Pathogenic B Cells in Sjogren's Syndrome

干燥综合征是一种全身性自身免疫性疾病，最常见的靶向外分泌腺，其特征在于持续性眼和口干燥以及包括血管、皮肤、肾脏、关节和肺部疾病在内的腺体外受累，沿着淋巴瘤风险增加。唾液腺淋巴细胞浸润是该病的病理学表现。这些患者的血清通常含有抗Ro（SS-A）和La（SS-B）的自身抗体。存在其他特异性，包括对毒蕈碱受体的特异性。有强有力的数据支持显著的自身反应性B细胞扩增、高反应性 以及Sjogren患者的外分泌腺中的抗体形成，包括抗Ro和抗La特异性B细胞的存在。强有力的证据表明，浸润干燥综合征患者唾液腺的B细胞产生的自身抗体是导致外分泌腺功能障碍的部分原因。 这项建议将测试的假设，这是这种情况下，并将解决这种功能障碍的致病机制。我们将利用一种创新的、人源化的干燥综合征模型，其中将人唾液组织移植到NOD SCID小鼠中。因此，移植小鼠已经可用（见初步数据）。此外，我们将使用一种创新的生产重组单克隆抗体的方法来研究干燥综合征患者唾液腺中产生的自身抗体库。我们已经从小唾液腺中收获了B细胞，并开始了生产重组单克隆抗体的过程（见初步数据）。首先，我们将从干燥综合征患者唾液腺浸润的B细胞中生产重组单克隆抗体。然后，将测试这些单克隆抗体的致病性，即在正常小鼠或异种移植的Sjogren小鼠模型中减少唾液流的能力。我们将研究致病性自身抗体的结合特异性。此外，这些抗体引起特征性唾液腺功能障碍的致病机制将得到阐明。

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.