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Cutaneous Immunology. HuBio 567— The Skin Fall 2002 University of Washington School of Medicine Roy Colven, MD. Cutaneous Immunology Summary Points. The immune system protects us from foreign micro-invasion. The immune system sometimes screws up. The skin has its own immune system.

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Cutaneous immunology

Cutaneous Immunology

HuBio 567—The Skin

Fall 2002

University of Washington School of Medicine

Roy Colven, MD

Cutaneous immunology summary points
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.

Cutaneous immunology overview
Cutaneous ImmunologyOverview

I. Brief review of general immunology

II. Skin immune system biology

III. Skin immune system pathology

Immunity innate adaptive

First line of defense


Rapid onset

No protective immunity

No memory

Phagocyte- mediated


Very specific


Protective immunity possible

Memory possible

Lymphocyte- mediated

Immunity Innate & Adaptive

Adaptive immunity lymphocytes

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.

Adaptive immunity antigen receptors
Adaptive ImmunityAntigen Receptors

From, Janeway, CA, Immunobiology, 5th ed.

Adaptive immunity professional antigen presenting cells
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

Mhc molecules
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

Antigen presenting cells
Antigen Presenting Cells

From, Janeway,

CA, Immunobiology,

5th ed.

Adaptive immunity recipe for successful antigen presentation
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!

Adaptive immunity to activate a lymphocyte
Adaptive ImmunityTo Activate a Lymphocyte…

From, Janeway, CA, Immunobiology, 5th ed.

Cytokines more than alphabet soup
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

Cell adhesion molecules molecular velcro
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

Effector t cells
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

Cd8 cytotoxic t cell
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

Cd4 helper t cells
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”

Th1 th2 paradigm
Th1/Th2 Paradigm

Cell-mediated immunity








Humoral immunity

IL-12, IFN






Cd4 helper t cells th1 th2 paradigm
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

Cd4 helper t cells th1 th2 paradigm1
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

What determines th1 vs th2 response
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

Cutaneous immunology overview1
Cutaneous ImmunologyOverview

I. Brief review of general immunology

II. Skin immune system biology

III. Skin immune system pathology

Inherent nonimmune skin defenses
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

Inherent skin defenses cont d
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

Innate immune features of the skin
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

Mast cells
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

Mast cells1

? Role in skin homeostasis

Nerve, blood vessel maintenance?

Function as initial responders

Pro-inflammatory effects

Vasoactive chemicals mediate urticaria

Histamine and leukotrienes

Mast Cells

Cells of the cutaneous adaptive immune response
Cells of the Cutaneous Adaptive Immune Response

  • Langerhans’ cell

  • Dermal dendrocytes

  • Keratinocytes

  • T-cells

  • Endothelial cells

Cells of the cutaneous adaptive immune response1
Cells of the Cutaneous Adaptive Immune Response

  • Macrophages

  • B-cells

  • Veiled cells

  • ( T-cells)

Langerhans cells
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

Langerhans cells epidermal transients
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

Langerhans cell migration
Langerhans’ Cell Migration


From Janeway, CA

Immunobiology, 5th ed.

Dendritic cell maturation lc fdc
Dendritic Cell Maturation:LCFDC

  • Phagocytic

  • Ag processing

  • MHC I, II

  • Costimulatory molecules

  • Naïve T-cell stimulation

  • Birbeck granules


Dermal dendritic cells
Dermal Dendritic Cells

  • Papillary dermis

  • Perivascular

  • Dendritic morphology

  • MHC II +

  • Subpopulations with phenotypic and functional overlap

    • Antigen presentation

    • Phagocytosis

  • Plasticity?

Dermal dendrocytes langerhans cells to lump or split

Dermal dendrocytes

No Birbeck granules

Factor XIIIa +

CD1a, ATPase -

Blood vessel-assoc.

Langerhans cells

Birbeck granules

Factor XIIIa -

CD1a, ATPase +


Dermal Dendrocytes & Langerhans Cells:To Lump or Split

Keratinocytes as immune cells
Keratinocytes As Immune Cells

Old view: Keratinocytes...

  • Are passive barrier cells

  • Are passive victims of immune attack

Keratinocytes as immune cells1
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

Endothelial cells cutaneous inflammation
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

Cutaneous lymphocyte antigen cla
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

T cells
 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

The skin immune system
The Skin Immune System


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

The skin immune system1
The Skin Immune System


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

Cutaneous immunology overview2
Cutaneous ImmunologyOverview

I. Brief review of general immunology

II. Skin immune system biology

III. Skin immune system pathology

Contact dermatitis
Contact Dermatitis

  • Erythematous, weepy, scaly, geometric plaques

  • Irritant- or allergen-induced

  • Major cause of occupational illness

  • Histology: Epidermal spongiosis

Allergic contact dermatitis pathogenesis
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?

Contact sensitization

Contact Allergen

Contact Sensitization

From Janeway, CA

Immunobiology, 5th ed.

Allergic contact dermatitis pathogenesis1
Allergic Contact DermatitisPathogenesis

  • Elicitation--subsequent exposures

  • Allergen taken up by DC’s

  • Memory T-cells recognize Ag:MHC 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?

Contact elicitation
Contact Elicitation

From Janeway, CA

Immunobiology, 5th ed.

Allergic contact dermatitis immunopathology
Allergic Contact DermatitisImmunopathology

Cell-mediated immunity








Humoral immunity

IL-12, IFN






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

Contact DermatitisIrritant vs. Allergic

Atopic dermatitis
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

Atopic dermatitis immunopathology
Atopic DermatitisImmunopathology

Cell-mediated immunity








Humoral immunity

IL-12, IFN






Staph antigens and atopic dermatitis
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

Leprosy hansen s disease
Leprosy (Hansen’s 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

The spectrum of leprosy
The Spectrum of Leprosy





Skin lesions/bacilli

Cell-mediated immunity


Leprosy host response
Leprosy: Host Response

Cell-mediated immunity









Humoral immunity

IL-12, IFN







What determines immune response in leprosy
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?

Pemphigus vulgaris
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

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

Epidermal Targets of Autoantibody Attack

Autoantibodies in pemphigus are pathogenic evidence
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

The cause of autoimmunity as of september 13 2001
The Cause of Autoimmunityas of September 13, 2001




Primary hiv infection
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

Dendritic cells targets of hiv infection
Dendritic Cells:Targets 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

Dendritic cells as hiv vectors
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

Hiv immunopathogenesis strategic attack
HIV Immunopathogenesis:Strategic 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

Significance of recognizing primary hiv infection
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


  • 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

Psoriasis evidence of t cell mediation
Psoriasis: Evidence of T-Cell Mediation

  • Early cells in psoriatic lesions

  • Cyclosporine, anti-CD4 monoclonal Ab’s as treatment

  • Blocking T cell:APC 2nd signal prevents psoriatic lesion

  • Psoriasis altered in HIV infection

  • Bone marrow transplant recipients

  • Streptococcal superantigens can induce psoriasis

Psoriasis new immunologic approaches to treatment
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

Cutaneous immunology summary points1
Cutaneous ImmunologySummary Points

  • The immune system protects us from foreign micro-invasion.

  • The skin has its own immune system.

  • The skin immune system isn’t perfect and sometimes screws up.

  • Inflammatory skin disorders are understandable.

  • New, more specific, treatments emerging.