R e v i s ta d a S o c ie d a d e B r a s ile ir a d e M e d ic in a T r o p ic a l 2 5 ( 2 ) : 1 2 5 - 1 3 4 , a b r - ju n , 1 9 9 2
A RTIGO D E REV ISÃO
H U M A N IM M U N E RESPONSES DU R IN G
SCHISTOSOM IASIS M A N SO N I
G iovan ni G azzinelli and D aniel G. C olley
S tu d ie s o f im m u n e r e s p o n s e s a s th e y o c c u r in p a tie n ts w ith s c h is to s o m ia s is a p p e a r to p r o g r e s s r e la tiv e to c o r r e n t te c h n o lo g ic a l a d v a n c e s , a n d to a d v a n c e d e s p ite th e u n d e r s ta n d a b le in a b ility to p u r s u e i n v i v o m a n ip u la tio n s in th is h o s t/p a r a s ite s y s te m . E m p h a s is is m o s t o fte n p la c e d o n m a k in g im m u n o lo g ic a l c o m p a r is o n s b e tw e e n s u c h p a tie n t g r o u p s a s r e in fe c te d /n o n -r e in fe c te d , in te s tin a ls /h e p a to s p le n ic , h ig h /lo w in te n s itie s o f in fe c tio n , in fe c te d /u n in fe c te d w ith in e n d e m ic a r e a s , a n d th o s e b o r n o f in fe c te d /u n in fe c te d m o th e r s . B a s e d o n th e s e ty p e s o f c o m p a r is o n s , r e a s o n a b le c o n je c tu r e s c a n b e m a d e r e g a r d in g th e im m u n o lo g ic a l o c c u r r e n c e s d u r in g th is c h r o n ic e x p o s u r e c o n d itio n . S o m e c o n s id e r a tio n is n o w b e in g g iv e n to th e im m u n e m e c h a n is m s o f s o m e o f th e o b s e r v a tio n s m a d e , a n d w h ile s o m e o f th e s e m u s t th e n b e c a r r ie d b a c k to e x p e r im e n ta l m o d e ls f o r f u r t h e r m a n ip u la tio n - b a s e d a n a ly s is , n e w te c h n o lo g ic a l d e v e lo p m e n ts c o n tin u e to a s s is t in th e f ie ld / b e n c h a b ility to a s k q u e s tio n s th a t m ig h t a s s is t o u r u n d e r s ta n d in g to a p o in t w h e r e th is k n o w le d g e c a n b e a p p lie d to s h a p in g d e v e lo p m e n ta l a p p r o a c h e s to v a c c in e d e v e lo p m e n t a n d th e g o a l o f a lle v ia tin g m o r b id ity .
K e y - w o r d s : S c h is to s o m ia s is . Im m u n e r e s p o n s e s . Im m u n o r e g u la tio n .
T h e im m u n e sy stem s o f hum ans in fected w ith
S c h i s t o s o m a m a n s o n i
are
ex p o sed to a w id e
variety o f c o m p le x , parasite-d erived antigenic
substan ces, and are k n ow n to respond w ith m ultiple
im m u n e m ech an ism s. R eason ab le progress has
b een m ade b y sev eral group s o f in vestig ators in
th e c a ta lo g in g o f th e se r e sp o n se s and th eir
reg u lation . T h e results o f such studies are usually
interp reted in regard to o n e o f tw o v ery differen t
c o n t e s t s a)
r e s is t a n c e to r e in fe c t io n after
ch em oth erap y;
b ) m o rb id ity as seen in the
differential clin ical form s o f infection, or related to
fecal e g g coun ts (intensity o f in fectio n) (1 -3 ). T his
w o r k in g
p a p e r
w i l l
su m m a r iz e
th e se
im m u n olo g ical
fin d in gs and then outline h o w
these findings are currently, o rm igh tb e, interpreted.
