1. Cytokines l Low molecular weight glycoproteins, which are transiently produced by almost any nucleated cell l A group of regulatory molecules, which function as important mediators of cell communication under normal as well as pathological conditions and also have therapeutic potential 6/3/2016

2. Cytokines l Exert their biological activities at picomolar concentrations via interaction with specific cell surface receptors, which are expressed at relatively low numbers by respective cell (10 to 10,000 per cell) l Multiple overlapping activities: –they may induce each other –interfere with the expression of their receptors, and thus can affect cell function in a synergistic, additive, or antagonistic way 6/3/2016

3. 1. Interleukins l IL-1, IL-6, and IL-8 –multifunctional nonspecific mediators –early host defense mediators released shortly after injury by a variety of cells –regulate proliferation as well as differentiation of inflammatory and noninflammatory cells l IL-2, IL-4, IL-5, IL-6, IL-7, IL-9, and IL-10 –more specific factors –mainly produced by lymphocytes –responsible for T and B cell proliferation as well as differentiation 6/3/2016

4. 2. Tumor Necrosis Factors l TNF-  (cachectin) may be involved in the down regulation of the induction of contact hypersensitivity l TNF-  (lymphotoxin) is lymphocyte-derived cytotoxic factor 6/3/2016

5. 3. Colony Stimulating Factors l Keratinocytes are able to produce all types of CSF l IL-3 (multi-CSF) affects the formation of bone marrow stem cell colonies l Granulocyte/macrophage-CSF (GM-CSF) l Granulocyte-CSF (G-CSF) l Macrophage-CSF (M-CSF) 6/3/2016

6. 4. Interferons l Mediators protecting cells from viral infection l Exhibit various effects on cell proliferation and differentiation l INF- , INF- , and INF-  6/3/2016

7. 5. Growth Factors l Involved in cell proliferation, in cell surface alteration, and immunoregulation l Transforming growth factor-  (TGF  ) l Transforming growth factor-  (TGF  ) l Acidic fibroblast growth factor (aFGF) l Basic fibroblast growth factor (bFGF) l Platelet derived growth factor (PDGF) 6/3/2016

8. Autocrine and Paracrine Effects l Normal skin produces and releases a large variety of growth factors and chemotactic substances that are involved in autocrine and paracrine regulation of skin function –e.g., EGF, FGF, TGF- , TGF- , interleukins, parathyroid hormone-like growth factor l All major epidermal and dermal cells participate in the response following cytokine release 6/3/2016

9. l Keratinocytes produce two forms of IL-1 –IL-1  and IL-1  –IL-1 receptor expression is autoinduced by IL-1 stimulation l induces the production of various cytokines and helps coordinate the response to injury l increased production of cytokines –IL-1, IL-6, GM-CSF, prostaglandin E (PGE) l increases cell proliferation l increases the levels of melanocyte stimulating hormone receptor on melanocytes and enhances melanocyte production of melanin l regulator for lymphocyte, macrophage, and natural killer cell function l fibroblasts are stimulated to produce more collagen and to release additional cytokines 6/3/2016

10. Autocrine and Paracrine Effects l Modulation of the growth and differentiation of skin cells may involve a direct effect of a toxic compound on the cellular genome or an interaction with a receptor with subsequent alteration of gene expression l A potential outcome of interaction of these agents with cells is an alteration in the normal autocrine and paracrine regulatory loops that exist in the skin 6/3/2016

11. para-phenylenediamine, or PPD

12. 6/3/2016 Allergic Contact Dermatitis Type IV hypersensitivity = delayed-type hypersensitivity l Epidermis harbors dendritic cells (Langerhan’s) with antigen-presenting capacity and cells belonging to the T-cell lineage l Epidermis functions as a source as well as a target for several cytokines, which play a crucial role in the pathogenesis of inflammatory and immunologically mediated skin diseases

13. 6/3/2016 Allergic Contact Dermatitis l Qualitative and quantitative similarities in the cytokine response between chemicals with sensitizing (immune specific) and irritant (inflammatory) properties and chemicals with irritant properties l Qualitative and quantitative differences in cellular response between immune specific and non-specific inflammatory responses

14. 6/3/2016 Allergic Contact Dermatitis immune specificnon-specific  TH 1 (  ), DC(  )  PMN(  ),  monocytes/macrophages(  )  monocytes(  ),  mast cells(  )  macrophages(  )  mast cells(  ) l systemic versus local response l dose and dose rate l cytotoxic T lymphocytes and DNA damage

15. Allergic Contact Dermatitis l Phase 1 –sensitization and activation –cognitive phase (5-7 days) l Phase 2 –elicitation l inflammation l resolution –neutralization, removal, and elimination of the hapten 6/3/2016

17. Skin and the Skin Associated Immune System: Delayed-type Hypersensitivity (Type-IV Allergic Contact Dermatitis) Two-Phase Response – 1. Sensitization and Activation 2. Elicitation: a) inflammation and b) resolution Cell Types / Cytokines Keratinocytes: IL-1, IL-3, IL-6, TNF , GM-CSF, TGF , TGF , MIP-1 , MIP-2, chemokines Langerhan’s Cells (APC) MHCII restricted, TNFR +, IL-6R +, B7 Lymphocytes, intraepidermal MHCII restricted, CD4 +, TH1 memory cell or MHCI, CD8 +, TH2 memory cell - Perivascular Macrophages (resident) TNF ,  -IFN, IL-1, IL-6, chemokines Local Draining Lymphnode Naive T-cells (CD4 + TH1, CD8 + TH2) IL-2, IL-4, TGF  1. SENSITIZATION 1-fluoro-2,4-dinitrobenzene NO 2 FL NO 2 Keratinocyte Cytokines HCC* 1 Cytokine 2 3 Lymphatic 4 *HCC – hapten carrier complex Afferent Efferent HEV APC + TH 1 ACTIVATION and CLONAL EXPANSION of TH 1 CELLS that are Hapten Specific TH 1 MEMORY CELLS ENDS COGNITIVE PHASE Mast Cell Capillary Macrophage IL-2 DISSEMINATION 1. Haptenic bearing site 2. Systemic 6 5 APC TH 1 CD4 + Arterial Venous LDLN

18. 6/3/2016 2. ELICITATION Two-Phase Response – 1. Additional presentation of hapten 2. Rapid proinflammatory response to remove hapten 1. Ends with resolution (elimination of hapten) 2. Sustained exposure may result in wound response Skin and the Skin Associated Immune System: Delayed-type Hypersensitivity (Type-IV Allergic Contact Dermatitis)

19. Allergic Contact Dermatitis l Sustained exposure and dysregulation of the response may result in a wound response and continued inflammation and attempts at fibrosis (granulomatous reaction) l Sensitizing and irritant properties of a chemical may show qualitative and quantitative differences in response to the dose and dose rate of exposure 6/3/2016

20. Allergic Contact Dermatitis l Low level exposures to a sensitizing chemical may induce an inflammatory response out of proportion the dose required by an irritant chemical to produce the same level of inflammatory response l Overall, the increased burden of inflammation may increase the induction of reactive oxygen species and systemic disease