April 28 2010 01:26 PM

Basic research is helping us understand what we've been seeing on farms. We can make immune systems stronger.

The author is in the Periparturient Disease of Cattle Research Unit, National Animal Disease Center, ARS, USDA, Ames, Iowa.

Mastitis prevention starts with healthy cows that have healthy immune systems. We've learned that milk fever cows are eight times more likely to have mastitis.

UCH research is focused on understanding factors that affect the immune system. Nutrition, stress, and reproductive status are examples of generalized conditions that can have a dramatic impact on the functionality of the immune system.

Previously, we thought that the effects of these general health factors only had a minor effect on immune function. However, as we learn more about cellular and molecular immune pathways, these general health issues and their effects on the immune system are being defined at the molecular level.

For example, feed components, such as vitamins, have a direct effect on which genes are turned on or off in immune cells. Therefore, understanding how vitamins interact with the immune system will help in developing disease control and management strategies that will aid in maintaining good health in our cattle, resulting in greater production, improved breeding, or faster growth.

Nutrients play big role . . .
Research has shown that nutrition can affect the ability of an animal's immune system to fight disease. Calcium and vitamin D have a significant effect on the functionality of immune cells.

One metabolic disease that has been associated with immune system disorder is hypocalcemia or milk fever. Cows with milk fever are eight times more likely to develop mastitis than cows with normal blood calcium levels.

Severe hypocalcemia leads to the loss of proper skeletal muscle control. Clinical hypocalcemia occurs in 5 to 7 percent of cows around calving time. Additionally, subclinical hypocalcemia occurs in 25 percent of heifers and more than 50 percent of second-lactation cows.

Currently, we think that even subclinical hypocalcemia would result in less muscle tone in the smooth muscle that makes up the teat sphincter. This loss of muscle tone would cause the teat canal to remain partially open and expose the mammary gland to bacteria. Intracellular calcium regulates many cellular functions necessary for immune cells to detect and destroy bacteria.

It has long been recognized that vitamin D deficiency causes less resistance to infection. First, vitamin D affects serum calcium homeostasis. Cows with hypocalcemia have impaired immune cells. Second, vitamin D influences which proteins immune cells produce which, in turn, can affect the ability of the immune cell to destroy bacteria.

Bacteria fighters . . .
Monocytes are a precursor immune cell that can ingest and kill many bacterial pathogens. They also can secrete antimicrobial molecules that kill or slow the growth of many bacteria. In humans, lower serum concentrations of the vitamin D precursor 25(OH)D3 are correlated with a reduced ability of monocytes to kill bacteria that cause tuberculosis. The antibacterial ability of the monocytes from individuals with low vitamin D levels was restored when the cells were transferred into serum from individuals with higher serum vitamin D levels.

Production of specific antimicrobial proteins by the immune cells depends on the level of vitamin D. A number of important questions remain to be answered about the role of vitamin D in the immune system. For example, what level of 25(OH)D3 in the serum is necessary for full immune function, and what differences are there between humans and cattle? Are we feeding enough vitamin D to achieve levels in the serum to properly optimize the immune system to fight disease such as mastitis?

The causes of stress in animals are as varied as its impacts. Types of stress include heat, negative energy balance, transportation, pregnancy, and mixing of unfamiliar animals. Some ways that an animal will manifest stress is in the form of sickliness and failure to thrive. These very general manifestations now are being defined on a cellular and molecular level. Various immune cells, such as neutrophils, T-cells, and dendritic cells, are affected when a cow is stressed, and the expression levels of specific proteins important for immune function are affected during stress.

The initiation of a stress response involves the release of hormones such as cortisol, epinephrine, and norepinephrine. This response is known to have a dramatic effect on the immune system. There are a number of stresses that have been shown to have an effect on the immune system. For example, chronic stress in pigs caused by mixing unfamiliar animals results in subordinate pigs having fewer white blood cells compared to dominant animals.

One of the most well-studied molecular effects of stress on the immune system is the effect of cortisol on the expression of a protein which is expressed on the surface of immune cells. This protein helps to target the immune cell to an infected part of the body, and cortisol causes its loss of the surface of the cell. The loss of this targeting protein is one factor associated with greater susceptibility of the cow to mastitis.

The immune system is significantly affected during pregnancy. There are important interactions between the immune system and cells and tissues of the reproductive system. These interactions are critical for the maintenance of pregnancy but are also responsible for immune suppression that is associated with greater risk of disease. The period around calving is the time when these complex physiological changes occur simultaneously, having a negative effect on the cow's health. Many studies have demonstrated that the immune system of a dairy cow at calving is suppressed. This suppression begins one to two weeks before calving and can last until four weeks after calving. Several immune functions are inhibited during this time.

The dairy cow loses massive amounts of calcium during lactation and, especially at the beginning of lactation, is susceptible to hypocalcemia. To study the effect of lactation on the immune system, normal cows were compared to those that had undergone a mastectomy. Specific immune cell functions were assessed in the mastectomized cows and compared to normal ones.

Some types of immune cell function were inhibited in mastectomized cows compared to normal animals during transition. Such immune cell depression during the time of calving could be attributed to the metabolic demands of milk production. These observations fit nicely with the molecular observations described above showing hypocalcemia's effect on immune function.

Breeding affected, too . . .
One example of the immune system's importance to reproduction is illustrated by the interaction between immune cells and the corpus luteum. The corpus luteum is the remnant of the ovulatory follicle. Its function is to produce progesterone which is essential to maintain pregnancy.

In the absence of an embryo, the corpus luteum regresses. Regression of the corpus luteum is necessary to allow a new follicle to ovulate and a subsequent chance of conception. As the corpus luteum regresses, the number of immune cells in the corpus luteum rises. Proteins expressed by these luteal-immune cells have the ability to inhibit progesterone synthesis by bovine-luteal cells, causing complete regression of the corpus. Understanding this mechanism may help in the generation of new methods to improve fertility in cattle.

To achieve the goal of generating better health practices that prevent or cure diseases, we must not only have a better understanding of the mechanism and functions of the immune system but also understand how that system is integrated into the whole animal.

For example, in order to have the greatest potential for a vaccine's success, the animal's immune system must be working at optimal levels. Therefore, optimal diets must be given to ensure proper immune function, and stresses must be reduced to eliminate suppression of the immune response.

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