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Mammary Gland Immunity and Mastitis Susceptibility cquired immunity

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Mammary Gland Immunity and Mastitis Susceptibility cquired immunity Powered By Docstoc
					Journal of Mammary Gland Biology and Neoplasia, Vol. 7, No. 2, April 2002 ( C 2002)




Mammary Gland Immunity and Mastitis Susceptibility

Lorraine M. Sordillo1,2 and Katie L. Streicher1



                                 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. However, the
                                 cellular and soluble immune components associated with mammary tissues and secretion also
                                 can play an important role in protecting the gland from infectious diseases, such as mastitis.
                                 Mastitis can affect essentially all lactating mammals, but is especially problematic for dairy
                                 cattle. The most recent 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). The overall impact of mastitis on
                                 the quality and quantity of milk produced for human consumption has provided the impetus
                                 to better understand the pathophysiology of the mammary gland and develop ways to enhance
                                 disease resistance through immunoregulation. As such, the bovine species has played a critical
                                 and prominent role in our current understanding of mammary gland immunobiology. This
                                 paper provides a comprehensive overview of mammary gland immunity and how the stage of
                                 lactation can impact important host defenses. While this review emphasizes the bovine system,
                                 comparisons to humans and other domestic mammals will be addressed as well.

                                 KEY WORDS: mammary immunology; mastitis; neutrophils; lymphocytes; cytokine.



INTRODUCTION                                                            factors that attempt to eliminate the foreign organism,
                                                                        and subsequent exposure to the same pathogen in-
     Through genetic selection and technological ad-                    duces a more pronounced response. In contrast, non-
vances in milk removal, the bovine mammary gland                        immune components of mammary gland immunity
yields far more milk than is needed to nourish the                      consist of a variety of disease-resistance mechanisms
newborn calf. Factors associated with the intense man-                  that are not specific to a particular pathogen and are
agement of dairy cattle can profoundly affect mam-                      not augmented by repeated exposure to the same for-
mary gland defense mechanisms and the ability of the                    eign molecule. While both immune and nonimmune
host to resist mastitis. Mammary gland immunity, de-                    factors interact extensively to provide adequate pro-
fined as the protection and resistance to infectious dis-                tection against mastitis, the magnitude, duration, and
ease, is facilitated through a variety of immune and                    effectiveness of mammary gland immunity are influ-
nonimmunological factors. The immune response is                        enced greatly by particular etiological agents.
characterized by the ability to recognize and discrim-                       Technological advances in immunology have
inate between foreign substances and the body’s own                     provided new research tools that have facilitated
molecules. Upon recognition of invading pathogens,                      the study of mammary gland immunity and disease
the immune system enlists both cellular and soluble                     pathogenesis. As a consequence, the last two decades

1 Department of Veterinary Science, The Pennsylvania State Uni-         Abbreviations used: CSF, colony stimulating factor; GH, growth
  versity, University Park, Pennsylvania.                                hormone; IGF, insulin-like growth factor; IFN, interferon; IL, in-
2 To whom correspondence should be addressed at 115 Henning              terleukin; Ig, immunoglobulin; MHC, major histocompatibility
  Building, The Pennsylvania State University, University Park,          complex; NK, natural killer; TNF, tumor necrosis factor; SCC,
  Pennsylvania 16870.                                                    somatic cell count; IMI, intramammary infection.


                                                                  135
                                                                                        1083-3021/02/0400-0135/0   C   2002 Plenum Publishing Corporation
136                                                                                            Sordillo and Streicher


