Ocular Periphery and Disorders (eBook)

Front Cover 1
Ocular Periphery and Disorders 4
Copyright Page 5
Contents 6
Contributors 10
Introduction 14
Section I: Extraocular and Eyelid Muscles: Structure, Function, and Pathophysiology 16
Eyelid Anatomy and the Pathophysiology of Blinking 18
Glossary 18
Organization of the Eyelid System 18
Modifiability of the Blink System 21
Benign Essential Blepharospasm and Hemifacial Spasm 22
Further Reading 23
Differentiation and Morphogenesis of Extraocular Muscles 24
Glossary 24
Introduction 24
Origins of Extraocular Muscles 24
Determination of Eye Muscle Precursors 26
Molecular Signatures and Muscle Differentiation 27
Muscle Morphogenesis 29
Summary 31
Further Reading 31
Extraocular Muscles: Extraocular Muscle Anatomy 32
Glossary 32
Gross Anatomy of the EOM within the Orbit 32
Histological Anatomy of the EOMs 36
Overall Organization 36
Innervation 36
Skeletal Muscle Fiber Types 37
Myosin Isoform Complexity in the EOM 37
Nonuniform Expression of MyHC Isoforms along the Muscle Length 38
Other Molecules Heterogeneously Expressed 40
Continuous Remodeling in Normal Adult EOM 40
Acknowledgments 41
Further Reading 41
Extraocular Muscles: Extraocular Muscle Metabolism 42
Glossary 42
Insights from Gene Expression Profiling 42
Lactate: An Oxidizable Substrate for the Extraocular Muscle 43
Creatine Kinase, the Missing ATP Buffer in the Extraocular Muscle 43
Mitochondrial Content in the Extraocular Muscles 44
Mitochondria as Calcium Sinks in the Extraocular Muscle 45
Are Extraocular Muscle Mitochondria Different? 45
Matching Mitochondrial Capacity to Contractile Function 46
Matching Energy Supply to Demand 47
Acknowledgments 47
Further Reading 47
Extraocular Muscles: Proprioception and Proprioceptors 48
Glossary 48
Proprioception 48
Muscle Spindles 49
Occurrence, Distribution, and Number of Muscle Spindles 49
Structure of Muscle Spindles 49
Function of Muscle Spindles 50
Golgi Tendon Organs 50
Occurrence, Distribution, and Number of Golgi Tendon Organs 50
Structure of Golgi Tendon Organs 51
Function of Golgi Tendon Organs 51
Palisade Endings 51
Occurrence, Distribution, and Number of Palisade Endings 51
Structure of Palisade Endings 52
Molecular Characteristics of Palisade Endings 52
Function of Palisade Endings 52
Further Reading 53
Abnormal Eye Movements due to Disease of the Extraocular Muscles and Their Innervation 54
Glossary 54
Introduction 54
Effects of Disorders of the EOMs on Eye Movements 54
Effects of Disorders of the Neuromuscular Junction on Eye Movements 55
Effects of Disorders of the Oculomotor, Trochlear, and Abducens Nerves on Eye Movements 57
Effects of Disorders of the Brainstem Circuitry on Eye Movements 57
Horizontal Movements 57
Vertical Movements 58
Congenital Misalignment of the Eyes (Infantile Strabismus) and Attendant Nystagmus 58
Effect of Visual System Disorders on Eye Movements 59
Infantile Forms of Nystagmus in Individual with Normal Visual Systems 59
Conclusions 59
Further Reading 59
Extraocular Muscles: Functional Assessment in the Clinic 60
Glossary 60
Normal Eye Movements 60
Ocular Motility Assessment in the Clinic 61
Clinical Treatment for Primary Eye Motility Disorders 62
Acknowledgments 63
Further Reading 63
Section II: Structure and Function of the Tear Film, Ocular Adnexa, Cornea and Conjunctiva in Health and Pathogenesis in Disease 64
Tear Film 66
Glossary 66
The Role of the Tear Film 66
Structure and Thickness of the Tear Film 66
The Lipid Layer 67
Tear Evaporation 68
The Aqueous Layer 68
Tear Production 69
The Mucin Layer 70
Tear Distribution and Stability 70
Tear Film Osmolarity 72
Drainage of Tears 73
Absorption of Tears by the Ocular Surface 74
Further Reading 74
Meibomian Glands and Lipid Layer 75
Glossary 75
Overview 75
The Lipid Layer of the Tear Film 76
Meibomian Glands 77
Anatomy and Histology 77
Development 78
Composition of Meibomian Lipids 78
Meibomian Lipid Turnover and Synthesis 78
Pathology of the Meibomian Gland 79
Chronic Blepharitis 80
Chalazion 81
Surgical Damage 81
Contact Lenses and the Lipid Layer 81
Further Reading 81
Lacrimal Gland Overview 83
Glossary 83
Anatomy of the Main Lacrimal Gland 83
Cell Types within the Lacrimal Gland 83
Acinar Cells 83
Ductal Cells 83
Myoepithelial Cells 84
Bone-marrow-derived Cell Population 84
Innervation of the Lacrimal Gland 84
Blood Supply 85
Contents of Lacrimal Fluid 85
Mechanisms of Protein Secretion in the Lacrimal Gland 85
Mechanisms and Regulation of Electrolyte and Water Secretion by the Lacrimal Gland 87
Acinar Cells 87
Ductal Cells 88
Conclusion 88
Further Reading 88
Lacrimal Gland Hormone Regulation 89
Glossary 89
Gender-Related Dimorphisms 89
Sex Steroids 90
Androgens 90
Estradiol and Progesterone 92
Prolactin 92
Exocrine Products and Autocrine/Intracrine and Paracrine Mediators 92
Influences of Prolactin, Estradiol, and Progesterone during Pregnancy 93
