Immunobiology of the Bovine Mammary Gland.
Introduction
Mammary gland immunity, defined as the protection and resistance to infectious disease, is
facilitated through a variety of immune and nonimmunological factors 1. The immune
response is characterized by the ability to recognize the difference between foreign
substances and the body’s own molecules. Upon recognition of invading pathogens, the
immune system enlists both cellular and soluble factors that attempt to eliminate the foreign
organism 1. In contrast, non- immune components of mammary gland immunity consist of a
variety of disease-resistance mechanisms that are not specific to a particular pathogen and are
not increased by repeated exposure to the same foreign molecule. The last 2 decades have
seen major progress in understanding the bovine mammary gland defense system and its
function in preventing disease 1.
The mammary gland is protected by a variety of defense mechanisms, which can be separated
into two distinct categories: innate immunity and specific immunity 2.
- Innate immunity, also known as nonspecific responsiveness, is the predominant defense
during the early stages of infection. Nonspecific responses are activated quickly at the site of
infection by numerous stimuli; however, they are not increased by repeated exposure to the
same insult. Nonspecific or innate responses of the mammary gland are mediated by the
physical barrier of the teat end, macrophages, neutrophil and by natural killer- like cells 2.
Acquired immunity, or specific immunity system recognizes specific determinants of a
pathogen that facilitate selective elimination. Recognition of pathogenic factors is controlled
by antibody molecules, macrophages, and several lymphoid populations. Because of the
“memory” of certain lymphocytes, specific immune responses can be strengthened by
repeated exposure to a pathogen. In the mammary gland, both innate and acquired protective
factors are coordinated to provide optimal protection from disease 2.
Mastitis
Introduction
The production of immunoglobulins within the bovine mammary gland is very intensive due
to the fact that the cow’s teat provides a channel for pathogens to enter the gland 3 .Lactation
is considered the final phase of the mammalian reproductive cycle, and the mammary gland
provides milk for nourishment and disease resistance to the newborn. In addition, lactation is
the period where the mammary gland is most susceptible to environmental pathogens due to
the expulsion of the mucous plug by the suckling of the newborn. The teat becomes exposed
to airborne pathogens, pathogens transmitted from newborns, clostridial infections and (most
importantly in dairy cows) the spread of pathogens from cow to cow during milking by the
milker’s hands or the liner of the milking unit. Thus the role of immunoglobulins is of prime
importance in the natural defence of the bovine mammary gland and the prevention of
Role of Immune System in Mastitis
Mastitis is anything causing inflammation of the mammary gland, and infectious mastitis is
caused by a plethora of microbes 4 . Data from 1990s tells us that estimates from the National
Mastitis Council suggest that mastitis affects one third of all dairy cows and will cost the
dairy industry over 2 billion dollars annually in the United States in lost profits (National
Mastitis Council (1996) Current Concepts in Bovine Mastitis, National Mastitis Council,
Madison, WI) 5 . Immunity against infectious diseases of cattle is mediated by diverse, yet co-
dependent, cellular and humoral defence mechanisms. Many environmental and genetic
factors (genetic predispositions etc.,) influence the ability of livestock to mount effective
defence strategies against the various pathogens and normal flora that they are exposed to
daily throughout their lifetime. Innate resistance to infectious diseases reflects the inherent
physiological attributes of an animal that make it more or less susceptible to disease
development by a particular pathogen 4. There are several cell lineages that comprise the
immune system (e.g., B-cells, T-cells, neutrophils, eosinophils, basophils, macrophages and
mast cells). Each of these cell types has distinct responsibilities in providing host defence.
Innate or non-specific immunity represents the various immune components that are not
intrinsically affected by previous contact with an infectious agent. The innate response is
carried out by the physical barrier of the teat, neutrophils, natural killer-like cells and
macrophages. Lymphocytes provide the adaptive immune reactions that are antigen specific
in nature and possess memory for future encounters with the same pathogen 6.
Antibodies/Immunoglobulins (Igs) are soluble glycoproteins that carry out the effector
function for humoral and/or specific immune responses. Produced by antigen-activated B
lymphocytes (which differentiate into Igs secreting plasma cells), immunoglobulins are either
synthesised locally in lacteal secretions or are transported via serum.
