Mechanisms that regulate bovine adaptive immune responses and impact disease outcome

牲畜疾病是现代农业的一个问题，影响动物和人类的健康。这项研究旨在评估调节牛免疫力的机制，以改善乳制品健康。免疫系统由帮助控制传染病的细胞和分子组成。更好地理解调节免疫系统的机制有望促进识别具有上级免疫力的个体，并有助于发现用于动物健康的新疗法。围产期奶牛由于从妊娠后期到高产量产奶的压力过渡而处于身体和代谢压力下。疾病的发生在这个时候达到高峰，影响牛奶的数量、质量和安全。以前，我们和其他人已经表明，围产期免疫反应（IR）是次优的，这有助于，至少部分，增加疾病。然而，人们对调节围产期免疫力的因素知之甚少，只有少数在牛免疫学和遗传学方面具有专业知识的小组正在研究提高对重要牛疾病免疫力的方法。最近对小鼠和人的研究表明，T细胞反应受到遗传和表观遗传的影响，包括T细胞分化为分别在1型和2型IR中占主导地位的T辅助细胞1和T辅助细胞2。1型应答主要是细胞介导的，对控制细胞内病原体很重要，而2型应答主要是抗体介导的，在控制细胞外病原体中占主导地位。充分产生这两种反应的能力是至关重要的，但通常个人会在一个方向或另一个方向上有偏见，这些偏见在怀孕期间会发生变化。关于1型和2型IR的控制，特别是牛围产期期间的变化，知之甚少。因此，本提案旨在使用遗传和表观遗传学工具研究分娩前、分娩期间和分娩后牛1型和2型免疫应答的变化，以更好地了解免疫调节。核心假设是牛围产期免疫力的改变是由于1型和2型IR的变化，这些变化受到遗传和表观遗传因素的影响。

Livestock diseases are a concern for modern agriculture, affecting both animal and human health. This research seeks to evaluate mechanisms that regulate bovine immunity with a goal to improve dairy health. The immune system is composed of cells and molecules that help control infectious disease. A better understanding of the mechanisms that regulate the immune system is expected to facilitate identification of individuals with superior immunity, and help in the discovery of novel therapeutics for animal health. Peripartum cows are under physical and metabolic pressure due to the stressful transition through late pregnancy into high volume milk production. Disease occurence peaks at this time, affecting milk quantity, quality and safety. Previously, we and others have shown that peripartum immune responses (IR) are suboptimal and this contributes, at least in part, to increased disease. However, little is known about the factors that regulate peripartum immunity, and only a handful of groups having expertise in both bovine immunology and genetics are investigating ways to improve immunity to important cattle diseases. Recent studies of mouse and man show that T-cell responses are under both genetic and epigenetic influences, including T-cell differentiation into T-helper 1 and T-helper 2 cells that dominate in type 1 and 2 IR, respectively. Type 1 responses are predominately cell-mediated, important to control intracellular pathogens, whereas type 2 responses are mainly antibody-mediated dominating in control of extracellular pathogens. The ability to adequately produce both responses is critical, but often individuals will have a bias in one direction or another, and these biases are known to shift during pregnancy. Relatively little is known about the control of type 1 and type 2 IR, particularly changes during the bovine peripartum period. Therefore this proposal is designed to investigate changes in bovine type 1 and 2 immune responses before, during and after parturition using genetic and epigenetics tools to better understand immune regulation. The core hypothesis being that alterations in bovine peripartum immunity are due to shifts in type 1 and type 2 IR that are influenced by both genetic and epigenetic factors.