Mastitis and immunology

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Editor’s note: First in a mastitis series

Mastitis is something your dairy clients probably fight on an ongoing basis. But instead of only looking at mastitis as a treat-after-the-fact disease, it may be simpler and more cost effective to understand how the cow herself fights off mastitis and how you can help her in that battle.

“Mastitis is a multifactorial disease like many diseases, and it involves the environment, the pathogens that cause the disease and the host,” says Lorraine Sordillo, PhD, associate professor of veterinary science, The Pennsylvania State University. “If you ignore the contributing factor of the cow, mainly her host defenses, then you’re missing a third of the pie when you’re trying to combat the disease.”

“The cow’s immune system is a very complex interaction of cellular and humoral components,” says Austin Belschner, DVM, Pharmacia & Upjohn. “If it is working as designed, there should be very little clinical mastitis.”

Teat defenses

So how do the cow’s natural defenses against mastitis work? “It’s important to consider the cow’s natural and acquired defenses,” says Jim Cullor, DVM, PhD, University of California - Davis.

“Natural immunity is the skin, teat canal, keratin and other factors, and acquired immunity is the cow’s immune system and her ability to recognize disease and mount an immune defense against it,” he adds. “Intramammary infection results when an agent successfully penetrates the teat canal and reaches milk-producing tissues. This cannot be accomplished without overcoming many defense mechanisms designed to prevent penetration of the organisms, suppress bacterial growth and counteract the potentially detrimental effects of bacterial cell wall products being released into the milk matrix.”

The teat end is considered to be the first line of defense against invading pathogens, but there are many factors than can cause its defenses to fail. “Injury to teat ends, overwhelming exposure due to mud or dirty environments, improperly functioning  machines, calving stress, poor milking hygiene and techniques and the use of improper intramammary therapies that decrease neutrophil function, such as gentamicin, are all factors that lead to the breakdown of the teat’s defenses,” adds Belschner. “Teat end injuries are caused by weather induced chapping, irritation due to poor quality teat dips and sanitizers, stomped teats and infectious conditions such as mammillitis and traumatic injury.”

The first barrier to pathogens in the teat are its sphincter muscles that maintain tight closure between milkings and hinder bacterial penetration. Increased patency of these muscles is directly related to increased incidence of mastitis.

The teat canal is lined with keratin which is crucial to the maintenance of the barrier function of the teat end and removal of keratin has been correlated to increased susceptibility to bacterial invasion and colonization. Teat keratin is a waxy material that is derived from stratified squamous epithelium. Keratin’s structure enables trapping of invading bacteria, thus hindering their migration into the gland cistern. Within the keratin lining, antimicrobial agents have been identified, and fatty acids present in the teat are bacteriostatic.

“When cows are allowed to lay down right after milking and not stand up and let the sphincter close, then that opens them up for a pathogen invasion,” adds Cullor. “Directly after milking, cows should have feed and water available so they stand up at least 15 to 20 minutes after milking and give the sphincter time to close.”

Cellular defenses

Bacteria that traverse the teat end opening must then escape the antibacterial activities of the mammary gland microenvironment in order to establish disease. Milk SCC consists of, among others, neutrophils, macrophages, lymphocytes and some epithelial cells, says Sordillo. During a bacterial intramammary infection (IMI), total SCC can increase to >10(6)/ml of milk within just a few hours. If bacteria are able to survive the immediate host response of leukocyte release, inflammation continues. Prolonged diapedesis of leukocytes causes damage to mammary parenchyma tissue, resulting in decreased production of milk. The duration and severity of the inflammatory response have a major impact on the quantity and quality of milk produced.

“The maximum functional capability of the cells responsible for mammary gland defense may be influenced by stage of lactation and time of the dry period, genetic background, composition of the secretion, types of antimicrobials employed, and anti-inflammatory agents administered to the patient,” explains Cullor.

Sordillo says some of the cell types involved in immune response to a mastitis infection include:

