Brain Development: Normal Processes and the Effects of Alcohol ...

170 ETHANOL-AFFECTE D DEVELOPMENT
nonstressed conditions, they may in fact be more vulnerable
t o th e advers e effect s o f stres s o n immun e
function (Eske s et al., 2004).
Mechanisms Underlyin g
the Effects of Ethanol
on the Developing Immune Syste m
Direct and Indirect Effects
of Ethanol on the Fetus
Ethanol ca n directl y disrupt the developmen t o f the
fetal thymus. The highl y specified microenvironment
of the thymu s provided by epithelial an d mesenchy -
mal cell s i s pivotal i n attractin g immature lymphoi d
precursors to enable them to be selected and differen -
tiated int o matur e T cells . Exces s ethano l exposur e
during th e developmen t o f the thymu s inhibit s th e
ontogeny o f the thymi c epitheliu m an d disrupt s th e
microenvironment fo r maturation o f T cells , whic h
leads to impaired T cell immunity (Bockman, 1997) .
These data are interesting in light of the share d clinical
characteristics o f FASD and DiGeorg e syndrome
(Ammann et al., 1982) . The latte r is a congenital im -
mune deficienc y syndrome involvin g mainly T cell s
and cause d by an abnormality in the developmen t of
neural crest-derive d component s o f the thymu s and
parathyroid gland s (Kirb y and Bockman , 1984) . Tar -
geted effect s o f ethanol o n neural crest are describe d
in Chapter 17 .
Selective effect s o f ethanol o n thymi c CR H an d
POMC gene expression in male fetuses have been reported.
Significan t increase s i n thymi c CR H an d a
decrease i n thymi c POM C gen e expressio n hav e
been observe d on G1 9 (Revsko y et al., 1997) . Thes e
changes d o no t appea r t o be relate d t o COR T con -
centrations in the fetus or pregnant female, but possibly
ar e induce d b y th e feta l testosteron e surge .
Similarly, the ontogen y of GR sites per thymocyte i n
FEE animal s in the first 2 months o f life differ s fro m
that in control animal s (Chiappelli et al., 1992) . This
indicates a rol e for th e glucocorticoi d hormone s i n
the differentia l thymi c developmen t describe d i n
FEE and control animals.
Altered IL-2/IL-2 receptor interaction s ma y play a
role in the developmen t of altered immune function
in FEE animal s (Weinberg and Jerrells, 1991; Taylor
et al., 1993 ; Chang et al, 1994). For example, despite
showing a reduced proliferative response to mitogens,
FEE animal s have norma l amount s o f IL-2 produc -
tion, IL- 2 recepto r expressio n an d distribution , cal -
cium influ x i n T cells , an d bindin g o f IL- 2 t o it s
receptor. Th e internalizatio n and/or utilization of IL-
2 by lymphoblasts, however, is reduced, an d th e half -
time fo r dissociatio n o f IL- 2 fro m it s recepto r i s
increased i n T cell s fro m FE E animals . Therefore ,
impaired intracellula r signalin g events , mediate d b y
IL-2/IL-2R interactions , ma y underli e th e immun e
deficits observe d i n FE E animals . In contrast , direct
treatment o f lymphocyte s wit h acetaldehyde-seru m
protein, whic h form s i n viv o a s a metabolit e o f
ethanol consumption , result s i n decrease d IL- 2 pro -
duction bu t no t IL- 2 recepto r expressio n (Brau n
et al. , 1995) . This result suggests that, a t least under
some conditions , decrease d IL- 2 productio n con -
tributes to impaired proliferative responses.
Altered neurotransmitte r regulatio n o f immun e
function ma y play a role in altered immun e function
of FE E animals . Prenata l exposur e t o ethano l de -
creases concentration s o f NE an d (3-adrenoreceptor s
in the lymphoid organs and diminishes synaptic transmission
i n the splee n an d thymus , but no t the hear t
(Gottesfeld e t al. , 1990) . Altere d NEergi c synapti c
transmission, including a higher rat e of NE turnove r
leading to reduced NE concentratio n and reduce d (3adrenoreceptor
density , could affect immune capacit y
in terms of NE-mediated IL-2 secretion an d cytotoxi c
T cell responses .
Immunity at the
Fetoplacental Interface
Immunity a t th e fetal-placenta l interfac e i s biase d
toward humoral immunity; cell-mediated immunity is
suppressed t o preven t feta l rejection . Cell-mediate d
immunity i s skewed towar d Th 2 response s an d pro -
duction o f cytokine s suc h a s IL-3 , IL-4 , an d IL-5 ,
rather tha n towar d Thl response s and production of
cytokines such as IL-2 and IFN-y (Lin et al, 1993). It
has been suggested that progesterone an d CD4 + regulatory
T cell s are the key factors enabling the fetus to
evade immune rejection by the pregnant female, thus
allowing th e femal e t o maintai n pregnancy . Proges -
terone suppresse s cytotoxi c activit y o f lymphocyte s
from pregnan t wome n vi a progesteron e receptor s
(Szekeres-Bartho e t al, 1990) . A timely increas e i n
CD4 + /CD25 + regulator y T cells , systematicall y and
locally at the interface between the fetus and pregnant