Reproductive Hormone Influences on Other Mucosal Immune System Tissues 94
Counterpoises between Contradictory Signals 95
Further Reading 97
Lacrimal Gland Signaling: Neural 98
Glossary 98
Anatomy of the Lacrimal Gland 98
Neural Control of Lacrimal Gland Secretion 98
Signal Transduction Pathways Activated in the Lacrimal Gland 99
Cholinergic Agonist-Activated Signal Transduction Pathways 99
PLC-coupled signaling pathway 99
PLD-coupled signaling pathway 101
MAPK-coupled signaling pathway 102
VIP-Activated Signal Transduction Pathways 102
Adenylate cyclase-coupled signaling pathway 102
MAPK-coupled signaling pathway 103
a1-Adrenergic Agonist-Activated Signal Transduction Pathways 103
Ca2+- and PKC-coupled signaling pathways 103
MAPK-coupled signaling pathway 104
NO-coupled signaling pathway 104
Further Reading 104
Lids: Anatomy, Pathophysiology, Mucocutaneous Junction 106
Glossary 106
Anatomy 106
Pathophysiology 107
Dermatochalasis 107
Ptosis 108
Retraction 108
Entropion 109
Trichiasis 110
Distichiasis 110
Ectropion 110
Floppy Lid Syndrome 110
Common Malignant Eyelid Tumors 110
Benign Eyelid Tumors 112
Inflammatory and Infectious Disorders of the Lids 112
Further Reading 113
Overview of Electrolyte and Fluid Transport Across the Conjunctiva 114
Glossary 114
Introduction 114
Conjunctival Epithelium 115
Bioelectric Studies on the Isolated Rabbit Conjunctiva 117
Electrolyte Transport Systems of the Rabbit Conjunctiva 118
Regulation of Epithelial Ion Transport in Rabbit Conjunctiva 119
Fluid Transport Studies across Isolated Rabbit Conjunctiva 120
Further Reading 122
Conjunctival Goblet Cells 123
Glossary 123
Goblet Cell Development 123
Function of Conjunctival Goblet Cells 124
Control of Goblet Cell Proliferation and Mucin Secretion 125
Goblet Cell Proliferation 126
Goblet Cell Mucin Secretion 127
Clinical Implications of Mucin Deficiency on the Ocular Surface 128
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Vitamin A Deficiency 129
Topical Preservatives 129
Ocular Cicatrical Pemphigoid 129
Laser-assisted In Situ Keratomileusis 129
Ocular Allergies 129
Summary 130
Further Reading 130
Ocular Mucins 131
Glossary 131
Introduction 131
Mucin Architecture 131
Mucin Families 133
Surface-associated mucins 133
Secreted mucins 133
Biosynthesis and Turnover 134
Synthetic pathways 134
Glycosylation 135
Glycosyltransferases 135
Turnover 135
Recycling 135
Degradation 136
Control of Secretion 136
Individual Variation 136
Mucin Function 136
Gel Formation 137
Anchoring to the Ocular Surface 138
Physical and Chemical Barriers 138
Lubrication 139
Tear Breakup 139
Antimicrobial Activity 139
Immune Protection 139
Clinical Relevance and Pathology 139
Contact Lens Wear 139
Dry Eye Syndromes 140
Further Reading 140
Tear Drainage 141
Glossary 141
History 141
Development 141
Anatomy and Dimensions 142
Comparative Anatomy 142
Tear Transport through Canaliculi 143
Tear Transport through Lacrimal Sac and Nasolacrimal Duct 144
Innate Immune Mechanisms 145
Adaptive Immune Mechanisms 145
Absorption of Tear Fluid Components 146
Conclusions 146
Further Reading 147
Cornea Overview 148
Glossary 148
Anatomy of the Layers 148
Epithelium 148
Epithelial Basement Membrane 148
Bowman's Membrane 148
Stroma 149
Descemet's Membrane 149
Endothelium 149
Function 149
Protective Barrier 149
Transparency 149
Disease Processes 150
Epithelial Disease 150
Epithelial staining patterns 150
Epithelial iron deposition 150
Band keratopathy 151
Chemical/thermal burns 151
Medication toxicity 151
Thygeson's punctate keratitis 151
Subepithelial Disease 151
Epithelial basement membrane dystrophy 151
Subepithelial infiltrates 151
Stromal Disease 152
Infection 152
Dystrophies 152
Degenerations 152
Descemet's copper deposition 153
Endothelial Disease 153
Fuchs' dystrophy 153
Pseudophakic bullous keratopathy 153
Surgery 153
Surgical Intervention of Epithelial Disease 154
Amniotic membrane graft 154
Conjunctival flap 154
Corneal glue 154
Disodium ethylenediaminetetraacetic acid chelation 154
Limbal stem cell transplant 154
Phototherapeutic keratectomy 154
Pterygium excision 154
Stromal puncture 155
Tarsorrhaphy 155
Surgical Intervention of Stromal Disease 155
Anterior lamellar keratoplasty 155
Penetrating keratoplasty 155
Corneal biopsy 155
Corneal laceration repair 155
Refractive surgery 155
Prosthetic keratoplasty 156
Surgical Intervention of Endothelial Disease 156
Descemets Stripping Automated Endothelial Keratoplasty 156
Further Reading 157
Corneal Epithelium: Cell Biology and Basic Science 158
Glossary 158
The Corneal Epithelium Has Vital Functions in Vision 158
The Apical Squames Possess Specializations to Promote Tear Film Spreading 159
The Epithelial Basal Cells Adhere to the Underlying Basement Membrane via tight Adhesive Junctions called Hemidesmosomes 160
The Palisades of Vogt 161
