Understanding biological mechanisms underlying absorption of immunoglobulins in newborn ruminants

在犊牛中，断奶前发病率和死亡率仍然很高，分别为24%和6%。发病率和死亡率风险的一个强有力的预测因素是未能吸收初乳中的免疫球蛋白。出生时，小牛没有免疫球蛋白，这是抵御疾病所必需的;直到它们产生自己的免疫球蛋白，小牛的整个适应性免疫反应依赖于吸收初乳中喂养的免疫球蛋白的能力。由于新生小牛免疫球蛋白吸收的时间窗较短，免疫球蛋白吸收效率较低，范围为25 - 50%。经典研究表明，免疫球蛋白的吸收在生命的前六个小时迅速减少。饲喂初乳以及初乳中的高细菌载量都进一步降低免疫球蛋白吸收，直到出生后24小时免疫球蛋白吸收停止。免疫球蛋白吸收的停止被称为“肠道闭合”，直到最近，人们才认为在生命的24小时内是相对不变的。我们团队最近的研究表明，免疫球蛋白吸收窗口实际上可以通过补充丁酸盐来控制。尽管丁酸盐对免疫球蛋白吸收有负面影响，但免疫球蛋白吸收窗口可以营养操纵的事实本身就具有改善免疫球蛋白吸收功效的巨大潜力。拟议研究的目的是提高我们对新生小牛免疫球蛋白吸收如何调节的理解。我的假设是免疫球蛋白吸收主要是FcRn依赖性的，并受细胞增殖和上皮屏障完整性建立的调节。为了验证这一假设，拟议的研究有几个具体目标：1）确定上皮成熟对免疫球蛋白转运的作用; 2）研究FcRn依赖性和细胞旁转运在免疫球蛋白吸收中的作用; 3）研究管腔细菌负荷对免疫应答和紧密连接形成的影响。为了检验这一假设并满足特定目标，将进行一系列实验，包括体内和体外方法，并使用从转运动力学到显微镜到转录组学的各种分析技术，以全面了解小牛免疫球蛋白吸收。拟议的工作将支持一个博士，两个硕士和两个本科生。总之，拟议的研究将提高我们对小牛免疫球蛋白转运调节的理解，从而加强我们对影响大分子吸收生理学的生物系统的理解。

In calves, pre-weaning morbidity and mortality remain high, at 24% and 6%, respectively. A strong predictive factor of morbidity and mortality risk is a failure to absorb immunoglobulins in colostrum. At birth, calves have no immunoglobulins, which are needed to fight off disease; until they produce their own immunoglobulins, the calf's entire adaptive immune response rests on the ability to absorb immunoglobulins fed in colostrum. Efficiency of immunoglobulin absorption is low, ranging from 25 - 50%, owing to the short time window for immunoglobulin absorption in neonatal calves. Classical research demonstrated immunoglobulin absorption to decrease rapidly in the first six hours of life. Both feeding of colostrum as well as a high bacterial load in colostrum further decrease immunoglobulin absorption, until cessation of immunoglobulin absorption at 24h of life. The cessation of immunoglobulin absorption is known as "gut closure" and was, until recently, thought to be relatively immutable at 24h of life. Recent research from our team indicates that the immunoglobulin absorption window can actually be manipulated by supplementing colostrum with butyrate. Despite the negative impact of butyrate on immunoglobulin absorption, the mere fact that the immunoglobulin absorption window can be nutritionally manipulated holds great potential to improve efficacy of immunoglobulin absorption. The objective of the proposed research is to improve our understanding of how immunoglobulin absorption is regulated in newborn calves. My hypothesis is that immunoglobulin absorption is predominantly FcRn-dependent and is regulated by cellular proliferation and establishment of epithelial barrier integrity. To test this hypothesis, the proposed research has several specific objectives: 1) Determine the role of epithelial maturation on immunoglobulin transport; 2) Investigate the role of FcRn-dependent and paracellular transport in immunoglobulin absorption; and 3)Investigate the impact of luminal bacterial load on immune response and tight junction formation. To test this hypothesis and meet the specific objectives, a series of experiments will be conducted that include in vivo and in vitro methods, and use a variety of analytical techniques from transport kinetics to microscopy to transcriptomics for a holistic approach to improving our understanding of immunoglobulin absorption in young calves. The proposed work will support one PhD, two MSc, and two undergraduate students. In all, the proposed research will improve our understanding of the regulation of immunoglobulin transport in young calves, thereby bolstering our understanding of the biological systems influencing absorption physiology of macromolecules.