Immunosuppression
Modern farming practices are placing a monumental amount of stress on dairy cows as
producers seek to optimise milk yields and somatic cell counts. Studies have shown there is a
negative correlation between milk production capacity and resistance to mastitis. A national
survey carried out by ADHB Dairy found that, of 90 dairy herds across England and Wales
almost a quarter of herds reporting greater than 100 cases per 100 cows per year 7. In
addition, an overwhelming amount of evidence of immunological dysfunction of
lymphocytes and neutrophils in periparturient cattle has been generated in research institutes
around the world. Periparturient immune dysregulation impacts the occurrence of infectious
diseases of virtually any organ system of livestock 6. The cow’s immune system will become
progressively more compromised at the end of gestation; which lasts between 280-290 days,
and as a result the mammary gland will become more and more infected. Moreover, seasonal
weather conditions will further the dampening effect on the immune system, as calving
generally occurs in either Spring or Autumn, when temperatures are low, and forage quality
is poor. Supplement to this, the fact that the majority of pregnant cows will be housed indoors
in close proximity to one another during the winter months, which will dramatically increase
the risk and speed of pathogens spreading from animal to animal. 1 or 2 weeks after calving
the dam’s immune system will reach its lowest point and those subclinical infections begin to
win the battle with the cow’s immune system and clinical mastitis results. Of the pathogens
that cause clinical mastitis; E.coli, Staphylococcus aureus, Staphylococcus epidermidis and
Streptococcus uberis are the most prominently encountered. Bacteriology results obtained
from 480 clinical mastitis samples submitted for culture revealed Streptococcus uberis and
Escherichia coli to be the most commonly isolated organisms, accounting for 23.5% and
19.8% of cases respectively in the UK 7. A possible reason for the immunosuppression is the
spike in levels of estrogen and progesterone having inhibitory effects on the function of
immunglobulins. Many of the hormonal and metabolic changes that prepare the mammary
gland for lactation take place during the 3 weeks preceding parturition 8. Lymphocyte and
neutrophil function could possibly be affected by prepartal increases in estrogen, prolactin
and growth hormone. Unfortunately the exact physiological reasons as to why this may occur
have not been fully understood, but the evidence remains, and it is known that the
periparturient immunosuppression reaches its optimum around 1-2 weeks after calving.
Colostrum
Colostrum is a special milk secreted by the cow during the first two to three days after
calving which is vital for the health of the calf. Colostrum in bovines is essential for
transferring passive immunity to the newborn calf because no immunity is transferred
prenatally via the placenta. Therefore calves are born with no immunity against disease. In
the early part of life they depend entirely on the passive immunity acquired by drinking
colostrum from their dam. Colostrum contains higher levels of nutrients and immunglobulins
than regular milk, which play a critical role in the health of the newborn as an immune
The concentrations of protein and vitamins A, D and E in colostrum are about five times that
of normal whole milk. The protein content of colostrum is 17–18% compared with 2.5–3.5%
in regular milk. Newborn calves can only absorb immunoglobulins from colostrum through
their intestine efficiently within the first 24 hours after birth. Therefore, it is very important
that the calf either suckles naturally or is fed colostrum within this time frame in order to
achieve the highest possible level of immunoglobulins (IgG) in the calf’s blood. Failure of
passive transfer occurs when a calf has less than 10g of IgG per liter of blood when it is 24 to
36 hours of age. Research has shown a direct correlation between immunoglobulin levels in
the calves' blood and the success rate of calves. Calves without adequate passive immunity
are twice as likely to suffer disease and four times more likely to die, compared with calves
that have an adequate level of passive immunity. The chances of a calf becoming ill increases
by 10% for each hour delay of colostrum intake in the first 12 hours of life. Delaying
colostrum feeding to the calf for even 6 hours results in lower absorption and greater
susceptibility to infections 11.As we can see from the table below, as blood immunoglobulin levels increase calves' growth
rates increase, their feed utilization becomes more efficient and their mortality rates decrease
13.