R e s p o n s e s o f p e r i p h e r a l b l o o d m o n o n u c l e a r c e l l s t o s c h i s t o s o m e a n t i g e n s
A
f e w h u m a n im m u n o lo g y s tu d ie s in
C e n t r o d e P e s q u i s a s R e n é R a c h o u ( F I O C R U Z ) , B e l o H o r i z o n t e , M G , B r a z i l , a n d t h e V e t e r a n s A f f a i r M e d i c a l C e n t e r a n d D e p a r t m e n t o f M i c r o b i o l o g y a n d I m m u n o l o g y , V a n d e r b i l t U n i v e r s i t y S c h o o l o f M e d i c i n e , N a s h v i l l e , T N 3 7 2 1 2 . S u p p o r t f r o m N a t i o n a l I n s t i t u t e s o f H e a l t h , U N D P / W o r l d B a n k / W H O S p e c i a l P r o g r a m m e f o r R e s e a r c h a n d T r a i n i n g i n T r o p i c a l D i s e a s e s , C o n s e l h o N a c i o n a l d e D e s e n v o l v i m e n t o C i e n t i f i c o e T e c n o l ó g i c o d o B r a s i l , e F u n d a ç ã o d e A m p a r o 'a P e s q u i s a d e M i n a s G e r a i s ( B r a s i l ) .
R e c e b i d o p a r a p u b l i c a ç ã o e m 1 8 / 1 2 / 9 1 .
sch isto so m ia sis have b een d on e u sin g c e lls from the
spleens o f hepatosplenic patients rem ov ed at su rgery ,
but by far m o st studies h a v e a n alysed the reactivities
o f peripheral b lo o d m on on u clear c e lls (P B M C ). It
m ust b e rem em bered, th erefo re, that w h ile is the
on ly lo g ic a lly availab le w in d o w in to th e im m u n e
system , it suffers by o n ly a g lim p se o f w hat m ig h t be
occu rin g in th e peripheral ly m p h o id organ s, or even
m ore critica lly , at th e sites o f resistan ce effecto r
in v o lv em en t or le sio n fo rm a tio n . N e v e r th e le s s,
P B M C
have
b een
studied in m u ltip le w a y s,
in v o lv in g their p ro lifera tiv e ca pacity, their a b ility to
interact w ith an tigen -con ta in in g n id i, and their
ab ilities to m ake and realease cy to k in e s.
P r o l i f e r a t i o n
T h e m o st c o m m o n ly reported a ssa y is the
proliferative resp on se o f P B M C in th e p resen ce o f
sch isto so m e an tig en ic m aterials or p h y to m ito g en s.
Several groups have fo llo w e d th ese resp o n ses to
d ifferen t sch isto so m e-d er iv ed m aterials 614263258 62.
A r tig o d e R e v is ã o . G a z z in e lli G , C o lle y D G . H u m a n im m u n e r e s p o n s e s d u r in g s c h is to s o m ia s is m a n so n i. R e v is ta d a S o c ie d a d e B r a s ile ir a d e M e d ic in a T r o p ic a l 2 5 :1 2 5 -1 3 4 , a b r- ju n , 1 9 92 .
b e so m e dom in an t com p on en ts w h ich govern the
o vera ll resp o n siv en ess to b e d o n e to d issect th ese
r e s p o n s e s in reg a rd to in d iv id u a l a n tig e n ic
co m p o n en ts w ith in su ch extracts5 (B D oughty:
person al co m m u n ica tio n ).
U n til v ery recently all such studies w ere assayed
o n ly b y th e le v e l o f incorporation o f 3H -T dR into
th e D N A o f th o se c e lls stim ulated to proliferate in
th ese a ss a y . Current stu d ies also inclu d e p h en otypic
stu d ies o f th e resp o n d in g blast c e lls b y flo w
cy to m etric a n a ly sis59- T h ese prelim inary studie s
in d ica te that th e c e lls resp on d ig to S E A , id and the
“ su p er-an tigen ” sta p h y lococca l enteroto xin B do
so in d iffer en t p ro p o rtio n s, as p h en o ty p ica lly
ch aracterized b y their C D m arkers, T cell receptor
and interleukin receptor expression. Further analysis
and correla tion s w ith fun ctional attributes assig n ed
to d ifferent p h en otyp es m ay help in an understanding
o f th e in teractio n s in these responses.
W h ile true lon gitu d in al studies are fe w 12 14 57 ,
in g en era l, it is clear that patients w ith early
in fectio n s respond stro n g ly to S E A , w h ile response
to S W A P and C E R C d ev elo p m ore s lo w ly 34 53- A s
in fectio n p ro g resses in to the m ore chron ic phases,
a gen eral pattern is seen w ic h leads to lo w er
anti-SE A p ro lifera tiv e resp o n ses in th e fa ce o f higher
r e s p o n se s to S W A P and v a ria b le a n ti-C E R C
resp o n siv en ess. A ls o , i f in fectio n s are cured and
th e form er patients are not re-exp osed to the threat
o f sc h isto so m e in fe c tio n their P B M C ex p ress very
h ig h l e v e l s o f a n t i- S E A p r o l if e r a t i o n 15 35.