Bowman's Layer Is an Acellular Zone Located Immediately under the Corneal Epithelial Basement Membrane 161
The Collagen- and Proteoglycan-Rich Corneal Stroma with Its Stromal Cells, Descemet's Membrane, and the Corneal Endothelial Cells are all Vital to the Health of the Cornea 161
The Avascular Cornea 163
Further Reading 164
Corneal Nerves: Anatomy 165
Glossary 165
Origins of Corneal Nerves 165
Architecture of the Corneal Innervation 165
Limbal Plexus 165
Stromal and Subepithelial Plexuses 166
Subbasal Nerve Plexus 167
Intraepithelial Nerve Terminals 168
Corneal Nerve Neurochemistry 169
Corneal Nerve Remodeling 170
Corneal Nerve Regeneration after Ocular Surgery 170
Refractive Surgery 171
Cataract Surgery 171
Penetrating Keratoplasty 171
Mechanisms of Nerve Regrowth 172
Further Reading 172
Corneal Nerves: Function 173
Glossary 173
Functional Properties of Corneal Sensory Receptors 173
Response of Corneal Receptors to Local Inflammation 176
Effects of Injury on Corneal Nerves 177
Sensitivity of the Intact Cornea 177
Sensitivity of the Injured Cornea 177
Further Reading 178
Corneal Epithelium: Wound Healing Junctions, Attachment to Stroma Receptors, Matrix Metalloproteinases, Intracellular Communications 179
Glossary 179
Corneal Epithelial Wound Healing: Introduction 179
Corneal Epithelial Wound Healing: Phases of Wound Healing Process 179
Corneal Nerves 181
Corneal Epithelial Wound Healing: Cell-Cell and Cell-Matrix Junctions 181
Cell-Cell Junctions: Gap Junctions 181
Cell-Cell Junctions: Tight Junctions 182
Cell-Cell Junctions: Adherens Junctions 182
Cell-Cell Junctions: Desmosomes 182
Cell-Matrix Junctions: Hemidesmosomes and Adhesion Complexes 182
Secreted Factors Involved in Corneal Epithelial Wound Healing 183
Matrix Metalloproteinases 184
Corneal Epithelial Wound Healing: Conclusion 184
Further Reading 185
Corneal Epithelium: Transport and Permeability 186
Glossary 186
Introduction 186
Corneal Hydration Control and Transparency 186
Importance of Transport Mechanisms to Epithelial Function 187
Primary and Secondary Ionic Transport Mechanisms 188
Coupling of Ionic Transport Mechanisms to Stromal Deturgescence 188
Other Transport Mechanisms 189
Receptor-Mediated Control of Corneal Epithelial Ionic Transport Functions 190
Cell-Volume Control and Epithelial Renewal 190
Ca2+ Channel and Pump Activity 190
K+, Cl-, and Na+ Channels 191
Summary 191
Further Reading 191
Stem Cells of the Ocular Surface 193
Glossary 193
The Ocular Surface 193
Anatomy 193
Development 194
Homeostasis and Repair 194
Properties of Stem Cells 195
Stem Cells in the Corneal Epithelium 195
Characteristics of Limbal Stem Cells 195
Limbal Stem Cell Niche 196
Limbal Stem Cell Deficiency 196
Understanding the Role for LSC in Corneal Homeostasis 197
Conjunctival Stem Cells 197
Corneal Stromal Stem Cells 198
Corneal Endothelial Stem Cells 198
Conclusions 198
Acknowledgments 199
Further Reading 199
The Surgical Treatment for Corneal Epithelial Stem Cell Deficiency, Corneal Epithelial Defect, and Peripheral Corneal Ulcer 200
Glossary 200
Introduction 200
Corneal Epithelial Transplantation for Total Stem Cell Deficiency 201
In Vivo Expansion of Corneal Epithelial Cells (Keratolimbal Allografts) 201
History and concept of ocular surface reconstruction 201
Indications 201
Surgical procedure 201
Postoperative management 202
Other surgical procedures 202
Ex Vivo Expansion of Corneal Epithelial Cells 202
History and concepts 202
AM as a suitable carrier for corneal epithelial cell culture 202
Cell culture procedure 203
Indications 203
Surgical procedure 204
Postoperative management 204
Clinical outcome of allogeneic cultivated corneal epithelial transplantation 204
Ex Vivo Expansion of Oral Mucosal Epithelial Cells 204
Concept 204
Cell culture procedure 204
Indications 205
Surgical procedure and postoperative medications 205
Clinical outcome of cultivated autologous oral mucosal epithelial transplantation 205
Phototherapeutic Keratectomy for Corneal Epithelial Disorders 206
PTK for Corneal Epithelial Defect 206
Indications 206
Surgical procedure 206
Postoperative management 206
Tectonic Lamellar Keratoplasty for Peripheral Corneal Ulcers 206
Concept 206
Rheumatoid Arthritis 206
Mooren's Ulcer 206
Further Reading 207
Refractive Surgery 208
Glossary 208
Short Historical Background of Corneal Refractive Surgery 209
The LASIK Procedure 210
Corneal Refractive Surgery, Wound Healing, and Haze 210
Corneal Refractive Surgery, Optical Aberrations, and Visual Quality 210
Causes for Spherical Aberration Increase Following Corneal Refractive Surgery 212
Corneal Biomechanical Effects in Refractive Surgery 213
Other Side Effects and Complications of PRK and LASIK 213
Safety, Efficacy, and Satisfaction of LASIK 213
Toward an Optimization of the Corneal Refractive Surgery Procedure 214
Further Reading 215
Refractive Surgery and Inlays 216
