Expert Answers - Dec. 19, 2008

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Answer provided by John Lippolis, of the periparturient diseases of cattle unit at the National Animal Disease Center. His answer is from the proceedings of the Cornell Nutrition Conference held this past October in Syracuse, N.Y.

Q: What impact does nutrition have on immune function?

A: The impact of nutrition on health is the subject of a significant body of research. This research has shown that nutrition can affect the ability of an animal’s immune system to fight a disease. This connection between nutrition and immune function has been described at the cellular level and even the molecular level. A significant amount of research is being focused on the cellular and molecular processes affected by calcium and vitamins A and D. Calcium and vitamins A and D have been shown to have a significant effect on the functionality of immune cells.


Several epidemiological studies have shown an association between a diagnosed metabolic disease and subsequent development of mastitis. One metabolic disease that has been associated with immune system disorder is hypocalcemia or milk fever. A study of over 2,000 cows showed that cows with hypocalcemia were eight times more likely to develop mastitis than cows with normal blood calcium levels (Curtis et al, 1983). Severe hypocalcemia leads to the loss of proper skeletal muscle control. Clinical hypocalcemia occurs in 5 to 7 percent of transition dairy cows. Additionally, subclinical hypocalcemia occurs in 25 percent of heifers and greater than 50 percent of second-lactation cows (Dr. Ronald L. Horst, personal communication). Contraction rate and strength of smooth muscle tissue have been shown to be directly related to the level of calcium in the blood (Daniel, 1983). A current hypothesis is that even a sub-clinical hypocalcemic cow would have decreased muscle tone in the smooth muscle that makes up the teat sphincter, and that this loss of muscle tone would cause the teat canal to remain partially open, thus exposing the mammary gland to environmental pathogens.

In addition to calcium’s critical role in muscle function, it also plays an essential role in intracellular signaling. In immune cells, intracellular calcium regulates many cellular functions, including cytokine production, cytokine receptor expression and cell proliferation. Recently, it has been shown that stimulated peripheral mononuclear cells from hypocalcemic cows have a muted intracellular calcium response compared to cows with normal blood calcium levels. Furthermore, when stimulated peripheral mononuclear cells from hypocalcemic cows were compared with stimulated peripheral mononuclear cells obtained from the same cows after intravenous treatment with a calcium solution, a muted intracellular calcium response was demonstrated only when the animals were hypocalcemic (Kimura et al, 2006). A muted intracellular calcium response would have a significant effect on the functional capacity of the cells of the immune system.

Maintenance of proper blood calcium levels is critical for an animal’s health. There are two effective means of preventing periparturient hypocalcemia, both of which are diets used in the weeks prior to calving. The first diet reduces calcium intake prior to calving. The theory for this approach is that a mild hypocalcemia prior to lactation will cause the animal’s transport machineries to up-regulate, making the absorption of calcium more efficient (Green et al, 1981). Then, as lactation begins and the demand for calcium rapidly increases, the capacity for calcium transport has already been increased. The second means of preventing periparturient hypocalcemia is the use of the Dietary Cation-Anion Difference (DCAD) diet. Researchers in the early 1970s showed that the use of anionic salts in the diet could prevent hypocalcemia in dairy cows (Ender et al, 1971; Dishington, 1975). Since that time, numerous studies have shown that adjustment of the cation-anion balance can reduce the incidence of hypocalcemia seen in periparturient cows (Block, 1984; Goff et al, 1981).