have seen major progress in understanding the bovine          diminished mammary gland defense mechanisms (8).
mammary gland defense system and its function in              It is interesting to note that other mammals, includ-
preventing disease. In the 1980s, considerable atten-         ing women, also suffer from increased susceptibility to
tion was focused on the identification and functional          mastitis during the immediate postpartum period (9).
characterization of bovine mammary gland leuko-               However, changes in mammary gland defense mecha-
cyte populations. Different leukocyte subpopulations          nisms during the periparturient period and the subse-
were conveniently identified by flow cytometry us-              quent impact on susceptibility to new intramammary
ing monoclonal antibodies developed to recognize              infections have been characterized more extensively
unique surface molecules. Since 1990, this research           for the bovine than any other mammal. As such, the
has extended to the study of bovine cytokines and             bovine species has played a crucial role in illuminat-
their potential roles in the pathophysiology and con-         ing our current understanding of mammary gland im-
trol of mastitis. The availability of gene and pro-           munobiology as it relates to bacterial infections. The
tein sequences led to the development of several              challenge that confronts researchers now is to gain a
strategies to identify these cytokines, including mono-       better understanding of the complex interactions be-
clonal antibodies, primers for polymerase chain reac-         tween the pathogenesis of particular bacteria, host
tions, and quantification with bioassays and ELISA.            responses needed to eliminate the pathogens from
Moreover, recombinant cytokines were produced to              the mammary gland, and ways to enhance mammary
explore their immunomodulatory and therapeutic                gland immunity before disease is established.
uses for disease control. Mammary gland immunity
is a rapidly evolving field of research in veterinary
medicine. Therefore, it is most opportune to review           DEFENSE MECHANISMS
the current knowledge of various immune and nonim-
mune components of host defense and the underlying                  The mammary gland is protected by a variety of
mechanisms of disease resistance.                             defense mechanisms, which can be separated into two
                                                              distinct categories: innate immunity and specific im-
                                                              munity. Innate immunity, also known as nonspecific
SUSCEPTIBILITY TO MASTITIS                                    or nonimmune responsiveness, is the predominant de-
                                                              fense during the early stages of infection. Nonspecific
      The incidence of mastitis increases when defense        responses are present or are activated quickly at the
mechanisms of the mammary gland are impaired.                 site of infection by numerous stimuli, but are not aug-
Dairy cattle are exposed to numerous genetic, physi-          mented by repeated exposure to the same insult. If
ological, and environmental factors that can compro-          nonspecific defense mechanisms function adequately,
mise host immunity and increase the incidence of mas-         most pathogens are readily eliminated within a short
titis (1,2). Emphasis on genetic selection to maximize        period of time and before the specific immune system
milk production has increased metabolic stresses as-          is activated. Rapid elimination of bacteria often will
sociated with milk synthesis and secretion, and a nega-       not result in noticeable changes in milk quality or pro-
tive correlation exists between milk production capac-        duction. Nonspecific or innate defenses of the mam-
ity and resistance to mastitis (3). Therefore, it is likely   mary gland are mediated by the physical barrier of
that resistance to mastitis will deteriorate in dairy cat-    the teat end, macrophages, neutrophils, natural killer
tle populations that are under selection for improved         (NK) cells, and certain soluble factors.
milk production. Removal of milk by milking ma-                     If a pathogen is able to evade or is not completely
chines can cause trauma of teat end tissues which facil-      eliminated by the innate defense system, the specific
itates colonization by mastitis-causing organisms. To-        or acquired immune system is triggered. Acquired
tal confinement housing, increased cow densities per           immune responses recognize specific antigenic deter-
unit area, and use of bedding materials that support          minants of a pathogen. If a host should encounter
bacterial growth also can have a marked impact on             the same antigen more than once, a heightened state
the susceptibility of dairy cattle to mastitis by over-       of immune reactivity would occur as a consequence
whelming important local defense mechanisms (4).              of immunological memory. In comparison with the
However, one of the more significant factors known to          first exposure to a bacterial antigen, a memory re-
influence mammary gland defense capabilities is lac-           sponse would be much faster, considerably stronger,
tation stage (5–7). Dairy cattle are especially suscepti-     longer lasting, and often more effective in clearing the
ble to mastitis during the periparturient period due to       pathogen. Vaccination protocols are based on these
Immunobiology of the Mammary Gland                                                                                       137


unique features of the specific immune response. The          increased intramammary pressure (8,13). The mam-
immune system is able to distinguish self from nonself       mary gland is especially susceptible to mastitis during
and selectively react only to foreign antigens through       this time, partially due to the dilation of the teat canal
genetically diverse, membrane-bound proteins called          and leakage of mammary secretions.
major histocompatibility complex (MHC) molecules.
A specific immune response only will occur if anti-
gens are combined with an MHC molecule on the                Cellular Defenses
surface of certain cells, a process referred to as anti-
gen presentation. Recognition of pathogenic factors                If bacteria are able to overcome the anatomical
for elimination is mediated by macrophages, several          defense provided by the teat end, they still must evade
lymphoid populations, and immunoglobulins (Ig) or            the antibacterial activities of the mammary gland in
antibodies.                                                  order to establish disease. The total number and ac-
     In the mammary gland, it is necessary for both in-      tivity of mammary gland leukocyte populations play
nate and acquired immunity to be highly interactive          early and vital roles in determining the severity and
and coordinated in order to provide optimal protec-          duration of intramammary infections. Resident and
tion from mastitis. Because of the highly integrated         newly recruited mammary leukocytes consist of sev-
nature of mammary defense mechanisms, this review            eral types, including neutrophils, macrophages, and
will further characterize mammary immune factors             lymphocytes that are capable of mediating either in-
into anatomical, cellular, and soluble components and        nate or acquired immune responses (see Table I).
discuss important changes that occur in host defense               Neutrophils are nonspecific leukocytes that are
during the periparturient period.                            actively recruited to the site of infection and are the
                                                             principal cell type found in mammary tissues and
                                                             secretions during the early stage of the inflammatory
Anatomical Defenses
                                                                 Table I. Summary of Mammary Gland Cellular Defenses
     The teat end is considered the first line of de-
                                                                     Factor                    Biological function
fense against mastitis since this is the route by which
invading pathogens can gain entrance to the mam-             Neutrophils            Phagocytosis and intracellular killing of
mary gland. The teat contains sphincter muscles that                                  bacteria; secretion of antibacterial
maintain tight closure between milkings and hin-                                      factors
                                                             Macrophages            Phagocytosis and intracellular killing of
der bacterial penetration. Increased patency of the                                   bacteria; antigen presentation in
sphincter is directly related to increased incidence of                               conjunction with MHC
mastitis. The teat canal also is lined with keratin, which   Natural killer cells   Nonimmune lymphocytes that secrete
is crucial to the maintenance of the barrier function                                 antibacterial proteins upon activation
of the teat end; removal of the keratin has been cor-        T lymphocytes
                                                               CD4+ (T helper)    Production of immunoregulatory
related to increased susceptibility to bacterial inva-                              cytokines following antigen
sion and colonization. Teat keratin is a waxy material                              recognition with MHC class II
that is derived from stratified squamous epithelium.                                 molecules; memory cells following
Accumulation of keratin can provide a physical ob-                                  antigen recognition
struction to bacteria, hindering their migration into          CD8+ (T cytotoxic) Lysis of altered or damaged host cells
                                                                                    when complexed with MHC class I
the gland cistern. In fact, the keratin structure can                               molecules; production of cytokines
completely occlude the duct during the nonlactating                                 that can down-regulate certain
period (10). Within the keratin lining, antimicrobial                               leukocyte functions
agents have been identified (11). The esterified and             γ δ T lymphocytes  Biological role in the mammary gland
nonesterified fatty acids present in teat keratin are                                is speculative
                                                             B lymphocytes
bacteriostatic and include myristic acid, palmitoleic          Mature B cells     Display membrane-bound antibody
acid, and linoleic acid. Cationic proteins associated                               molecules to facilitate antigen
with the keratin lining can bind electrostatically to                               presentation; memory cells following
mastitis pathogens, alter their cell walls, and render                              antigen interactions
them more susceptible to osmotic pressure (11,12). As          Plasma cell        Terminally differentiated B lymphocytes
                                                                                    that synthesize and secrete antibody
parturition approaches, considerable fluid accumula-                                 against a specific antigen
tion occurs within the bovine mammary gland, causing
138                                                                                       Sordillo and Streicher


