Defective Saliva Secretion in Autoimmune NOD mice

自身免疫性 NOD 小鼠唾液分泌缺陷

• 批准号: 7210886
• 负责人: SEUNGHEE CHA
• 金额: $ 18.08万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7210886
• 关键词: Acinar Cell; Affect; Affinity; Age; Antibodies; Antigens; Applications Grants; Attention; Autoantibodies; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Binding; Biological; Bladder; CD4 Positive T Lymphocytes; Calcium; Calcium Signaling; Cell Line; Cell membrane; Cells; Chimeric Proteins; Conflict (Psychology); Daily; Development; Diagnostic; Disease; Dryness; Epitope Mapping; Epitopes; Exhibits; Fc Immunoglobulins; Fc Receptor; Female; Fluids and Secretions; Functional disorder; Future; GTP-Binding Proteins; Goals; Hour; Human; Hypergammaglobulinemia; Image; Immune; Immunoglobulin Class Switching; Immunoglobulin Constant Region; Immunoglobulin G; Immunoglobulin Variable Region; Immunoglobulins; Immunotherapy; In Vitro; Inbred NOD Mice; Incubated; Individual; Infiltration; Infusion procedures; Interleukin-4; Knockout Mice; Laboratories; Lacrimal gland structure; Lead; Lymphocyte; Measures; Mediating; Molecular; Monitor; Mouse Strains; Mus; Muscarinic Acetylcholine Receptor; Muscarinics; Non obese; Pathogenesis; Pathologic Processes; Pathway interactions; Patients; Personal Satisfaction; Production; Research; Research Personnel; Role; Saliva; Salivary; Salivary Glands; Score; Serum; Shapes; Signal Pathway; Signal Transduction Alteration; Sjogren' s Syndrome; Smooth Muscle; Specificity; Surface; Symptoms; System; Therapeutic; Time; Transgenic Organisms; Week; Xerostomia; anti-IgG; antigen antibody binding; aquaporin 5; autoimmune exocrinopathy; base; day; diabetic; eye dryness; interest; prevent; programs; receptor; response; saliva secretion; trafficking

DESCRIPTION (provided by applicant): Sjogren's syndrome (SjS), an autoimmune disorder, targets mainly the salivary and lacrimal glands, resulting in dry mouth and dry eye symptom, respectively. Despite recent numerous studies to understand the disease pathogenesis, the exact mechanism for secretory dysfunction in SjS is not currently available. We have shown that autoantibodies targeting muscarinic 3 receptor (M3R) are capable of inducing dryness by transferring purified serum IgG or F(ab')2 fragments from disease-prone non-obese diabetic (NOD) mice or human primary SjS patients into the B-cell deficient NOD.Igu null mouse. Furthermore, we proved that the NOD.IL-4 KO mouse does not lose secretory function despite all disease-associated phenotypic changes except for the absence of lgG1anti-M3R autoantibodies, suggesting lgG1 isotypic function is critical to secretory dysfunction in the NOD mouse. Therefore, to understand the exact role of lgG1 directing M3R, we posit that the importance of lgG1 is not necessarily within the premise of its classical effector functions of constant region but resides in its variable region whose fine specificity is shaped by lgG1 isotype (presumably, lgG4 in humans). In this R21 application, we propose to investigate three Specific Aims: Specific Aim 1: Determine if loss of secretion in SjS is dependent on isotypic autoantibodies, especially lgG1 anti-mouse anti-M3R autoantibodies (lgG4 in humans). Specific Aim 2: To investigate if the effect of isotypic antibodies in secretory dysfunction is initiated by altered intracellular calcium release independent of constant region of lgG1 anti-mouse M3R autoantibodies (lgG4 in humans). Specific Aim 3: Determine if altered intracellular calcium release by binding of lgG1 anti-mouse M3R autoantibodies (lgG4 in humans) to the receptor blocks the translocation of aquaporin 5 to the plasma membrane, thus leading to loss of secretion in SjS. If our hypotheses are proven to be correct, the priority of SjS research will be given to the epitope mapping of M3R for the development of diagnostic and therapeutic strategies to restore secretory capacity in SjS patients.

描述（由申请人提供）：干燥综合征（SjS）是一种自身免疫性疾病，主要针对唾液腺和泪腺，分别导致口干和干眼症状。尽管最近进行了大量研究来了解该疾病的发病机制，但目前尚不清楚 SjS 分泌功能障碍的确切机制。我们已经证明，针对毒蕈碱 3 受体 (M3R) 的自身抗体能够通过将易患病非肥胖糖尿病 (NOD) 小鼠或人类原发性 SjS 患者的纯化血清 IgG 或 F(ab')2 片段转移到 B 细胞缺陷型 NOD.Igu 空小鼠中来诱导干燥。此外，我们证明，尽管存在所有与疾病相关的表型变化，除了不存在IgG1抗M3R自身抗体外，NOD.IL-4 KO小鼠并没有丧失分泌功能，这表明IgG1同种型功能对于NOD小鼠的分泌功能障碍至关重要。因此，为了理解lgG1指导M3R的确切作用，我们假设lgG1的重要性不一定在其恒定区经典效应功能的前提下，而是存在于其可变区中，其精细特异性由lgG1同种型（可能是人类中的lgG4）决定。在此 R21 应用中，我们建议研究三个具体目标： 具体目标 1：确定 SjS 中的分泌丧失是否依赖于同种型自身抗体，特别是 IgG1 抗小鼠抗 M3R 自身抗体（人类中的 IgG4）。具体目标 2：研究同型抗体在分泌功能障碍中的作用是否是由细胞内钙释放的改变引发的，与 IgG1 抗小鼠 M3R 自身抗体（人类中的 IgG4）恒定区无关。具体目标 3：确定 IgG1 抗小鼠 M3R 自身抗体（人类为 IgG4）与受体结合所改变的细胞内钙释放是否会阻止水通道蛋白 5 易位至质膜，从而导致 SjS 分泌丧失。如果我们的假设被证明是正确的，SjS研究的重点将放在M3R表位图谱上，以开发恢复SjS患者分泌能力的诊断和治疗策略。