Molecular Mechanisms Linking HLA-DQ and Autoimmunity

连接 HLA-DQ 和自身免疫的分子机制

• 批准号: 8029482
• 负责人: Luc Teyton
• 金额: $ 65.3万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8029482
• 关键词: Address; Affinity; Animal Model; Animals; Antibodies; Antigens; Aspartic Acid; Attitude; Autoantigens; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Binding; Celiac Disease; Charge; Complex; Coupled; Development; Disease; Disease Progression; Electrostatics; Equipment; Evaluation; Explosion; Funding; Genetic; Genetic Polymorphism; Genome; Gliadin; Grant; HLA-DQ Antigens; HLA-DQ8 antigen; Histocompatibility Antigens Class II; Human; Human Resources; Immune; Immune response; Inbred NOD Mice; Insulin; Insulin-Dependent Diabetes Mellitus; Laboratories; Link; MHC Class II Genes; Major Histocompatibility Complex; Measurement; Mediating; Medical; Minor; Modeling; Molecular; Muramidase; Mus; Mutant Strains Mice; Mutation; Nature; Onset of illness; Pathology; Peptide/MHC Complex; Peptides; Positioning Attribute; Proteins; Published Comment; Role; Shapes; Structure; T-Cell Receptor; T-Lymphocyte; TCR Activation; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Training; Transgenic Mice; United States National Institutes of Health; Work; aspartylglutamate; autoreactive T cell; base; dimer; fascinate; genome wide association study; human leukocyte antigen gene; in vivo; mutant; new therapeutic target; novel strategies; novel therapeutic intervention; small molecule; therapy development

DESCRIPTION (provided by applicant): Insulin-dependent diabetes mellitus (IDDM) and celiac disease are two of the most common immune-mediated diseases in humans. In order to develop new treatment for both conditions, we have decided to study the mechanisms underlying their association to the same Major Histocompatibility Complex (MHC) class II molecules, HLA-DQ8. These molecules share with HLA-DQ2, HLA-DR0405 and I-Ag7 a mutation at position 57 of their chain that eliminates a conserved aspartic acid and modifies the charge and shape of the P9 pocket. We have evaluated the functional consequences of this mutation in mouse and human when the bound peptide has no Asp/Glu residue at position 9 (P9). In all instances, this situation leads to the selection of Asp/Glu residues in CDR3 of T cell receptor (TCR). The pairing Asp/Glu in CDR3 with non-Asp/Glu P9 peptide increases TCR/pMHC affinity dramatically and supports T cell expansion. The determination of the first structure of an I-Ag7/T cell receptor complex, coupled with biophysical measurements, revealed that this phenomenon was induced at a distance by non-TCR contact residues through electrostatic forces. In the current proposal we propose to explore further the role that the shift between low and high TCR affinity, related solely on the nature of the P9 residue of the peptide ("the P9 switch Model"), may have in disease onset and development. To explore this fascinating possibility, we propose 3 specific aims. Aim 1: Evaluation of the role of position 57 of MHC in T cell repertoire selection. We hypothesize that position 57 of MHC directly select T cells of higher affinity when peptides do not carry Asp/Glu at P9. Already shown for exogenous antigens such as gliadin and lysozyme, we will evaluate this mode of recognition for self-antigens such as BDC2.5, GAD65 and insulin in the context of I-Ag7 and HLA-DQ8. Aim 2: Mechanisms supporting the role of position 57 in T cell receptor interactions. We will combine biophysical and structural studies to understand the gain in affinity that occurs when a TCR retaining a Asp/Glu residue in its CDR3 recognizes a peptide with a neutral residue at P9 in the context of I-Ag7 or HLA-DQ8. Aim 3: Using animal models to test the pertinence of the P9 switch model in autoimmune responses. We have circumstantial evidence showing that the T cell recognition of some antigens hinges on the nature of 57 of MHC and the associated peptide. However, we now have to provide a direct link between this unique mode of recognition and the expansion of autoreactive T cells in vivo and show their role in disease. We will address the issue directly by T cell and retrogenic transfer studies in mice carrying I-Ag7 (NOD, C57BL6.g7). In addition, studies in a mutant I-Ag757D mutant mouse will challenge directly our model. We believe that we have identified a unique molecular link between I-Ag7/HLA-DQ8 and T cell recognition and hypothesize that this link supports the expansion of autoreactive T cells in HLA-DQ8- associated diseases. At stake is the possibility to redefine MHC molecules as direct targets for treatment and the development of small molecules or antibodies binding to HLA-DQ molecules to modify their function. PUBLIC HEALTH RELEVANCE: Insulin-dependent diabetes mellitus (IDDM) and celiac disease are two of the most common autoimmune diseases in humans. To develop new therapeutic approaches we are trying to understand the mechanisms of their association with MHC class II molecules such as HLA-DQ8 and propose the first comprehensive model ever to be tested.

