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Transition: eye of the needle for immunity

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01 April 2014, at 1:00am

Susan McKay presents the first of three reports on a recent ‘immunity science symposium’, organised by Elanco, which reviewed the challenges faced during the period leading up to calving

MOST veterinarians know that the period of time leading up to and preceding calving is one of the most “stressful” times in a dairy cow’s life. These physiological stresses mean that management during this vital 90 days – two months before and one month after calving – is the key to performance for the duration of that lactation and beyond.

In a recent presentation given at the Elanco Immunity Science Symposium, Professor Holm Zerbe of Ludwig- Maximilians University, Germany, described how everything changes at the point of transition – from energy balance, to immunity, subsequent effects on fertility and the manifestation of puerperal disorders. It’s the “eye of the needle” through which a dairy cow must pass to have a healthy and productive cycle of lactation.

The top causes of dairy cow culling are commonly identified as fertility problems and udder disease, with only 2-3% attributed to metabolic disorders. That assertion is likely to underestimate the actual impact of metabolic disease as a causal agent in related conditions, such as metritis and mastitis, and therefore it is likely to be a hidden cause of culling.

Vets dealing with the consequences of transition will be well aware of the impact: around 40% of cows are likely to experience uterine disease within a week of parturition2 and up to 60% may have mastitis within the first eight weeks of lactation.

The challenge is that during pregnancy cows are immunosuppressed and the foetus is essentially a tolerated antigen but post-parturition the immune system switches to full power to decontaminate the uterine environment. Yet, we know that this is also the time that cows become vulnerable to infection, often suffering from production-related diseases.

The science regarding the efficacy of the immune response is gradually becoming better understood, providing a better rationale for immune system failures during this period. There are opportunities to improve dairy cow welfare and productivity for veterinarians who appreciate the importance of timely intervention that supports farmers and herds during the “vital 90 days” – this critical period around transition.

Added to the major metabolic changes occurring in pregnancy is the stress imposed by the cow going into negative energy balance due to extensive demands for energy to produce milk, exacerbated by a drop in dry matter intake.

In the first 100 days in milk (DIM), yield has been shown to increase regardless of energy intake. It is only after 100 DIM that milk yield can reduce in response to restricted energy intake. This disconnect means that the metabolic problems that occur in early lactation are not due only to negative energy balance but are rather a problem of poor metabolic regulation.

Challenges

Professor Nahum Shpigel, speaking at the same event, identified the challenges imposed by reducing body weight over subsequent lactations year on year. This leads to greater negative energy balance in subsequent lactations, predisposing to repeated bouts of mastitis. The link between negative energy balance and reduced neutrophil function is an important factor in this process.

Negative energy balance is also closely associated with early embryonic death, anoestrus and fertility problems. Conditions such as puerperal metritis and retained placenta suggest that in this post-partum period what vets are really seeing is not only attributable to energy balance but also the consequences of a dysregulated immune system.

At the centre of this concern over failures of innate immunity are neutrophils (also referred to as polymorphonuclear granulocytes – PMNs or neutrophillic granulocytes) which are responsible for binding and phagocytosing pathogens. The activity of these PMNs is down-regulated in the post-partum period, as measured by antibody dependent and antibody independent cellular cytoxocity (ADCC and AICC).

It is known that PMN function and expression reduces after calving in cows with a fatty liver and the worse the negative energy balance is, the more severe and prolonged is the uterine inflammation. Neutrophils in cows experiencing negative energy balance have reduced myeloperoxidase activity, are less bacteriocidal, are less effective at phagocytosis and contain less glycogen – their main energy source.

This close relationship between energy balance and immunity should be obvious, given that we know that fat is a metabolically active tissue that secretes macrophages and cytokines, inducing a pro-inflammatory state early in post-partum.

However, the situation is much more complex in that the “anti- inflammatory” pathway is more favourable to a successful pregnancy. Before parturition there is higher mRNA expression related to mitotic cell division and tissue differentiation.

