Research in Veterinary Science 126 (2019) 94–102

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Research in Veterinary Science

journal homepage: www.elsevier.com/locate/rvsc

The impact of heat stress on the immune system in dairy cattle: A review T
a a a a b c,d a,⁎
M. Bagath , G. Krishnan , C. Devaraj , V.P. Rashamol , P. Pragna , A.M. Lees , V. Sejian
a
ICAR-National Institute of Animal Nutrition and Physiology, Adugodi, Bangalore 560030, Karnataka, India
b
School of Agriculture and Food, Faculty of Veterinary and Agricultural Sciences Dookie Campus, Dookie College, The University of Melbourne, Victoria 3647 Australia
c
The University of Queensland, School of Agriculture and Food Sciences, Animal Science Group, Gatton, QLD 4343, Australia
d
University of New England, School of Environmental and Rural Science, Armidale, NSW 2350, Australia

A R T I C LE I N FO A B S T R A C T

Keywords: Heat stress is well documented to have a negative influence on livestock productivity and these impacts may be
Cell mediated immunity exacerbated by climate change. Dairy cattle can be more vulnerable to the negative effects of heat stress as these
Climate change adverse impacts may be more profound during pregnancy and lactation. New emerging diseases are usually
Cortisol linked to a positive relationship with climate change and the survival of microrganisms and/or their vectors.
Dairy cattle
These diseases may exaggerate the immune suppression associated with the immune suppressive effect of heat
Heat stress
Humoral immunity
stress that is mediated by the hypothalamic-pituitary-adrenal (HPA) and the sympathetic-adrenal–medullary
Nutrition (SAM) axes. It has been established that heat stress has a negative impact on the immune system via cell
mediated and humoral immune responses. Heat stress activates the HPA axis and increases peripheral levels of
glucocorticoids subsequently suppressing the synthesis and release of cytokines. Heat stress has been reported to
induce increased blood cortisol concentrations which have been shown to inhibit the production of cytokines
such as interleukin-4 (IL-4), IL-5, IL-6, IL-12, interferon γ (IFNγ), and tumor necrosis factor-α (TNF- α). The
impact of heat stress on the immune responses of dairy cows could be mediated by developing appropriate
amelioration strategies through nutritional interventions and cooling management. In addition, improving
current animal selection methods and the development of climate resilient breeds may support the sustainability
of livestock production systems into the future.

1. Introduction influenced by the genotype, health and immune status of individual

Heat stress is associated with a significant economic burden to li-
vestock producers globally (St-Pierre et al., 2003). If modelling pre-
dictions are accurate, climate change is likely to have a significant
impact on the stability and sustainability of livestock production en-
terprises worldwide. One predicted consequence of climate change is
the increased prevalence and intensity of heat load periods (Solomon
et al., 2007). Climatic trends differ from one summer to another and
prediction models suggest that there will be continued large variability
in the climatic behaviour of heat load events in future years (Robinson,
2001; Westcott, 2011).
Heat stress occurs when an animal is unable to maintain equilibrium
between heat accumulation and heat dissipation (Hahn, 1985;
Bertipaglia et al., 2007). Climatic factors that influence heat accumu-
lation in dairy cattle include ambient temperature (TA, °C) relative
humidity (RH, %), solar radiation (SR, W/m2) and wind speed (WS, m/
s) (Bond et al., 1967; Blackshaw and Blackshaw, 1994; Brown-Brand
et al., 2006b). The impact of heat stress on dairy cattle is also
cow (Pragna et al., 2017). Heat stress is well documented to reduce dry
matter intake (DMI) in cattle, which consequently has a negative in-
fluence on nutrient absorption overall impacting the immune system
and inflammatory response of cattle (Yadav et al., 2016). The impact of
heat stress is variable and ranges from animal discomfort to death in
extreme circumstances (Vitali et al., 2009).
During periods of heat stress the hypothalamic-pituitary-adrenal
(HPA) and the sympathetic-adrenal–medullary (SAM) axis are activated
for maintaining homeostasis in response to stressful stimuli (Sejian
et al., 2018). The production of cortisol during periods of acute stress
acts as a stimulus for the immune system, however during chronic stress
cortisol secretion has been associated with immune suppression (Ju
et al., 2014; Jin et al., 2011). Consequently, the suppression of the
immune system results in the animal becoming more susceptible to
disease and immune challenges. Of the two immune responses, the
innate and the adaptive, the adaptive response is more complex and
requires prolonged immunological challenge to become functionally
active. Although the innate and adaptive immune responses are distinct

⁎
Corresponding author.
E-mail address: drsejian@gmail.com (V. Sejian).