F urth erm ore, it h as recen tly been seen that those
in d iv id u a ls w h o liv e in en d em ic areas and have
co n tin u ed w ater c o n t a c t , but are repeatedly sto o
l-n eg a tiv e (w h o are presum ed to h a v e self-cu red or
bep u tatively resistant; antigenic extracts and purified
m o ie tie s5 (G G azzin elli: data n o t p u b lish ed ).
N u m ero u s d ifferen t correlations o f h igh or lo w
p ro lifera tiv e resp o n ses to variou s extracts h a v e
been m ade w ith clin ica l stages and form s o f the
in fectio n . S o m e correla tions are seen o n ly in areas
o f h ig h in ten sity in fe c tio n s12 15, w h ile n o t b ein g
o b serv ed in p op u la tio n s w ith m oderate or lo w
num bers o f e g g per gram (ep g ) o f fec es. W ith the
em erg en ce or m o re stu d ies, it is b eco m e apparent
that both the in ten sity and th e prevalen ce o f a g iv en
a r e a m a y i n f l u e n c e o r s h a p e th e g e n e r a l
resp o n siv en ess o f th e p opu la tion under study (G
G a zzin elli: w o rk in p rogress).
In vitro
g r a n u l o m a f o r m a t i o nT h e im m u n o p a th o lo g y o f ex p erim en ta l
S . m a n s o n iin fectio n is gen erally attributed to the
gran ulom a form ation around tissu e-d ep o sited e g g s ,
and is consid ered to b e a T cell-m ed ia ted im m u ne
response. E x cep t for th e w ork o f R o ck lin et a l62,
w h o ob served a correla tion b etw een su p p ression o f
SE A stim ula ted cultures and sm aller rectal e g g
-in d u ced g ra n u lo m a s, m o st -in fo r m a tio n ab ou t
granulom a form ation /m od u la tio n in hu m an s has
been obtained b y exam in ing in feced p atients’ P B M C
reactivity to an tig en-conju gated p o ly a cry la m id e
beads in a so -ca lled ,
i n v i t r o ,granu lom a assay23.
T h ese studies su g g est that im m u n o reg u lation in
chron ic sch isto so m ia sis is pred om in an tly cellu lar
in nature, p articu laly im p lica tin g a C D 8 + T
ly m p h o cy te in the regulation o f this reactiv ity. In
ad d ition it has benn reported that a n ti-id io ty p ic
(a n ti-id ) C D 4 + and C D 8 + T cell-su b sets can
dow n -regu la te a u to lo g o u s granulom a form ation
i nv i t r o
w h en p rev io u sly incubated w ith eith er an
anti-S E A hum an Ig m A b or p o ly c lo n a l a n ti-anti-S E A
antib odies im m u n oaffm ity-p u rified fro m a p o o l o f
sera from ch ron ically in fected patients. T h e se
an tib o d ies sup press th e a u to lo g o u s gran u lo m a
form ation b y interaction w ith a n ti-id T c e lls . T his
effe c t w as n ot ob served w ith Fab fragm ents o f an
ti-S E A an tib iod ies, su g g estin g cro sslin k in g o f T cell
m em bran e com p on en ts is required to in d u ce this
p h en o m en on , as it is for th e in d u ctio n o f a n ti-id T
c e ll p r o life r a tio n 23. S p e c ific and n o n -s p e c ific
hum oral factors can a lso m odula te th e im m u n e
rep on se at th e
i n v i t r ogranu lom a le v e l36. W hen
treated w ith sera from ch ro n ic sch isto so m ia sis
p a t ie n t s , P B M C fr o m p a t ie n t s w it h a c t iv e
sch isto so m e in fectio n s induced in h ib ition o f
i n v i t r ogranulom a form ation . S ig n ifica n t m od u la tio n
also occurred u pon treatm ent o f P B M C w ith isola ted
im m une c o m p lex es (IC ), or w ith m anufactured IC
o f S E A and pu rified IgG from p o o led chron ic
sch isto so m ia sis sera. In contrast, th e incubation o f
P B M C w ith F (ab ’) 2 fragm ent Ig G -S E A IC d id not
in d u ce any su p p ressio n o f th e gra n u lo m a to u s
reactivity to S E A . A d d itio n o f in d om eth acin to the
granulom a culture sig n ific a n tly reduced
i n v i t r ogranulom a m odulation . C ircu lating IC m ay regulate
granulom atous
h y p ersen sitiv ity
to
S . m a n s o n ie g g s in p a t ie n t s w i t h c h r o n i c i n t e s t i n a l
A r tig o d e R e v is ã o . G a z zin e lli G , C o lle y D G . H u m a n im m u n e r e s p o n s e s d u r in g s c h is to s o m ia s is m a n s o n i. R e v is ta d a S o c ie d a d e B r a s ile ir a d e M e d ic in a T r o p ic a l 2 5 :1 2 5 -1 3 4 , a b r- ju n , 1 9 92 .
secrete sup p ressive prostaglandins36.
