Cutaneous Immunology

1. Cutaneous Immunology HuBio 567—The Skin Fall 2002 University of Washington School of Medicine Roy Colven, MD

2. Cutaneous ImmunologySummary Points • The immune system protects us from foreign micro-invasion. • The immune system sometimes screws up. • The skin has its own immune system. • Inflammatory skin disorders are understandable. • New, more specific, treatments emerging.

3. Cutaneous ImmunologyOverview I. Brief review of general immunology II. Skin immune system biology III. Skin immune system pathology

4. First line of defense Nonspecific Rapid onset No protective immunity No memory Phagocyte- mediated Activated Very specific Slower Protective immunity possible Memory possible Lymphocyte- mediated Immunity Innate & Adaptive

5. Unique antigen receptor constructed early Selected and activated by non-self proteins Clones persist (memory cells) Lymphocytes with self-recognizing receptors are culled Adaptive ImmunityLymphocytes • T-cells • Mature in thymus • Paracortical area • Antigen receptor: • T-cell receptor • B-cells • Mature in bone marrow • Lymphoid follicle • Antigen receptor: • Immunoglobulin • molecule From, Janeway, CA, Immunobiology, 5th ed.

6. Adaptive ImmunityAntigen Receptors From, Janeway, CA, Immunobiology, 5th ed.

7. Adaptive Immunity“Professional”Antigen Presenting Cells • Dendritic cells, macrophages, B-cells • Efficiently process antigens • Cytosolic and vesicular compartments • Express MHC I and II molecules • Antigen peptides fit in MHC cleft • MHC:peptide complex to cell surface • Provide costimulatory 2nd signal

8. MHC Molecules • Function: Bind processed antigen and transport to cell surface • MHC I: • All nucleated cells • Process Ag from cytosolic compartment • Present to CD8+ cytotoxic T-cells • HLA-A, B, C • MHC II: • Dendritic cells, macrophages, B-cells • Process Ag from vesicular compartment • Present to CD4+ helper T-cells • HLA-DR, DP, DQ

9. Antigen Presenting Cells From, Janeway, CA, Immunobiology, 5th ed.

10. Adaptive ImmunityRecipe for Successful Antigen Presentation Place in a lymph node... • 1 antigen presenting cell (APC) with MHC molcules (I or II) • 1 antigen processed by APC • 1 naïve T cell (CD8+ or CD4+) with unique and specific T-cell receptor • Add costimulatory second signal and a pinch of IL-2 • Stir.…Proliferate, differentiate!

11. Adaptive ImmunityTo Activate a Lymphocyte… From, Janeway, CA, Immunobiology, 5th ed.

12. Cytokines: More than Alphabet Soup • Cell communication via released peptides • High affinity receptors • Low concentration, big effect • Impact over short distances: Auto-, juxta-, paracrine • Wide range of cellular effects • Examples: Interleukins, TNF, interferons

13. Cell Adhesion Molecules:Molecular Velcro • Cell surface molecules with matching ligands on other cells • Allow cell-to-cell binding for communication and homing • Expression of CAMs variable and under complex control • Example: Intercellular adhesion molecule-1 (ICAM-1) on APC’s binding to lymphocyte function-associated antigen-1 (LFA-1) on T-cells

14. Effector T-Cells • CD8+ cytotoxic T lymphocyte (CTL) • “The Hitman” • Kills on contact • CD4+ helper T lymphocyte • “The Bureaucrat” • Directs other cells to do the dirty work Effector T-cells do not require costimulatory signal

15. CD8+ Cytotoxic T-cell • Directly cytotoxic to cells via binding to Ag:MHC I complex • Cytosolic antigens (e.g., viruses) • Induces apoptosis • Cytotoxicity is specific and directional • Cytotoxins include: • Perforin, granzymes • Also produces cytokines • IFN-, TNF

16. CD4+ Helper T-Cells • Binds to APCs via Ag:MHC II complex • Then directs other effector cells (macrophages, B cells) to kill pathogens or neutralize toxins • Uses cytokines as its “memos”

17. Th1/Th2 Paradigm Cell-mediated immunity IL-2 Th1 TNF IL-12 IFN IL-10 Th0 Humoral immunity IL-12, IFN IL-4 IL-4 Th2 IL-5 IL-10

18. CD4+ Helper T-Cells:Th1/Th2 Paradigm • Th1 (type 1) • IL-2, TNF, IFN- • Activate macrophages and CTL’s for intracellular pathogen killing and cytotoxicity • Facilitate cell-mediated immunity • Inhibit Th2 cell proliferation

19. CD4+ Helper T-Cells:Th1/Th2 Paradigm • Th2 (type 2) • IL-4, 5, 10 • Activate B cells and antibody production to neutralize extracellular pathogens & toxins • Facilitate humoral immunity • Inhibit Th1 cell proliferation

20. What Determines Th1 vs. Th2 Response? • Type of pathogen • Innate immune response to it • Macrophages, NK cells release IL-12, IFN- • Mast cells, basophils,  T cells release IL-4 • Host’s immune constitution • Density of Ag presented on APC • High density Th1 • Low density Th2

21. Cutaneous ImmunologyOverview I. Brief review of general immunology II. Skin immune system biology III. Skin immune system pathology

22. Inherent (Nonimmune) Skin Defenses • Physical • Resistance to mechanical trauma • Relatively water impermeable • Physical separation between self and nonself • Chemical • Free fatty acids • Free radical trapping • Antimicrobial peptides