process associated with bacterial infection (14). While   development of specific immune responses through
neutrophil numbers are relatively low in the healthy      antigen processing and presentation in association
mammary gland (<105 cells/mL), their numbers can          with MHC class II antigens (26,27).
constitute greater than 90% of the total mammary                Dramatic alterations in the functional capabili-
leukocyte population during mastitis (>106 cells/mL).     ties of mammary gland macrophages occur during the
These nonspecific cells travel from the blood to the       periparturient period and have been directly linked
mammary gland in response to a variety of inflamma-        with disease incidence. Although bovine macrophage
tory mediators in order to phagocytose and kill bac-      numbers are highest in the last week of gestation,
terial pathogens (15). Neutrophils have bactericidal      the phagocytic capacity of these cells is decreased,
effects that are mediated through a respiratory burst     possibly due to the lower opsonic activity in mam-
that produces hydroxyl and oxygen radicals (16). In       mary secretions. This decrease could be mediated by
addition, neutrophils are a source of small antibac-      a decrease in IgM, which facilitates phagocytosis by
terial peptides, defensins, which can kill a variety of   both macrophages and neutrophils (2). Similar to the
mastitis-causing pathogens (17). During the peripar-      bovine system, the opsonic activity of components
turient period, a number of neutrophil functions are      within porcine mammary secretions was significantly
altered or impaired (5,16,18,19). At this time the num-   lower during the periparturient period, which could
ber of immature neutrophils in the bovine blood in-       lead to less efficient phagocytosis (28). Additionally,
creases, while the number of mature neutrophils in        MHC II expression by bovine macrophages during
the blood and mammary secretions is lowest. Neu-          the peripartum period is decreased, which could con-
trophil populations also exhibit impaired function of     tribute to poor antigen presentation and result in
major defense-related activities, such as phagocyto-      a weaker specific immune response from mammary
sis, respiratory burst activity, superoxide anion pro-    gland lymphocytes (6,26).
duction, random cellular migration, and chemotaxis,             Lymphocytes are able to recognize antigens
around parturition (5). Chemotactic neutrophil mi-        through specific membrane receptors which define
gration from blood could be impaired further due to       the immunological characteristics of specificity, diver-
the decreased proportion of cells expressing the ad-      sity, memory, and self/nonself recognition. Subsets of
hesion receptor CD62L (L-selectin) that is necessary      lymphocytes are divided into two main groups: T and
for penetration through the endothelium to sites of       B lymphocytes. The T lymphocytes can be classified
infection (20).                                           further into αβ T lymphocytes, which include CD4+
      Macrophages represent the dominant cell type        (T helper) and CD8+ (T cytotoxic or T suppres-
seen in milk and tissues of healthy, lactating mammary    sor) lymphocytes, and γ δ T cells. In healthy human,
glands. During bacterial pathogenesis, macrophages        porcine, and bovine mammary glands, αβ T lympho-
may serve to facilitate either innate or acquired im-     cytes prevail and predominantly express the CD8+
mune responses. Similar to neutrophils, the nonspe-       phenotype, in contrast to peripheral blood, which has
cific functions of macrophages are to phagocytize          primarily the CD4+ phenotype (7,29,30). Lymphoid
bacteria and destroy them with proteases and re-          cells in both human and bovine milk also display
active oxygen species. The phagocytic rate of these       a memory cell phenotype (31,32). However, CD4+
cells can be increased dramatically in the presence       lymphocytes are the most prominent cell type at all
of opsonic antibodies against particular pathogens        lactation stages in caprine mammary glands (33). De-
(21,22). However, mammary macrophage numbers              pending on the stage of lactation and tissue location,
tend to be lower during inflammation and they pos-         the percentages of lymphocyte subsets can vary sig-
sess fewer Fc receptors, possibly decreasing their rate   nificantly and major shifts in trafficking patterns are
of phagocytosis when compared to neutrophils (23).        correlated with susceptibility to disease (7,25,34).
Therefore, the ability of macrophages to secrete sub-           During mastitis, CD4+ T lymphocytes prevail
stances that facilitate the migration and bacterici-      and are activated in response to recognition of
dal activities of neutrophils is believed to be of        antigen-MHC class II complexes on antigen-
greater importance to the nonspecific defense of the       presenting cells, such as B cells or macrophages.
mammary gland than acting as professional phago-          These cells function to activate lymphocytes and
cytes. Indeed, activated macrophages are triggered        macrophages by their ability to secrete certain cy-
to release prostaglandins, leukotrienes, and cytokines    tokines. Depending on the repertoire of cytokines
that can greatly augment local inflammatory pro-           produced, the T helper cell response can facili-
cesses (15,24,25). Macrophages also play a role in the    tate either a cell-mediated (Th1 type) or a humoral
Immunobiology of the Mammary Gland                                                                                139