https://doi.org/10.1016/j.rvsc.2019.08.011
Received 17 March 2019; Received in revised form 1 July 2019; Accepted 2 August 2019
0034-5288/ © 2019 Elsevier Ltd. All rights reserved.
M. Bagath, et al.
from each other, they interact in a well-coordinated approach to re-
move and protect the body from pathogens and/or foreign substances.
The adaptive immune system can be further divided into Cell-Mediated
Immunity (CMI) and Humoral Immunity (HI). T-lymphocytes are ac-
tively involved in the CMI, while the B-lymphocyte plays a vital role in
HI. Both the CMI and the HI maintain the balance to ensure that im-
mune function remains effective, which can be inhibited during ex-
posure to stressors (Smith and Vale, 2006).
With increasing prevelence and intensity of adverse weather events,
dairy cattle may become increasingly susceptible to heat stress. In re-
sponse to future climate change projections, suitable amelioration
strategies need to be developed to maintain the health, productivity and
well-being of dairy cattle during periods of heat stress. Therefore, the
purpose of this review is to describe the influence of heat stress on the
immune system of dairy cattle. This may provide valuable information
towards understanding and identifying appropriate amelioration stra-
tegies to maintain the integrity of the immune system of dairy cattle
during periods of extreme climate.
2. Heat stress and dairy cattle production
Dairy cattle experience heat stress when they are exposed to en-
vironmental conditions above their thermo-neutral zone. As heat stress
increases there is a reduction in DMI, growth, feed conversion effi-
ciency (Brown-Brand et al., 2005), reproductive performance (Jordan,
2003), milk production, and milk quality (Wheelock et al., 2010;
Rhoads et al., 2009). Heat stress is also associated with hypofunction of
the thyroid gland which subsequently results in reduced metabolic heat
production (Omidi et al., 2015). Therefore, reduction in thyroid hor-
mone concentration can be considered as an adaptive mechanism to
reduce metabolic heat production during periods of hot climatic con-
ditions (Lacetera et al., 1996).
3. Interaction between heat stress and the immune system of
dairy cattle
The SAM and HPA axis play an integral role in regulating responses
to stressors. Stimulation of the HPA axis results in the production of
cortisol, which is associated with a suppression of the immune system
in cattle (Grandin, 1997). Fig. 1 highlights the various impacts of heat
stress on the immune response of dairy cattle. The effect that heat stress
has on inducing glucocorticoids is varied due to the different cytokines
produced (Elenkov, 2004). However, the inhibition of cytokine pro-
duction by glucocorticoids may be a protective mechanism in an at-
tempt to prevent excessive immune suppression. Glucocorticoids in-
fluence the balance of T-helper 1 (Th1) and T-helper 2 (Th2) through
the inhibition of IL-12, whereas catecholamines inhibit IL-12 and en-
hanced IL-10 production (Sophia et al., 2016). Therefore, glucocorti-
coids and catecholamines may suppress cellular immunity and result in
a preferential shift towards Th2-mediated HI (Elenkov et al., 2000).
The response of the immune system is one of the mechanisms de-
veloped to defend against environmental challenges (Stephanou et al.,
2011). One common theory is that stressors suppress components of the
immune system, thus enhancing the susceptibility of an animal to dis-
ease. Heat stress stimulates the signal transduction pathways, altering
gene expression of the immune cell mediators resulting in the activation
of the heat shock response promoting cytokine activity. Distinct cyto-
kine patterns are responsible for the effector functions and development
of Th1 and Th2 cell responses. T-helper 1 cells activate cellular im-
munity and inflammatory responses, whereas Th2 cells regulate HI and
promote anti-inflammatory responses (Hendrix and Nitsch, 2007). The
ability of animals to selectively produce Th1 cytokines (IFN-γ and IL-
12) and Th2 cytokines (IL-10, IL-4, IL-13) is an important component in
regulating the Th1:Th2 cytokine balance (Park et al., 2005). Hy-
perthermia is associated with a down regulation of Th1 cytokines and
an upregulation of Th2 cytokines, thus suppressing the CMI (Webster,
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Research in Veterinary Science 126 (2019) 94–102
2002; Lacetera et al., 2005). Heat stress impairs the cellular immune
response by increasing the cortisol concentrations, which binds to DNA
inhibiting the expression of genes involved in T-cell activation and
cytokine production (Caroprese et al., 2012; Sgorlon et al., 2012). The
anti-inflammatory properties of corticosteroids results in a decrease in
phagocytic cell activity and alter lymphocyte function (Caroprese et al.,
2012). Heat stress influences the immune system by altering the
Th1:Th2 ratio as the immune system attempts to maintain homeostasis,
however shifts from homeostasis may result in animals becoming im-
munocompromised and subsequently become more susceptible to dis-
eases (Elenkov et al., 2000). Therefore, maintaining the Th1:Th2 bal-
ance could be a critical factor in minimising the impact of
immunological challenges during the summer season.
4. Impact of heat stress on immune responses of dairy cattle to
vaccination
Heat stress is associated with numerous health concerns in livestock
and is also associated with limiting an animal's ability to build an im-
