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）：自身免疫性疾病Sjogren综合征（SJS）主要针对唾液和泪腺，分别导致口干和干眼症状。尽管最近进行了许多了解疾病发病机理的研究，但目前尚无SJS分泌功能障碍的确切机制。我们已经表明，靶向毒蕈碱3受体（M3R）的自身抗体能够通过将纯化的血清IgG或F（AB'）转移到易于疾病的非肥胖糖尿病（NOD）小鼠或人类原发性SJS患者中，从而诱导干燥。此外，我们证明了尽管所有与疾病相关的表型变化，但除了缺乏LGG1ANTI-M3R自身抗体外，尽管所有与疾病相关的表型变化，但表明LGG1同型功能对NOD小鼠的分泌功能障碍至关重要。因此，要了解指导M3R的LGG1的确切作用，我们认为LGG1的重要性不一定在其常数区域的经典效应器函数的前提下，而是位于其可变区域中，其良好的特异性是由LGG1同种型塑造的（据可能是人类的LGG4）。在此R21应用中，我们建议研究三个特定目的：具体目标1：确定SJS中分泌的损失是否取决于同种型自身抗体，尤其是LGG1抗小鼠抗M3R抗M3R自身抗体（人类的LGG4）。具体目的2：研究同种抗体在分泌功能障碍中的影响是否是通过与LGG1抗小鼠M3R自身抗体（人类LGG4）的恒定区域无关的细胞内钙释放启动。具体目标3：确定通过LGG1抗小鼠M3R自身抗体（人类中的LGG4）结合到受体上的细胞内钙释放是否改变，会阻断Aquaporin 5对质膜的易位，从而导致SJS中分泌的损失。如果我们的假设被证明是正确的，那么SJS研究的优先级将被对M3R的表位映射提供，以开发诊断和治疗策略，以恢复SJS患者的分泌能力。