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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.
• 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
• First line of defense   • Activated
• Nonspecific             • Very specific
• Rapid onset             • Slower
• No protective           • Protective immunity
  immunity                  possible
• No memory               • Memory possible
• Phagocyte-              • Lymphocyte-
  mediated                  mediated
                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
    B-cells                        T-cells
•Mature in bone marrow         •Mature in thymus
•Lymphoid follicle             •Paracortical area
•Antigen receptor:             •Antigen receptor:
  Immunoglobulin                 T-cell receptor
  molecule
                                From, Janeway, CA, Immunobiology, 5th ed.
    Adaptive Immunity
Antigen Receptors




                        From, Janeway, CA,
                        Immunobiology, 5th ed.
               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
• 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           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
• 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         Th1
  – Low density          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
•   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
     •   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)    Epidermis (LC)
      Afferent lymph (VC)     Lymph node (FDC)
• Functions
  – Antigen capture and processing
  – Presentation of antigen
  – Costimulation of naïve T-cells
  – Produce activating cytokines
   Antigen
                         Langerhans’
                            Cell
                          Migration




From Janeway, CA
Immunobiology, 5th ed.
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   FDC
• Phagocytic
• Ag processing
• MHC I, II
• Costimulatory
  molecules
• Naïve T-cell
  stimulation
• Birbeck granules   +
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      Langerhans cells
• No Birbeck granules   • Birbeck granules
• Factor XIIIa +        • Factor XIIIa -
• CD1a, ATPase -        • CD1a, ATPase +
• Blood vessel-assoc.   • 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           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          • Less common
• Reaction minutes     • No or delayed
  to hours after 1st     reaction after 1st
  contact                contact
• Direct cellular      • Ag presented to T-
  injury by chemical     cells
• No immunologic       • Immunologic
  memory                 memory
    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
                                  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
        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)
• 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              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?
 • 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           Bullous pemphigoid
• Desmoglein 3              • BP Ag 1 (230 kD):
  (130 kD)                    Intra-basal
                              keratinocyte
                            • BP Ag 2 (180 kD):
                              Transmembrane
• Target:                   • Target:
  Desmosome                   Hemidesmosome
  – Keratinocyte cohesion     – 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.

				
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