C y t o k i n e p r o d u c t i o n
L ittle in form ation is a vaila b le on cyto k in e
p rod uction b y P B M C o f sch isto so m a l patients,
relative to the num ber o f P B M C proliferative studies.
F o rtu n ately , th e last few yers has begu n to see this
lack n o w b eg in n in g to b e rectified by several group s
o f in v estig a to rs. F eld m eier and co llea g u es 29 31
reported a reversal o f sup p ession o f concanavalin A
stim u lation o f P B M C from patients w ith high
in ten sities o f in fectio n b y ex o g e n o u s IL -2. T heir
further stu d ies in d ica te that a d eficit o f both IF N
-gam m a and IL -2 p rod u ction after both concanavalin
A and S E A exp osu re is reversed upon chem otherapy
w ith in 3 m onth s [intestinal (IN T ) patients] or 6
m o n th s [ h e p a t o s p le n ic (H S ) p a t ie n t s ] a fte r
treatm ent67. B ah ia-O liveir a et al5 have stated that
S W A P -in d u ced prod uction o f IF N -gam m a is very
lo w by Int p a tien ts’P B M C , but P B M C o f endem ic
norm als respond to S W A P exp osu re by reasonable
p rod u ction o f IF N -gam m a. It w a s found the sam e
situ a tion , w ith strong IF N -gam m a production by
P B M C o f en d em ic norm als, but n ot those o f IN T
patients, upon exp osu re to S E A (IRC
Viana:
p ersonal com m u n ication , 1 9 9 2 ). In th ese exam p le s
the p ro lifera tiv e and cy to k in e prod uction responses
o ccu r in parallel. W ilso n et a l.66 noted that PB M C
fro m sc h isto so m ia sis patients gen erally yield ed
h igh er le v e ls o f IL-1 than th o se from unin fected
c o n tro ls, w ith greater le v e ls prod uced by th o se w ith
h ig h in ten sities o f in fectio n . A subgroup o f patients
w ith strong adherent c e ll su p pression prod uced
lo w e r le v e ls o f IL -1 than did other patients. Earlier
stu d ies reported p rod uction o f L eu k ocyte Inh ibition
F actor and M ito g e n ic F actor33 46 and neutrophil
C h em otaxis F actor21 b y eith er P B M C o f form er
p atients, or patients' sp len ocy tes.
C urrent im m u n o lo g ic a l e v id e n c e , in both
m u rin e and hum an sy ste m s, lin k s ly m p h o cy te
fu n ction s c lo se ly w ith their production and/or u sa ge
o f g iv e n cy to k in e s52. T hus it is clear that further
k n o w led g e o f the cytok in e repertoire used by patients
P B M C in differen t settin g s and to different antigen s
is d esirab le. W ith th e adven t o f th e appropriate
a n tib o d ie s fo r c y t o k in e d e t e c tio n 61, and th e
m o l e c u l a r c a p a b y l i t i e s o f d e m o n s t r a t i n g
transcription
o f sp e c ific cy to k in e m R N A s39 in
m urine sch istosom iasis, the opportunities for studies
on th is im portant top ic are b eg in n in g to u n fo ld .
R e s p o n s e s o f P B M C t o i d i o t y p e s o n a n t i - s c h i s t o s o m e a n t i b o d i e s
Investigation s in both experim ental and clin ica l
sc h isto so m ia s is d em o n strate th e o c c u r e n c e o f
id io ty p ic/a n ti-id io ty p ic (Id/a -Id) in teractio n s, and
s o m e
i n t e r e s t i n g
c o r r e l a t i o n s
w i t h
im m u n oregu lation , m o rb id ity an d r esista n ce17.
