Intravenously Administered Anti-recoverin Antibody Alone Does Not Pass through the Blood-Retinal Barrier
1
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Purpose: Cancer-associated retinopathy is a paraneoplastic retinal degeneration which may primarily result from auto-immune mediated apoptosis. It has been hypothesized that high titer of auto-antibodies are able to cross the blood-retinal barrier (BRB) and to enter retinal cells to activate apoptotic pathway which has been already well-established. However, it still remains to be elucidated whether auto-antibodies could cross BRB in the retina. Herein, we demonstrated that intravenously administrated anti-recoverin antibodies could not pass through BRB and not lead to retinal cell death. Methods: Anti-recoverin antibody was intravenously injected to C57BL/6 mice, which were sacrificed 1 and 7 days to obtain eye. Vascular endothelial growth factor was intravitreally injected to induce BRB breakdown, which was confirmed by fluorescein angiography and western blotting for zonula occludens (ZO)-1, ZO-2 and occludin. To investigate the location of anti-recoverin antibody in the retina, immunofluorescein was performed. The retinal toxicity of intravenous anti-recoverin antibody was evaluated by histological examination and transferase-mediated dUTP nick-end labeling. Immunofluorescein staining for glial fibrillary acidic protein was done to address glial activation as well. Results: Intravenously administrated anti-recoverin antibodies were exclusively distributed on retinal vessels which were co-localized with CD31, and led to neither increase of glial fibrillary acidic protein expression, as an indicator of retinal stress, nor apoptotic retinal cell death. Moreover, even in the condition of vascular endothelial growth factor-induced BRB breakdown, anti-recoverin antibodies could not migrate across BRB and still remained on retinal vessels without retinal cytotoxicity. Conclusions: Our results suggest that high titer of intravascular anti-recoverin antibodies could not penetrate into the retina by themselves, and BRB breakdown mediated by dysregulation of tight junction might not be sufficient to allow anti-recoverin antibodies to pass through BRB.
Abstract
Purpose: Cancer-associated retinopathy is a paraneoplastic retinal degeneration which may primarily result from auto-immune mediated apoptosis. It has been hypothesized that high titer of auto-antibodies are able to cross the blood-retinal barrier (BRB) and to enter retinal cells to activate apoptotic pathway which has been already well-established. However, it still remains to be elucidated whether auto-antibodies could cross BRB in the retina. Herein, we demonstrated that intravenously administrated anti-recoverin antibodies could not pass through BRB and not lead to retinal cell death. Methods: Anti-recoverin antibody was intravenously injected to C57BL/6 mice, which were sacrificed 1 and 7 days to obtain eye. Vascular endothelial growth factor was intravitreally injected to induce BRB breakdown, which was confirmed by fluorescein angiography and western blotting for zonula occludens (ZO)-1, ZO-2 and occludin. To investigate the location of anti-recoverin antibody in the retina, immunofluorescein was performed. The retinal toxicity of intravenous anti-recoverin antibody was evaluated by histological examination and transferase-mediated dUTP nick-end labeling. Immunofluorescein staining for glial fibrillary acidic protein was done to address glial activation as well. Results: Intravenously administrated anti-recoverin antibodies were exclusively distributed on retinal vessels which were co-localized with CD31, and led to neither increase of glial fibrillary acidic protein expression, as an indicator of retinal stress, nor apoptotic retinal cell death. Moreover, even in the condition of vascular endothelial growth factor-induced BRB breakdown, anti-recoverin antibodies could not migrate across BRB and still remained on retinal vessels without retinal cytotoxicity. Conclusions: Our results suggest that high titer of intravascular anti-recoverin antibodies could not penetrate into the retina by themselves, and BRB breakdown mediated by dysregulation of tight junction might not be sufficient to allow anti-recoverin antibodies to pass through BRB.
