For many years much attention has been paid to adaptive immunity, the branch of the immune response that improves with repeated exposure, and so is responsible for development of “immune memory”. This is the branch we are focused on improving with vaccination.
However, in recent years research focused on the innate immune response has shown that the innate immune response is much more complex than was previously appreciated. “Many cells that are not considered to be ‘immune cells’, such as the epithelial cells that line the mammary gland, urogenital tract, and respiratory tract, have been shown to participate in innate immunity by expressing certain cell surface markers or secreting molecules that can protect the cow against infection directly, or indirectly by activating immune cells,” explains Amelia Woolums, DVM, PhD, Dipl. ACVIM, Dipl. ACVM, University of Georgia.
“This means that there are newly recognized pathways that we may be able to manipulate to improve the resistance of cattle to a variety of infections.”
Because the innate immune response is that part of the immune response that is always “on” and doesn’t take any time to be activated, this means that we might be able to improve the “baseline” or “resting” immune response of cattle. “We might be able to make them more able to resist infection at a moment’s notice by improving or manipulating innate immune functions,” Woolums says.
It has been shown that the innate immune system’s components interact with the adaptive immune system to improve adaptive responses. “If we can find ways to manipulate the innate immune system, we may not only improve the cow’s baseline resistance to infection, but we might also be able to improve the cow’s future resistance to infections by improving immune memory, which is the result of the adaptive immune response,” Woolums notes.
For example, molecules such as defensins and cathelicidins, which are antimicrobial peptides produced by a variety of cells in the body and which are involved in the innate immune response, can sometimes act like adjuvants. “That is, they can improve future responses by the adaptive immune response to infectious agents,” Woolums explains. “Because of this, researchers are working to see if adding certain defensins or cathelicidins to vaccines can improve vaccines.”
Innate immunity and the pro-inflammatory response are absolutely essential to mobilize antigen University. “If there is no inflammation from the innate immune response, there is no vaccine response.”
Immunity against disease is a very complex and dynamic process, so it is only natural for us to try to break it down into more basic categories such as innate, adaptive, humoral and cellular, to better comprehend processes our bodies undertake to combat organisms that can make us sick or even worse, adds Marcus Kehrli, Jr., DVM, PhD, National Animal Disease Center, Ames, Iowa.
“In reality, new findings constantly remind us the immune response is composed of a complex series of responses with overlapping relationships between the different categories we define,” Kehrli explains. “This complexity is no different for the bovine immune system. Activation of the innate immune system in many instances is a required co-stimulatory factor for triggering adaptive immunity.”
Genetically-programmed differences in components of the innate immune response may be related to an animal’s susceptibility to certain infections, or an animal’s risk of developing more severe disease if they are infected with a certain agent. For example, genetically programmed differences in various molecules involved in the innate immune response have been shown to be related to a cow’s likelihood of being infected with Mycobacterium avium ss paratuberculosis, the causative agent of Johne’s disease. “It’s conceivable that we might select cattle for resistance to certain diseases based on their genes for various components of the innate immune response,” Woolums adds.
Susceptibility or resistance to a disease such as Johne’s is likely controlled by a variety of genes — probably dozens — so it might be complicated to identify the way to best select cattle for genetic disease resistance disease. “Ongoing research into components of the innate immune response will no doubt form the basis for future efforts to select cattle for disease resistance,” Woolums says.
How innate immunity matures
Studies suggest that although the immune system of newborn calves is functional, it’s not fully developed. Some functional activities of the neutrophil are not fully mature during the first 1-3 months of life (only 50% to 70% of adult levels); they gradually mature to an adult capacity around 1 year of age, Kehrli notes. “Studies in other species suggest the onset of puberty as a point when immune function reaches mature capacity.”
Kehrli says it has been suggested that the lower functional activity of neutrophils in young calves may in part be responsible for their increased susceptibility to infectious disease. “These age effects are also known for the adaptive immune system where we know that newborn calves have a reduced capability of producing interferon-γ that may take a couple weeks to approach a more adult capacity.”