Glossary 216
Introduction 216
Radial Keratotomy 216
Photorefractive Keratectomy 217
Laser-assisted in situ Keratomileusis 217
Laser-Assisted Subepithelial Keratectomy 218
Epithelial Laser in situ Keratomileusis (epi-LASIK) 219
Femtosecond Laser in situ Keratomileusis (FS-LASIK) 219
Treatment of Hyperopia 219
General Side Effects of Laser Refractive Surgery 220
Wave front and Laser Refractive Surgery 220
Corneal Inlays 220
Intracorneal Rings (ICR) 221
Conclusion 221
Further Reading 221
Contact Lenses 222
Glossary 222
Introduction 222
Types of Contact Lenses 222
How Contact Lens Wear Affects the Ocular Surface 224
Effects of Contact Lens Wear on the Corneal and Limbal Epithelium 224
Alteration of the Lens: Cornea Resurfacing Mechanism 225
Adverse Events 225
Inflammation 225
Infection 225
Mechanical effects 226
Current Hot Topics in Contact Lens Research 226
Contact Lens Care Products 226
Corneal Infection 226
Orthokeratology 226
Summary 227
Further Reading 227
Imaging of the Cornea 228
Glossary 228
Slit-Lamp Biomicroscopy 228
Specular Microscopy 229
Confocal Microscopy 230
Ultrasound Biomicroscopy 230
Anterior Segment Optical Coherence Tomography 232
Acknowledgments 233
Further Reading 233
The Corneal Stroma 234
Glossary 234
Stromal Anatomy 235
Stromal Development 235
Stromal Cells 237
Transparency 238
Stromal Extracellular Matrix 238
Conclusion 240
Acknowledgments 240
Further Reading 240
Corneal Dystrophies 241
Glossary 241
Introduction 241
Anterior Dystrophies 241
Epithelial and EBM Dystrophies 241
EBM Dystrophy 241
Meesman's 242
Bowman's Layer Dystrophies 242
Reis-Buckler's 242
Thiel-Behnke 242
Stromal Dystrophies 243
Lattice 243
Granular 244
Granular type 1 244
Granular type 2 244
Macular 245
Rare Stromal Dystrophies 245
Gelatinous drop-like dystrophy 245
Schnyder's crystalline dystrophy 245
Central cloudy dystrophy 246
Congenital hereditary stromal dystrophy 246
Posterior amorphous dystrophy 246
Fleck dystrophy 246
Posterior Dystrophies 246
Fuchs' Endothelial 246
Posterior Polymorphous Membrane 247
Congenital Hereditary Endothelial Dystrophy 247
Further Reading 248
Corneal Imaging: Clinical 249
Glossary 249
Introduction 249
Confocal Microscopy 249
Historical Overview 249
How it Works 249
Clinical Applications 250
The normal cornea 250
Pachymetry 251
Applications in Pathology 251
Other applications 252
Anterior Segment OCT 252
Historical Overview 252
How it Works 253
Clinical Applications 253
Conclusion 259
Further Reading 270
Corneal Scars 271
Glossary 271
Introduction 272
Ocular Wound Healing 275
Corneal Wound Healing 276
Cell-Cell Communication 276
Cytokines and GFs 276
TGF-ß signaling pathways 278
Cell-ECM Communication 279
Suppressing or amplifying factors 279
Bone marrow-derived stem cells 280
Cellular responses 280
Three Phases of Corneal Wound Healing 281
Inflammatory phase (lasts up to 2-4weeks after injury) 281
Active wound-healing phase (lasts up to 4-6months after injury) 282
Remodeling phase (occurs from 4-6months to 3-4years after injury) 282
Termination of the fibrotic repair response (about 3-4years after injury) 282
Modulation of Scarring 283
Currently Available Scar-Reducing Therapies 283
Emerging Scar-Reducing Therapies 284
Conclusion 285
Acknowledgments 285
Further Reading 285
Corneal Endothelium: Overview 287
Glossary 287
Anatomy 287
General Description 287
Cell-to-Cell Junctions 287
Embryology 288
Initial Development 288
Role of Transcription Factors 289
Biochemistry and Metabolism 290
Glucose and Energy Metabolism 290
Cell Division and Replenishment 291
Cytokines and Immune Privilege 292
Proteins Synthesized for External Transport 293
The Role of the Corneal Endothelium in Deturgescence 294
Introduction 294
The Biochemistry of Active Deturgescence 294
The Physiological Control of Active Deturgescence 295
Genetic Diseases of the Corneal Endothelium 296
Fuchs' Endothelial Dystrophy 296
Related Posterior Membrane Dystrophies 296
Further Reading 296
Regulation of Corneal Endothelial Function 298
Glossary 298
Corneal Endothelial Function 298
Stromal Swelling Pressure and Maintenance of Transparency 298
Endothelial Barrier Function 298
Nutrition/Waste Removal 299
Corneal Endothelial Transport 299
Active Transport 299
Bicarbonate/Carbonic Anhydrase 300
Anion Transporters and Channels 300
Aquaporin-1 (AQP1) 301
Pump Mechanism 301
Barrier Integrity 301
MLC Phosphorylation and Actomyosin Contraction 302
Effect of MLC Phosphorylation on Corneal Endothelium Barrier Integrity 302
Transplantation Failure and Tumor Necrosis Factor 303
Regulation of Transport Activity and Barrier Integrity 303
Adenosine, Soluble Adenylate Cyclase, and cAMP 303
Role of cAMP-PKA axis in the Regulation of Barrier Integrity 304
Summary and Perspective 304
Further Reading 304
Regulation of Corneal Endothelial Cell Proliferation 305
Glossary 305
Background 305