描述（由申请人提供）：胰岛素依赖型糖尿病（IDDM）和乳糜泻是人类最常见的两种免疫介导的疾病。为了开发针对这两种疾病的新治疗方法，我们决定研究它们与相同的主要组织相容性复合物（MHC）II类分子HLA-DQ 8相关的机制。这些分子与HLA-DQ 2、HLA-DR 0405和I-Ag 7在其链的位置57处共享突变，该突变消除了保守的天冬氨酸并改变了P9口袋的电荷和形状。我们已经评估了这种突变在小鼠和人中的功能后果时，结合的肽没有在位置9（P9）的Asp/Glu残基。在所有情况下，这种情况导致选择T细胞受体（TCR）的CDR 3中的Asp/Glu残基。CDR 3中的Asp/Glu与非Asp/Glu P9肽的配对显著增加TCR/pMHC亲和力并支持T细胞扩增。I-Ag 7/T细胞受体复合物的第一结构的测定，加上生物物理测量，揭示了这种现象是通过静电力在一定距离处由非TCR接触残基诱导的。在当前的提议中，我们提议进一步探索仅与肽的P9残基的性质相关的低和高TCR亲和力之间的转变（“P9开关模型”）在疾病发作和发展中可能具有的作用。为了探索这种迷人的可能性，我们提出了三个具体目标。目的1：探讨MHC 57位在T细胞库选择中的作用。我们假设，当肽在P9不携带Asp/Glu时，MHC的位置57直接选择具有更高亲和力的T细胞。已经显示的外源性抗原，如麦胶蛋白和溶菌酶，我们将评估这种模式的识别自身抗原，如BDC2.5，GAD 65和胰岛素的背景下，I-Ag 7和HLA-DQ 8。目的2：支持位置57在T细胞受体相互作用中的作用的机制。我们将结合联合收割机的生物物理和结构研究，以了解当在其CDR 3中保留Asp/Glu残基的TCR在I-Ag 7或HLA-DQ 8的背景下识别在P9处具有中性残基的肽时发生的亲和力增益。目的3：利用动物模型验证P9开关模型在自身免疫反应中的相关性。我们有间接证据表明，T细胞对某些抗原的识别取决于MHC及其相关肽的性质。然而，我们现在必须提供这种独特的识别模式与体内自身反应性T细胞扩增之间的直接联系，并显示它们在疾病中的作用。我们将通过携带I-Ag 7的小鼠（NOD，C57BL6.g7）的T细胞和逆转录转移研究直接解决这个问题。此外，在突变I-Ag 757 D突变小鼠中的研究将直接挑战我们的模型。我们相信，我们已经确定了I-Ag 7/HLA-DQ 8和T细胞识别之间的独特分子联系，并假设这种联系支持HLA-DQ 8相关疾病中自身反应性T细胞的扩增。目前的关键是重新定义MHC分子作为治疗的直接靶点，以及开发与HLA-DQ分子结合的小分子或抗体以改变其功能。 公共卫生相关性：胰岛素依赖型糖尿病（IDDM）和乳糜泻是人类最常见的两种自身免疫性疾病。为了开发新的治疗方法，我们正试图了解它们与MHC II类分子（如HLA-DQ 8）相关的机制，并提出第一个全面的模型进行测试。