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After a few weeks the calves build up their own acquired immunity to different pathogens
through direct exposure. The role of colostrum as an immune booster is not limited to the calf
but can be administered to newborns of different species. Bovine colostrum is also widely
used in infant humans and immunocompromised adults for the treatment and/ or prevention
of enteric infections by bacterial, viral and protozoal pathogens 10. In fact, consumption of
raw cow's milk in the early life of a child was shown to be the most important factor in
protecting against the predisposition to developing allergic hypersensitivity reactions (atropy)
12 such as eczema and asthma.
Immunglobulins in mammary secretions originate from both the bloodstream and the
mammary glands themselves. Immunoglobulins in the mammary glands are produced locally
by plasmacytes located adjacent to the secretory epithelium. Plasmocytes predominate in the
involuted mammary gland and only occasional leukocytic cells are seen in mammary tissue
sections taken during lactation 11. The epithelial cells in the bovine mammary gland are
converted from a non-secretory state to a secretory state by a series of cellular changes called
lactogenesis. Colostrum is produced during the first stage of lactogenesis in lactating cows.
However colostrum is only secreted in the second stage of lactogenesis. The immunglobulins
originating from the mammary glands are mainly in the IgA and IgM classes, while the
immunglobulins originating from the mother's blood are mainly IgGs 11.
- Bovine colostrum typically contains between 50 – 150mg/ml of immunglobulins. The
approximate percentage of different immunglobulin classes in bovine colostrum is as follows:
IgG makes up roughly 85 to 90% of the immunoglobulins present (of which IgG1 accounts
for 80 to 90%), IgM about 7%, and IgA about 5% 11. The mammary transport of
immunoglobulins in the cow is highly selective. In contrast, the intestinal absorption phase in
the calf is nonspecific for class of immunoglobulins and is operative essentially only during
the first 24 h after birth under normal conditions 11.
A number of studies have examined the area of infusion of antigen into the ruminant lactating
gland 11. It has been found that antigen infusion often fails to elicit a local antibody response.
However, infusion into the dry gland may result in a local IgA response that can persist into
the following lactation. This response may be enhanced by simultaneous stimulation of the
intestine 11. Some scientists have speculated that selecting cows for their high milk yield for
many years may have led to alterations in the histology of the mammary gland which
interferes with the establishment of IgA producing cells. This reasoning would help to
explain the relative insensitivity of the bovine mammary gland to antigen infusion.
Conclusion
The mammary gland provides comprehensive protection against pathogens by means of both
innate and acquired immunity. Nowadays however with an ever growing dairy industry and a
huge emphasis on milk production (milk quotas rescinded in Ireland 2015) cows are
becoming more and more susceptible to pathogen infections. With this we are seeing an
increase in the amount of cases of mastitis worldwide.
In contrast with greater understanding now in colostrum importance in newborn calve there
has been a decrease in calf mortality in recent years. More and more farmers are looking into
the immunobiological values of colostrum and are starting to make significant changes to the
steps in calf welfare post birth. However such that the market they are in producers
occasionally seek methods to improve the Ig content of colostrum, or look for alternatives to
maternal colostrum. The current generation of products designed to supplement or replace
colostrum have utility in increasing circulating IgG concentration, but much more research is
needed to more completely understand the role of non-Ig components of colostrum and their
effects on long-term animal production and welfare 14.
References
1. Journal of Mammary Gland Biology and Neoplasia, Vol. 7, No. 2, April 2002 (⃝C 2002)
2. L. M. SORDILLO,1 K. SHAFER-WEAVER, and D. DeROSA .Department of Veterinary
Science, Center for Mastitis Research, The Pennsylvania State University, University Park 16802-
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3. Mammary Gland Immunity and Mastitis Susceptibility-Lorraine M. Sordillo and Katie L. Streicher
4.-J. C. Detilleux, M. E. Kehrli, J. R. Stabel, A. E. Freeman, and D. H. Kelley (1995). Study of
immunological dysfunction in periparturient Holstein cattle selected for high and average milk
production
5.National Mastitis Council (1996) Current Concepts in Bovine Mastitis, National Mastitis Council,
Madison, WI
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7. http://www.mastitiscontrolplan.co.uk/the-uk-situation 21/04/2016 ADHB Dairy national survery.
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thymic regylatory T cell maturation preventing the development of atopy? Journal of Translational
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13.http://www.publish.csiro.au/?act=view_file&file_id=9780643107427_Chapter5.pdf
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