Transcript Cutaneous Immunology

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.
• Inflammatory skin disorders are
understandable.
• New, more specific, treatments
emerging.
Cutaneous Immunology
Overview
I. Brief review of general immunology
II. Skin immune system biology
III. Skin immune system pathology
Immunity
Innate & Adaptive
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First line of defense
Nonspecific
Rapid onset
No protective
immunity
• No memory
• Phagocytemediated
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Activated
Very specific
Slower
Protective immunity
possible
• Memory possible
• Lymphocytemediated
Adaptive Immunity
Lymphocytes
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Unique antigen receptor constructed early
Selected and activated by non-self proteins
Clones persist (memory cells)
Lymphocytes with self-recognizing receptors
are culled
B-cells
•Mature in bone marrow
•Lymphoid follicle
•Antigen receptor:
Immunoglobulin
molecule
T-cells
•Mature in thymus
•Paracortical area
•Antigen receptor:
T-cell receptor
From, Janeway, CA, Immunobiology, 5th ed.
Adaptive Immunity
Antigen Receptors
From, Janeway, CA,
Immunobiology, 5th ed.
Adaptive Immunity
“Professional”
Antigen Presenting Cells
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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
• 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
From, Janeway,
CA, Immunobiology,
5th ed.
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!
Adaptive Immunity
To Activate a Lymphocyte…
From, Janeway, CA,
Immunobiology, 5th ed.
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 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
• 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
• 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
• 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
Cell-mediated immunity
IL-2
Th1
IL-12
TNF
IFN
IL-10
Th0
Humoral immunity
IL-4
IL-12, IFN
IL-4
Th2
IL-5
IL-10
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 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?
• 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
– Low density
Th1
Th2
Cutaneous Immunology
Overview
I. Brief review of general immunology
II. Skin immune system biology
III. Skin immune system pathology
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)
• 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
• No specialization for skin
• Cells
– Phagocytes: Macrophages, neutrophils,
NK cells
– Mast cells
• Circulating chemicals
– Complement
• Locally produced chemicals
– Cytokines, histamine
Mast Cells
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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 Cells
• ? Role in skin homeostasis
– Nerve, blood vessel maintenance?
• Function as initial
responders
– Pro-inflammatory effects
• Vasoactive chemicals
mediate urticaria
– Histamine and leukotrienes
Cells of the Cutaneous
Adaptive Immune Response
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Langerhans’ cell
Dermal dendrocytes
Keratinocytes
T-cells
Endothelial cells
Cells of the Cutaneous
Adaptive Immune Response
• Macrophages
• B-cells
• Veiled cells
 ( T-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
• Migration and maturation
Bone marrow
Blood (M)
Afferent lymph (VC)
Epidermis (LC)
Lymph node (FDC)
• Functions
– Antigen capture and processing
– Presentation of antigen
– Costimulation of naïve T-cells
– Produce activating cytokines
Antigen
From Janeway, CA
Immunobiology, 5th ed.
Langerhans’
Cell
Migration
Stoitzner, J Inv Dermatol, 2002
Stoitzner, J Inv Dermatol, 2002
Stoitzner, J Inv Dermatol, 2002
Stoitzner, J Inv
Dermatol, 2002
Stoitzner, J Inv
Dermatol, 2002
Dendritic Cell Maturation:
LC
• Phagocytic
• Ag processing
• MHC I, II
• Costimulatory
molecules
• Naïve T-cell
stimulation
• Birbeck granules
+
FDC
Dermal Dendritic Cells
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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
Keratinocytes As
Immune Cells
Old view: Keratinocytes...
• Are passive barrier cells
• Are passive victims of immune
attack
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
• 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)
• 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
• Resident in epithelia; do not recirculate
• Restricted T-cell receptors
• Bridge between innate and adaptive
immunity
• Dendritic  T-cell network found in
mouse epidermis
» Presence and function in human skin
controversial
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 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
Overview
I. Brief review of general immunology
II. Skin immune system biology
III. Skin immune system pathology
Contact Dermatitis
• Erythematous, weepy, scaly,
geometric plaques
• Irritant- or allergen-induced
• Major cause of occupational illness
• Histology: Epidermal spongiosis
Allergic Contact Dermatitis
Pathogenesis
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 Allergen
Contact
Sensitization
From Janeway, CA
Immunobiology, 5th ed.
Allergic Contact Dermatitis
Pathogenesis
• 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
From Janeway, CA
Immunobiology, 5th ed.
Allergic Contact Dermatitis
Immunopathology
Cell-mediated immunity
IL-2
Th1
IL-12
TNF
IFN
IL-10
Th0
Humoral immunity
IL-4
IL-12, IFN
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 Tcells
• Immunologic
memory
Atopic Dermatitis
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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
Cell-mediated immunity
IL-2
Th1
IL-12
TNF
IFN
IL-10
Th0
Humoral immunity
IL-4
IL-12, IFN
IL-4
Th2
IL-5
IL-10
Staph antigens and
Atopic Dermatitis
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Mechanisms of stimulation:
Innate immune response to infection
Superantigen stimulation of T cells
IgE sensitization to staph enterotoxins
Staph alpha toxin-mediated release
of TNF from keratinocytes
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
Lepromatous
Tuberculoid
Susceptibility
Resistance
Skin lesions/bacilli
Cell-mediated immunity
Antibodies
Leprosy: Host Response
Cell-mediated immunity
IL-2
Th1
IL-12
Tuberculoid
TNF
IFN
IL-10
Th0
Humoral immunity
IL-4
IL-12, IFN
IL-4
Th2
Lepromatous
IL-5
IL-10
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
• 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
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
Health
Disease
Something
Happens
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
• 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
• 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
• 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
• 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
• 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
• 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
• TNF inhibition
– Antibodies to TNF
– Soluble TNF receptors
• Costimulatory
blockade
• Adhesion molecule
inhibition
– LFA-1
– CD2
• IL-2 activation
blockade
Cutaneous Immunology
Summary 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.