mune response. Administering vaccines in cattle during periods of heat
stress may not allow for the development of an optimum immune re-
sponse, therefore potentially rendering the vaccine ineffective (Hu
et al., 2007). Furthermore, heat stress reduces the natural barriers of an
animal to bacteria and also potentially increases the level of endotoxin,
which may have further undesirable effects on vaccines containing
whole cells of target bacteria (Lambert, 2009). Glucocorticoids released
during heat stress activate latent viruses, via i) directly acting on the
viral genome, and by ii) decreasing the immunological memory re-
sponses. Chronic heat stress negatively impacts the immune system in
mice and increases their susceptibility to infections by increasing the
number of CD4+, CD25+, Foxp3+, IL-10 and TGF-β which is asso-
ciated with a suppression of the adaptive immune response (Meng et al.,
2013). Hu et al. (2007) reported that chronic heat stress negatively
influenced the immune responses of DNA vaccination by impairing the
CMI. Overall these studies suggest that heat stress negatively influences
the responsiveness of the ruminant immune system.
5. Molecular mechanisms governing immune responses during
heat stress in dairy cattle
Heat stress elicits numerous physiological and cellular adaptation in
an attempt to counteract the impact of stress and to protect the body
from its harmful effects (Sonna et al., 2002). These mechanisms help in
the elimination of pathogens, both specifically and non-specifically.
Cortisol efficiently negates the heat stress response and has an anti-
inflammatory influence on the immune response, whilst catecholamines
are considered to have an inflammatory effect (Kovács et al., 2000).
Therefore, heat stress negatively influences the immune response by
stimulating HPA and SAM axis, followed by the stimulation of the
primary and the secondary lymphoid organs resulting in the production
of antibodies, cytotoxic cells, cytokines, chemokines and heat shock
proteins (HSPs) (Collier et al., 2008; Evans et al., 2015). The genes
regulating stressor proteins such as HSPs, NOD-like receptors (NLRs),
Toll-like receptors (TLRs), RIG-I like receptors (RLRs), C-type lectin
receptors (CLRs), the AIM2-like receptors (ALRs), cytokines and che-
mokines also play a vital role in the regulation of the immune system
(Vidya et al., 2018).
Cortisol regulates the immune system by targeting the genes related
to cytokines, chemokines, inflammatory proteins and their receptors as
well as cell adhesion (Löwenberg et al., 2008; Cruz-Topete and
Cidlowski, 2015a, 2015b). At the transcription level cortisol binds to
the glucocorticoid receptor to repress the transcriptional activity of the
activator protein-1 (AP-1) and NF-κB, thus regulating the expression of
various cytokines (Liberman et al., 2007; Busillo and Cidlowski, 2013).
Cortisol inhibits MAPK signalling pathways, through MAPK phospha-
tase-1 which causes inhibition of p38 MAPK repressing multiple
M. Bagath, et al.
Fig. 1. Description of various impacts of heat stress on the immune system in dairy cattle.
inflammatory genes (Wu et al., 2005). As cortisol concentrations in-
crease and bind with its receptors, there is an inhibitory effect on the
immune system which is associated with a repression on the anti-in-
flammatory action of immune cells.
Under in vitro conditions the polymorphonuclear cells exposed at
39 °C and 41 °C did not show any change in the caspase-3 and caspase-7
activity respectively, however there were changes in the phagocytosis
and ROS production when exposed to 41 °C (Lecchi et al., 2016). Min
et al. (2016) showed that during heat stress condition in dairy cows 85
proteins were differentially abundant, while the complement compo-
nents C1, C3, C5, C6, C7, C8, and C9, complement factor B, and factor H
were down-regulated. These results imply that the immune system of
these dairy cows exposed to heat stress was compromised. The immune
system within the udder is also compromised via the suppression of
CMI, thus facilitating the risk of infection, apoptosis of mammary cells
and reduced milk production (Thompson-Crispi et al., 2014).
6. Role of heat stress and HSPs in immunity
Intracellular HSPs, particularly HSP70 and HSP90, are involved in
antigen processing and presentation, in addition to their functions as
molecular chaperones (Archana et al., 2017). Heat shock proteins are
associated with the cytoplasmic antigenic peptide and aid in the peptide
translocation and processing (Ishii et al., 1999). The HSP70 family are
associated with the transporters affiliated with antigen processing
(TAP) and require ATP-for transportation of antigenic peptides from the
cytosol to the endoplasmic reticulum (Kamiguchi et al., 2008). Heat
shock proteins are also associated with the TLR pathways, where HSP70
and HSP60 play a role in the stimulation of TLR4 for the proliferation of
dendritic cells (DC) (Fang et al., 2011). Damaged cells in an affected
area release HSPs that activate DC, thus inducing inflammatory reac-
tions by secreting inflammatory cytokines. Increase in the duration of
stress leads to more damaged cells, which are positively correlated with
an increasing amount of extracellular HSPs and innate immune re-
sponse (Calderwood et al., 2016). This suggests that HSPs have a role in
boosting the innate immunity.
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Research in Veterinary Science 126 (2019) 94–102
7. Heat stress and innate immunity and leukocyte population in
dairy cattle
