Cutaneous Immunology

1
Cutaneous Immunology

• HuBio 567The 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

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Immunity Innate Adaptive

• 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

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Adaptive ImmunityLymphocytes

• Unique antigen receptor constructed early
• Selected and activated by non-self proteins
• Clones persist (memory cells)
• Lymphocytes with self-recognizing receptors are
  culled

• 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.
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Adaptive ImmunityAntigen Receptors
From, Janeway, CA, Immunobiology, 5th ed.
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Adaptive Immunity ProfessionalAntigen
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
• MHCpeptide complex to cell surface
• Provide costimulatory 2nd signal

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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

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Antigen Presenting Cells
From, Janeway, CA, Immunobiology, 5th ed.
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Adaptive Immunity Recipe 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!

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Adaptive Immunity To Activate a Lymphocyte
From, Janeway, CA, Immunobiology, 5th ed.
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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

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Cell Adhesion MoleculesMolecular 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 APCs binding to lymphocyte
  function-associated antigen-1 (LFA-1) on T-cells

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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

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CD8 Cytotoxic T-cell

• Directly cytotoxic to cells via binding to AgMHC
  I complex
• Cytosolic antigens (e.g., viruses)
• Induces apoptosis
• Cytotoxicity is specific and directional
• Cytotoxins include
• Perforin, granzymes
• Also produces cytokines
• IFN-?, TNF

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CD4 Helper T-Cells

• Binds to APCs via AgMHC II complex
• Then directs other effector cells (macrophages, B
  cells) to kill pathogens or neutralize toxins
• Uses cytokines as its memos

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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
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CD4 Helper T-CellsTh1/Th2 Paradigm

• Th1 (type 1)
• IL-2, TNF, IFN-?
• Activate macrophages and CTLs for intracellular
  pathogen killing and cytotoxicity
• Facilitate cell-mediated immunity
• Inhibit Th2 cell proliferation

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CD4 Helper T-CellsTh1/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

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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
• Hosts immune constitution
• Density of Ag presented on APC
• High density Th1
• Low density Th2

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Cutaneous ImmunologyOverview

• I. Brief review of general immunology
• II. Skin immune system biology
• III. Skin immune system pathology

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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

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Inherent Skin Defenses(contd)

• Photoprotective
• Melanin as a UV chromophore
• Injury repair
• Microbiological
• Home for colonizing, nonpathogenic bacteria that
• Compete for nutrients
• Compete for attachment
• Produce antibacterial substances

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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

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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

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Mast Cells

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

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Cells of the Cutaneous Adaptive Immune Response

• Langerhans cell
• Dermal dendrocytes
• Keratinocytes
• T-cells
• Endothelial cells

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Cells of the Cutaneous Adaptive Immune Response

• Macrophages
• B-cells
• Veiled cells
• (?? T-cells)

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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

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Langerhans CellsEpidermal 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

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Langerhans Cell Migration
Antigen
From Janeway, CA Immunobiology, 5th ed.
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Stoitzner, J Inv Dermatol, 2002
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Stoitzner, J Inv Dermatol, 2002
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Stoitzner, J Inv Dermatol, 2002
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Stoitzner, J Inv Dermatol, 2002
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Stoitzner, J Inv Dermatol, 2002
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Dendritic Cell Maturation LC
FDC

• Phagocytic
• Ag processing
• MHC I, II
• Costimulatory molecules
• Naïve T-cell stimulation
• Birbeck granules

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Dermal Dendritic Cells

• Papillary dermis
• Perivascular
• Dendritic morphology
• MHC II
• Subpopulations with phenotypic and functional
  overlap
• Antigen presentation
• Phagocytosis
• Plasticity?

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Dermal Dendrocytes Langerhans CellsTo Lump
or Split

• Dermal dendrocytes
• No Birbeck granules
• Factor XIIIa
• CD1a, ATPase -
• Blood vessel-assoc.

• Langerhans cells
• Birbeck granules
• Factor XIIIa -
• CD1a, ATPase
• Epidermal

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Keratinocytes As Immune Cells

• Old view Keratinocytes...
• Are passive barrier cells
• Are passive victims of immune attack

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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

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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

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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

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?? 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

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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

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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

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Cutaneous ImmunologyOverview

• I. Brief review of general immunology
• II. Skin immune system biology
• III. Skin immune system pathology

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Contact Dermatitis

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

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Allergic Contact DermatitisPathogenesis

• Sensitization (Induction)--1o exposure
• Contact allergen usually a hapten
• LMW, links with endogenous protein
• Picked up by LCs and presented to naïve T-cells
  in lymph node
• CLA upregulated on activated T-cells
• Specific effector T-cells home to skin
• Often nothing happensWhy?

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

• Elicitation--subsequent exposures
• Allergen taken up by DCs
• Memory T-cells recognize AgMHC complex in situ
  (in the skin)
• T-cells proliferate in situ
• IL-2, TNF, IFN-? expressed
• Inflammatory response ensues
• Question What turns this process off?

