Cutaneous Immunology: Innate Immune Responses. Skin Biology Lecture Series
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1 Cutaneous Immunology: Innate Immune Responses Skin Biology Lecture Series
2 The Immune Response: Innate and Adaptive Components Source: Wolff, Goldsmith, Katz, Gilchrest, Paller, Leffell. Fitzpatrick s Dermatology in General Medicine, 8 th Ed. Copyright The McGraw-Hill Companies. All rights reserved. Figure 10-1.
3 Innate and Adaptive Immunity Innate Immunity Constitutively active Rapid No memory Non-specific Adaptive Immunity Inducible Slow/Delayed Memory Specific Innate immune responses provide the first line of defense against pathogens Innate immunity stimulates later adaptive immunity The two arms of the immune systems work together in concert
4 Innate Immune System: Anatomical and Chemical Barriers Barriers protect against pathogen entry and invasion Protective physical factors include: Skin (stratum corneum) Epithelial surfaces Cilia Chemical Barriers include Tears, saliva (lysozyme, phospholipase destabilize cell walls and membranes) Sweat (fatty acids inhibit bacterial growth)
5 Innate Immune Response: Steps Source: Wolff, Goldsmith, Katz, Gilchrest, Paller, Leffell. Fitzpatrick s Dermatology in General Medicine, 8 th Ed. Copyright The McGraw-Hill Companies. All rights reserved. Figure 10-2.
6 Complement System: Three Pathways Source: Wolff, Goldsmith, Katz, Gilchrest, Paller, Leffell. Fitzpatrick s Dermatology in General Medicine, 8 th Ed. Copyright The McGraw-Hill Companies. All rights reserved. Figure e
7 Complement System Pathways can be activated through either innate (nonspecific) or adaptive (specific) immune responses Activation leads to: Increased vascular permeability (C3a, C5a) Activation of phagocytosis (C3) Lysis of pathogens (MAC, C5b-C9) Opsonization of pathogens (C3b) Chemotaxis of cells (C5a)
8 Toll-Like Receptors Source: Wolff, Goldsmith, Katz, Gilchrest, Paller, Leffell. Fitzpatrick s Dermatology in General Medicine, 8 th Ed. Copyright The McGraw-Hill Companies. All rights reserved. Figure 10-3.
9 Toll-Like Receptors Important link between innate and adaptive immunity Receptors on B cells T cells Monocytes Granulocytes Dendritic cells Adipocytes Intestinal epithelial cells Dermal endothelial cells Pattern recognition receptors Activation induces NF-kappa beta Source: Wolff, Goldsmith, Katz, Gilchrest, Paller, Leffell. Fitzpatrick s Dermatology in General Medicine, 8 th Ed. Copyright The McGraw-Hill Companies. All rights reserved. Figure 11-4.
10 Nuclear Factor Kappa Beta Activation Source: Wolff, Goldsmith, Katz, Gilchrest, Paller, Leffell. Fitzpatrick s Dermatology in General Medicine, 8 th Ed. Copyright The McGraw-Hill Companies. All rights reserved. Figure 11-2.
11 Toll-Like Receptors TLR1, TLR2, TLR6: lipoproteins and peptidoglycans present in viral envelopes and Gram-positive bacteria TLR4: lipopolysaccharide (LPS) on Gram-negative bacteria TLR3, TLR7/8, TLR9: nucleic acids Implicated in systemic lupus erythematosus (SLE) TLR3: viral double-stranded (ds) RNA TLR7/8: viral single-stranded (ss) RNA TLR9: bacterial or viral CpG-deoxyribo nucleic acid (DNA)
12 What common condition is mediated by TLR2 signaling? Source: Wolff, Goldsmith, Katz, Gilchrest, Paller, Leffell. Fitzpatrick s Dermatology in General Medicine, 8thEd. Copyright The McGraw-Hill Companies. All rights reserved. Figure 80-4
13 What common condition is mediated by TLR2 signaling? Answer: Acne TLR2 signaling through activation by Propionibacterium acnes This is an example of how toll like receptors can also cause tissue injury
14 Cytokines: Tumor Necrosis Factor Family Well-recognized cytokine family Can induce apoptosis or NF-kB activation TNF-alpha, causes cachexia, fever TNF-beta (lymphotoxin alpha), inhibited by IL-10 Source: Wolff, Goldsmith, Katz, Gilchrest, Paller, Leffell. Fitzpatrick s Dermatology in General Medicine, 8 th Ed. Copyright The McGraw-Hill Companies. All rights reserved. Figure 11-5.