Cell Cycle Progression, G1/S Transition and its Cell Cycle Regulators 305
G1 Phase Cell Cycle Arrest in CECs in vivo 306
Cell-Cell Contact Inhibition 306
The Presence of Antiproliferative TGF-ß2 in the Aqueous Humor 308
The Interaction Between CECs and Extracellular Matrix 308
What Do We Know From Primary and Subcultured CECs 308
Age-Related Decrease in Sensitivity to Mitogen or Growth Factors in Cultured HCECs 308
Comparison of Proliferative Capacity of HCECs from Central and Peripheral Regions 309
Overexpression of E2F2 Promotes Proliferation of CEC 309
PKC Signaling Pathways in Regulating Proliferation of CECs 309
FGF-2 Signaling Pathway 309
Summary 309
Further Reading 309
Artificial Cornea 311
Glossary 311
The Need for Artificial Corneas 311
Desired Characteristics for an Implantable AC 312
Synthetic Artificial Corneas or Keratoprosthesis 313
Self-Assembled Corneal Equivalents 314
Bioengineered ACs that Address Regeneration 315
Future Directions 317
Further Reading 317
Drug Delivery to Cornea and Conjunctiva: Esterase- and Protease- Directed Prodrug Design 318
Glossary 318
Topical Ocular Drug Delivery 318
Role of Cornea in Topical Drug Delivery 320
Role of Conjunctiva in Ocular Drug Delivery 323
Transconjunctival Pathway 325
Subconjunctival Delivery 328
Conclusion 328
Further Reading 328
Knock-Out Mice Models: Cornea, Conjunctiva, Eyelids and Lacrimal Gland 330
Glossary 330
Introduction 330
Transgenesis 330
Gene Targeting 330
Tissue-specific gene ablation using Cre-LoxP system 331
Pitfalls of Cre-LoxP system: Cryptic Cre expression by germ cells during gametogenesis 331
Inducible Cre-LoxP system 331
Strategies of Cornea-Specific Genetic Modification: Transgenic and Knock-Out/Knock-In Mice 332
Identification of Ocular-Surface Tissue-Specific Promoter 332
Stromal keratocyte-specific promoter 332
Corneal-epithelium-specific promoter 333
Ocular-surface epithelium-specific Pax6 promoter (Pax6OS) 333
Ocular Surface Tissue-Specific Driver Mouse Lines 333
Corneal stroma-specific mouse lines 333
Corneal-epithelium-specific mouse lines 334
Ocular surface tissue-specific Pax6OS-rtTA mouse line 336
Roles of Growth Factors on Ocular Surface Tissue Morphogenesis during Development and Wound Healing Elucidated from Transgenic 336
TGFß Receptor Signaling Pathways during Development and Corneal Wound Healing 338
Role of TGFß2 on development 338
Role of TGF-ß signaling in wound healing of corneal epithelium 338
Role of FGF7 in Maintenance of Corneal Homeostasis 338
EGFR/EGF, TGFa Signaling Pathways on Eyelids Morphogenesis 339
Conclusion: The Clinical Relevance of Tet-ON Mouse Models in Elucidating Pathophysiology of Ocular Surfaces Diseases 340
Acknowledgments 340
Further Reading 341
Gene Therapy for the Cornea, Conjunctiva, and Lacrimal Gland 342
Glossary 342
Introduction 342
Corneal Gene Therapy Methods 342
Viral Vectors 345
Nonviral Vectors 346
Use of Gene Therapy to Treat Corneal Diseases 347
Corneal Graft Rejection 347
Corneal Wound Healing 347
Corneal Alkali Burn 348
Corneal Scarring or Haze 348
Corneal Neovascularization 349
Corneal Dystrophies 349
Other Corneal Disorders 349
Lacrimal Gland Gene Therapy 349
Conjunctiva Gene Therapy 350
Acknowledgments 350
Further Reading 351
Section III: Immune Regulation of the Cornea and Conjunctiva and its Dysregulation in Disease 352
Adaptive Immune System and the Eye: Mucosal Immunity 354
Glossary 354
Organized Inductive Sites 355
Effector Sites 356
Specialized Niches 356
Transfer of Immunoglobulins to the Milieu Extérieur 358
pIgR and dIgA 358
Acute Regulation of pIgR Traffic 358
A Mechanism That Constitutively Secretes Autoantigens to the Stroma 359
FcgammaRn and IgG1 360
Mucosal Tolerance and Response to Infection 360
Implications for Ocular Surface Pathophysiology 360
Further Reading 361
Adaptive Immune System and the Eye: T Cell-Mediated Immunity 362
Glossary 362
Innate and Adaptive Immunity 362
Antigen Trafficking, Processing, and Presentation to T cells 363
T-cell activation 363
T cell differentiation and effector function 365
T-cell immune responses in the eye 367
Further Reading 368
Innate Immune System and the Eye 369
Glossary 369
Introduction 369
Passive Innate Defense System 369
Anatomic and Physical Barriers 369
Eyelids and eyelashes 369
Tear film 369
Corneal epithelium 370
Posterior lens capsule 370
Retinal pigment epithelium 370
Chemical Barriers 371
Lysozyme 371
Secretory phospholipase A2 371
Cathelicidin (LL-37) 371
Defensins 371
Lactoferrin 372
Lipocalin-A 372
Secretory IgA 372
Complement 372
Active Innate Defense System 372
Pattern Recognition Receptors 372
Toll-like receptors 372
NOD-like receptors 372
Complement 373
Cytokines, Chemokines, and Effector Cells 374
Initiation and amplification 374
Clearing the pathogen 374
Innate Immune Privilege 374
Link between Innate and Adaptive Immunity 374
Conclusion 375
Further Reading 375