Depending on the stimuli, various components of the immune
system may be activated. The innate immune response is the first line of
defense that acts immediately when the body is exposed to an infection
or immune challenge (Medzhitov, 2007). It includes physical barriers
such as the skin and mucosal membranes, mucosal secretions, tears,
saliva, urine, digestive and vaginal acids. If these physical barriers fail
to eliminate the pathogen, then the innate immune system responds by
facilitating the migration of neutrophils, monocytes (in the blood), and
macrophages (in the tissue) to the site of infection and use invariant
receptors to detect a wide array of pathogens (Sophia et al., 2016).
Upon detecting a pathogen, these cells phagocytize the pathogen by
engulfing and kill the pathogenic organism by endolysosomal path-
ways. Innate immunity provides priming opportunity and allows for the
development of the adaptive immune system to produce antibodies
against target pathogens (Janeway, 1999).
Leukocytes form the principal components of the immune system,
their primary function is to protect and defend the body against the
invading infectious agents such as bacteria, viruses, fungi, and parasites
(Chandra et al., 2012). Leukocyte population is affected under heat
stress condition in dairy cattle (Lacetera et al., 2005). Salem (1980)
reported that leukocyte concentration decreased during summer in both
cows and buffaloes. Gwazdauskas et al. (1980) indicated that total
leucocyte counts and differential leucocyte counts were altered in re-
sponse to chronic stress in cattle. The increase in leukocytes is sug-
gestive of an altered immunological activity in buffalo calves exposed
to acute thermal shock (Omran et al., 2013). Chandra et al. (2012)
reported that the mean values of leukocytes varied from 12.37 ± 0.74
to 14.34 ± 0.55 (×103cells/μl) and from 9.53 ± 0.67 to
13.57 ± 0.23 (× 103cells/μl) in growing and adult Sahiwal cows,
respectively during summer seasons under in vivo conditions. The mean
concentrations of total leukocytes in Tharparkar and Karan Fries cattle
varied from 13.72 ± 0.52 to 13.88 ± 0.73 and 12.76 ± 0.58 to
13.20 ± 0.40 (× 103cells/μl), respectively, when exposed to different
M. Bagath, et al.
temperature conditions and it was concluded that there were no sig-
nificant difference in the total leukocyte count in both breeds (Pandey
et al., 2017). Abdel-Samee (1987) reported that leukocytes increase by
21–26% in Friesian cattle under heat stress conditions due to thyr-
omolymphatic involution. Nouty et al. (1986) observed higher total
leukocytes count during summer months as compared to other seasons
in Holstein breed of cattle and they attributed this to the heat stress
experienced by these animals during summer season. The mean total
leukocytes were higher in summer than in monsoon or winter (Naik
et al., 2013). This could be due to release of corticosteroids or epi-
nephrine hormones due to summer stress which in turn increased leu-
kocyte count (Jain, 1993).
A study conducted on young calves under different housing condi-
tions it was established that neutrophil levels increased and the number
of lymphocytes were lower in animals that were stalled compared to
housed animals in loose house system (Friend et al., 1987). Stull and
McMartin (1992) reported that the neutrophils to lymphocytes (N:L)
ratio were higher during heat stress exposure. The mean neutrophil
count was significantly higher in summer than in winter and monsoon
seasons because of high heat stress incidence during the summer
months in Punganur bred of cattle under in vivo studies (Naik et al.,
2013). This increase might be due to an accelerated mobilization of
mature neutrophils from marrow, due to the release of glucocorticoids
during heat stress (Jain, 1993). This finding was in contrary to the re-
sults reported by Narayan et al. (2007) who observed a decrease in
neutrophil count during summer in Holstein-Friesian crossbred cows
under in vivo conditions.
Lymphocytes are involved in a variety of immunological functions
such as immunoglobulin production and modulation of immune de-
fense (Campbell, 1996). Heat stress was established to negatively in-
fluence the lymphocyte proliferation under in vitro conditions (Lacetera
et al., 2005; Kamanga-Sollo et al., 2011). Elvinger et al. (1991) reported
that lymphocyte from Holstein cows at high temperature (42 °C) for
60 h showed a reduction in proliferation compared with incubation at
38.5 °C during in vitro studies. However, there were no effects in Hol-
stein cows during in vivo conditions. Further, Lacetera et al. (2006)
showed that at 41 °C and 42 °C lymphocyte proliferation under in vitro
conditions declined in both Brown Swiss and Holstein cows. There was
also a significant decrease in the lymphocyte counts and an increase in
neutrophil counts in Sahiwal and Karan Fries heifers when exposed to
40 °C (Mayengbam, 2008). Furthermore, it was established that the
monocytes count increased during summer and this was attributed to
the increased cortisol secretion (Jain, 1993). However, under in vivo
conditions the mean eosinophil count was established to be lower
during summer and higher during monsoon in Punganur cattle (Naik
et al., 2013). Similarly, the mean basophil count was statistically lower
under in vivo conditions in summer as compared to either monsoon or
winter in Holstein-Friesian crossbred cows (Narayan et al., 2007).
8. Heat stress impact on cell-mediated immune response in dairy
cattle