He says some researchers are attempting to discover methods to enhance the adaptive immune system when vaccinating calves for diseases of concern on a particular farm. “When a calf is born, it is not only immature in the capacity of its immune system, but the repertoire of antibodies from the adaptive immune system is extremely naïve and is primarily limited to passively acquired antibodies and adoptively transferred lymphocytes from the dam’s colostrum. Scientists have investigated methods to accelerate the maturation of the immune system in young calves; unfortunately, there is nothing on the horizon that will fully achieve that goal today.”
Woolums adds that while the innate immune response is active in the newborn calf, it is true that certain aspects of the response improve with age. “For example, the ability of neutrophils to phagocytize bacteria is better in adult cattle compared to calves in the first week of life.” Another example is the concentration of complement proteins, which are present in serum and which participate in the innate defense against bacterial and viral infection. Certain complement proteins are present in lower concentrations in young calves than in adults.
Old age is also associated with decline in some innate immune functions, although this has been studied more in other species (e.g., humans) than in cattle. However, researchers have shown that the production of oxygen radicals by neutrophils, which is an important tool in the antimicrobial defense mediated by these cells, is decreased more in multiparous cows as compared to first calf heifers, as shown in a 2002 Journal of Dairy Science study by Mehrzad et al.
“Although I am unaware of any published data on when immune function begins to wane in adult cattle, studies in humans suggest menopause as a point where immune function begins a gradual decline,” Kehrli says.
First lines of defense
The innate immune system relies on neutrophils as “first responders.” “Neutrophils are often called first responders because they are usually the first immune cell to get to the scene of a presentation cells and replication, recruitment and movement of both B- and T-lymphocytes, says Chris Chase, DVM, PhD, Dipl. ACVM, South Dakota State problem such as infection or tissue damage,” Woolums says.
Kehrli often speaks of neutrophils as being the “Marines” of the immune system in that they are the first to hit the beach with overwhelming force when duty calls to combat an infection. “The early inflammatory response that neutrophils help execute is often critical in determining the outcome of an infection,” he says. “We know that delays in the inflammatory response typically result in a more severe disease episode, so it’s likely that neutrophils often get little attention in that they frequently do their job with little notice.”
In the mammary gland there are many intramammary infections, and the vast majority of bacterial invasions are quickly resolved and remain below our ability to even detect that they occurred. “Certainly the neutrophil would be the most noticeable contributor to the innate immune system in terms of sheer numbers of cells involved, but we should never underestimate the contributions of other cells, cytokines or humoral factors of innate immunity,” Kehrli adds.
Woolums agrees and says neutrophils don’t deserve all the glory. “Other cells, such as those that are in direct contact with the outside world including skin epithelial cells, mammary gland cells, and epithelial cells of the respiratory, urogenital and gastrointestinal tracts, are also critical to innate immunity.”
Epithelial cells provide a simple but vital function — they form a mechanical barrier to infection. The cilia of the respiratory epithelial cells of the upper respiratory tract exclude many infectious agents and irritating particles simply by beating in an upward direction, so that mucus on the surface of the respiratory tract, which traps agents and particles, is kept out of the lower respiratory tract.
“Epithelial cells that are infected by viruses or exposed to bacteria or other infectious agents quickly express surface molecules and secrete other factors that set off the inflammatory response that immediately begins to counteract infection or tissue injury, which also is vital for activating the adaptive immune response,” Woolums says.
And while the neutrophil is the major player, Chase adds that a lot of the damage (immunopathology) that occurs, for example with bronchopneumonia, is the result of the release of neutrophils and their granules.
Innate immunity can’t do it alone
Innate immunity isn’t enough to protect against disease. “Given that vertebrates are the only animals with a sophisticated adaptive immune system, we might argue that the innate immune system is limited in that it provides no immunological memory to previous disease episodes with the same pathogen,” Kehrli explains. “Immunological memory provides the basis for our vaccination programs that have helped enable eradication of many diseases.”
Clearly there are examples of diseases in humans (small pox and polio) and animals (rinderpest) today that have been brought under control or eradicated as a result of effective vaccines. “If we only had an innate immune system, these diseases would still be with us today,” Kehrli says.
“This is why the two systems work so well together,” Woolums adds. “The innate response is immediately effective, all the time, but it doesn’t get better or faster with repeated exposure. The adaptive immune response takes time (days to weeks), but it gets better and faster with repeated exposure.”