Dynamic Immunoregulatory Processes that Sustain Immune Privilege in the Eye 376
Glossary 376
Introduction 376
Induction of ACAID 377
Ocular Phase of ACAID 377
Thymic Phase of ACAID 377
Splenic Phase of ACAID 377
Sympathetic Nervous System and ACAID 377
ACAID T Regulatory Cells 378
What is the Relevance of ACAID? 379
Vitreous Cavity-Associated Immune Deviation 379
Ocular Regulatory Cells Induced In Situ 379
Conclusions 380
Further Reading 380
Immunosuppressive and Anti-Inflammatory Molecules that Maintain Immune Privilege of the Eye 382
Glossary 382
Immunosuppression and Anti-Inflammatory Activity in Aqueous Humor 382
The Immunoregulatory and Immunosuppressive Factors of The Immune-Privileged Eye 383
Transforming Growth Factor-Beta 383
Alpha-Melanocyte-Stimulating Hormone 384
Other Neuropeptides 385
Other Molecules 385
Application of the Lessons of Immune Privilege 386
Conclusion 386
Further Reading 387
Antigen-Presenting Cells in the Eye and Ocular Surface 388
Glossary 388
Introduction 388
Antigen-Presenting Cells of the Ocular Surface 389
Corneal APCs 389
Epithelial Langerhans cells 389
Stromal APCs 390
Corneal APCs in Inflammation 391
The Function of APCs in Corneal Transplantation 392
The Function of APCs in Microbial Keratitis 392
Conjunctival APCs 392
Role of APCs in Allergic Eye Disease 393
APCs of the Uvea 393
Anterior Chamber-Associated Immune Deviation 393
Role of APCs in Age-Related Macular Degeneration 393
Role of APCs in EAU 394
APCs of the Retina 394
APCs of the Sclera 394
Conclusions 395
Further Reading 395
Dry Eye: An Immune-Based Inflammation 396
Glossary 396
Defining the Problem 396
Epidemiology of Dry Eye 396
Dry Eye Syndrome in Peri- and Post- menopausal Women 397
Patients on Anti-androgen Therapy 397
Clinical Features of Dry Eye 397
Chronic Pain 397
Ocular surface neuropathy in dry eye 397
Comorbidities 397
Quality of Life Impact 398
How We Secrete Normal Tears 398
The Lacrimal Functional Unit 398
The general role of the LFU in homeostasis and disease 398
Events on the Ocular Surface 399
Environmental Impact on the Ocular Surface 399
Afferent arm of the immune response: immunoregulation 400
Efferent arm of the immune response: immunoregulation 400
Afferent arm of the immune response during autoimmune-based inflammation 401
Efferent arm of the immune response during autoimmune-based inflammation 402
Past, Future, and Current Therapies 403
Artificial Tears 403
Corticosteroids 403
Cyclosporine 403
Mucin Secretagogues 403
Tetracyclines 404
Further Reading 404
Penetrating Keratoplasty 405
Glossary 405
Penetrating Keratoplasty: Indications and Survival 405
Corneal Immune Privilege 405
Immune-Privileged Tissue 405
Immune-Privileged Site 406
Clinical Features of Corneal Graft Rejection 406
Pathogenesis of Rejection 407
Afferent Mechanisms and Components 407
Histocompatibility antigens 407
Direct and indirect alloantigen recognition 407
T-lymphocyte activation 408
Effector Mechanisms 408
T lymphocytes 408
Macrophages 409
NK cells 409
Breakdown of immune privilege? 409
Treatment of Rejection 409
Prevention of Rejection 409
Further Reading 410
Immunopathogenesis of HSV Keratitis 411
Glossary 411
Natural History of Herpes Stromal Keratitis 411
Eradication of Replicating HSV-1 from the Corneal Epithelium 411
HSV-1 Colonization of Sensory Ganglia 412
Herpes Stromal Keratitis 412
T Cells in HSK 412
Cytokines and Their Role in HSK 412
Antigen-Presenting Cells in HSK 413
Chemokine Involvement in HSK 413
Angiogenesis in HSV-1 Stromal Keratitis 414
Models of HSK Pathogenesis 414
Epidemiology and Pathogenesis of Human HSK 414
Management of Human HSV Stromal Keratitis and Implications on Pathogenesis 415
Acknowledgments 415
Further Reading 415
Immunopathogenesis of Onchocerciasis (River Blindness) 416
Glossary 416
The Role of Endosymbiotic Wolbachia Bacteria in Onchocerciasis 416
Role of Wolbachia in Pathogenesis - Evidence from Infected Individuals 416
The Role of Wolbachia in the Pathogenesis of ocular onchocerciasis - Lessons from the Murine Model of O. volvulus/Wolbach 417
Wolbachia and TLRs in the Cornea 417
Identification of a Wolbachia TLR2/TLR6 Ligand 418
Conclusion 419
Acknowledgments 419
Further Reading 420
Immunopathogenesis of Pseudomonas Keratitis 421
Glossary 421
Introduction 421
PMN, Cytokines, and Chemokines 422
T Cells and IL-12 423
IL-18 and IFN-. 423
IFN-. and SP 423
Neuropeptides 423
SP 423
VIP 424
TLR 424
Apoptosis 425
Neuropeptides 425
New Animal Model 426
Further Reading 426
Immunobiology of Acanthamoeba Keratitis 428
Glossary 428
Introduction 428
Anatomical and Physiological Barriers to Corneal Infections with Acanthamoeba 429
Innate Immune System and Resistance to Acanthamoeba Infections 429
Role of Macrophages in the Resistance to Acanthamoeba Infections 429
Role of Neutrophils in the Resistance to Acanthamoeba Infections 429