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Contact Elicitation
From Janeway, CA Immunobiology, 5th ed.
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Allergic Contact DermatitisImmunopathology
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
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Contact Dermatitis Irritant vs. Allergic

• More common
• Reaction minutes to hours after 1st contact
• Direct cellular injury by chemical
• No immunologic memory

• Less common
• No or delayed reaction after 1st contact
• Ag presented to T- cells
• Immunologic memory

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Atopic Dermatitis

• Itch and xerosis
• Acutely weepy to chronic dermatitis
• Flexures, face commonly involved
• Childhood onset often
• Personal history of allergic rhinitis and/or
  asthma
• Family history of atopy prominent
• Histology Epidermal spongiosis

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Atopic DermatitisImmunopathology
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
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Staph antigens andAtopic Dermatitis

• Mechanisms of stimulation
• Innate immune response to infection
• Superantigen stimulation of T cells
• IgE sensitization to staph entero-toxins
• Staph alpha toxin-mediated release of TNF from
  keratinocytes

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Leprosy (Hansens Disease)

• Developing countries
• India, African continent, Southeast Asia, South
  America, Mexico
• Immigrants to US
• Few cases acquired in US, related to armadillo
  exposure
• Mycobacterium leprae
• Clinical spectrum of disease correlates to immune
  response

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The Spectrum of Leprosy
Lepromatous
Tuberculoid
Susceptibility
Resistance
Skin lesions/bacilli
Cell-mediated immunity
Antibodies
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Leprosy Host Response
Cell-mediated immunity
IL-2
Th1
TNF
IL-12
IFN
Tuberculoid
IL-10
Th0
Humoral immunity
IL-12, IFN
IL-4
IL-4
Th2
IL-5
IL-10
Lepromatous
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What Determines Immune Response in Leprosy?

• Poverty, poor nutrition
• Genetics
• HLA-DR 2, 3 assoc. w/ tuberculoid form
• HLA-DQ 1 assoc. w/ lepromatous form
• Coexisting diseases, e.g.,
• HIV
• Intestinal parasites?

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Pemphigus Vulgaris

• Onset 5th-7th decades
• Though can occur at any age
• Oral erosions often presenting sign
• Bullae are flaccid, erosions numerous and slow to
  heal Nikolsky sign
• Histology Suprabasal epidermal split
• IF Interkeratinocyte IgG

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Epidermal Targets of Autoantibody Attack

• Pemphigus vulgaris
• Desmoglein 3 (130 kD)
• Target Desmosome
• Keratinocyte cohesion

• Bullous pemphigoid
• BP Ag 1 (230 kD) Intra-basal keratinocyte
• BP Ag 2 (180 kD) Transmembrane
• Target Hemidesmosome
• Dermal-epidermal junction adhesion

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Autoantibodies in Pemphigus are Pathogenic
Evidence

• PV patients sera in skin culture evokes
  histologic changes of PV
• Passive transfer of pemphigus IgG to neonatal
  mice causes disease
• Transient PV in neonates of affected mothers

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The Cause of Autoimmunityas of September 13, 2001

• Health Disease
• Something
• Happens

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Primary HIV Infection

• Initial exposure to HIV leading to productive
  infection
• 10-40 of cases asymptomatic
• Associated with significant viremia
• Transmission risk high
• Ends with HIV seroconversion

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Dendritic CellsTargets of HIV Infection

• Langerhans cells (LCs) express CCR5 and CD4
• LCs prime target cell in epithelial transmission
  of HIV
• HIV entry and productive infection can occur
  within LCs
• LCs selective for M-tropic HIV strains

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Dendritic Cells as HIV Vectors

• LCs can also trap and transport HIV without
  productive infection
• LCs present HIV antigen to naïve T
  cells activation
• HIV-specific activated T cells primed for HIV
  infection by LC vector

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HIV ImmunopathogenesisStrategic Attack

• CD4 T-cell ultimate target
• Especially activated CD4 cells
• HIV-specific CD4 response impaired early
• Cytotoxic T lymphocyte response wanes over time
• Progressive CD4 lymphopenia
• T-cell receptor repertoire crippled

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Significance of Recognizing Primary HIV Infection

• Reduce transmission during period of high titer
  viremia
• Early intervention could...
• lower viral set point
• prevent establishment of sanctuary sites for HIV
• allow the generation of an HIV-specific CD4 cell
  response

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Psoriasis

• Affects 1-2 of population
• Salmon-pink, sharply demarcated plaques with
  micaceous scale
• Elbows, knees classic
• Also common scalp, trunk, genitals, nail
  involvement
• Other variants guttate, pustular, erythrodermic
• Arthritis in 5 of psoriatic patients

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Psoriasis Evidence of T-Cell Mediation

• Early cells in psoriatic lesions
• Cyclosporine, anti-CD4 monoclonal Abs as
  treatment
• Blocking T cellAPC 2nd signal prevents psoriatic
  lesion
• Psoriasis altered in HIV infection
• Bone marrow transplant recipients
• Streptococcal superantigens can induce psoriasis

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Psoriasis New Immunologic Approaches to
Treatment

• TNF inhibition
• Antibodies to TNF
• Soluble TNF receptors
• Costimulatory blockade
• Adhesion molecule inhibition
• LFA-1
• CD2
• IL-2 activation blockade

74
Cutaneous ImmunologySummary Points

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