15 Cytokines: Interleukin Family IL-1, IL-6, and TNF-α critical role in acute-phase response induces fever for host defense TNF-α potent inflammatory response to control infection IL-8 mediator of PMN chemotaxis to the site of infection IL-12 Activates T cells and NK cells Regulator of T-helper 1 (Th1) responses Important to induction of adaptive immune response IL-10 Inhibits cytokine release downregulates class II MHC expression inhibits release of reactive oxygen species anti-inflammatory activity
16 IL-10 production is associated with the progressive forms of which infections? Source: Wolff, Goldsmith, Katz, Gilchrest, Paller, Leffell. Fitzpatrick s Dermatology in General Medicine, 8thEd. Copyright The McGraw-Hill Companies. All rights reserved. Figure
17 IL-10 production is associated with the progressive forms of which infections? Leishmaniasis Schistosomiasis Trypanosomiasis
18 Innate Immune System: Antimicrobial Peptides β-defensin-1 (hbd-1) produced by keratinocytes low-molecular-weight antimicrobial peptide constitutively expressed in epidermis activity against Gram-negative bacteria β-defensin-2 (hbd-2) inducible by microbes activity against Gram-negative bacteria β-defensin-3 (hbd-3) activity against Gram-positive bacteria Source: Ali et al. JID (2001) 117,
19 Innate Immune System: Peptides Antimicrobial Peptides: Psoriasin (S100A7) made by keratinocytes, activity against E. Coli Cathelicidins Cationic peptides encoded by a single gene Precursor hcap18 made by keratinocytes, mast cells, neutrophils, and eccrine glands Neuropeptide α-msh: binds melanocortin receptor 1 (MC1R) MC1R expressed on melanocytes, phagocytes, and likely keratinocytes anti-inflammatory actions
20 In which dermatosis is cathelicidin downregulated? Source: Wolff, Goldsmith, Katz, Gilchrest, Paller, Leffell. Fitzpatrick s Dermatology in General Medicine, 8thEd. Copyright The McGraw-Hill Companies. All rights reserved. Figure 14-8.
21 In which dermatosis is cathelicidin downregulated? Atopic dermatitis Skin barrier disruption and reduced antimicrobial activity make atopic patients susceptible to infections Infections include: S. aureus vaccinia virus (eczema vaccinatum) herpes simplex virus (eczema herpeticum)
22 Innate Immune System: Eicosanoids Lipid mediators of inflammation derived from arachidonic acid made by keratinocytes Mediators produce prostaglandin E2, which has proinflammatory and immunosuppressive properties Other eicosanoids: Neutrophil chemoattractant leukotriene B4 - has pro-inflammatory, anti-inflammatory and immunosuppressive actions Eicosanoids include prostaglandins, prostacyclin, thromboxane, and leukotrienes
23 Innate Immune System: Reactive Oxygen Species (ROS)
24 Cellular Barriers: Langerhans Cell Activation Antigen presenting cells (APCs) Dendritic cells Present in epidermis, suprabasal Once activated travel to lymph nodes Source: Wolff, Goldsmith, Katz, Gilchrest, Paller, Leffell. Fitzpatrick s Dermatology in General Medicine, 8 th Ed. Copyright The McGraw-Hill Companies. All rights reserved. Figure 12-3.
25 PMNs Innate Immune System: PMNs and Macrophages Normally not present in skin Migrate to site during infection and inflammation Receptors recognize pathogens directly Phagocytose microbescoated with antibody and with complement C3b Granules contain myeloperoxidase, elastase, lactoferrin, collagenase, other enzymes superoxide radicals (O 2 ) generated Macrophages Take up pathogens, recognize them, and destroy them Use TLRs and complement receptors Activation triggers cytokine release
26 Innate Immune System: Eosinophils Occur in small numbers in peripheral tissues Express: Ig receptors Receptors for complement components Receptors for arachidonic acid metabolites (LKT B4, prostaglandin E2) Chemokine receptors Contain: major basic protein eosinophilic cationic protein eosinophil-derived neurotoxin Can directly damage tissues may contribute to organ system dysfunction in hypereosinophilic syndrome
27 Innate Immune System: Natural Killer (NK) Cells
28 Innate Immune System: Keratinocytes An integral part of the immune system Secrete cytokines and chemokines, arachidonic acid metabolites, complement components, neuropeptides, eicosanoids, ROS, and antimicrobial peptides Constitutive production of IL-1, IL-7, transforming growth factor-β (TGF-β) In severe sunburn, increased serum levels of IL-1, IL-6, and TNF-α cause fever, leukocytosis, acute-phase response UV radiation induces IL-6 and IL-10, can induce autoantibodies and worsen autoimmune diseases such as lupus erythematosus. Keratinocytes synthesize complement and related receptors C3b receptor [complement receptor 1 (CR1), CD35] Epstein-Barr virus receptor CR2 (C3d receptor, CD21) C5a receptor (CD88) membrane co-factor protein (CD46) decay-accelerating factor (CD55) complement protectin (CD59)
29 CD46 Common surface protein regulates complement and attachment and ingestion of foreign particles by neutrophils and macrophages CD55 Decay accelerating factor 70 kda surface membrane protein regulates complement system Prevents assembly of C3b complex or accelerates disassembly of convertase, blocking creation of the membrane attack complex (MAC) CD59 Innate Immune System: CD Proteins Protectin Inhibits complement-mediated cell lysis by preventing formation of the membrane attack complex
30 The end
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