Humoral Factors of the Innate Immune System that Affect Resistance to Acanthamoeba Infections 430
Adaptive Immune System and Resistance to Acanthamoeba Infections 430
Role of the Mucosal Immune System in Resistance to AK 431
Evading the Adaptive Immune Response 431
Anti-Disease Vaccine for AK 432
Conclusions 433
Further Reading 433
Molecular and Cellular Mechanisms in Allergic Conjunctivitis 434
Glossary 434
Ocular Allergies 434
Seasonal Allergic Conjunctivitis 434
Perennial Allergic Conjunctivitis 434
Vernal Keratoconjunctivitis 435
Atopic Keratoconjunctivitis 435
Cellular Mechanisms in Ocular Allergy 436
Conjunctival MCs 436
Conjunctival Eosinophils and Neutrophils 437
Conjunctival Lymphocytes 437
Conjunctival Epithelial Cells 438
Conjunctival Fibroblasts 439
Molecular Mechanisms 439
Costimulatory Molecules in Ocular Allergy 439
IgE in ocular allergy 439
Cytokines and Chemokines in Ocular Allergy 440
Further Reading 440
Pathogenesis of Fungal Keratitis 441
Glossary 441
Contact-Lens-Associated Fungal Keratitis 441
Biofilm Formation in Contact-Lens-Associated Keratitis 441
Keratitis Caused by Candida 441
Fungal Keratitis Associated with Trauma 442
Role of Matrix Metalloproteinases in Fungal Keratitis 442
Role of Innate Immunity in Fungal Keratitis 442
Murine Model of Aspergillus Keratitis 443
Conclusions 444
Acknowledgments 444
Further Reading 445
Conjunctiva Immune Surveillance 446
Glossary 446
Conjunctival Morphology and Function Are Closely Interacting for Immune Surveillance 447
Epithelial Defense Mechanisms 447
Epithelial morphology and function 447
Epithelial Immune Surveillance Takes Care of Environmental Antigens 447
Physical and physicochemical barriers keep antigens outside 447
The mechanical washing effect of the tear film wipes away antigens and detritus 448
Epithelial innate immune defense factors 448
PRRs on epithelial cells provide an externalalarm system 448
The conjunctival epithelium secretes diverse AMPs 450
Conventional antibacterial factors are surprisinglyversatile defense tools 450
Conjunctival Lamina Propria: Morphology and Function of the Diffuse Mucosal Immune System 450
Diffusely arranged lymphoid and innate cells contribute to conjunctival immune surveillance 450
Different subtypes of lymphocytes occur in the conjunctiva 450
The conjunctiva contributes actively to the secretory immune system 451
Local conjunctival plasma cells produce mainly the anti-inflammatory IgA 451
SIgA performs diverse protective and antiinflammatory functions at the ocular surface 451
Lamina Propria Leukocytes Provide Immediate Innate Response against Invading Pathogens and can Orchestrate an Inflammatory Reac 451
Protective functions of conjunctival lamina propria leukocytes 452
HEVs Provide the Regulated Immigration of Bone-Marrow-Derived Cells into the Tissue 452
Conjunctival Lymphoid Follicles Have a Typical Morphology and Function 452
The Topographical Distribution of CALT is in the Right Place to Assist Corneal Immune Surveillance 452
CALT is a Part of the Complete Eye- Associated Lymphoid Tissue 453
Mechanisms of Conjunctival Immune regulation 453
CALT Is Physiologically Biased to Tolerogenic, Anti-Inflammatory Responses 453
Deregulation of EALT Is a Central Component of Inflammatory Ocular Surface Disease 455
Further Reading 457
Defense Mechanisms of Tears and Ocular Surface 459
Glossary 459
Introduction 459
Defense Mechanisms of Tears 459
Defense Mechanisms of the Ocular Surface Epithelia 462
Mechanical/Physical Defenses 462
Pathogen Recognition 463
Antimicrobial Peptides 463
Other Contributions to Ocular Surface Epithelial Defense 465
Concluding Remarks 465
Acknowledgments 465
Further Reading 466
Corneal Epithelium: Response to Infection 467
Glossary 467
Introduction 467
Basic Structure and Function 467
Corneal Infection 468
TLRs and TLR-Related Molecules 468
Cytokines/Chemokines 469
Antimicrobial Molecules 469
ß-Defensins 469
Cathelicidins 470
Complement System 470
Secretory IgA 470
Adhesion Molecules 470
Neuropeptides 471
Innervation of the Corneal Epithelium 471
Substance P 471
Vasoactive intestinal peptide 471
Thymosin-ß4 472
Conclusion 472
Further Reading 473
Inflammation of the Conjunctiva 474
Glossary 474
Inflammation 474
The Conjunctiva and Cornea 475
Tear Fluid: A Reservoir of Inflammatory Cells and Modulators 475
Allergic Reactions in the Conjunctiva 476
Infection of the Conjunctiva or Cornea 477
Tear Fluid as a Diagnostic Indicator of Inflammation 477
Connection of the Conjunctiva and Cornea via Tear Fluid 478
Further Reading 479
Concept of Angiogenic Privilege 480
Glossary 480
Introduction: Angiogenesis and Lymphangiogenesis 480
Corneal Angiogenic Privilege 480
Corneal Avascularity 480
Angiogenic and Anti-Angiogenic Molecules Involved in Corneal Neovascularization 481
Vascular endothelial growth factors 481
Vascular endothelial growth factor 482