The adaptive immune system is composed of both cellular and hu-
moral responses (Elenkov, 2008). However, studies on the impact of
heat stress on CMI of cattle are inconclusive (Lacetera et al., 2006).
Under in vitro condition, peripheral blood mononuclear cells (PBMC)
are affected under heat stress conditions in cattle and buffaloes and the
responses are variable depending on the physiological state of the an-
imals (Lacetera et al., 2006). Hot weather increased the proliferation of
PBMC in cows in a temperate climate under in vitro conditions (Soper
et al., 1978). Lacetera et al. (2006) observed that the PBMC isolated and
stimulated with concanavalin A from both Brown Swiss and Holstein
cows showed that the Holstein PBMC were more tolerant to heat stress
than the Brown Swiss during chronic heat stress exposure under in vitro
conditions.
Elvinger et al. (1991) reported that exposure of lactating Holstein
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Research in Veterinary Science 126 (2019) 94–102
cows to heat stress under in vitro conditions resulted in the decline of
lymphocyte proliferation in culture incubated for 60 h at 42 °C after
stimulation with mitogens. Similarly, Kamwanja et al. (1994) reported
that the exposure of bovine lymphocytes to a heat shock of 45 °C for 3 h
under in vitro conditions decreased the number of viable cells and re-
duced the PBMC response to mitogens. The impaired function of bovine
lymphocytes during periods of heat stress may be associated with re-
duced cellular immunity, which influences the Th1 and Th2 balance in
favor of the secretion of Th2 cytokines ultimately affecting lymphocyte
proliferation (Lacetera et al., 2005; Lacetera et al., 2006). Exposure of
bovine lymphocytes under in vitro heat shock reduced the lymphocyte
proliferation response to mitogen and reduction in the number of viable
cells in Angus cattle (Elvinger et al., 1991). In cows, heat stress had an
immunosuppressive effect on lymphocyte proliferation in response to
the T cell mitogen Con An under in vitro conditions (Lacetera et al.,
2006). The proportion of lymphocyte and neutrophil has been reported
to increase during summer months compared with monsoon and winter
seasons in Punganur cattle under in vivo conditions (Naik et al., 2013).
Similarly, Narayan et al. (2007) reported that in Holstein Friesian ×
Sahiwal cross breeds lymphocyte count increased during in vivo heat
stress studies. Numerous studies have evaluated the relationships be-
tween heat stress and cellular immune function in bovines (Elvinger
et al., 1991; Soper et al., 1978; Kamwanja et al., 1994; Kelley et al.,
1982a; Lacetera et al., 2002). However, there is some conjecture re-
garding the impact of heat stress on lymphocyte function, where some
authors have reported an improvement (Soper et al., 1978), an im-
pairment (Elvinger et al., 1991; Kamwanja et al., 1994) and no influ-
ence of heat exposure (Lacetera et al., 2002; Kelley et al., 1982b).
9. Heat stress impact on humoral immune response in dairy cattle
Heat stress is associated with decreased milk production, impaired
reproduction and increased disease incidence in lactating dairy cows. In
dry cows, heat stress has been reported to affected milk yield in the
subsequent lactation and compromised the immune function during the
transition period (Collier et al., 2006a, 2006b; Do-Amaral et al., 2010;
Do-Amaral et al., 2011; Tao et al., 2012). High ambient temperature
during late gestation also influences the transfer of passive immunity to
the calf. Calves exposed to heat stress had lower serum IgG levels than
the calves in a cool environment (Tao et al., 2012). This may indicate
that passive immune transfer in calves exposed to heat stress in-utero is
compromised, which may be associated with impaired IgG absorption
in the intestine in post-natal life (Tao et al., 2012). Increased plasma
concentrations of IgG has been reported during late gestation in heifers
in the heat stressed groups, whereas non-heat stressed heifers showed
lower plasma concentrations of IgG due to the diversion of antibodies
from the bloodstream to colostrums (Nardone et al., 1997). These au-
thors suggested that heat stress has a negative effect on the transfer of
maternal immunoglobulin to colostrum in dairy cows exposed to the
hot environment. In addition, Nardone et al. (1997) also reported that
colostrum from heat stressed dairy cow contained lower IgGs (22.3%
less) than the cows kept in the cooler environments. However Shearer
et al. (1992) observed higher concentrations of IgG in colostrum of
cows exposed to natural summer heat than cows exposed to other
season of the year. Table1 describes the impact of heat stress on the
humoral immune system in dairy cattle.
There are diverse reports on the impact of heat stress on the hu-
moral immune response in livestock (Lacetera et al., 2006; Bhan et al.,
2012; Pandey et al., 2017). As described in Table 1 the impact of heat
stress on the leukocyte population varied among the studies in dairy
cattle. In most of the studies the leukocyte population decreased
(Gwazdauskas et al., 1980; Elvinger et al., 1991; Lacetera et al., 2006)
while in few studies it increased (Nouty et al., 1986; Omran et al., 2013;
Naik et al., 2013). However, there are also reports describing no effect
of heat stress on leukocyte population in dairy cattle (Pandey et al.,
2017; Pandey et al., 2017). These differences of heat stress on the
M. Bagath, et al. Research in Veterinary Science 126 (2019) 94–102

