ANTIGENICITY OF PROTEINS MODIFIED BY ALCOHOL METABOLITES

研究表明，长期摄入酒精会导致 蛋白质发生化学变化。 据信 通过醇脱氢酶将醇代谢为乙醛（AA）， 多不饱和脂肪对丙二醛的脂质过氧化作用 导致蛋白质与这两种醛类的加合。 事实上，AA和MDA已被证明以协同方式反应， 形成一种独特的加合物（MAA），在体外以及 体内实验。 这种MAA加合物已被证明能诱导 对MAA表位和载体的强抗体应答 蛋白质，而不使用佐剂。 我们假设，在慢性乙醇消耗后， 蛋白质也诱导对MAA表位的独特免疫应答， 如可溶性载体蛋白上未修饰的表位。的能力 MAA修饰的可溶性蛋白诱导的免疫应答是依赖性的 抗原加工抗原呈递的独特特征，以及 T细胞免疫调节回路的机制。 本研究项目的主要目标是确定和 表征对MAA加合物的体液和细胞免疫应答 proteins. 为了确定主要参与摄取的细胞类型， 通过MAA修饰的蛋白质的加工和呈递，并评估 这些免疫机制是否在发育和/或 酒精性肝病的进展。 我们建议解决 慢性乙醇消费对这些问题使用以下 具体目的：1）表征MAA加合蛋白质的能力， 诱导抗体（体液免疫）应答，无需佐剂 可溶性蛋白上的表位; 2）表征T细胞对MAA的应答 免疫后加合的可溶性蛋白; 3）确定细胞 参与摄取、处理和呈现的类型 MAA加合蛋白。

It has been shown that long term alcohol ingestion can lead to the development of chemical changes to proteins. It is believed that metabolism of alcohol by alcohol dehydrogenase to acetaldehyde (AA) and lipid peroxidation of polyunsaturated fats to malondialdehyde (MDA) results in the adduction of proteins with both of these aldehyde species. In fact, AA and MDA have been shown to react in a synergistic manner to form a distinct adduct (MAA) that has been found in in vitro as well as in vivo experimentally. This MAA adduct has been shown to induce a strong antibody response to both the MAA epitope(s) and to the carrier protein without the use of adjuvants. We hypothesize that following chronic ethanol consumption MAA-modified proteins induce and unique immune response to the MAA-epitope, as well as, to nonmodified epitopes on soluble carrier proteins. The ability of MAA-modified soluble proteins to induce and immune response is dependent on unique features of antigen processing antigen presentation, and mechanisms of T-cell immunoregulatory circuits. The principal objective of this research project is to define and characterize the humoral and cellular immune responses to MAA-adducted proteins. To determine the cell types primarily involved in the uptake, processing and presentation of proteins modified by MAA and assess whether these immune mechanisms play a role in the development and/or progression of alcohol liver disease. We propose to address the effects of chronic ethanol consumption on these problems using the following specific aims: 1) Characterize the ability if MAA adducted proteins to induce and antibody (humoral immune) response without adjuvant to the MAA epitopes on soluble proteins; 2)Characterize the T cell response to MAA adducted soluble proteins following immunization; 3) Determine the cell types that are involved in the uptake, processing, and presentation of MAA-adducted proteins.