title: Annexin-A1 restricts Th17 cells and attenuates the severity of autoimmune disease.
abstract: Annexin-A1 (Anx-A1) is an endogenous anti-inflammatory molecule and while described as a repressor of innate immune responses, the role of Anx-A1 in adaptive immunity, and in particular in T helper (Th) cell responses, remains controversial. We have used a T-cell mediated mouse model of retinal autoimmune disease to unravel the role of Anx-A1 in the development of autoreactive Th cell responses and pathology. RBP1-20-immunized C57BL/6 Anx-A1(-/-) mice exhibit significantly enhanced retinal inflammation and pathology as a result of an uncontrolled proliferation and activation of Th17 cells. This is associated with a limited capacity to induce SOCS3, resulting in un-restricted phosphorylation of STAT3. RBP1-20-specific CD4(+) cells from immunized Anx-A1(-/-) animals generated high levels of Th17 cells-associated cytokines. Following disease induction, daily systemic administration of human recombinant Anx-A1 (hrAnx-A1), during the afferent phase of disease, restrained autoreactive CD4(+) cell proliferation, reduced expression of pro-inflammatory cytokines IL-17, IFN-γ and IL-6 and attenuated autoimmune retinal inflammatory disease. Furthermore, in man, Anx-A1 serum levels when measured in active uveitis patient sera were low and associated with the detection of IgM and IgG anti-Anx-A1 antibodies when compared to healthy individuals. This data supports Anx-A1 as an early and critical regulator of Th17 cell driven autoimmune diseases such as uveitis.
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, London EC1V 9EL, UK. Electronic address: s.yazid@ucl.ac.uk.
authors.forename: Samia
authors.initials: S
authors.lastname: Yazid
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, London EC1V 9EL, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gardner
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, London EC1V 9EL, UK.
authors.forename: Livia
authors.initials: L
authors.lastname: Carvalho
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, London EC1V 9EL, UK; Academic Unit of Ophthalmology, School of Clinical Sciences, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Chu
authors.affiliation: William Harvey Research Institute, QMUL, London EC1M 6BQ, UK.
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Flower
authors.affiliation: William Harvey Research Institute, QMUL, London EC1M 6BQ, UK.
authors.forename: Egle
authors.initials: E
authors.lastname: Solito
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, London EC1V 9EL, UK; Academic Unit of Ophthalmology, School of Clinical Sciences, University of Bristol, Bristol BS8 1TD, UK; University Hospitals Bristol NHS Foundation Trust, Bristol BS1 3NU, UK; National Institute for Health Research, Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, UK.
authors.forename: Richard W J
authors.initials: RW
authors.lastname: Lee
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, London EC1V 9EL, UK; National Institute for Health Research, Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, UK.
authors.forename: Robin R
authors.initials: RR
authors.lastname: Ali
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, London EC1V 9EL, UK; Academic Unit of Ophthalmology, School of Clinical Sciences, University of Bristol, Bristol BS8 1TD, UK; School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK; University Hospitals Bristol NHS Foundation Trust, Bristol BS1 3NU, UK; National Institute for Health Research, Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, UK. Electronic address: a.dick@ucl.ac.uk.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Dick
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000008:administration & dosage* / Q000235:genetics; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005136:Eye Proteins / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000276:immunology; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000235:genetics; D012177:Retinol-Binding Proteins / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects* / Q000502:physiology; D014605:Uveitis / Q000139:chemically induced / Q000276:immunology*; D000099214:Retinol-Binding Proteins, Interstitial
chemical_list: D017305:Annexin A1; D016207:Cytokines; D005136:Eye Proteins; D018836:Inflammation Mediators; D010446:Peptide Fragments; D011994:Recombinant Proteins; D012177:Retinol-Binding Proteins; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000099214:Retinol-Binding Proteins, Interstitial; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; C573274:annexin A1, mouse
keywords: Annexin-A1; Autoimmune; SOCS3; STAT3; Th17; Uveitis