N-3 PUFAs and antigen presenting cells

描述(申请人提供)：N-3多不饱和脂肪酸(PUFAs)发挥免疫抑制作用，并具有巨大的潜力作为营养食品治疗炎症相关疾病。在临床上使用这些脂肪酸作为免疫抑制剂的一个主要限制是对它们的靶点和分子机制缺乏了解。本实验室的体外研究表明，n-3多不饱和脂肪酸通过主要组织相容性复合体(MHC)I类抗原提呈途径，通过改变APC质膜的生物物理结构来抑制APC的功能。这项提议的目标是在整个动物水平上测试我们的体外模型，以建立生物学相关性。我们的中心假设是，n-3PUFA酰链形成组织上不同的纳米级质膜域，扰乱鞘脂/富含胆固醇的脂筏的分布，从而扰乱MHC I类分子的横向组织(特定目标1)。通过改变MHC-I类的侧向组织，APC不会形成稳定的免疫突触，从而抑制APC有效地激活原始CD8+T细胞的能力(特异性目标2)。我们还将通过MHC II类途径来验证我们的假设，以解决n-3PUFAs对APC质膜组织和随后的功能的影响是否仅限于一条抗原递呈途径，或者是否可以推广到另一条途径(特定目标2)。为了测试我们的模型，我们将依靠生物物理显微镜和功能免疫学分析的组合。如果我们的假设是正确的，我们将确定饮食中的n-3PUFAs可以在纳米尺度上破坏脂质和蛋白质膜组织，从而抑制APC功能。鉴于APC在清除自身抗原和感染性病原体方面的作用，这里提出的研究将有助于开发n-3多不饱和脂肪酸作为治疗炎症性和自身免疫性疾病的营养食品，同时将它们的潜在缺点降至最低。 公共卫生相关性：N-3多不饱和脂肪酸(PUFAs)对治疗炎症相关疾病具有潜在的治疗价值；然而，其靶点和机制尚不清楚。这项拨款提案旨在测试n-3多不饱和脂肪酸如何改变特定免疫细胞功能的新模型。这项提案产生的数据将有助于发展n-3多不饱和脂肪酸作为营养食品。

DESCRIPTION (provided by applicant): N-3 polyunsaturated fatty acids (PUFAs) exert immunosuppressive effects and have great potential as nutraceuticals for the treatment of inflammation associated disorders. A major limitation of using these fatty acids in the clinic as immunosuppressants is a poor understanding of their targets and molecular mechanisms. In vitro studies from our laboratory show that n-3 PUFAs suppress the function of antigen presenting cells (APCs) through the major histocompatibility complex (MHC) class I antigen presentation pathway by modifying the biophysical organization of the APC plasma membrane. The goal of this proposal is to test our in vitro model at the whole animal level in order to establish biological relevance. Our central hypothesis is that n-3 PUFA acyl chains form organizationally distinct nanometer scale plasma membrane domains that disrupt the distribution of sphingolipid/cholesterol-rich lipid rafts and thereby disrupt the lateral organization of MHC class I molecules (Specific Aim 1). By altering MHC class I lateral organization, the APC does not form a stable immunological synapse, which suppresses the ability of the APC to efficiently activate a na¿ve CD8+ T cell (Specific Aim 2). We will also test our hypothesis with the MHC class II pathway to address whether the effects of n-3 PUFAs on APC plasma membrane organization and subsequent function are limited to one pathway of antigen presentation or if the effects can be generalized to another pathway (Specific Aim 2). To test our model, we will rely on a combination of biophysical microscopies and functional immunological assays. If our hypothesis is correct, we will establish that dietary n-3 PUFAs can disrupt lipid and protein membrane organization on a nanometer scale and thereby suppress APC function. Given that APCs have a role in the removal of autoantigens and infectious agents, the studies proposed here will assist in the development of n-3 PUFAs as nutraceuticals for the treatment of inflammatory and autoimmune disorders, while minimizing their potential drawbacks. PUBLIC HEALTH RELEVANCE: N-3 polyunsaturated fatty acids (PUFAs) have potential therapeutic value for the treatment of inflammation associated disorders; however, their targets and mechanisms are poorly understood. This grant proposal aims to test a new model on how n-3 PUFAs modify the function of specific immune cells. Data generated from this proposal will contribute to the development n-3 PUFAs as nutraceuticals.