Pathogenic B Cells in Sjogren's Syndrome

干燥综合征中的致病性 B 细胞

• 批准号: 8102494
• 负责人: Robert Hal Scofield
• 金额: $ 41.78万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-21 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102494
• 关键词: Address; Affect; Antibodies; Antibody Formation; Antigens; Autoantibodies; Autoimmune Process; B-Lymphocytes; Binding; Biochemical; Blood Vessels; Cells; Characteristics; Cross Reactions; Data; Disease; Disease model; Epitopes; Exocrine Glands; Functional disorder; Gland; Harvest; Human; Immunoglobulin G; Immunoglobulin-Secreting Cells; Impairment; Individual; Induction of Apoptosis; Joints; Kidney; Knowledge; Lead; Lung diseases; Lymphocytic Infiltrate; Lymphoma; Methods; Minor salivary gland structure; Modeling; Monoclonal Antibodies; Mus; Muscarinic Acetylcholine Receptor; Muscarinics; NOD/SCID mouse; Oklahoma; Pathogenicity; Patients; Physiological; Process; Production; Receptors, Antigen, B-Cell; Recombinants; Risk; SCID Mice; Saliva; Salivary; Salivary Glands; Serum; Signal Transduction; Sjogren' s Syndrome; Skin; Specificity; Spleen; Structure of germinal center of lymph node; Symptoms; T-Lymphocyte; Testing; Tissues; Translational Research; Transplantation; Xerostomia; aquaporin 5; autoreactive B cell; eye dryness; human disease; innovation; mouse model; receptor; salivary cell; systemic autoimmune disease; water channel

Sjogren's syndrome is a systemic autoimmune disease that most commonly targets the exocrine glands and is characterized by persistent dry eyes and mouth as well as extra-glandular involvement including blood vessel, skin, kidney, joints, and lung disease along with an increased risk of lymphoma. Salivary gland lymphocytic infiltrates are a pathological finding in the disease. The serum of these patients commonly contains autoantibodies to Ro (SS-A) and La (SS-B). Other specificities are present, including those towards muscarinic receptors. There are strong data supporting significant autoreactive B cell expansion, hyperreactivity and antibody formation in exocrine glands of Sjogren's patient, including the presence of anti-Ro and -La specific B cells. The evidence is strong that B cells infiltrating the salivary glands of Sjogren's patients make autoantibodies that are in part responsible for the exocrine glandular dysfunction. This proposal will test the hypothesis that this is the case, and will address the pathogenic mechanisms underlying this dysfunction. We will utilize an innovative, humanized model of Sjogren's in which human salivary tissue is transplanted into NOD SCID mice. So transplanted mice are already available (see Preliminary Data). In addition, we will use an innovative method of producing recombinant monoclonal antibodies to study the autoantibody repertoire produced in the salivary gland of humans with Sjogren's. Already we have harvested B cells from minor salivary glands and begun the process of producing recombinant monoclonals antibodies (see Preliminary Data). First, we will produce recombinant monoclonal antibodies from B cells infiltrating the salivary glands of humans with Sjogren's syndrome. Then, these monoclonal antibodies will be tested for pathogenicity, that is, the ability to reduce salivary flow in either normal mice, or the xenotransplanted Sjogren's mouse model. We will study the binding specificity of pathogenic autoantibodies. Furthermore, the pathogenic mechanisms by which these antibodies cause the characteristic salivary gland dysfunction will be elucidated.

Sjogren综合征是一种系统性的自身免疫性疾病，最常见的是针对外分泌腺体，其特征是持续的干眼睛和口腔以及glo骨外受累，包括血管，皮肤，肾脏，关节和肺部病以及淋巴瘤的风险增加。唾液腺淋巴细胞浸润是该疾病的病理发现。这些患者的血清通常包含自身抗体（SS-A）和LA（SS-B）。存在其他特异性，包括毒蕈碱受体的特异性。有强大的数据支持明显的自动反应性B细胞扩展，过度反应性 Sjogren患者的外分泌腺中的抗体形成，包括抗RO和-LA特异性B细胞的存在。有证据表明，B细胞渗入Sjogren患者的唾液腺产生的自身抗体，部分原因是外分泌腺功能障碍。 该提案将检验以下假设，即这种情况，并将解决该功能障碍的致病机制。我们将利用一种创新的，人性化的模型，其中人类唾液组织被移植到点头SCID小鼠中。因此，已移植的小鼠已经可用（请参阅初步数据）。此外，我们将使用一种创新的方法来产生重组单克隆抗体来研究用Sjogren的人类唾液腺中产生的自身抗体库。我们已经从较小的唾液腺中收集了B细胞，并开​​始产生重组单克隆抗体的过程（请参阅初步数据）。首先，我们将从B细胞中产生重组单克隆抗体，浸润人类患有Sjogren综合征的唾液腺。然后，将测试这些单克隆抗体的致病性，即降低正常小鼠中唾液流动的能力，或者sjogren sjogren的小鼠模型。我们将研究病原自身抗体的结合特异性。此外，将阐明这些抗体引起特征性唾液腺功能障碍的致病机制。