(Th2 type) immune response (35). While the initial           in a non-MHC-restricted way (41). The cytotoxic abil-
characterization of the Th1 vs. Th2 paradigm in mice         ity of γ δ T lymphocytes suggests that they may be able
is now considered somewhat oversimplified, inter-             to destroy altered epithelial cells, including malignant,
leukin (IL)-2 and interferon (IFN)-γ were character-         breast carcinoma cell lines (42). These cells also may
ized as the major cytokines produced during the Th1          play a role in infectious diseases and therefore provide
response and IL-4, IL-5, and IL-10 dominate during           an important line of defense against bacterial infec-
the Th2 response. However, it is known that IL-10            tions. Relative to the blood, both humans and rumi-
can be produced by and regulate all subtypes of Th           nants express greater levels of γ δ T lymphocytes in
cells (36). During the periparturient period, CD4+           mammary secretions and parenchyma (43). The con-
cells produce less IL-2 and IFN-γ , but more IL-4 and        tributions of γ δ T cell variations to overall mammary
IL-10, compared to CD4+ cells obtained during later          immunity are not as clear because the biological func-
stages of lactation (37). The significance of the shift       tions of γ δ T cells are still speculative.
to a Th2-type response on disease susceptibility in the            The primary role of B lymphocytes is to pro-
mammary gland has not been defined.                           duce antibodies against invading pathogens. Unlike
      The CD8+ T cells have either a cytotoxic or            macrophages and neutrophils, B lymphocytes uti-
suppressor function, such that they either eliminate         lize their cell surface receptors to recognize specific
host cells expressing foreign antigen (in association        pathogens. Similar to macrophages and dendritic cells,
with MHC class I) or they control the immune re-             B lymphocytes can function as antigen-presenting
sponse by suppressing the activation of these cells          cells as they internalize, process, and present anti-
during bacterial infections. It has been suggested that      gen in the context of MHC class II molecules to T-
CD8+ cytotoxic cells may act as scavengers, remov-           helper lymphocytes. Upon presentation of the pro-
ing old or damaged secretory cells, the presence of          cessed antigen, IL-2 is secreted by the T lymphocytes,
which could increase the susceptibility of the mam-          which in turn induces proliferation and differentia-
mary gland to infections (32). Suppressor T lympho-          tion of the B lymphocyte into either plasma cells that
cytes are thought to control or modulate the im-             produce antibody or memory cells. Unlike T lympho-
mune response to bacterial infections. Researchers           cytes, the percentages of B lymphocytes remain fairly
have demonstrated that CD8+ lymphocytes activated            constant between stages of lactation (7).
during bacterial infections can suppress important                 Natural killer (NK) cells are large, granular lym-
host immune responses. Evaluation of lacteal secre-          phocytes that have cytotoxic activity independent of
tions from mammary glands of dairy cows infected             MHC, utilizing their Fc receptors to participate in
with Staphylococcus aureus revealed a subpopula-             antibody-dependent, cell-mediated cytotoxicity. The
tion of activated CD8+ lymphocytes that are capable          NK cell binds tumor or virus-infected cells and de-
of altering or suppressing the proliferative responses       granulates to secrete perforin that destroys the target
of CD4+ lymphocytes (38). The immunoregulatory               cell by membrane disruption. NK cells also are capa-
roles of CD8+ lymphocytes also greatly depend on             ble of killing both gram-positive and gram-negative
lactation stage. Cells obtained from mid-lactation           bacteria, and therefore could be important in pre-
dairy cattle exhibited cytotoxic activity and mainly         venting mammary infection (44). Changes in this cell
expressed IFN-γ , while CD8+ lymphocytes obtained            population during the periparturient period have not
during the postpartum period exhibited no cytotoxic          been studied extensively, but the potent bactericidal
activity and mainly expressed IL-4 (39). These data          activity of these cells makes them worthy of future
suggest that a preferential trafficking of CD8+ sup-          study.
pressor lymphocytes into mammary gland tissues and
secretions may be responsible for the lower respon-
siveness of local lymphocyte populations compared            Soluble Defenses
with those from later stages of lactation.
      The γ δ T cells are not as well characterized, but          Both specific and innate soluble factors repre-
data have suggested that they can be cytotoxic and           sent an important line of defense within the mam-
may provide a unique line of defense against bacte-          mary gland that can elicit effective protective re-
rial infections. The γ δ T lymphocytes preferentially        sponses to invading pathogens. The primary soluble
migrate to epithelial surfaces and do not circulate ex-      effectors of the specific immune response are anti-
tensively (40). There are indications that γ δ T lympho-     bodies produced by antigen-activated B lymphocytes.
cytes, like natural killer cells, can mediate cytotoxicity   There are four classes of Ig known to influence the
140                                                                                            Sordillo and Streicher