Table 1
Description of heat stress impact on humoral immune response in dairy cattle.
Stress Animal Effect on leukocytes References

Summer stress Holstein-Friesian cows and buffaloes Leukocytes decreases Salem (1980)
Chronic stress Holstein-Friesian cows Leukocytes decreases Gwazdauskas et al. (1980)
Summer Holstein cows Leukocytes Increases Nouty et al. (1986)
Heat stress Friesian cows Leukocytes Increases Abdel-Samee (1987)
Summer stress Sahiwal cow Leukocytes decreases Bhan et al. (2012)
Heat stress Buffalo Leukocytes Increases Omran et al. (2013)
Summer Punganur cattle Leukocytes Increases Naik et al. (2013)
Heat stress Tharparkar and Karan Fries heifers No changes Pandey et al. (2017)
Heat stress Angus cattle Lymphocytes decreases Elvinger et al. (1991)
Heat stress Holstein cows Lymphocytes decreases Kamwanja et al. (1994)
Heat stress Brown Swiss and Holstein cows Lymphocytes decreases Lacetera et al. (2006)
Heat stress Buffalo Lymphocytes decreases Devaraj and Upadhyay (2007)
Heat stress Holstein-Friesian cow Neutrophils decreases Narayan et al. (2007)
Lymphocyte increases
No changes in Eosinophils
Heat stress Sahiwal and Karan Fries heifers Neutrophils increases Mayengbam (2008)
Summer stress Punganur cattle Neutrophils and lymphocytes increases Naik et al. (2013)
Summer stress Tharparkar and Karan Fries No changes Pandey et al. (2017)
Heat stress Tharparkar and Karan Fries heifers No changes in Neutrophil, lymphocytes and monocytes Pandey et al. (2017)