The innate immune system is also highly involved in placental release and decontamination post-partum. It has been hypothesised that around parturition, the “anti-inflammatory” state associated with pregnancy, acts against the desired pro-inflammatory response needed to protect against pathogens post-parturition. This “pro versus anti” inflammatory balance may affect the severity of mastitis. In some cases the response to bacteria is much reduced and this has been attributed to reduced PMN function in the post-partum period.

Cells of the innate immune system express pattern recognition receptors (PRR). PRRs are able to recognise specific areas on the pathogen: PAMPS (pathogen-associated molecular patterns).

In the peri-partum period a difference in the PRR expressed may mean that the animal has an aberrant inflammatory response to bacteria and therefore does not respond effectively.

Response can change

During the symposium several speakers explored this area in more depth, describing the process at a molecular level and explaining why in transition cows the immune response can change according to host and pathogen related factors.

The impact of stress and circulating cortisol may also play a part in this immune system dysregulation. Insulin like growth factor (IGF-1) has been found to be higher in cows with lower serum NEFA levels and those cows are more likely to remain healthy post-partum. This may prove to be a useful biomarker in the future for risk assessment in the transition cow.

There are clearly many links between fat metabolism, inflammation and immunity. While energy balance has an impact on immunity due to the effects on neutrophil expression and function, there are other factors at work that mean immune dysregulation is a feature of the periparturient period and has profound effects during the vital 90 days of transition.

References

1. Zerbe, H. (2013) Transition period: the eye of the needle. How does energy balance interact with immunity, puerperal disorders and sub- fertility? Elanco Immunity Science Symposium: Vienna.

2. Sheldon, I. M., Cronin, J., Goetze, L., Donofrio, G. and Schuberth, H. J. (2009) Defining post-partum uterine disease and the mechanisms of infection and immunity in the female reproductive tract in cattle. Biology of Reproduction 6: 1,025-1,032.

3. Burvenich, C., Van Merris, V., Mehrzad, J., Diez-Fraile, A. and Duchateau L. (2003) Severity of E. coli mastitis is mainly determined by cow factors. Veterinary Research 34: 521-564. 

4. Gross, J., van Dorland, H. A., Bruckmaier, R. M. and Schwarz, F. J. (2011) Performance and metabolic profile of dairy cows during a lactational and deliberately induced negative energy balance with subsequent realimentation. Journal of Dairy Science 4: 1,820-1,830. 

5. van Straten, M., Friger, M. and Shpigel, N. Y. (2009) Events of elevated somatic cell counts in high-producing dairy cows are associated with daily body weight loss in early lactation. Journal of Dairy Science 92: 4,386-4,394. 

6. Zerbe, H., Schneider, N., Ossadnik, C., Wensing, T., Kruip, T.,A.,M., Grunert, E. and Leibold, W. (1998) Eigenschaften neutrophiler Granulozyten aus Blut und Uterus peripartaler Kühe. Veterinary Medicine of Austria 85: 304-309. 

7. Zerbe, H., Schneider, N. and Leipold, W. (2000) Altered functional and immunophenotypical properties of neutrophilic granulocytes in post-partum cows associated with fatty liver. Theriogenology 54: 771-786. 

8. Ster, C., Loiselle, M. C. and Lacasse P. (2012) Effect of post-calving serum nonesterified fatty acids concentration on the functionality of bovine immune cells. Journal of Dairy Science 95 (2): 708-717. 

9. Seyfert, H. (2013) Innate immunity: activation of the initial immune response during pathogen- specific mastitis. Elanco Immunity Science Symposium: Vienna. 

10. Shpigel, N. (2013) Neutrophils – not just killing machines. Facilitator of bacterial colonisation and inflammation control. Elanco Immunity Science Symposium: Vienna. 

11. Werling, D. (2013) Innate immunity: communication between innate and acquired systems. How this may affect vaccines. Elanco Immunity Science Symposium: Vienna. 

12. Piechotta, M., Kedves, K., Araujo, M. G., Hoeflich, A. et al (2013) Hepatic mRNA expression of acid labile subunit and deiodinase 1 differs between cows selected for high versus low concentrations of insulin-like growth factor 1 in late pregnancy. Journal of Dairy Science 96 (6): 3,737-3,749.