VEGF-C and VEGF-D 482
Basic fibroblast growth factor 482
Inhibitory PAS (Per/Arnt/Sim) domain protein 482
Cornea and Corneal Epithelium 483
Limbal Barrier Function 483
Angiogenic Privilege and Immune Privilege 483
Further Reading 484
Corneal Angiogenesis 485
Glossary 485
Introduction 485
Angiogenesis 485
Etiology and Epidemiology of Corneal NV 485
Clinical Manifestations 486
Mechanisms Underlying the Maintenance of Corneal Avascularity 486
Corneal Angiogenic Privilege: The Balance between Angiogenesis and Anti- Angiogenesis 488
Angiogenic Molecules 488
Vascular endothelial growth factor 488
Basic fibroblast growth factor 489
Matrix metalloproteinases 490
Lipid mediators 490
Anti-Angiogenic Molecules 490
Angiostatin 490
Endostatin and neostatins 490
Pigment-epithelial-derived factor 490
Arresten, canstatin, and tumstatin 490
Therapy 491
Medical Treatments 491
Surgical Treatment 491
Further Reading 492
Avascularity of the Cornea 493
Glossary 493
Corneal Histology 493
Corneal Avascularity and Optical Clarity 494
Endogenous Anti-Angiogenic Mechanisms 494
Loss of Corneal Avascularity 496
Immune Privilege of the Avascular Cornea 496
Corneal Transplant and Avascularity 496
Corneal Alymphaticity and Allograft Rejection 496
The Avascular Cornea as an Angiogenesis Study Platform 497
Conclusions 497
Further Reading 497
Section IV: Visual Acuity Related to the Cornea and its Disorders 500
Pupil 502
Glossary 502
Advantages of a Mobile Pupil 502
Overview of the Pathways Controlling Pupil Diameter 502
Iris Musculature 504
Pupillary Light Reflex 504
Description 504
Afferent Pathway 504
Intrinsically photosensitive retinal ganglion cells 505
Pretectal olivary nucleus 505
Efferent Pathway 506
Sympathetic Influences on the PLR 506
The Pupillary Near Response 506
Description 506
Efferent Pathway of the PNR 506
Afferent Influences on the PNR 506
Additional Cortical Influences on Pupillary Responses 507
Visually Mediated Cortical Influences on Pupillary Behavior 507
Task-Evoked Pupillary Responses 507
Influence of Alertness on Pupillary Behavior 507
Arousal 507
Sleep 508
Ascending Neuromodulatory Systems 508
Acknowledgments 508
Further Reading 508
Acuity 509
Glossary 509
Detection and Resolution Acuity 509
Measurement of Visual Acuity 509
Reporting Visual Acuity 511
Optical and Neural Limits on Visual Acuity 511
Visual Acuity across the Retina 512
Visual Acuity over Life 512
Visual Standards 512
Hyperacuity 512
Dynamic Visual Acuity 513
Further Reading 513
Contrast Sensitivity 515
Glossary 515
Contrast-Detection Threshold 515
Psychophysical Assessment of Vision 515
Spatial Frequency Channels 516
Contrast Sensitivity Function 517
Temporal Contrast Sensitivity 518
Further Reading 520
Astigmatism 521
Glossary 521
The Definition and Etymology of Astigmatism 521
Ocular Astigmatism: Prevalence and Age-Related Changes 522
The Origin of Ocular Astigmatism 522
Image Formation and Refractive Specification in Astigmatism 523
Standard Notation for Specifying Astigmatic Refraction 523
Ocular Image Formation in Astigmatism 524
Classification of Ocular Astigmatism 524
Astigmatic Blurring and Visual Perception 524
Oblique Astigmatism 526
Ocular Astigmatism During Near Work 526
Specialized Notations for Specifying Astigmatic Refraction 527
The Measurement of Ocular Astigmatism 528
Keratometry 528
Wave Front Analysis 528
The Correction of Ocular Astigmatism 530
Spectacles 530
Contact Lenses 530
Surgery 530
Not Correcting Ocular Astigmatism 531
Summary 531
Further Reading 531
Myopia 532
Glossary 532
Definition of Myopia: Health and Economic Implications 532
Natural History of Myopia 533
Structural Correlates, Molecular and Anatomical Changes in Myopia 533
Classifications of Myopia 534
Epidemiology of Myopia 535
Etiology of Myopia 535
Correction and Prevention: Clinical Management of Myopia 537
Positive Additions for Nearwork 538
Contact Lenses 538
Vision Therapy and Biofeedback Training 538
Pharmacological Treatment 539
Correction and Prevention: Clinical Management of Myopia? 539
Further Reading 539
Amblyopia 540
Glossary 540
What Is Amblyopia? 540
Amblyopia Is a Significant Public Health Problem 540
Types of Amblyopia 540
The Site(s) of Amblyopia 540
Sensitive Periods for the Development of Amblyopia 541
Traditional Treatment of Amblyopia 541
Clinical Studies 542
Experimental Treatment of Amblyopia Beyond the Sensitive Period 542
Perceptual Learning as a Clinical Tool for Treating Amblyopia 543
Acknowledgments 543
Further Reading 543
Hyperopia 544
Glossary 544
Definition and Classifications of Hyperopia 544
Prevalence 545
Normal Time Course of Hyperopia 545
Clinical Presentations of Hyperopia 546
Risks of Uncorrected Hyperopia 546
Importance of Early Detection of Significant Hyperopia 546
Examination Techniques of Hyperopia 546
Management of Hyperopia 547
Conclusion 549
Further Reading 549
Subject Index 550