leukocyte population across the studies could be attributed to the breed
difference. Generally it was observed that in indigenous breeds the level
of leukocytes increased after exposure to heat stress in dairy cattle
(Mayengbam, 2008; Naik et al., 2013; Pandey et al., 2017) while in
majority of the studies its level increased in exotic breeds (Nouty et al.,
1986; Abdel-Samee, 1987).
Godden (2008) reported that exposure of cows to heat stress during
late pregnancy reduced colostrum quality, with lower concentrations of
IgG, IgA along with a reduced total protein, casein, lactalbumin, fat,
and lactose. Similarly, Adin et al. (2009) reported that multiparous
Holstein dry cows exposed to heat stress showed a reduction in milk
yield and its IgG contents in subsequent lactation. Bernabucci et al.
(2013) reported that colostrum of heat-stressed cows contained lower
levels of casein, lactalbumin, and reduced concentrations of IgG and
IgA, but did not affect the percentage of lactoglobulin or the con-
centration of IgM. These changes in colostrum may be attributed to the
negative impact of heat stress on DMI resulting in nutritional restric-
tion, reduced mammary blood flow resulting in impaired transfer of IgG
and nutrients from the blood circulation to the mammary gland, and/or
impaired immune response of mammary gland plasma cells that pro-
duce IgA (Godden, 2008).
10. Heat stress impact on immune system-related gene expression
patterns in dairy cattle
When exposed to increasing THI, lactating cows showed a decrease
in leukocyte number along with the decreasing TNF-alpha and IL-10
cytokines (Zhang et al., 2014). Similarly, the TNFα production was
decreased and cows had an increase in SOCS-1 and SOCS-3 lymphocyte
mRNA differential expression in multiparous Holstein cows (Do-Amaral
et al., 2010). Additionally, multiparous Holstein cows subjected to heat
stress for a period of 46 days before calving showed lesser hepatic PRL-
R, SOCS-3, and CAV-1 level compared to control animals in the hepatic
mRNA expression (Do-Amaral et al., 2011). Further, the hormones
prolactin and cortisol has been shown to exert influences over the HSPs
expression associated with immune responses in cows subjected to heat
stress (Collier et al., 2008). Table 2 describes the impact of heat stress
on the immune system related gene expression in dairy cattle.
Thompson et al. (2014) reported higher IL-10 expression in heat
stressed cows compared with cows housed under thermoneutral con-
ditions. Similarly, Italian Friesian cows subjected to heat stress, with
average THI of 72, showed an increase in serum IL-10 secretion in heat
stressed animals (Caroprese et al., 2009). Furthermore, Dado-Senn et al.
(2018) reported increased IL34, IL27RA, IL6R, IL10RB and IL1R1
expression in bovine mammary tissues subjected to heat stress. Hall
et al. (2014) reported higher expressions of IL-18 receptor and RANTES
cytokine in Holstein cows supplemented with OmniGen-AF (Anti-
caking agent with B-complex vitamins) during heat stress exposure.
These results suggest that OmniGen-AF may improve immune function
in cows exposed to heat stress, thus providing an opportunity negate the
impact of heat stress on the immune system.
11. Proposed strategies to improve immune competency of dairy
cattle during heat stress
Ameliorative strategies to support immune system during periods of
heat stress could be achieved by adopting suitable management stra-
tegies. Mitigation management in production species can be achieved
by three major pathways i) physical modification of the environment;
ii) improved nutritional management; and iii) genetic and phenotypic
selection for thermo-tolerance. The animals must be maintained on
quality feed with low fibre and optimum protein and energy (Sejian
et al., 2015). The incorporation of appropriate energy, minerals, vita-
mins, antioxidants, prebiotics and probiotics with balanced nutrition
are highly essential to ameliorate heat stress in dairy cows (Smith et al.,
1997; Popovic, 2004; Paulrud, 2005). Amino acids play a vital role in
the immune response during heat stress in dairy cows, as the utilisation
of amino acids for milk production is decreased and more emphasis is
given to immune response and gluconeogenesis (Guo et al., 2018). The
supplementation of selenium reduced the frequencies of clinical mas-
titis and somatic cell count in heat stressed dairy cows (Smith et al.,
1997). The incorporation of zinc in the diets of dairy cattle during
summer, facilitated in keratinization of keratin layer of udder and may
be associated with a reduction in the incidence of mastitis (Popovic,
2004. Paulrud, 2005). Similarly, supplementation of zinc to heat
stressed PBMC subjected at 42 °C collected from periparturient Sahiwal
and Karan Fries dairy cows, showed attenuation of HSPs response and
augments the immunity in the PBMC by decreasing the IL-6 level in the
serum (Sheikh et al., 2017). Furthermore, the supplementation of
gamma-aminobutyric acid also decreased IL-4, IL-6, IL-2, and TNF-a in
a dose dependent manner in the heat stressed dairy cows (Cheng et al.,
2016). Copper and iron supplementation augmented the development
of immune organs such as thymus, spleen, lymph node and enhances
the phagocytic activity of neutrophils and macrophages which are es-
sential for the proliferation of immune cells and antibody production
(Lukasewycz and Prohaska, 1990). Further, Vivier et al. (2008) also
reported that supplementation of chromium helped in the development
of primary immune responses with increased IgM and IgG.

