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

166 ETHANOL-AFFECTE D DEVELOPMENT
time, splenic T cells have adult levels of expression of
CD3, CD4 , an d CDS and are able to respond to mitogens
(Ka y et al., 1970) , an d spleni c accessor y cells
are full y functiona l i n deliverin g co-stimulatory signals
(Hol t an d Jones , 2000). Fetuse s stil l hav e fewe r
memory T cells than adults do at this time (Hol t and
Jones, 2000). Yolk sack-derived pro- B cells develop in
the liver and acquire surface immunoglobulin (Ig ) M,
IgD, and CD2 0 expression by 10-13 weeks of gestation
(Hofma n et al., 1984) . B cells ar e detectabl e i n
lymph node s fro m 16-1 7 weeks, in splee n a t 16-2 1
weeks, an d ar e abundant i n bon e marro w at 16-2 0
weeks of gestation (West , 2002).
The structur e of the thymus develops as a result of
epitheliomesenchymal interactions. Endoderm of the
third pharyngeal pouch differentiate s int o thymic epithelium.
Neural crest cells then migrat e through th e
branchial arche s an d becom e th e mesenchym e tha t
will form the layers around the epithelial primordium
of the thymus and the connective tissue framework. T
cell progenitor s arriv e in th e thymu s fro m th e live r
during the ninth wee k of gestation, an d th e structur e
of th e thymu s differentiate s int o a corte x an d a
medulla at 10-1 2 week s (West, 2002). Prothymocytes
express CD 7 i n th e feta l live r at 7 week s and CD 3
at 8- 9 week s of gestation, whe n thes e cell s migrat e
to the thymus (Holt and Jones, 2000). Gene rearrangement
start s a t aroun d wee k 11 , an d expressio n o f
the T cel l receptor s (TCR) , CD4 , an d CD 8 fol -
lows. Thymi c "education " o f immature CD4 + /CD8 +
(double-positive) T cell s take s plac e i n th e secon d
trimester b y positiv e selection , wit h th e abilit y o f
TCR t o bin d t o polymorphi c part s o f nonagonis t
MHC-encoded molecules on nonlymphoid cells, and
by negativ e selectio n of TCR, wit h hig h affinit y to
self-antigens t o avoi d autoimmunit y (vo n Boehme r
et al, 2003). Export of mature CD4+ or CD8+ (single
positive) cell s begin s afte r wee k 13 , and a rapi d expansion
o f the T cel l poo l happen s durin g 14-1 6
weeks (Kay et al., 1970 ; Berr y et al, 1992) . At 13-14
weeks, thymocytes acquire proliferative ability to most
mitogens. During the second trimester , susceptibility
to environmenta l factor s cause s disruptio n o f th e
thymic educatio n processe s an d cel l proliferation ,
leading to a defective T cell repertoire.
As roden t gestatio n (~ 3 weeks ) i s substantially
shorter tha n tha t o f humans (~4 0 weeks) , immun e
system developmen t o f newbor n ra t an d mous e
pups occurs at a time equivalent to the end of the sec -
ond trimeste r i n human s (Zaja c an d Abel , 1992) .
Therefore, studie s i n roden t model s o f prenata l
ethanol exposur e have focused primarily on the early
events in ontogeny of the immune system, i.e., during
the late gestational period and early postnatal life .
Impaired Immunit y following Prenatal
Exposure to Ethanol
Children prenatall y expose d t o alcoho l hav e a n in -
creased incidenc e o f bacteria l infections , suc h a s
meningitis, pneumonia , recurren t otiti s media , gas -
troenteritis, sepsis , urinar y tract infections , an d fre -
quent uppe r respirator y trac t infection s (Johnso n
et al, 1981 ; Churc h an d Gerkin, 1988) . These children
als o have lower cell count s o f eosinophils and
neutrophils, decrease d circulatin g E-rosette-formin g
lymphocytes, reduce d mitogen-stimulate d prolifera -
tive response s b y periphera l bloo d leukocytes , an d
hypo-y-globulinemia (Johnson et al., 1981).
Research usin g animal model s t o investigat e im -
mune function of FEE offsprin g has (a) substantiated
the clinica l evidenc e o f impaire d immunit y associ -
ated wit h FASD and (b ) greatly increased ou r under -
standing of these immune deficits in terms of both th e
spectrum of effects i n differen t orga n systems and th e
mechanisms mediatin g th e immunoteratogeni c ef -
fects o f ethanol . Deficit s i n innat e immunit y hav e
typically no t bee n observe d i n anima l studies . Fo r
example, on e larg e stud y o n nonhuma n primate s
(Macaco, nemestrina) show s that i n uter o ethano l ex -
posure doe s not result in significant differences i n total
numbers of white blood cells, leukocyte subsets, or
monocyte phagocyti c activit y compare d t o tha t i n
control subjects (Grossmann et al., 1993). In contrast,
marked deficit s in adaptiv e immunity involving both
cell-mediated an d humora l immunit y ar e eviden t
in FE E animals . Furthermore , a s describe d i n th e
discussion below , a marke d sexua l dimorphis m i n
ethanol effect s ha s been observed , wit h the majorit y
of deficits occurring in male offspring .
Deficits i n Adaptive Immunit y
Inborn errors of immunocompetent cells in children
with FASD result in immunodefiency disorders or increased
susceptibilit y to infections. Recurrent opportunistic
infection and infectio n caused b y ubiquitous
microorganisms, such a s bacteria, viruses , and fungi ,
typically occu r wit h deficit s in cell-mediate d immu -
nity, wherea s deficit s i n B cells , immunoglobulins ,