   Table II. Summary of Mammary Gland Soluble Defenses        production profile is somewhat similar in sows, as
                                                              there is a reduced number of IgA-bearing cells in
   Factor                   Biological function
                                                              mammary secretions at parturition (21). In humans,
Cytokines          Proinflammatory and immunoregulatory        IgA secretion was shown to be significantly reduced in
                     factors                                  the normal milk of women who ultimately developed
Complement         Bacteriolytic and/or facilitates
                                                              mastitis, compared to women who remained mastitis-
                     phagocytosis
Lysozyme           Cleaves carbon bonds and disrupts          free (9,47). During the periparturient period, changes
                     bacterial cell walls                     in the levels and activity of these Ig isotypes contribute
Lactoferrin        Sequesters iron to prevent bacterial       to the generalized immunosuppression that leads to
                     uptake; disrupts bacterial cell wall;    increased incidence of disease.
                     regulates mammary leukocyte activity
                                                                    In addition to the specific effects of antibodies,
Antibodies
 IgG1              Selectively transported into mammary       the mammary gland has nonspecific bacteriostatic fac-
                     secretions; opsonizes bacteria to        tors that work together with or independent of Ig. One
                     enhance phagocytosis                     such factor is lactoferrin, an iron-binding protein pro-
  IgG2             Transported into secretions during         duced by epithelial cells and leukocytes that functions
                     neutrophil diapedesis; opsonizes
                                                              to bind free ferric ions in milk, thereby preventing the
                     bacteria to enhance phagocytosis
  IgA              Associated with the fat portion of milk;   growth of bacteria that need iron for growth (48,49).
                     does not bind complement or opsonize     In ruminants, lactoferrin and IgG1 act synergistically
                     particles; can cause agglutination,      to inhibit Escherichia coli and Klebsiella pneumoniae,
                     prevent bacterial colonization, and      but other bacteria like Streptococcus agalactiae can
                     neutralize toxin
                                                              actually use lactoferrin as an iron source. In the lactat-
  IgM              Efficient at complement fixation,
                     opsonization, agglutination and toxin    ing bovine mammary gland, the lactoferrin concentra-
                     neutralization; only opsonic for         tion is lower than that seen during involution and in-
                     neutrophils in the presence of           flammation. In addition, the bacteriostatic activities of
                     complement                               lactoferrin can be abolished in the presence of citrate,
                                                              a buffer produced by epithelial cells which chelates
                                                              iron into a form that is readily usable by bacteria (50).
bacterial defense mechanisms of the mammary gland:            Accordingly, it has been suggested that lactoferrin’s
IgG1 , IgG2 , IgA, and IgM (45) (see Table II). In gen-       main role in mammary gland defense is to protect
eral, Ig reaches its peak concentrations in mammary           against coliform infection, especially during involu-
secretions during colostrogenesis and during inflam-           tion. In humans, studies have identified lactoferrin as
mation. IgG1 is the primary isotype found in healthy          a predisposing factor for mastitis by showing that low
mammary secretions, but IgG2 increases substantially          lactoferrin levels in normal milk correlate with the
during mammary gland inflammation. Several iso-                subsequent development of mastitis, and that lactofer-
types (IgG1 , IgG2 , and IgM) can act as opsonins to en-      rin deficiency contributes to an increased propensity
hance phagocytosis by neutrophils and macrophages.            of recurring mastitic infections (51).
On the contrary, IgA does not aide in bacterial op-                 Complement is a collection of proteins present
sonization, but functions instead in the agglutination        in serum and milk that can impact both innate and
of invading bacteria that can prevent the spread of           acquired immunity. The proteins that comprise the
bacterial disease in the mammary gland. Previous re-          complement system are synthesized mainly by hepa-
search has shown that the concentration of IgG in             tocytes, but other sources include monocytes and tis-
bovine serum is lower at parturition and suggested            sue macrophages. Many of the biological activities of
that the lack of the IgG2 isotype specifically correlates      complement are mediated through complement re-
to an increased incidence of mastitis (6). Interest-          ceptors located on a variety of cells. Effector functions
ingly, a lower incidence of mastitis has been corre-          of complement include lysis of bacteria, opsonization,
lated with high antibody responsiveness to ovalbumin          and the attraction of phagocytes to the site of comple-
in dairy cows (46). However, this study also showed           ment activation. For example, gram-negative mastitis-
that not all dairy cows experience a reduction in an-         causing bacteria such as Escherichia coli are especially
tibody responsiveness at parturition, implying that           sensitive to complement-mediated lysis. Complement
some animals may not develop disease due to a supe-           also functions in concert with a specific antibody
rior, natural ability to produce high levels of antibody      as an opsonin which will promote bacterial phago-
regardless of the lactation stage (46). The antibody          cytosis and intracellular killing by mammary gland
Immunobiology of the Mammary Gland                                                                                   141


