Transition: eye of the needle for immunity - Veterinary Practice
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InFocus

Transition: eye of the needle for immunity

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.

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