بسم الله الرحمن الرحيم

1. بسم الله الرحمن الرحيم

2. Epidermis as an immune organ By Doaa Hegab Ass. Lecturer of Dermatology & Venereology

3. Cutaneous immune responses involve the coordinated actions of epidermal and dermal cells along with the network of cytokines.

4. 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)

6. Keratinocytes(Immune-Competent epithelial Cells)

7. 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

8. Role of keratinocytes in the pathogenesis of skin diseases • Eczema • Psoriasis • Pemphigus • Erythema multiforme • GVHD

9. 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

10. Secretory function • Cytokine secretion • Autocrine function • Paracrine function • Endocrine function

11. Secretory function • Cytokine secretion Exposure to noxious stimuli (hypoxia, trauma, radiation, Haptens, microbes, toxins) Production and release of many cytokines

12. 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

13. 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

14. Secretory function Bacteria, viruses, fungi, parasites Keratinocytes AMP Defensins(1-4) cathelicidins Attack cell membrane Damage numerous intracellular structures

16. Secretory function • Neuropeptide secretion • Neuropeptides • Neurohormones

17. Secretory function Neuropeptides CGRP SP Somatostatin LC function

18. 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

19. Secretory function • Eicosanoids secretion • PGE2: pro-inflammatory and immunosupressive effect • LTB4: neutrophil chemotaxis

20. 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

21. Keratinocytes as inducers of immune response & as immunologic target cells • MHC I expression • MHC IIexpression

22. 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

23. Clinical application: MHC I/CD8 mediated cell death occurs in: • LP • GVHD • Other lichenoid dermatitis (drug reactions) • HS • CD • EM • TEN

24. 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.

25. 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).

26. 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

27. Pattern Recognition receptors • Toll like receptors • Nucleoside Oligomerization Domain receptors (NOD R)

28. 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

29. Trauma or infection Apoptosis NOD R AMP caspaces IL1 & IL18 Auto inflamation &autoimmunity Ps Vitiligo SLE RA Apoptosis

30. Langerhans cells (Epidermal Antigen-Presenting Cells)

32. 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.

33. 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.

34. 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

35. 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

36. 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

37. MHCI MHCII Bacteria Virus Parasite Cellular Ag Cellular debris Denaturated Pt

38. Ag presentation • Primary stimulation • Co-stimulation • Proliferation & differentiation signals

39. T cell CD3 APC CD80/86 IL12 Proliferation & differentiation signals IL2

41. VLA VCAM CD44 alpha(E)beta(7) of memory cells E-cadherin on keratinocytes

42. Interaction between integrin alpha(E)beta(7) of intraepithelial lymphocytes and E-cadherin on keratinocytes

43. Epidermal T cells • CD2 & CD5 +ve • CD7-ve • Basal & suprabasal location close to LC • TCR αβ • Memory cell phenotype (CD45Ro +ve) • CLA +ve

44. 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.

45. 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.

46. Melanocytes (Epidermal Pigment CellsWith Immune Properties)

48. 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.

49. 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.

50. Thank you