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                                    October issue
                                  (Vol. 28, Number 4)

                        SMOKING'S IMPACT ON
                              FOETAL AND
                       INFANT DEVELOPMENT:
                     THE IMMUNE SYSTEM PLAYS A
                            CRUCIAL ROLE
                      Australian team's breakthrough

         Smoking while pregnant not only affects the foetal airways,
         but the immune system too. This may explain the greater
         frequency of respiratory infections, asthma and other allergic
         lung conditions among infants born to smoking mothers. So
         finds a team led by Susan Prescott of the University of
         Western Australia in Perth, writing in the upcoming issue of
         the European Respiratory Journal (ERJ).

It has been evident for some years that newborns whose mothers smoked during pregnancy
are twice as likely to contract respiratory infections as babies born to non-smoking mothers.
Which is all the more alarming when one considers that respiratory infections are the leading
cause of infant mortality in developing countries. Until now, prospective studies could offer
no explanation for this increased neonatal vulnerability. So Susan Prescott and her
colleagues, from the School of Paediatrics and Child Health Research at the University of
Western Australia, had precisely that in mind when they launched the study whose results
appear in the new issue of the ERJ.

Their work was based on a very simple hypothesis: these babies are more vulnerable to
infections because the cigarettes smoked by their mothers during the pregnancy harmed the
development of their immune systems. "To be more precise", Prescott adds, "we were
focusing on the innate, or congenital, immune system. This provides protection until the baby
develops an acquired immune system, which becomes increasingly powerful through contact
with new antigens."
Dual role

The Australian researchers concentrated their efforts on a special category of biological
receptors known as "toll-like receptors" (TLRs), responsible for recognising pathogens and
activating immune response. These are found on the surface of many of the blood cells
involved in immune reactions.

TLRs are especially interesting because of the interface they represent between innate and
acquired immunity. They are involved in the body's immediate reactions (innate immunity)
to pathogens, and can recognise all sorts of bacterial, viral, fungal and parasitic intruders
even though there has never been any prior contact with them.

By attaching to these pathogens, the TLRs set off a chain of immune processes, including the
production of various substances, such as cytokines, to destroy or remove the pathogens.
But they also help regulate the programming of the acquired immune system. When
activated, they open signalling pathways that help activate the antigen marker cells and T-
regulator lymphocytes, two cell types that play a central role in acquired immunity.

Lower immune defences

The Perth team compared the serum immune responses of sixty newborns whose mothers
had smoked during pregnancy with that of 62 newborns whose mothers had either never
smoked or had stopped during pregnancy.

Mothers' tobacco consumption was assessed by means of questionnaires, and verified by
testing blood taken both from the mothers and from the umbilical cord at delivery for
cotinine, the main nicotine marker. Then the researchers set out to measure expression of
several cytokines linked to four particular TLRs, a completely original approach. "This is the
first prospective study to examine the effect of smoking during pregnancy in terms of these
aspects of newborn innate immune function", emphasises Paul Noakes, the ERJ article's first

This original approach bore fruit: the team found that maternal smoking led to a significant
impairment of production of interleukin-6 and tumour necrosis factor-alpha (TNF-a), two
inflammatory cytokines produced respectively by antigen marker cells and mononucleic cells
such as lymphocytes. "We also noticed a significant reduction in interleukin-10, a regulatory
cytokine preferentially produced by antigen marker cells when microbial stimulation is
present", Prescott adds. The study thus demonstrates that foetal exposure to cigarette smoke
is accompanied by changes that both weaken innate immune defences and slow the
development of the acquired immune system.

A link to the hygiene hypothesis

While the raw data obtained by the team are already extremely solid, they become even more
so when adjusted for confounding factors. Maternal allergies, household socio-economic
status or illegal drug use (such as marijuana or ecstasy) have no significant effect on innate
immune system response to TLR stimulation.

The results presented in the ERJ article thus demonstrate that, in addition to its well-known
adverse effect on foetal airway development, maternal smoking also impacts significantly on
immune development. This is an important discovery, providing as it does at least some of
the answers as to why babies born to smoking mothers are more prone to infection.

This project could lead to even more interesting discoveries in connection with the so-called
hygiene hypothesis, which postulates that early immune response to bacterial agents plays a
central role in the development and programming of the immune system. Bacterial
stimulation, when it results in the normal immune reactions, inhibits the signalling pathways
that lead to allergic reactions. "These are alarming results, suggesting that smoking during
pregnancy can adversely affect immune programming, which in turn can increase the risk of
allergic conditions later on. We plan further projects to explore this link", Noakes concluded.

Title of the original article:
Maternal smoking is associated with impaired neonatal toll-like-receptor-mediated immune