the epithelium and its resistance to infection.
slide34
LC are specialised antigen presenting cells (APC), taking up antigen in the local environment, processing it, and presenting it to the polyclonal T cell repertoire after their migration to the local lymph nodes (LN).
  • Consistent with this, LC activation by TLR/Nod-like receptor engagement of microbe-derived moieties, and by cytokines released by keratinocytes, increases their expression of MHC Class II; T cell costimulators such as CD80/CD86; and LN homing molecules such as CCR7.
  • Lc is uniquely dependent onTGF-βfor their development, survival and localisation
slide35

Keratinocytes

TLR/Nod receptor engagement of microbe-derived moieties

IL-1αandβ, GMCSF, TNFα

LC

Maturation of LC

*upregulation of MHC II

*upregulation of T cell co-stimulatory molecules, such as ICAM1, CD86, CD40 and CD11c

*upregulation of LN homing CCR7

Differentiation and activation of LC

enhanced capacity to take up, process & present antigen

slide36
Capture Ag
  • Process Ag
  • Present Ag on its surface (peptide MHC complex)
  • Migrate to regional LN
  • Initiate T cell mediated immune response by activation & differentiation into effector T cells
slide37

MHCI

MHCII

Bacteria

Virus

Parasite

Cellular Ag

Cellular debris

Denaturated Pt

slide38

Ag presentation

  • Primary stimulation
  • Co-stimulation
  • Proliferation & differentiation signals
slide39

T cell

CD3

APC

CD80/86

IL12

Proliferation & differentiation signals

IL2

slide41

VLA

VCAM

CD44

alpha(E)beta(7) of memory cells

E-cadherin on keratinocytes

slide42
Interaction between integrin alpha(E)beta(7) of intraepithelial lymphocytes and E-cadherin on keratinocytes
epidermal t cells
Epidermal T cells
  • CD2 & CD5 +ve
  • CD7-ve
  • Basal & suprabasal location close to LC
  • TCR αβ
  • Memory cell phenotype (CD45Ro +ve)
  • CLA +ve
slide44
The infiltration of diseased human skin, particularly the epidermis, by myriad T cells is a pathognomonic feature of inflammatory conditions such as AD and psoriasis.
  • According to conventional perspectives, these cells comprise a mixture of effector cells and memory cells that were originally primed in LNs by DC of the skin.
  • Whether disease recurrence is attributable to true memory cells reactive to specific autoantigens, or to bouts of effector cells reactive to persistent stimuli such as bacterial infection is a key issue that needs resolution.
slide45
Intraepithelial lymphocytes (IEL) are variably associated with different tissues constitutively in different species.
  • Tissue-associated T cells commonly comprise unconventional or innate-like cells for which the prototype is the gamma/delta T cell, and for which key criteria include the capacity to enter tissues without prior priming in the lymph nodes, and constitutive display of an “activated-yet-resting” or “pseudo-memory” state.
  • This is similar to the state of conventional memory T cells, that can (and do) readily enter tissues, and distinct from naïve conventional T cells that do not.
slide48
Melanocytes produce a number of cytokines & biologic response modifiers that may mediate inflammation in the epidermis and dermis.
  • Cytokines may have other autocrine and paracrine actions on melanocytes, influencing their growth, migration, enzymatic (tyrosinase) activity, and their expression of adhesion molecules, which are critical to cell-cell interactions.
slide49

constitutively produce

IL-l, -3, and -6, GMCSF, TNFα, and TGFβ

After exposure to specific cytokines or neuropeptides

increase the production of these cytokines and secrete IL-8 and monocyte chemotactic and activating factor.