FOREWARD. As many of you know, my recent research has been
looking at milk composition, infant growth, and maternal health in a population
of ethnic Tibetans living in the Himalayas of Nepal. The communities I work
with were within 50 miles of the epicenter of the earthquake on April 25. While the loss of life in these communities
was minimal (thankfully), there was considerable destruction of homes, clinics,
schools, and infrastructure (water, latrines). With the upcoming monsoon
season, there is considerable need for safe drinking water, food storage,
medical care, and safe homes. Several NGOs with long standing relationships
with the communities are currently fundraising for relief and rebuilding
efforts. Please consider donating to these organizations if you can afford to
do so (NepalSEEDS; Tsum-Nubri Relief Center). We are still committed to these communities, and will continue to
support infrastructure and research to promote maternal and child health.
MAY BLOG POST
In the last blog post – January – I discussed
the idea of immunological memory in milk, particularly the well described
association between maternal exposure to pathogenic bacteria in early life and
the immunological memory of those bacteria, by specific forms of secretory
Immunoglobulin-A (sIgA), many years later. Milk is incredibly dynamic, and this
is certainly true for the immune factors in milk. Three recent papers have
investigated this responsiveness in several samples, using a variety of immune
factors to measure immune activation in milk.
Breakey et al., (2015) have articulated this as a model of
two systems within the mammary gland – a protective paradigm, where some immune
factors in milk are always protecting against infection; and the responsive
paradigm, where active infection will increase the concentrations of immune
factors in milk. Of the hundreds of known (and many unknown!) immune factors in
milk, some will be generally protective, and others will be responsive
(Brandtzaeg 2010). A few, including secretory IgA, will be both.
Breakey et al., (2015) investigated the responsiveness of
immune factors in milk to current infection using two biomarkers – sIgA and
lactoferrin – in a sample of 29 Toba mother-infant dyads followed longitudinally.
Both of these biomarkers have come up before (for reviews: sIgA; lactoferrin).The
Toba are indigenous population from Argentina (Figure 1); previous generations
have subsisted as foragers, but more recently the population has become
increasingly concentrated in peri-urban areas, often in informal settlements
lacking access to sanitation and water facilities.
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| Figure 1: Location of the Toba. Image from wikicommons, author Nazareno98; produced in 2008. |
Milk samples and interviews were collected monthly, allowing
for the researchers to investigate milk composition before, during, and after
an infection in the infant. Infant infections during the preceding month were
collected during monthly interviews; all infants in the study had at least one
illness over the course of the longitudinal study. Mothers did not report
frequent illnesses, although this may have been underreporting.
In this sample, infants receiving milk with higher sIgA were
less likely to be ill, while infants receiving milk with more lactoferrin were
more likely to be ill. Although causation cannot be certain, the authors hypothesize
that lactoferrin content of milk increases during an infection (responsive)
while sIgA levels are more generally protective.
The study with the Toba follows two earlier studies of
immune responsiveness in milk, both done in WEIRD populations. The earliest, by
Riskin et al., (2012) remains one of my favorite papers. In this study, Riskin
et al., recruited 51 mother-infant dyads, younger than 3 months, from Haifa,
Israel into the study. 31 mother-infant pairs were hospitalized for fever at
the time of recruitment, with an additional 20 pairs serving as healthy
controls. Milk samples were collected from the mothers while the infants were
hospitalized, and then seven days later; samples from controls were collected
at one week intervals. Milk samples were analyzed for immune cells
(lymphocytes, neutrophils, macrophages, CD45+), sIgA, lactoferrin, TNF-alpha,
and IL-10 (Figure 2).
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| Figure 2: Important cells in the immune system. Not all are found in milk. Image credit: http://imgkid.com/immunity-cartoon.shtml |
For the purposes of analyses, the participants were grouped into 3
categories: controls (healthy mom, healthy baby; n=20), all sick (all infants
sick, moms sick or not; n=31), and sick infant (only baby sick; n=20). For the
control group, there were no changes in the immune factors measured in milk
from time 1 to time 2. However, for the sick group, there were significant
declines in CD45+ cells, lymphocytes, neutrophils, macrophages, IL-10, and
TNF-alpha. Lactoferrin and sIgA also declined, but the differences were minor.
It does not appear that the associations were simply responding to maternal
infection either. In the 20 mothers of sick infants who were not ill
themselves, milk cd14+ cells, neutrophils, and macrophages also showed a
significant decline from the original to the after measure. All other immune
factors also showed declines, but again these were relatively minor.
In an additional study of 21 mother-infant pairs, Hassiotou
et al., (2013) reported increased leukocytes, and sIgA in the milk of mothers
with infections compared to earlier and later samples from the same mothers
collected as part of a longitudinal study design. While both maternal and
infant infection increased leukocytes and sIgA in milk, this was most
pronounced for mothers with breast infections.
One of the leading hypotheses for how maternal physiology
may respond to infection in the infant is through oral contact. Saliva from the
infant’s mouth may enter the breast, carrying the pathogens responsible for the
infection. This would encourage a localized immune response to the pathogen in
the mammary gland itself (Hassiotou et al., 2013), although Riskin et al.,
(2012) also propose a model of subclinical infection in the mothers.
The capacity for milk to balance between innate and adaptive
immune responses is incredibly important, especially for infants living in
highly pathogenic, low resource environments such as the Toba, or my own
participants from Nubri (more on this to come). Certainly, having a milk to gut
superhighway for immune factors should be incredibly important in promoting gut
integrity, decreasing infant illness, protecting against growth faltering, and
promoting infant survival. Infant – or maternal – illness becomes then not a
reason to stop nursing, but a reason to nurse more.
References
Brandtzaeg P. (2010) The mucosal immune system and its
integration with the mammary glands. J Pediatr. 156(2 Suppl):S8-15
Breakey AA, Hinde K, Valeggia CR, Sinofsky A, Ellison PT.
(2015) Illness in breastfeeding infants relates to concentration of lactoferrin
and secretory Immunoglobulin A in mother's milk. Evol Med Public Health.
2015(1):21-31. doi: 10.1093/emph/eov002.
Hassiotou F, Hepworth AR, Metzger P, Tat Lai C, Trengove N,
Hartmann PE, Filgueira L. (2013) Maternal and infant infections stimulate a
rapid leukocyte response in breastmilk. Clin Transl Immunology. 2(4):e3. doi:
10.1038/cti.2013.1
Riskin A, Almog M, Peri R, Halasz K, Srugo I, Kessel A.
(2012) Changes in immunomodulatory constituents of human milk in response to
active infection in the nursing infant. Pediatr Res. 71(2):220-5. doi:
10.1038/pr.2011.34.
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