Transcript Slide - Smith Lab

Ocular Immunology
Kyle C. McKenna, Ph. D.
Associate Professor of Biology and Opthalmology
Franciscan University of Steubenville
University of Pittsburgh School of Medicine
[email protected]
[email protected]
Hypopyon
Ocular infiltrate of white blood cells
(leukocytes) which settle via gravity
to the bottom of the anterior chamber
“like sands through the hour glass”
How did the leukocytes get there?
Leukocytes (cells of the immune system travel
Via blood and enter the eye via vessels in the
iris, ciliary body, choroid, retina, and sclera
4
Basophil
Band Cell
Blood Smear
6
3 1
5
Eosinophil
Neutrophil Lymphocyte
Lymphocyte
5
Neutrophil
1
Monocyte
2
Innate Immunity
Neutrophil
Eosinophil
Adaptive Immunity
Basophil
Granulocytes
Monocytes
Lymphocytes
T Cells
B Cells
Mast Cells
Macrophages
ab T
gd T
Complement
CD4+
Thelper
CD8+
CTL
Antibody
Innate
• Immediate
• Includes anatomical
and biochemical
barriers
• Recognition of
conserved pathogen
associated molecular
patterns (PAMPs)
• No memory
generation
Adaptive
• Delayed
• Specific recognition of
pathogenic molecules
• Memory Generation
PAMP
PRR
Pathogen Recognition Receptor
Lipopolysaccharide (LPS)
TLR 4
Toll Like Receptor
Double Stranded RNA
TLR 3
DAMP
DRR
Damage associated molecular pattern
Damage Recognition Receptor
HMGB1
RAGE, TLR 2, 4 and 9
(High Mobility
Group box 1)
Receptor of advanced glycation endproduct
Nonoxidized (reduced) HMGB1 is released by normal cells upon necrotic but
Not apoptotic cell death
PAMPs and DAMPs promote
inflammation Redness
SWELLING
IL-1
IL-6
TNFa
Nitric oxide
IL-8
PAIN
Activated Antigen Presenting
Cells Leave via afferent lymphatics
Macs
DC
Increased Cell Surface molecules
MHC Class I & II
CD40, CD80, CD86
Produce inflammatory cytokines
IL-12
TNFa
Secondary Lymphoid Organs
Spleen
Innate immunity is immediate but alone insufficient
for pathogen control
Adaptive Immunity
B-Cells
Immunoglobulin
Antigen Receptor:
Proteins, Carbohydrates
Recognition:
Lipids, most any molecule
T-Cells
TCR
Processed Proteins Presented as
Peptides via MHC molecules by APC
Exogenous
Proteins via
MHC Class II
Endogenous
Proteins via
MHC Class I
Professional
APC
All Cells in
Body
From Eye
APC
Free
Antigen
T
T
T
T
B
T
B
T
B
T
B
T
FDC
B
B
T
B
B
B
T
T
T
T
T
More Proliferation
Here
Clonal Expansion
APC
Differentiation
Antibody Secreting
Plasma Cells
T helper Subsets
Diverse Repertoire
Of B cells and T cell
Increase Numbers
Of Antigen Specific
Clones
CTL
Memory Cells
Process of Expansion and Differentiation takes time which
is why AdaptiveImmunity is Delayed
Lytic granules
Containing
Granzyme B
CD8+
CTL
Lysis of infected Cells
What determines unique
Thelper differentiation?
IL-2
IFNg
PAMPS / APC
APC
LPS/TLR4
IL-4
IL-12
CD4+
T helper
IFNg
?
Filaria
IL-4, 5, 6, 10
IL-2
TH1
APC
TH2
B cells
B cells
IgG2a
Viral and Bacterial infections
IgG, IgE
Extracellular Helminthic Infections
Infections Activate Innate
Immunity via PAMPS
Activated APC
Leave eye Carrying
Pathogenic Molecules
Blood
Stream
Afferent
Lymphatics
Efferent
Lymphatics
T and B cell expansion
And differentiation occur
Lymph
Node
What is Type I Hypersensitivity?