  • Neutrophils
    Neutrophils are the predominant cell type found in mammary tissues and mammary secretions during early inflammation caused by pathogens, and can constitute >90% of total mammary gland leukocytes. These non-specific cells travel from the blood to the mammary gland in response to a variety of inflammatory mediators, such as cytokines, complement and prostaglandins. At the site of infection, neutrophils phagocytize and kill bacterial pathogens. Neutrophils are also a source of small antibacterial peptides, the defensins, which are able to kill a number of the pathogens that cause mastitis.
  • Macrophages
    Macrophages are the predominant cell type that are found in the milk and tissues of healthy involuted and lactating mammary glands. They are active mammary gland phagocytic cells that are capable of ingesting bacteria, cellular debris and accumulated milk components. The phagocytic and bactericidal activities of these cells are especially diminished during the periparturient period.
    Macrophages also play a key role in antigen processing and presentation. Generation of effective specific immunity involves both antigen-presenting cells and lymphocytes.
  • Lymphocytes
    Lymphocytes are the only cells of the immune system which can recognize antigens through membrane receptors that are specific for invading pathogens. The two distinct subsets are T and B lymphocytes. Suppressor T lymphocytes are thought to control or modulate the immune response. B lymphocytes produce antibodies against invading pathogens.
  • Soluble defenses
    Immunoglobulins function as the soluble effector of specific or humoral immune response. They are produced by antigen-activated B lymphocytes. Four classes of Ig are known to influence mammary gland defense against bacteria causing mastitis: IgG1, IgG2, IgA and IgM.
    In healthy glands, Ig concentration is low during lactation but slowly increases during nonlactating periods and reaches peak concentrations during colostrogenesis. High concentrations also occur during inflammation. IgA appears to contribute to agglutination, preventing bacterial colonization and toxin neutralization. IgG1 & 2 and IgM act as bacterial opsonins that enhance phagocytosis of neutrophils and macrophages.
    Other bacteriostatic components in the mammary gland which provide protection include: lactoferrin, complement, lysozyme and the lactoperoxidase-thiocyanate-hydrogen peroxide system.
    Complement is a collection of proteins that is present in serum and milk, which functions in concert with a specific antibody to cause lysis of invading bacteria. Concentrations of complement are highest in colostrum, inflamed mammary glands and during involution. Concentrations are lowest during lactation.
  • Cytokines
    Cytokines are naturally produced proteins that play an important role in essentially all aspects of host defense by regulating the activity of cells that participate in specific and non-specific immunity.

Enhance immunity

In the last decade there has been a lot of research that looks at when the cow is most susceptible to mastitis-causing pathogens. “Clearly the host defenses are compromised most around the time of calving,” says Sordillo, “a couple of weeks before calving to two weeks after. There are numerous studies which show there are changes in immune cell functions and trafficking patterns to the udder, and changes in the ability for her to mount an effective immune response to specific pathogens.”

There are ways you can enhance the immune system of the cow to help her fight off mastitis. “In simple terms, we need to manage the cow with good nutrition, good housing and a good environment,” says Cullor, “and we can also use vaccines to help prevent disease before it gets out of hand.”

Good nutrition and adequate levels of micronutrients (see sidebar) are critical for immune function. “Part of your normal management routine should be checking the nutritional status of your dry cows, heifers and lactating animals to be sure your feeds are adequately compensating for micronutrients that might be deficient otherwise, such as vitamin E and selenium,” says Sordillo. “When you have a deficiency of selenium and vitamin E, the host defenses are compromised.”

Vaccination can also be used as a mastitis-prevention tool. Vaccination programs are designed to potentiate the immune system of the host toward a unique, specific antigen, says Sordillo. Vaccination with core antigen vaccines have been proven to reduce new coliform infections and to reduce the severity of infection when cases do occur.

“When the cow has mastitis, somewhere her immune system has broken down,” adds Belschner. “The challenge is to find what is not working, what we can do to fix it or stop doing what we may be doing that is interfering with normal immune or defense functions.”

“Management factors including nutrition, hygiene, genetics and environmental conditions influence the cow’s ability to respond to mastitis challenges,” sums Cullor. “Remember, poor management can overcome good immunology.”

 

Micronutrients critical for immune function

The nutritional status of the cow is directly related to overall health and proper nutrition has long been associated with the ability of an animal to fight disease. Most available information on micronutrients and their immunomodulatory properties with regard to bovine mastitis focuses on selenium, vitamin E, vitamin A, beta-carotene, copper and zinc.

Overwhelming evidence for the protective role of selenium against bovine mastitis clearly warrants inclusion of dietary selenium supplementation in mastitis control programs, says Lorraine Sordillo, PhD. Vitamin E supplementation could provide great benefit to the control of bovine mastitis. Mastitis control programs should ensure that proper levels of vitamin A and beta-carotene levels are maintained in all cows. Of great concern is the proper dietary intake of zinc by dairy cows as a means to maintain mammary immunity.

The necessity of nutritional supplementation, especially during the dry period before most deficiencies are likely to develop, should not be overlooked in the attempt to bolster the resistance of cows to mastitis. Sordillo offers the following on the role of micronutrients in immune function.

  • SELENIUM
    Function: Improves bactericidal capabilities of neutrophils. Decreases severity and duration of mastitis. Enhances neutrophil killing of Staph. aureus, Candida albicans and E. coli.
    Deficiency: Decreased efficiency in neutrophil function
  • VITAMIN E
    Function: Increased neutrophil bactericidal activity.
    Deficiency: Decreased incidence of clinical mastitis. In combination with Se, decreased prevalence of IMI at calving.
  • VITAMIN  A
    Function: Decreased somatic cell count. Moderated glucocorticoid levels. Stimulates immune cell populations.
    Deficiency: Increased severity of mastitis.
  • BETA-CAROTENE
    Function: Increased bactericidal function of phagocytes. Increased mitogen-induced proliferation of lymphocytes. Stimulates immune cell populations.
    Deficiency: Increased severity of mastitis.
  • COPPER
    Deficiency: Decreased neutrophil killing capability. Increased susceptibility to bactericidal infection.
  • ZINC
    Function: Linked to proper immune function. Essential for integrity of skin, physiologic barriers.
    Deficiency: Decreased leukocyte function. Increased susceptibility to bacterial infection. High calcium diets can exacerbate zinc deficiency problems.


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