title: Connecting the innate and adaptive immune responses in mouse choroidal neovascularization via the anaphylatoxin C5a and γδT-cells.
abstract: Neovascular age-related macular degeneration (AMD) is characterized by choroidal neovascularization (CNV). An overactive complement system is associated with AMD pathogenesis, and serum pro-inflammatory cytokines, including IL-17, are elevated in AMD patients. IL-17 is produced by complement C5a-receptor-expressing T-cells. In murine CNV, infiltrating γδT- rather than Th17-cells produce the IL-17 measurable in lesioned eyes. Here we asked whether C5a generated locally in response to CNV recruits IL-17-producing T-cells to the eye. CNV lesions were generated using laser photocoagulation and quantified by imaging; T-lymphocytes were characterized by QRT-PCR. CNV resulted in an increase in splenic IL-17-producing γδT- and Th17-cells; yet in the CNV eye, only elevated levels of γδT-cells were observed. Systemic administration of anti-C5- or anti-C5a-blocking antibodies blunted the CNV-induced production of splenic Th17- and γδT-cells, reduced CNV size and eliminated ocular γδT-cell infiltration. In ARPE-19 cell monolayers, IL-17 triggered a pro-inflammatory state; and splenocyte proliferation was elevated in response to ocular proteins. Thus, we demonstrated that CNV lesions trigger a systemic immune response, augmenting local ocular inflammation via the infiltration of IL-17-producing γδT-cells, which are presumably recruited to the eye in a C5a-dependent manner. Understanding the complexity of complement-mediated pathological mechanisms will aid in the development of an AMD treatment.
authors.affiliation: Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Coughlin
authors.affiliation: Research Service, Ralph H. Johnson VA Medical Center, Charleston, SC 29401, USA.
authors.forename: Gloriane
authors.initials: G
authors.lastname: Schnabolk
authors.affiliation: Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Kusumam
authors.initials: K
authors.lastname: Joseph
authors.affiliation: Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Himanshu
authors.initials: H
authors.lastname: Raikwar
authors.affiliation: Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Kannan
authors.initials: K
authors.lastname: Kunchithapautham
authors.affiliation: Alexion Pharmaceuticals, 352 Knotter Drive, Cheshire CT 06410, USA.
authors.forename: Krista
authors.initials: K
authors.lastname: Johnson
authors.affiliation: Alexion Pharmaceuticals, 352 Knotter Drive, Cheshire CT 06410, USA.
authors.forename: Kristi
authors.initials: K
authors.lastname: Moore
authors.affiliation: Alexion Pharmaceuticals, 352 Knotter Drive, Cheshire CT 06410, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, USA.|Research Service, Ralph H. Johnson VA Medical Center, Charleston, SC 29401, USA.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Rohrer
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002829:Choroid / Q000276:immunology* / Q000473:pathology; D020256:Choroidal Neovascularization / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D015936:Complement C5a / Q000037:antagonists & inhibitors / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate; D007275:Injections, Intravenous; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D008028:Light Coagulation / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000276:immunology*; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: D057134:Antibodies, Neutralizing; D020381:Interleukin-17; D044087:Receptor, Anaphylatoxin C5a; D016692:Receptors, Antigen, T-Cell, gamma-delta; D015936:Complement C5a