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

female, play s a n importan t rol e i n maintainin g
tolerance vi a suppressio n o f a n allogenei c respons e
directed agains t th e fetu s (Szekeres-Barth o e t al. ,
1990; Aluvihar e e t al. , 2004) . I n uter o exposur e t o
ethanol coul d alte r th e balanc e betwee n regulator y
T cells and T effecto r cells , and thus contributes to
the increase d incidenc e o f spontaneou s abortion s
and premature births. This conclusion i s supported
by observations of elevated cor d bloo d Ig E concentrations
i n ethanol-expose d infants , indicatin g in -
creased activit y o f Th2-typ e response s (Somerse t
et al. , 2004) . Long-ter m alteration s i n CD4 + regu -
latory T cells in FEE male s may play a role in mediating
deficit s i n T cel l functio n (Zhan g e t al. ,
2005a). Dexamethasone-induced apoptosi s an d res -
cue by IL-2 of CD4+/CD25+ T regulator y cells fro m
FEE animal s an d control s hav e bee n examined .
CD4+/CD25+ regulator y T cell s fro m FE E male s
were more resistant to dexamethasone-induced apoptosis
i n th e presenc e o f IL-2, resulting i n increase d
survival o f T regulator y cells . A s T regulator y cell s
are suppressive in nature, th e increase d number s of
surviving T regulator y cell s coul d pla y a rol e i n
ethanol-induced immun e deficits.
Neuroendocrine-Immune Interactions
The CN S i s critical fo r th e developmen t an d mat -
uration o f th e feta l immun e syste m throug h bot h
sympathetic activit y an d neuroendocrin e mediators ,
such as growth hormone an d the HPA and HPG hor -
mones (Fig . 10.4) . Th e sympatheti c nervou s system
innervates lymphoid organs, and lymphocytes express
receptors fo r CRH , ACTH , cortisol , NE , an d epi -
nephrine. Th e glucocorticoi d hormone s ca n exer t
profound influences on T cell function throug h their
interaction with GRs on T cells, which modulate trafficking
an d homing , proliferation , activation , an d
apoptosis (Gonzal o e t al , 1994 ; Dhabha r e t al ,
1996). Fo r example, transgeni c mic e wit h decrease d
GR binding capacity but normal basal concentration s
of ACTH an d COR T sho w a partia l blockag e o f T
cell differentiatio n and decrease d apoptosi s in the fetal
period but no t in adult life (Sacedo n e t al.7 1999) .
In addition, glucocorticoids cause a shift from Thl to
Th2 responses and a change from a pro-inflammatory
cytokine patter n (e.g. , IL-1 an d TNF-ot ) t o a n anti -
inflammatory cytokin e pattern (e.g. , IL-1 0 and IL-4 )
(DeRijk e t al. , 1997 ; Elenko v an d Chrousos , 1999) .
ETHANOL EFFECTS ON ENDOCRINE AND IMMUNE FUNCTION 17 1
Growth hormon e increase s IFN- y productio n an d
MHC clas s I an d I I expressio n b y thymic epithelia l
cells, macrophages , dendriti c cells , fibroblasts , an d
extracellular matri x (Savin o an d Dardenne , 2000) .
These results suggest that growth hormone facilitate s
MHC-mediated influence s o n thymocyt e differentia -
tion. Thymic epithelia l cells and lymphocyte s in rat s
express estroge n an d androge n receptor s fro m G1 6
(Tanriverdi et al., 2003) and thus are influenced by circulating
sex steroid hormones. Furthermore, adminis -
tration o f gonadotropin releasin g hormon e (GnRH )
restores fetal thyrnic and liver-derived T cell proliferative
response s afte r surgica l ablation o f the forebrain
or the entir e brai n includin g th e hypothalamu s an d
pituitary in 18-day-ol d fetuses (Zakharova et al., 2000).
Thus, GnRH appear s to be involve d in regulation of
T cel l developmen t eve n during prenatal ontogene -
sis. These examples show how closely development of
the thymus is regulated by the neuroendocrine system.
Cytokines secreted by immune cells, such a s IL-1,
IL-2, IL-4, an d IL-6 , influence the functio n of hypothalamic
neurosecretor y an d thermoregulator y neu -
rons and pituitary cells (Cunningham an d De Souza,
1993; Rivier , 1994; Zalcma n e t al., 1994 ; Dun n an d
Wang, 1995) , resultin g in activation of the HP A axis
and inducing "sickness behavior" (Watkins and Maier,
2000; Dantzer, 2001). IL-1, IL-6, and TNF-oc are also
produced i n th e hypothalamu s b y microgli a an d
macrophages (Hetie r et al., 1988 ; Sebir e et al, 1993 )
and thus can directly influence neuroendocrine func -
tion. For example, IL-1 stimulates the release of CRH
and AV P from th e hypothalamu s (Sud a e t al, 1990 ;
Chover-Gonzalez e t al. , 1994) , an d IL-1 , IL-6 , an d
TNF-oc stimulate ACT H secretio n fro m th e anterio r
pituitary (Kehre r e t al. , 1988 ; Shar p e t al , 1989 ;
Lyson and McCann, 1991).
Given th e intimat e interaction s between th e neu -
roendocrine an d immun e system s (Fig. 10.4 ) durin g
development and in adulthood , feta l ethanol-relate d
developmental change s i n neuroendocrin e activit y
could affec t immun e competency . I n turn , feta l
ethanol-induced change s in cytokine secretion by immune
cell s can affec t neuroendocrin e activity . Therefore,
th e altere d HP A response s t o immun e signal s
(Lee and Rivier, 1993 ) and differential vulnerability to
stress-induced immun e suppressio n (Giberso n an d
Weinberg, 1995; Giberson et al, 1997) shown by FEE
rats compared to that of controls could be mediated by
the altered neuroendocrine-immune interactions.