neutrophils and macrophages (52). Complement con-           of this antimicrobial system against the pathogens that
centrations in mammary gland secretions have been           cause mastitis.
determined by measuring hemolytic and bactericidal               Numerous reports have shown the immunomod-
activities (53,54). The lowest concentrations of com-       ulatory capabilities of cytokines on important mam-
plement are observed in the milk of healthy mammary         mary leukocyte functions (56–58). The major groups
glands during lactation. In contrast, the highest con-      of cytokines studied to date include interleukins (IL),
centrations of complement are observed in colostrum,        colony-stimulating factors (CSF), interferons (IFN),
mastitic milk, and in mammary secretions obtained           and tumor necrosis factors (TNF) (see Table III).
during involution, presumably due to the mobiliza-          The term “interleukin” was originally introduced
tion of complement components by transudation from          to describe cell-free soluble factors that function
blood (54). While the overall significance of the com-
plement system in mammary gland defense has yet to
be fully defined, available information does suggest         Table III. Cytokine Effects on Mammary Immune and Inflamm-
                                                                                    atory Responses
a predominant role as a proinflammatory mediator
during coliform mastitis (53).                              Cytokine                      Observations
      Lysozyme is a bactericidal protein that is present
in milk and functions by cleaving peptidoglycans from       IL-1           Mediates acute phase inflammatory response
the cell wall of Gram-positive bacteria, as well as                        Increases neutrophil numbers
from the outer membrane of Gram-negative bacte-                            Enhances neutrophil phagocytosis and
                                                                             bactericidal activity
ria. Lysozyme may enhance the binding of lactoferrin                       Triggers neutrophil migration into infected
to bacterial cell walls. In porcine and human milks,                         mammary gland
lysozyme, in combination with complement and se-            IL-2           Enhances mammary mononuclear cell
cretory IgA, exhibits significant bactericidal activity                       proliferation
to E. coli in vitro (55). Because ruminant milk con-                       Enhances cytotoxic and bactericidal
                                                                             activities of lymphocytes
tains only a small concentration of IgA and consid-                        Increases plasma cell numbers
erably less lysozyme than human milk, this system                          Activates NK cells
may offer little protection to the bovine mammary           IL-8           Induces inflammation
gland.                                                                     Mediates IL-1 induced neutrophil migration
      The enzyme lactoperoxidase, in the presence of                       Potent chemoattractant
                                                            G-CSF          Increases numbers of blood and milk
thiocyanate and hydrogen peroxide, is bacteriostatic                         neutrophils
for Gram-positive and Gram-negative bacteria. How-                         Increases milk SCC
ever, several factors can vary the effectiveness of this                   Increases phagocytosis and bactericidal
system in mammary gland epithelial cells. Lactoper-                          activity
oxidase is produced in small concentrations by the                         Decreases neutrophil migration
                                                            GM-CSF         Enhances chemotactic and bactericidal
mammary gland. The levels of thiocyanate in the                              activities of neutrophils
mammary gland are dependent on the specific di-                             Enhances cytotoxic activity
etary composition of the cow. The hydrogen perox-                          Increases number of phagocytic cells
ide in the mammary gland is generated by enzymatic          M-CSF          Regulates proliferation and differentiation
constituents of milk and, if present, by Streptococci.                       of macrophages
                                                                           Potent macrophage chemoattractant
The lactoperoxidase-thiocyanate-hydrogen peroxide           IFN-γ          Enhances neutrophil phagocytosis and
system exerts its antibacterial properties through the                       bactericidal activity
production of hypothiocyanate, a reactive metabo-                          Reverses suppressive effects of mammary
lite formed from the oxidation of thiocyanate (55).                          gland secretions
Myeloperoxidase produced by neutrophils catalyzes           TNF-α          Enhances acute phase inflammatory
                                                                             response
the same peroxidase reaction as lactoperoxidase and                        Enhances neutrophil phagocytosis and
additionally catalyzes the oxidation of chloride, the                        bactericidal activity
product of which provides the bactericidal activity of                     Enhances endothelial adhesion molecule
this system. In humans, myeloperoxidase is entirely                          expression
responsible for the catalytic activity of this antimicro-
                                                            Note. IL = interleukin, G-CSF = granulocyte colony-stimulating
bial system in milk (55). However, the low oxygen ten-      factor, GM-CSF = granulocyte-monocyte colony-stimulating fac-
sion of the mammary gland can inhibit the production        tor, M-CSF = macrophage colony-stimulating factor, IFN-γ =
of hydrogen peroxide, thus limiting the effectiveness       interferon-γ , and TNF-α = tumor necrosis factor-α.
142                                                                                         Sordillo and Streicher


