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

The end