Cutaneous Immunology: Innate Immune Responses Advance... · 2015. 9. 3. · Complement System •...
Transcript of Cutaneous Immunology: Innate Immune Responses Advance... · 2015. 9. 3. · Complement System •...
Skin Biology Lecture Series
Cutaneous Immunology: Innate Immune Responses
The Immune Response: Innate and Adaptive Components
Source: Wolff, Goldsmith, Katz, Gilchrest, Paller, Leffell. Fitzpatrick’s Dermatology in General Medicine, 8thEd. Copyright The McGraw-Hill Companies. All rights reserved. Figure 10-1.
Innate and Adaptive Immunity
Innate Immunity Adaptive Immunity
Constitutively active Inducible
Rapid Slow/Delayed
No memory Memory
Non-specific 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
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)
Source: Wolff, Goldsmith, Katz, Gilchrest, Paller, Leffell. Fitzpatrick’s Dermatology in General Medicine, 8thEd. Copyright The McGraw-Hill Companies. All rights reserved. Figure 10-2.
Innate Immune Response: Steps
Source: Wolff, Goldsmith, Katz, Gilchrest, Paller, Leffell. Fitzpatrick’s Dermatology in General Medicine, 8thEd. Copyright The McGraw-Hill Companies. All rights reserved. Figure e10-2.1.
Complement System: Three Pathways
Complement System
• Pathways can be activated through either innate (non-specific) 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)
Source: Wolff, Goldsmith, Katz, Gilchrest, Paller, Leffell. Fitzpatrick’s Dermatology in General Medicine, 8thEd. Copyright The McGraw-Hill Companies. All rights reserved. Figure 10-3.
Toll-Like Receptors
Source: Wolff, Goldsmith, Katz, Gilchrest, Paller, Leffell. Fitzpatrick’s Dermatology in General Medicine, 8thEd. Copyright The McGraw-Hill Companies. All rights reserved. Figure 11-4.
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, 8thEd. Copyright The McGraw-Hill Companies. All rights reserved. Figure 11-2.
Nuclear Factor Kappa Beta Activation
• 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)
Toll-Like Receptors
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
• Answer: Acne
• TLR2 signaling through activation by Propionibacterium acnes
• This is an example of how toll like receptors can also cause tissue injury
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 11-5.
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
• 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
Cytokines: Interleukin Family
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 206-9.
IL-10 production is associated with the progressive forms of which infections?
Schistosomiasis
Leishmaniasis
Trypanosomiasis
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
Innate Immune System: Antimicrobial Peptides
Source: Ali et al. JID (2001) 117, 106–111
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
Innate Immune System: Peptides
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.
• 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)
In which dermatosis is cathelicidin downregulated ?
• Lipid mediators of inflammation • derived from arachidonic acid • made by keratinocytes • Mediators produce prostaglandin E2, which has pro-
inflammatory and immunosuppressive properties • Other eicosanoids: • Neutrophil chemoattractant leukotriene B4
- has pro-inflammatory, anti-inflammatory and immunosuppressive actions
• Eicosanoids include prostaglandins, prostacyclin, thromboxane, and leukotrienes
Innate Immune System: Eicosanoids
Innate Immune System: Reactive Oxygen Species (ROS)
Source: Wolff, Goldsmith, Katz, Gilchrest, Paller, Leffell. Fitzpatrick’s Dermatology in General Medicine, 8thEd. Copyright The McGraw-Hill Companies. All rights reserved. Figure 12-3.
Cellular Barriers: Langerhans Cell
Activation
• Antigen presenting cells (APCs) • Dendritic cells • Present in epidermis, suprabasal • Once activated travel to lymph nodes
• PMNs • 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 (O2
–) generated
• Macrophages • Take up pathogens, recognize them, and destroy them • Use TLRs and complement receptors • Activation triggers cytokine release
Innate Immune System: PMNs and Macrophages
• 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
Innate Immune System: Eosinophils
Innate Immune System: Natural Killer (NK) Cells
• 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)
Innate Immune System: Keratinocytes
• 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
– Protectin – Inhibits complement-mediated cell lysis by preventing
formation of the membrane attack complex
Innate Immune System: CD Proteins
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