Cutaneous immunology
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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

Nonspecific

Rapid onset

No protective immunity

No memory

Phagocyte- mediated

Activated

Very specific

Slower

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

IL-2

Th1

TNF

IL-12

IFN

IL-10

Th0

Humoral immunity

IL-12, IFN

IL-4

IL-4

Th2

IL-5

IL-10


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 densityTh1

    • Low densityTh2


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

Antigen

From Janeway, CA

Immunobiology, 5th ed.


Cutaneous immunology

Stoitzner, J Inv Dermatol, 2002


Cutaneous immunology

Stoitzner, J Inv Dermatol, 2002


Cutaneous immunology

Stoitzner, J Inv Dermatol, 2002


Cutaneous immunology

Stoitzner, J Inv Dermatol, 2002


Cutaneous immunology

Stoitzner, J Inv Dermatol, 2002


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 +

Epidermal

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

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


The skin immune system1

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


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

IL-2

Th1

TNF

IL-12

IFN

IL-10

Th0

Humoral immunity

IL-12, IFN

IL-4

IL-4

Th2

IL-5

IL-10


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

IL-2

Th1

TNF

IL-12

IFN

IL-10

Th0

Humoral immunity

IL-12, IFN

IL-4

IL-4

Th2

IL-5

IL-10


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

Lepromatous

Tuberculoid

Susceptibility

Resistance

Skin lesions/bacilli

Cell-mediated immunity

Antibodies


Leprosy host response

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


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

HealthDisease

Something

Happens


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 cellsactivation

  • 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


Psoriasis

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


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.


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