as communicator molecules between leukocytes. Al-           granulocytes. Treatment of bovine peripheral blood
though all cytokines share this basic property, many        and mammary gland neutrophils with rbGM-CSF
of the well-characterized cytokines are designated as       significantly increased the chemotactic and bacterici-
IL; IL-2 is the most extensively characterized of all       dal capabilities of these cells. Intramammary infusion
the bovine cytokines. Originally described as T-cell        of rbGM-CSF at doses of up to 5 mg did not signif-
growth factor, IL-2 is primarily produced by T lym-         icantly affect total milk somatic cell counts (SCC),
phocytes of the Th1 phenotype and is responsible for        but increased the ability of resident neutrophils to
clonal expansion of the initial T lymphocyte immune         produce superoxide and increased the percentage of
response and establishment of immunologic mem-              phagocytic cells (56). Because an early and rapid re-
ory following mitogenic or antigenic stimulation. This      gression of functionally competent neutrophils from
cytokine also plays a role in B lymphocyte growth           the blood stream is critical for the control of new in-
and differentiation, enhancing thymocyte prolifera-         tramammary infections (IMI), the enhancement of
tion, activating NK cells, and inducing cytotoxic T-cell    chemotaxis and phagocytosis by GM-CSF, as well
activation. There is evidence that decreased endoge-        as the kinetics of this enhancement, could increase
nous IL-2 production contributes to diminished im-          the resistance of the mammary gland to invading
mune capabilities, which can lead to the development        pathogens.
of disease. In fact, studies showed that colostrum sam-          Interferons are a group of closely related pro-
ples that were obtained during the final week of ges-        teins of two major classes. Class I IFN consists of
tation had low IL-2 activity, which correlates with         three related types: IFN-α, IFN-β, and IFN-ω. The
diminished immune cell function and increased sus-          IFN-α and IFN-β are produced by a variety of cell
ceptibility to mastitis during this period. The possibil-   types in response to several inducers, including viral
ity of enhancing bovine mammary gland defenses with         infections, bacterial products, and tumor cells. In the
IL-2 to increase resistance to mastitis has received        bovine, the IFN-ω genes code for proteins produced
considerable attention. In vitro and in vivo studies in-    by the early embryonic trophoblast, and these are re-
dicated that recombinant bovine IL-2 may enhance            ferred to as IFN-τ . The second class of IFN consists of
the functional capabilities of populations of mononu-       a single protein, IFN-γ, which is unrelated to the class
clear cells within the mammary gland (55,59).               I IFN. Interferon-γ is a cytokine derived from T lym-
      The CSF are a group of cytokines required for         phocytes that is often produced in response to stim-
the proliferation and differentiation of a variety of       ulation by antigens or mitogens. Evidence suggests
hematopoietic stem cells. These growth factors are          that IFN-γ could elicit functional changes in phago-
distinct glycoproteins that bind to cells by a com-         cytic cells in the mammary gland that could make it
mon receptor and are produced by a variety of cells,        effective in the control of bovine mastitis (57). The
including fibroblasts, endothelial cells, macrophages,       in vitro treatment of bovine mammary gland neu-
and T cells. Each CSF tends to target a specific cel-        trophils with IFN-γ was shown to reverse the sup-
lular lineage to expand or activate its function. The       pressive effects of mammary gland secretions and sig-
pronounced influence of granulocyte (G)-CSF on               nificantly increase the functional capabilities of these
phagocytic cell populations suggests possible clini-        cells against S. aureus.
cal applications in the prevention of infectious bac-            The acute symptoms most often associated with
terial diseases, such as mastitis. Recombinant hu-          coliform mastitis are due to the rapid and unrestricted
man G-CSF has been administered subcutaneously              growth of the organism and the subsequent devel-
to cows in doses ranging from 1 to 5 µg/kg per              opment of an unlimited inflammatory reaction. Of
day, resulting in an increase in peripheral blood neu-      the acute phase cytokines produced during the early
trophils after 3–5 days of injections (60). Treatment       stages of infection, TNF-α is a major factor that causes
with G-CSF was shown to decrease random and di-             endotoxic shock during peracute coliform mastitis. El-
rected neutrophil migration and increase phagocyto-         evated sera and milk concentrations of TNF-α were
sis and bactericidal activity. Granulocyte-macrophage       found in cows that had died from acute E. coli masti-
(GM)-CSF was first identified by its capacity to induce       tis during the periparturient period (57). Monocytes
hematopoietic progenitor cells to develop into gran-        isolated from periparturient dairy cows can produce
ulocytes and macrophages. Several studies in dairy          more TNF-α following LPS stimulation than cells iso-
cows have shown that GM-CSF is not only an impor-           lated from cows in mid to late lactation (61). The en-
tant molecule for inducing the growth of these cell         hanced ability of localized cell populations to pro-
types, but also affects a variety of functions of mature    duce this potent proinflammatory mediator around
Immunobiology of the Mammary Gland                                                                             143