23. Inherent Skin Defenses(cont’d) • Photoprotective • Melanin as a UV chromophore • Injury repair • Microbiological • Home for colonizing, nonpathogenic bacteria that: • Compete for nutrients • Compete for attachment • Produce antibacterial substances

24. Innate Immune Features of the Skin • No specialization for skin • Cells • Phagocytes: Macrophages, neutrophils, NK cells • Mast cells • Circulating chemicals • Complement • Locally produced chemicals • Cytokines, histamine

25. Mast Cells • Bone marrow-derived • Dermal resident • Perivascular • Mediators • Preformed (histamine, e.g.) • Newly synthesized (cytokines, e.g.) • Various stimuli mediator release • Immunologic: IgE binding antigen • Nonimmunologic: Physical, drugs, complement

26. ? Role in skin homeostasis Nerve, blood vessel maintenance? Function as initial responders Pro-inflammatory effects Vasoactive chemicals mediate urticaria Histamine and leukotrienes Mast Cells

27. Cells of the Cutaneous Adaptive Immune Response • Langerhans’ cell • Dermal dendrocytes • Keratinocytes • T-cells • Endothelial cells

28. Cells of the Cutaneous Adaptive Immune Response • Macrophages • B-cells • Veiled cells • ( T-cells)

29. Langerhans’ Cells • Bone marrow-derived • Monocyte lineage • Transient epidermal cells • Dendritic cell • Cell surface molecules: CD1a, MHC II, ATPase, Fc receptor for IgG, C3 receptor, B7, several CAMs • Electron microscopy: Birbeck granules, convoluted nucleus

30. Langerhans’ Cells:Epidermal Transients • Migration and maturation Bone marrow Blood (M) Epidermis (LC) Afferent lymph (VC) Lymph node (FDC) • Functions • Antigen capture and processing • Presentation of antigen • Costimulation of naïve T-cells • Produce activating cytokines

31. Langerhans’ Cell Migration Antigen From Janeway, CA Immunobiology, 5th ed.

32. Stoitzner, J Inv Dermatol, 2002

33. Stoitzner, J Inv Dermatol, 2002

34. Stoitzner, J Inv Dermatol, 2002

35. Stoitzner, J Inv Dermatol, 2002

36. Stoitzner, J Inv Dermatol, 2002

37. Dendritic Cell Maturation:LCFDC • Phagocytic • Ag processing • MHC I, II • Costimulatory molecules • Naïve T-cell stimulation • Birbeck granules +

38. Dermal Dendritic Cells • Papillary dermis • Perivascular • Dendritic morphology • MHC II + • Subpopulations with phenotypic and functional overlap • Antigen presentation • Phagocytosis • Plasticity?

39. Dermal dendrocytes No Birbeck granules Factor XIIIa + CD1a, ATPase - Blood vessel-assoc. Langerhans cells Birbeck granules Factor XIIIa - CD1a, ATPase + Epidermal Dermal Dendrocytes & Langerhans Cells:To Lump or Split

40. Keratinocytes As Immune Cells Old view: Keratinocytes... • Are passive barrier cells • Are passive victims of immune attack

41. Keratinocytes As Immune Cells Newer view: Keratinocytes... • Produce cytokines • e.g., IL-1, TNF-, Chemokines • Respond to cytokines • e.g., IFN, IL-1 • Upregulate ICAM-1 • Present antigen ...Particularly when stimulated

42. Endothelial Cells &Cutaneous Inflammation • Increase permeability • When activated, endothelial cells... • cell surface expression of P-selectin for enhanced leukocyte margination • synthesis & expression of E-selectin for selective T-cell (CLA +) homing to the skin • expression of VCAM-1 & ICAM-1 to stop leukocytes and allow diapedesis • Immune response amplified

43. Cutaneous Lymphocyte Antigen (CLA) • Specific skin homing marker on T-cells • CLA+ lymphocytes are memory/effector cells (CD45RO +) • Cell adhesion to endothelial cell • E-selectin is ligand • With cutaneous inflammation, E-selectin up-regulated, CLA+ cells selected

44.  T-Cells • Resident in epithelia; do not recirculate • Restricted T-cell receptors • Bridge between innate and adaptive immunity • Dendritic gd T-cell network found in mouse epidermis • Presence and function in human skin controversial

45. The Skin Immune System Components 1. APCs: Langerhans cells, dermal dendrocytes, dermal macrophages 2. Keratinocytes 3. Endothelial cells 4. Skin-homing T-cells 5. Draining regional lymph vessels and nodes

46. The Skin Immune System Principles 1. Interface with environment 2. Unique nonimmune protection 3. Innate immune defenses 4. Specialized set of APCs 5. Skin homing memory T-cells 6. Antigen presentation in skin 7. Distinct response from other epithelia

47. Cutaneous ImmunologyOverview I. Brief review of general immunology II. Skin immune system biology III. Skin immune system pathology

48. Contact Dermatitis • Erythematous, weepy, scaly, geometric plaques • Irritant- or allergen-induced • Major cause of occupational illness • Histology: Epidermal spongiosis

49. Allergic Contact DermatitisPathogenesis Sensitization (Induction)--1o exposure • Contact allergen usually a hapten • LMW, links with endogenous protein • Picked up by LC’s and presented to naïve T-cells in lymph node • CLA upregulated on activated T-cells • Specific effector T-cells home to skin Often nothing happens…Why?

50. Contact Allergen Contact Sensitization From Janeway, CA Immunobiology, 5th ed.