Mechanisms that regulate bovine adaptive immune responses and impact disease outcome

牲畜疾病是现代农业的一个令人担忧的问题，影响动物和人类的健康。这项研究旨在评估调节牛免疫的机制，目的是改善奶牛的健康。免疫系统由帮助控制传染病的细胞和分子组成。更好地了解免疫系统的调节机制有望有助于识别具有优越免疫力的个体，并有助于发现动物健康的新疗法。围产期奶牛承受着身体和新陈代谢的压力，因为从妊娠晚期到大量产奶的压力过渡。此时是疾病发生的高峰期，影响牛奶的数量、质量和安全。以前，我们和其他人已经证明，围产期免疫反应(IR)是次优的，这至少在一定程度上导致了疾病的增加。然而，人们对调节围产期免疫的因素知之甚少，只有少数同时拥有牛免疫学和遗传学专业知识的小组正在研究如何提高对重要牛疾病的免疫力。最近对小鼠和人的研究表明，T细胞的反应受到遗传和表观遗传的影响，包括T细胞分化为T辅助细胞1和T辅助2细胞，这两种细胞分别在1型和2型胰岛素抵抗中占主导地位。1型反应主要由细胞介导，对控制细胞内病原体很重要，而2型反应主要是抗体介导的，主要控制细胞外病原体。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或另一个方向上有偏见，而这些偏见在怀孕期间会发生变化。关于1型和2型胰岛素抵抗的控制，尤其是牛围产期的变化，人们知之甚少。因此，这项建议旨在利用遗传学和表观遗传学工具，研究分娩前、分娩期间和分娩后牛的1型和2型免疫反应的变化，以更好地了解免疫调节。核心假设是牛围产期免疫的改变是由于1型和2型胰岛素抵抗的变化，这既受遗传因素的影响，也受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.