Immediate Hypersensitivity
Antibody Mediated (IgE)
IgE molecules are bound by FcEpsilon receptors on Mast Cells
Mast Cells release histamines which promote inflammation
Allergic Conjunctivitis
What is Type II Hypersensitivity?
Antibody Mediated
Cell lysis via Antibody Dependent Cellular Cytotoxicity
Comp
MAC
Rh Hemolytic anemia in newborns
Sympathetic ophthalmia, Uveitis
Phagocytosis
What is Type III Hypersensitivity?
Antibody Complex Mediated
Antibody Complexes Fix Complement Leading to production
Of anaphylotoxins which promote inflammation
Comp
MAC
Comp
MAC
Comp
MAC
C3a, C5a
Anaphlotoxins
Promote vasodilation
And leukocyte
infiltration
What is Type IV Hypersensitivity?
Delayed Type Hypersensitivity
T cell mediated (CD4 TH1 cells)
CD4+ T cells activate macrophages to release inflammatory mediators
(TNFa, Nitric Oxide) which causes nonspecific damage of innocent bystander
Tissues
Promote infiltration of neutrophils which further enhance inflammation
IFNg
CD4+
T helper
MAC
Nitric Oxide
TNFa
What is Type V Hypersensitivity?
Antibodies are generated which are stimulatory
Graves Disease
Anti-thyroid stimulating hormone receptor antibodies
stimulate the effects of Thyroid Stimulating Hormone
TSH
TSHR
Antibody
TCR and Immunoglobulin molecules are generated
by Random Somatic Rearrangement of gene segments
What is the potential complication of this process?
Generation of TCR and Immunoglobulin molecules that recognize self tissues
T cells expressing TCR with strong reactivity to self antigens are deleted
In the Thymus during T cell development
What is the consequence of overly stringent negative selection?
Decreased Repertoire of the T cell pool
Fact: T cells and B cells are generated with receptors that demonstrate
some affinity for self antigens.
Why are we not in a constant state of autoimmunity?
Peripheral tolerance mechanisms
Three Signals are Required for Full T cell activation
3
1. TCR : MHC/peptide
2. Costimulatory Molecules
3. Cytokine Production
In the absence of three signals
T cell anergy or tolerance is generated
Cytokines
How do PAMPS break tolerance to
Self antigens?
PAMPS increase costimulatory molecules
And cytokine expression
Uveitis
Classic T cell dependent Type IV hypersensitivity response
Infectious (syphilis, tuberculosis, toxoplasma gondii)
Noninfectious (self antigens)
[mouse models via immunization with IRBP, Retinal S-ag]
Disease Associations made with particular MHC molecules
HLA-B27 : Reiter’s syndrome
HLA-B5: Behcet’s Disease
HLA-29: Birdshot Choroidopathy
How could an immune response to an ocular antigen develop to
Cause autoimmune uveitis?
Retention of T cells with specificity to ocular antigens due to
Weak negative selection in individuals with particular HLA types
Previous infection or trauma primed for ocular antigens in an
Inflammatory context
Molecular Mimicry (Klebsiella, Chlymidia, Yersinia?)
Ocular Immune Privilege
Characterized by prolonged acceptance of foreign immunogenic grafts
In comparison to conventional sites
Corneal Allografts most successful
(no matching, minimal immunosuppression required)
Experimentally immunogenic tumors grow progressively in the anterior
Chamber but are eliminated by CD8+ T cells when transplanted in the
skin
Anatomical Barriers to Host
Immune Response
Cornea is avascular
Interior of Eye lacks demonstrable lymphatic drainage
Blood Aqueous Barrier
Blood Retinal Barrier
Biochemical Barriers to Host
Immune Response
Aqueous Humor contains Immunosuppressive soluble factors
(TGF-b, a-MSH, IL-10, MIF, CGRP, VIP, somatostatin)
Interior Cell Surface expresses Death inducing Molecules
(FasL, Trail, PD-1 and PD-2L)
T cell anergy, T cell death, T regulatory generation
Tolerance Induction to Ocular
Antigens
Introduction of foreign antigens into the anterior chamber, subretinal space
And vitreous cavity induces systemic tolerance to these antigens
Mediated by the generation of Tregulatory cells
CD4, CD8+
and Regulatory B cells