98
M. Bagath, et al. Research in Veterinary Science 126 (2019) 94–102

The supplementation of vitamin A preserved the mucosal and epi-

Do-Amaral et al., 2010

Dado-Senn et al., 2018

Thompson et al., 2014

Caroprese et al., 2009

thelial barrier which maintains healthy udder in dairy cows (Scherf
Zhang et al., 2014 et al., 1994). Rejeb et al. (2016) reported that the feeding of vitamin C
to the heat stressed dairy cows had an important role in the regulation
Reference

of immune functions. The combination of selenium and vitamin E im-

proved the immune function by positively influencing the chemotaxis,
phagocytic capacity and oxidizing property of neutrophils (Aziz and
Klesius, 1986). Supplementation of encapsulated niacin reduced the
Lymphocyte mRNArna expression

rectal temperatures in lactating cows under heat stress, as a result of

neutrophil mRNA expression

greater evaporative heat loss (Zimbelman et al., 2010).

Cows subjected to heat stress and supplemented with fermented
Chinese medicines (18 herbs) showed better immune functions based
Mammary tissue

on the decrease in the IL-1 in serum and also with IL-1 downregulation
Cells or tissue

at gene expression level after supplementation with 100 g/day.

Similarly the expression of the serum Bax level decreased (P < .01)
Serum
serum

and Bcl-2 level increased (P = .01) in cows supplemented with 100 g/

day supplementation. Serum IgG concentration also increased in com-
parison with non-supplemented group, pointing towards the improve-
Lipopolysaccharide binding protein, Thymosin β4, Annexin A1, Signal transducer and activator of transcription

ment in the immune function of the dairy cows (Shan et al., 2018).
Feeding of heat stressed animals with yeasts and plant extracts may
exert a positive effect in rumen metabolism and regulates the body
temperature (Conte et al., 2018). The addition of probiotics in the feed
improved the animal's health by inhabitating the whole digestive tract
and fortified the intestinal mechanical barriers to prevent the entry of
microbial pathogens (Popovic, 2004). Further, the combination of
prebiotics and probiotics activated phagocytosis and enhanced cytokine
the cytokine expression of IL34, IL27RA, IL6R, IL10RB, IL1R1 were up-regulated

(TNFα, IFNγ) and antibody production in response to vaccines (Kabir

et al., 2004; Hassanpour et al., 2013).
Feeding of OmniGen-AF to dairy cows reduces cortisol level and
improved the immune function with enhanced neutrophil function
during heat stress (McBride et al., 2016). Supplementing dams with
OmniGen-AF, an immunomodulating feed additive, 60 day before
drying off, that were then exposed to heat stress with cooling system for
46 days during dry period has calves that showed better growth, en-
Increased expression of TNFα and IL10 cytokines

hanced neutrophil function, higher plasma hepatoglobin concentration

(Skibiel et al., 2017). Similarly, calves born to dams exposed to heat
stress without evaporative cooling showed impaired passive and cell-
of IL1β, IL6, IL8, or TNFα no changes

mediated immune function and exhibited a higher susceptibility to-

wards infection (Tao et al., 2018).
TNFα production was decreased
Increase or decrease of gene/s

Under in vitro conditions the dairy Holstein cows PMBC subjected to

heat stress showed IL-2 proliferation, increase in Annexin V-bing and
3 showed upregulation.

HSP70 mRNA and protein expression. Under the heat stressed in vivo
conditions, Holstein cows supplemented with Zymosan had enhanced
DMI, milk yield, increased IgA, IL-2, TNF-α in serum, however hepatic
Increased IL10
Impact of HS on immune system related gene expression in dairy cattle.

HSP 70 expression and respiration rate were reduced, indicting zymo-

gens increased the productive performance and immunity in heat
stressed dairy cows (Sun et al., 2018).
THI 80.3

THI – 72

12. Conclusion
THI

Heat stress acts as the major challenge for maintaining the immune
–
–
–

status in livestock. Acute heat stress may have a stimulatory effect on

the immune system, however chronic heat stress may have an in-
Heat stressed uniparous mid-lactation Holstein

hibitory role on the capacity of the immune system to maintain

Heat stressed multiparous Holstein cows

homeostasis. Heat stress through the release of cortisol impairs the

cellular immune functions by inhibiting the expression of genes in-
volved in T-cell activation and cytokine production. Therefore, cortisol
has an inherent role in the regulation of anti-inflammatory response as
Multiparous Holstein cows
Multiparous Holstein cows

well as immune suppressor effects during heat stress exposure in dairy

cattle. Further, heat stress impedes both cell mediated and humoral
Italian Friesian cows

immunity thereby altering the balance for effectively maintaining the

immune functions in dairy cattle. Overall, the heat stress adversely
impacts the immune status of dairy cattle by reducing the production of
cows

antibodies, cytokines, chemokines and HSPs. The review also projects

Animal
Table 2

the significance of supplementing appropriate energy, minerals, vita-

mins, antioxidants, prebiotics and probiotics with balanced nutrition to

99
M. Bagath, et al.
ameliorate heat stress induced damage to immune functions in dairy
cows.
13. Future perspectives
Future research needs to evaluate broader aspects of the impact of
heat stress on the immunity of dairy cattle. Efforts are needed to es-
tablish the impact of heat stress on epigenetic changes in relation to
immunity and production. These changes might impart knowledge
about epigenetic-based immune system changes and the impact of heat
stress on subsequent progeny. Further, the complete signalling or any
other related pathways pertaining to immunity need to be evaluated to
establish the underlying biological mechanisms by which heat stress
alters the immune response in dairy cattle. In addition, refinements in
existing breeding policies are essential to identify climate resilient dairy
cattle that have the ability to produce, adapt and maintain immune
status during periods of hot weather.
Declaration of Competing Interest
The authors report no conflict of interest for this manuscript.
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