Mother nature seems to have a reason for periparturient immune suppression in almost all species studied.

Editor’s note: Part I of a two-part series. Click here to see part II of the series.

Cows possess a full array of natural immunological defenses; however, these defenses are not at their normal capacity during the calving period. This decrease in immune protection can leave the door open for post-calving diseases, such as mastitis, metritis and others. “Studies around the world have repeatedly demonstrated that during this time neutrophils have varying degrees of impairment in their ability to mobilize and defend a tissue in response to an invading pathogen,” says Mark Kehrli, DVM, PhD, National Animal Disease Center, Ames, Iowa. “Moreover, lymphocytes have reduced capacity for cell-mediated immunity, antibody production and production of cytokines critical to effective immune responses.”

Natural immunosuppression
Neutrophils are the first line of defense against disease pathogens. These cells, when fully active, can ingest and kill bacteria picked up from the environment during the calving process. “The problem is that too many cows are immunosuppressed at calving, and therefore these cells are not up to the job,” explains Jesse Goff, DVM, PhD, also with the NADC. “Then infections, usually a mixture of bacteria, can gain a foothold in the debris lining the uterus following calving.”

The normal cycling of estrogen and progesterone during the natural estrus cycle alters neutrophil function and host defense to some degree. During the normal estrus cycle when progesterone is high and estrogen is low, neutrophil function is suppressed. During pregnancy, progesterone is very high. “We know that high levels of progesterone have some of the same immunosuppressive effects as cortisol,” says Jim Roth, DVM, PhD, Iowa State University. “If you artificially inseminate a cow at the right time, estrogen is high, and the uterus is pretty resistant to infection. If you AI her at the wrong time, perhaps because your heat detection is off, you can get bacteria in the uterus when progesterone is high, and cows are much more likely to develop metritis.”

 

Marcus Kehrli, DVM, PhD, says it’s believed natural immunosuppression serves to prevent the cow from developing immunity against fetal antigens.

Roth says that aside from progesterone, naturally produced endorphins for pain relief during calving may also alter immune function. “Plus, the energy needed for lactation, especially if a cow gets into a negative energy balance, has an effect on immune function. There are a variety of things happening at one time to cause immunosuppression around parturition.”

There is a wide array of peptide (e.g., relaxin, prolactin, etc.) and steroid hormones (estrogens and progesterone) that are elevated near the end of pregnancy to help prepare the uterus, cervix and vagina for delivery and the mammary gland for feeding the newborn. There is also a surge of cortisol that occurs within a few hours of labor. “Individually, all of these factors have known effects on immunity,” says Kehrli. “So when you superimpose them on top of each other at the end of pregnancy, it becomes rather obvious that the immune system doesn’t stand much of a chance of operating at normal capacity.”

The experts are not sure why cows are naturally somewhat immunosuppressed during parturition. “Some people think natural immunosuppression at this time is a way for the mother to protect herself from fetal antigen,” says Goff. “That may be true, but today’s cows tend to go overboard. If a small, natural immunosuppression is needed, the dairy cow goes beyond what’s needed to something that is pathological. She fails to respond to vaccination at this time and fails to fight off pathogens that ordinarily she could handle. We see Johne’s disease, salmonellosis and other diseases in just-freshened cows because they are immunosuppressed, though they would ordinarily keep those organisms in check.”

 

Jesse Goff, DVM, PhD, says at calving, cows fail to respond to vaccination and fail to fight off pathogens.

It is important to understand that Mother Nature seems to have a reason for periparturient immune suppression in virtually all species studied, adds Kehrli. “It is our belief this takes place because of the anticipated exposure of the mother to fetal antigens after placental detachment. Some of the fetal antigens are from the father, and in most cases, it is not useful to develop immunity against them.” By reducing immune responses, the maternal immune system does not spend as much energy responding to paternal antigens as it otherwise might. “An unfortunate consequence, however, is that this leaves the postpartum female rather susceptible to infectious disease during the immediate peripartal period when immune suppression is most dramatic.”

It has been demonstrated that various humoral immunity factors such as complement proteins and conglutinin levels are reduced after calving. “Simply put, it is widely believed that virtually every branch of the immune system is dysfunctional to some extent in transition cows,” says Kehrli. Impairment in any one of the measures of immunity is unlikely to be all that detrimental by itself to the defense of a cow. “However, when the breadth of immune impairment is as extensive as we know it to be, it is far more believable that impaired immunity in transition cows is an important factor contributing to the development of infectious disease.”

Having suppressed phagocytic cell function makes cows more susceptible to bacteria which cause the biggest problems long-term. “A combination of stressers makes cows more susceptible, then if they also pick up a virus or if the stress recrudesces the IBR virus, that suppresses them further,” says Roth. “Coccidiosis or Salmonella can establish a foothold and cause further immune suppression. You get a vicious cycle where their immune system is suppressed, and they can’t defend their mammary gland, uterus or lungs very well.”

Some impairments to the immune system are detectable as early as seven to 10 days before calving. Fortunately for the cow, all of these impairments are transient in nature — some may only last a few hours, others may last two to four weeks before the immune system recovers to more “normal” levels. What is critical to understand about periparturient immune suppression is that it is the combination of environmental exposure to potential pathogens and impaired host defenses that dramatically increases the probability of a disease event. “If transition cows are kept in a clean, dry environment, they are far less likely to develop mastitis or metritis than if they are wading around and lying down in a slurry of mud and manure,” notes Kehrli. “The longer and more severely a cow’s immune system is impaired in a less than optimal environment, the more likely it is she will acquire an infectious disease of the uterus or mammary gland.”

 

Jim Roth, DVM, PhD, says there are a variety of things happening at one time to cause immunosuppression around parturition.

How long does natural immune suppression last? Roth says immune function is suppressed for about a week before and a couple of weeks after parturition, so a cow can have approximately three weeks of mild-to-moderate immune suppression surrounding calving.

Immunity and disease

Poor immune response at calving can contribute to conditions such as retained placentas. “The reproductive tract is certainly considered an immunologically privileged site — how else would a foreign tissue such as that of a fetus be able to survive if there was not a localized or regionally targeted suppression of host defense factors?” asks Kehrli. We believe that an impaired or delayed inflammatory response contributes to retained placental membranes. The cause of this impairment is rather complex. In simplest terms, we believe that many of the hormones that prepare the reproductive tract for labor have the capacity to suppress the immune system.”

In research Kehrli did at the National Animal Disease Center-USDA-ARS, he saw examples of cows with  severe metritis or retained placentas that mobilized virtually all of their circulating immune cells (e.g., neutrophils) to fight uterine infections. This mobilization left very few neutrophils in the blood stream to fight an infection that might start elsewhere in the body, such as the mammary gland. “These cows might develop an infection in the mammary gland that goes unchecked for a few hours until the circulating blood neutrophil numbers are restored from the bone marrow. By that time, it is too late for the cow and the infection in the udder may have grown so much that the disease now overwhelms her with a severe peracute case of mastitis.”

 

Naturally-produced endorphins for pain relief during calving as well as the release of other hormones may alter immune function.

The experts agree that it is possible that the impaired immune system of transition cows could contribute to the development of clinical disease caused by subclinical bacterial infections, such as salmonellosis or Johne’s disease, as well as recrudescence of some viral infections. Kehrli says that while he has limited data, it is his impression that, on average, older cows experience a greater degree of periparturient immune suppression than heifers. “This is consistent with the observation that older cows experience more mastitis and metritis than heifers. We don’t understand why this is so, and it seems paradoxical with the belief that heifers are more prone to the stress of parturition and dystocia than multiparous cows.”