T cells are generally divided into two general categories — cytotoxic and helper. In turn, helper T cells are subcategorized by the different cytokines they express. Each of the helper T cell types focuses the immune response towards a specific type of pathogenic challenge (Reiner, 2007). A recent study has shown that retinoic acid can affect which helper T cell types are generated. In addition to responding to different types of pathogens, the various helper T cell types are also associated with pathologies such as autoimmune and allergy responses. For example, the TH17 cell type is thought to be important for the immune response to extracellular bacterial infections. However, TH17 cells are also associated with autoimmune diseases, such as inflammatory bowel syndrome (Reiner, 2007). The bacterial flora of the gastrointestinal tract provides a unique challenge to the immune system to not react against normal gut bacteria. Inflammatory bowel disease is thought to be an immune response against the normal gut bacteria. Unknown is what mechanism redirects the immune systems away from a reaction against resident gut bacteria. Part of the answer may be answered by the action of retinoic acid on mesenteric lymph node dendritic cells. In the presence of cytokines that drive TH17 maturation, fewer TH17 cells were obtained when they were stimulated by mesenteric-derived dendritic cells compared to stimulation by splenic-derived dendritic cells (Mucida, et al, 2007). When retinoic acid is added, both splenic and mesenteric dendritic cell stimulation of TH17 cells are equally inhibited. When an inhibitor of vitamin A signaling is added to both splenic and mesenteric dendritic cells, they equally stimulate a large number of TH17 cells. Thus, vitamin A may be a critical component in the control of helper T-cell maturation in the gastroinstestinal tract. Immune system dysfunction caused by a vitamin A deficiency may be explained by this mechanism (Mucida et al, 2007). Retinoic acid has also been shown to augment the inhibition of IFN-g secretion by bovine lymphocytes caused by the addition of vitamin D (Ametaj et al, 2000). Therefore, dietary levels of vitamins A and D are important, especially as they may exacerbate immune dysfunction during the typical immunosuppression in the dairy cow seen around the time of calving.

It has long been recognized that vitamin D deficiency causes decreased resistance to infection (Rook, 1986; Reinhardt and Hustmyer, 1987), but this action was generally thought to be secondary to endocrine effects of vitamin D on calcium metabolism. More recently, vitamin D has been shown to have a direct autocrine effect on human immune cell functions. Thus, vitamin D affects the immune system through two pathways. First, the endocrine pathway affects serum calcium homeostasis. Cows generally suffer a decline in plasma 25-hydoxyvitamin D3 [25(OH)D3] around the time of calving as the calcium needs of the cow are in flux due to the demands of milk production (Horst et al, 2005). This periparturient period has been shown to be a time of general immune suppression and leaves the animals susceptible to various diseases (Kashiwazaki et al, 1985; Oliver and Sordillo, 1988; Kehrli et al, 1989; Kehrli et al, 1990; Cai et al, 1994). Through an autocrine pathway, vitamin D analogs directly affect DNA gene expression of immune cells. This is accomplished when the immune cells take up serum 25 (OH)D3 and convert it to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], which in combination with a nuclear transcription factor (vitamin D Receptor), can bind to specific DNA sequences and affects expression of multiple genes. The autocrine pathway for immune cell regulation requires sufficient circulating 25(OH)D3 such that activated immune cells can produce their own 1,25(OH)2D3 in their local environment at cell concentrations that activate key pathways that would not be activated by circulating endocrine produced 1,25(OH)2D3. Screening of human and mouse genomes revealed over 3,000 genes with a vitamin D response element to which 1,25(OH)2D3, in combination with the vitamin D-binding protein, affects gene expression (Wang et al, 2005), some of which are involved in immune cell regulation. Additionally, it was shown that stimulation of the TLR induces an enzyme that catalyzes the conversion of 25(OH)D3 to the active 1,25(OH)2D3. The production of 1,25(OH)2D3 was, in turn, necessary for the induction of antibacterial genes, such as cathelicidin (Liu et al, 2006). It was further demonstrated that lower serum concentrations of the precursor 25(OH)D3 were correlated with decreased ability of monocytes to kill bacteria (Liu et al, 2006). Thus, stimulation of immune cells with a TLR ligand in the presence of 25(OH)D3 resulted in the gene expression of additional products important for the antimicrobial response, and the lack of sufficient level of 25(OH)D3 had a negative impact on the immune response.

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