참고문헌 (23)
- Thirkill CE, "Cancer-associated retinopathy", Arch Ophthalmol, 105, pp.372~375 (1987)
- Thirkill CE, "Cancer-associated retinopathy(CAR syndrome)with antibodies reacting with retinal,optic-nerve,and cancer cells", N Engl J Med, 321, pp.1589~1594 (1989)
- Khan N, "Cancer associated retinopathy(CAR):an autoimmune-mediated paraneoplastic syndrome", Semin Ophthalmol, 21, pp.135~141 (2006)
- Chen W, "Anti-recoverin antibodies cause the apoptotic death of mammalian photoreceptor cells in vitro", J Neurosci Res, 57, pp.706~718 (1999)
- Maeda T, "Mechanisms of photoreceptor cell death in cancer-associated retinopathy", Invest Ophthalmol Vis Sci, 42, pp.705~712 (2001)
- Adamus G, "The occurrence of serum autoantibodies against enolase in cancer-associated retinopathy", Clin Immunol Immunopathol, 78, pp.120~129 (1996)
- Wiechmann AF, "Expression of recoverin mRNA in the human retina:localization by in situ hybridization", Exp Eye Res, 57, pp.763~769 (1993)
- Bazhin AV, "Low titre autoantibodies against recoverin in sera of patients with small cell lung cancer but without a loss of vision", Lung Cancer, 34, pp.99~104 (2001)
- Bazhin AV, "Retinal degeneration under the effect of antibodies to recoverin", Bull Exp Biol Med, 131, pp.350~352 (2001)
- Adamus G, "Antibodies to recoverin induce apoptosis of photoreceptor and bipolar cells in vivo", J Autoimmun, 11, pp.523~533 (1998)
- Ohguro H, "Cancer-associated retinopathy induced by both anti-recoverin and anti-hsc70 antibodies in vivo", Invest Ophthalmol Vis Sci, 40, pp.3160~3167 (1999)
- Lee SW, "SeCKS regulates angiogenesis and tight junction formation in blood-brain barrier", Nat Med, 9, pp.900~906 (2003)
- Choi YK, "AKAP12 regulates human blood-retinal barrier formation by downregulation of hypoxia-inducible factor-1alpha", J Neurosci, 27, pp.4472~4481 (2007)
- 김규원, "Blood-neural Barrier: Intercellular Communication atGlio-Vascular Interface", BMB reports, 39(4), pp.339~345 (2006), 한국생화학분자생물학회
- Kim JH, "The role of clusterin in in vitro ischemia of human retinal endothelial cells", CURRENT EYE RESEARCH, 32, pp.693~698 (2007)
- Kim JH, "Recruitment of pericytes and astrocytes is closely related to the formation of tight junction in developing retinal vessels", J Neurosci Res, 87, pp.653~659 (2009)
- Engelhardt B, "Mini-review:transendothelial migration of leukocytes:through the front door or around the side of the house?", Eur J Immunol, 34, pp.2955~2963 (2004)
- Erickson KK, "Vascular permeability in ocular disease and the role of tight junctions", Angiogenesis, 10, pp.103~117 (2007)
- Lewis GP, "Up-regulation of glial fibrillary acidic protein in response to retinal injury:its potential role in glial remodeling and a comparison to vimentin expression", Int Rev Cytol, 230, pp.263~290 (2003)
- Maeda A, "Effects of cytotoxic T lymphocyte antigen 4(CTLA4)signaling and locally applied steroid on retinal dysfunction by recoverin,cancer-associated retinopathy antigen", Mol Vis, 12, pp.885~891 (2006)
- Riches AC, "Blood volume determination in the mouse", J Physiol, 228, pp.279~284 (1973)
- Suzuki T, "Cancer-associated retinopathy with presumed vasculitis", Am J Ophthalmol, 122, pp.125~127 (1996)
- Miyamoto K, "Vascular endothelial growth factor(VEGF)-induced retinal vascular permeability is mediated by intercellular adhesion molecule-1(ICAM-1)", Am J Pathol, 156, pp.1733~1739 (2000)