the time of calving may explain the greater frequency     sired level. Immunomodulatory strategies may alter
of clinical coliform mastitis during the periparturient   host defense to evoke a change in the magnitude
period. The ability to modify its production during       or kinetics of immune or nonimmune responses to
coliform mastitis may lessen the morbidity and mor-       either a specific antigen or a range of antigenic stimuli.
tality associated with the acute form of this disease.    The principle targets of immunomodulation include
      Stresses due to pregnancy and parturition stim-     T and B lymphocytes, NK cells, cells of the mono-
ulate the production of a variety of stress hormones      cyte/macrophage series, and granulocytes. However,
that can have important effects on the immune re-         soluble components of the immune system, such as cy-
sponse. One group of these stress hormones known          tokines, immunoglobulins, and complement also are
to cross-regulate immune function is the corticos-        amenable to immunomodulatory strategies. Since im-
teroids. The synthetic glucocorticoid dexamethasone       munoregulatory agents can act on more than one cell
can decrease the total number, distribution, and func-    type, the final biological effect in the animal will de-
tion of leukocytes in bovine blood (2). As shown          pend on the contribution of the targeted immune com-
previously, studies of neutrophils during parturition     ponent to various immune responses and the relative
revealed a down-regulation of adhesion molecules          sensitivity to the immunomodulatory agent.
(CD62L and CD18), which correlates to neutrophil                The design of immunomodulatory strategies
dysfunction and disease development in cattle (62).       should consider critical host–pathogen interactions
A potential mechanism explaining this effect could        involved in the pathogenesis of disease. Mastitis is
be that the dexamethasone-induced down-regulation         caused by a wide array of bacteria with diverse modes
of the glucocorticoid receptor (GR) on neutrophils        of pathogenesis. Mastitis-causing pathogens possess
alters GR-mediated gene expression of CD62L, lead-        a spectrum of virulence factors that facilitate the
ing to impaired neutrophil migration during the peri-     colonization and infection of the mammary gland.
parturient period (62). Additionally, glucocorticoids     For example, certain mastitis-causing pathogens can
cause a decrease in γ δ T cells in the blood, lower IgM   evade host defenses by adhering to epithelial cells,
in mammary secretions, reduced expression of MHC          producing capsules to prevent ingestion and destruc-
on mononuclear cells, and an inhibition of cytokine       tion by neutrophils, producing endo- and enterotox-
production (24,63–65).                                    ins to destroy or inactivate leukocytes, and utilizing
      In addition to the effects mediated by the          intracellular invasion to escape immune surveillance.
corticosteroid family of stress hormones, a number        If successful, the bacteria and their by-products not
of other stress-associated factors have been shown        only exacerbate the inflammatory response, but also
to be altered at parturition. For example, changes        damage the surrounding secretory parenchyma and
in progesterone, estradiol 17β, insulin-like growth       vasculature. In order to prevent the establishment
factor 1 (IGF), and growth hormone (GH) have              of disease, the host must respond appropriately to
the potential to modify neutrophil and lymphocyte         neutralize the impact of these bacterial virulence fac-
function (6,66–68). In the porcine system, estradiol      tors. The purpose of any immunomodulator is to pro-
17β and cortisol concentrations were decreased            mote a more effective and sustained immunity to in-
in mammary secretions, which led to virtually no          fectious agents without the risk of toxicity or tissue
change in the phagocytic capacity of neutrophils,         damage. The design of effective immunomodulators
but a significant decrease in the opsonic activity of      for the control of mastitis is especially difficult be-
these secretions (28). In humans, psychological stress    cause the disease is caused by a wide variety of infec-
has been linked to lowered levels of IgA and cited        tious agents with distinctly different modes of patho-
as a major risk factor for mastitis in breastfeeding      genesis. Moreover, the impact of certain bacterial
women (9). Although no direct associations have           pathogens is determined by stressful environmental
been made, the possibility exists for a link between      and/or physiological conditions. Therefore, one needs
low levels of IgA, increased stress, and an increased     to completely understand the pathogenesis of specific
incidence of mastitis.                                    mastitis-causing pathogens to determine if prevention
                                                          or therapy with an immunomodulator is a viable op-
FUTURE PROSPECTS FOR                                      tion. In addition, it will be essential to identify the
IMMUNOMODULATION                                          type of immunomodulation (specific vs. nonspecific)
                                                          that would be most effective and establish the opti-
     Immunomodulation is a general term used to de-       mal timing and dosage of administration. The devel-
scribe the process of altering host immunity to a de-     opment of successful immunomodulatory strategies
144                                                                                                                   Sordillo and Streicher


to control mastitis will depend on continued research                       17. M. E. Selsted, Y. Q. Tang, W. L. Morris, P. A. McQuire, M. J.
into the mechanisms of host–pathogen interactions                               Nonotny, W. Smith, A. H. Henschen, and J. S. Cullor (1993).
                                                                                Purification, primary structures, and antibacterial activities of
and the application of this knowledge to develop
                                                                                the beta-defensins, a new family of antimicrobial peptides from
immunomodulators that are safe, effective, and ful-                             bovine neutrophils. J. Biol. Chem. 268:6641–6644.
fill consumer expectations.                                                  18. T. Q. Cai, P. G. Weston, L. A. Lund, B. Brodie, D. J. McKenna,
                                                                                and W. C. Wagner (1994). Association between neutrophil func-
                                                                                tions and periparturient disorders in cows. Am. J. Vet. Res.
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Description: Mammary Gland Immunity and Mastitis Susceptibility cquired immunity