Investigation of autoimmune anti-retinal antibodies in diabetes

糖尿病中自身免疫性抗视网膜抗体的研究

• 批准号: 8383097
• 负责人: JOHN R HECKENLIVELY
• 金额: $ 18.47万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8383097
• 关键词: Affect; Aldolase C; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antibody Suppression; Antigens; Autoantibodies; Autoimmune Process; Blindness; Blood Vessels; Cells; Clinic; Clinical; Complications of Diabetes Mellitus; Detection; Diabetes Mellitus; Diabetic Retinopathy; Disease; Disease Progression; Edema; Electroretinography; Event; Eye; Fluorescein Angiography; Frequencies; Functional disorder; Future; Gel; Immunologic Tests; Immunosuppression; Immunosuppressive Agents; Inflammation; Insulin-Dependent Diabetes Mellitus; Investigation; Laboratory Study; Lead; Literature; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Medical; Methods; Mission; Optical Coherence Tomography; Participant; Pathogenesis; Pathologic; Patients; Pattern; Pericytes; Persons; Pharmaceutical Preparations; Physicians; Physiology; Play; Prevention strategy; Process; Proteins; Recruitment Activity; Research; Research Personnel; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Retinal Edemas; Retinitis Pigmentosa; Role; Sampling; Sampling Studies; Serum; Staining method; Stains; Structure; Techniques; Testing; Therapeutic; United States; Vertebrate Photoreceptors; Vision; Western Blotting; aged; birdshot chorioretinitis; diabetic; effective therapy; enolase; experience; improved; melanoma; prevent; research clinical testing; research study; retinal rods; translational study

DESCRIPTION (provided by applicant): Anti-retinal antibodies (ARAs) definitely have an effect on many retinal diseases. We have consistently found that elevated ARAs exacerbate the disease or cause additional complications that regress when the antibodies are reduced. For example, cystoid and other forms of retinal edema in patients with retinitis pigmentosa are consistently associated with circulating ARAs. Several studies have demonstrated ARAs in patients with diabetes that may contribute to retinopathy-for example, loss of pericytes or retinal edema; however, whether ARAs plays a role in vision loss in these diseases is unclear. Previous experience with specific retinal diseases has demonstrated that identifying the ARAs in affected patients and illuminating their role in disease processes can lead to the use of effective treatments and methods of assessing disease progression. For instance, in patients with birdshot chorioretinitis, immunosuppressant agents are now used to achieve long-term suppression of antibodies and inflammation. Moreover, most patients with autoimmune retinopathy who have active ARAs regain function with immunosuppression and anti-inflammatory medications. In recent years, through investigations of ARAs in various retinal degenerations, we have discovered several antibodies involved in melanoma-associated retinopathy and we have reconfirmed the presence of several putative antibodies in cancer-associated retinopathy. In reviewing the medical literature on diabetic antibodies, several findings stand out, as they parallel findings in patients with autoimmune retinopathy (AIR). Of note, antibodies to aldolase-C and a-enolase have been found in patients with type 1 diabetes; these ARAs are known to be associated with disease changes in patients with AIR. As a preliminary study, we performed Western blots on serum samples obtained from 38 patients with various types of diabetes retinopathy and 12 healthy controls to look for the presence of ARAs. We found that the patients with diabetes consistently had more antibodies and more intense staining on their Western blots, compared with the controls. In this proposed project, we will test the hypothesis that elevated ARAs cause retinal dysfunctional in patients with diabetes and will determine which antibodies contribute to vision loss. Study participants recruited from our clinic will undergo clinical testing-specifically, dark adaptometry to measure final rod thresholds and standardized electroretinography to measure cone and rod function. Clinical tests will be performed to quantify the extent of any retinal edema and to check for vascular alterations. Functional changes will be compared with immunologic test parameters, including ARAs on Western blots, and retinal targets using patient antibodies with immunohistologic techniques. By correlating different patients' immunoreactive bands with similar staining patterns on immunohistology or identifying the same bands in multiple patients with the same clinical conditions, we will establish which antibodies are affecting the retina. Specific immunoreactive bands will be processed for mass spectrometry, and candidate proteins will be identified and the correct ones confirmed.

描述（由申请人提供）：抗视网膜抗体（ARA）肯定会对许多视网膜疾病产生影响。我们一直发现，升高的Aras加剧了该疾病或引起其他并发症，这些并发症会减少抗体时会消退。例如，色素性视网膜炎患者的囊状和其他形式的视网膜水肿一直与循环ARA有关。几项研究表明，糖尿病患者的ARA可能导致视网膜病变，例如，周细胞或视网膜水肿。但是，ARA是否在这些疾病中的视力丧失中起作用尚不清楚。以前具有特定视网膜疾病的经验表明，在受影响的患者中识别ARA并阐明其在疾病过程中的作用可以导致使用有效的治疗方法和评估疾病进展的方法。例如，在患有鸟类脉络膜炎的患者中，现在使用免疫抑制剂来长期抑制抗体和炎症。此外，大多数患有主动ARAS的自身免疫性视网膜病患者会通过免疫抑制和抗炎药恢复功能。近年来，通过对各种视网膜变性的ARA进行研究，我们发现了与黑色素瘤相关的视网膜病涉及的几种抗体，并且我们重新确认了与癌症相关性视网膜疗法中几种推定的抗体存在。在审查有关糖尿病抗体的医学文献时，有几个发现脱颖而出，因为它们与自身免疫性视网膜病（AIR）患者的发现平行。值得注意的是，在1型糖尿病患者中发现了对藻酶-C和A-烯醇酶的抗体。这些ARA与空气患者的疾病变化有关。作为一项初步研究，我们对从38例患有各种类型糖尿病性视网膜病和12种健康对照的患者获得的血清样品进行了蛋白质印迹，以寻找ARA的存在。我们发现，与对照组相比，糖尿病患者的蛋白质印迹始终具有更多的抗体和更强烈的染色。在这个拟议的项目中，我们将检验以下假设：升高的ARA会导致糖尿病患者的视网膜功能障碍，并确定哪种抗体会导致视力丧失。从我们的诊所招募的研究参与者将经过特定于临床测试，深色适应测定法，以测量最终的杆阈值和标准化电子图，以测量锥体和杆功能。将进行临床测试以量化任何视网膜水肿的程度并检查是否有血管变化。功能变化将与免疫学测试参数进行比较，包括蛋白质印迹的ARA，以及使用具有免疫组织学技术的患者抗体的视网膜靶标。通过将不同患者的免疫反应性带与免疫组织学相似的染色模式相关联或在具有相同临床疾病的多个患者中鉴定相同的条带，我们将确定哪些抗体影响了视网膜。将处理特定的免疫反应性带进行质谱，并确定候选蛋白并确认正确的蛋白质。