B ecause o f the sch istosom ia sis age-p revalen ce curves
docu m en ted from m any en d em ic areas, w h ere the
paks o f prevalen ce and in ten sity are o ften b etw een
15 and 35 years o f a g e, it is apparent that m any
children liv in g in en d em ic areas m u st h a v e been
b o m o f a c t iv e ly in fe c te d m o th ers. T h u s th e
d ev elo p in g im m une sy stem s o f th e se ch ild ren w ere
ex p o sed in utero to th e p o s sib ilitie s o f m anip ulation
b y sch istosom al an tigen s, so m e o f w h ic h m igh t
cross th e placenta or appear in m o th er’s m ilk , and
m aternal anti-sch istosom al an tib od ies w h ic h m ay
exp ress regulato ry id io ty p es, capab le o f shapin g
and in flu en cin g th e su b sequen t ex p re ssio n o f the
ch ild ’s im m u ne repertoire. T h ere is e v id e n c e that
su ch in flu e n c e s e x is t 27, and that c o r d b lo o d
m ononuclear c e lls (C B M C ) o f ch ild ren b o m to
in fected m others o fte n resp o n d to sch istosom al
a n tig e n ( N o v a t o - S i lv a e t al: s u b m itte d fo r
p u blication) and to th e Ids on th eir m oth er’s
anti-S E A antib odies, and th o se o f other ch ron ic IN T
p atients17 27.
anti-A r tig o d e R e v is ã o . G a z z in e lli G , C o lle y D G . H u m a n im m u n e r e s p o n s e s d u r in g s c h is to s o m ia s is m a n s o n i. R e v is ta d a S o c ie d a d e B r a s ile ir a d e M e d ic in a T r o p ic a l 2 5 : 1 2 5 -1 3 4 , a b r- ju n , 1 9 92 .
Id is ad m in istered at birth can alter th e lo n g ev ity o f
th e m o u se u p o n su b sequen t in fectio n 8 w eek s later.
T h o se r e ceiv in g a stim ulatory an ti-S E A m A b that
ex p re sses a cro ss-rea ctiv e Id liv e d lo n ger w ith their
in fectio n than th o se w h ich received com parable
in jectio n s o f th e anti-Id (S M E lo i-S a n tos: personal
co m m u n ica tio n s). O ther hum an studies w ith these
Id/a-Id in teractio n s are a lso b ein g fo llo w e d in
K en ya, w h ere th e o p portunities ex ist to scrutinize
the sy stem in m igrant p op u la tion s w h ere som e
ch ild ren born o f u n in fected m oth ers are raised in
en dem ic areas8. R egard less o f w hether the apparently
dram atic fin d in g s in neon atal m ice o ccu r in hum ans,
the lik e lih o o d that m any ch ild ren b o m in endem ic
areas m ay ex p ress d ifferent im m une repertoires
than n o n -en d em ic in d ivid u als, sh ou ld b e taken into
co n sid era tio n , in regard to both m orbid ity studies
and v a c c in e d evelop m en t.
A n t i b o d y r e s p o n s e s a g a i n s t s c h i s t o s o m e a n t i g e n s
T h e an tig en ic co m p lex ity o f
S . m a n s o n istages
in hum an h o sts e lic it m u ltip le antibody responses
during th e co u rse o f acu te and ch ron ic
human
sch isto so m ia sis. Patients w h o d ev elo p acute clin ical
d isea se (w h o are u su ally fro m n on -en d em ic areas)
clea rly d iffer in their im m u ne responses from those
o b served in m o st ch ron ically in fected patients from
areas en d em ic for sch isto so m ia sis. C om parison o f
im m u ne resp on ses in patients w ith acute and chronic
sc h isto so m ia sis sh o w that th o se w ith acute infectio n
ex h ib it sign ifican tly higher lev els o f P B M C response
i n v i t r o
to S E A , and h a v e high er le v e ls o f IgM and
IgG a n ti-sch isto so m e an tib od ies than d o in dividuals
w ith ch ro n ic sc h isto so m ia sis1258. A ls o , sera from
E g y p tia n s and B razilians w ith acute sch istosom iasis
re c o g n iz e p redom inantly
p o ly p ep tid e ep itop es,
prim arily in adult w o rm extracts5664. S ero lo g ica lly ,
acute and ch ron ic sch isto so m e in fectio n s can be
d istin g u ish ed on th e b a sis o f sp e cific IgM an d/or
Ig A titers42 47 54 and on th e b asis o f high IgG
anti-K L H titers44 8 .
In th e ch ron ic phase, a fe w studie s h a v e reported
so m e d iffer en ces o f an tib od y le v e l and sp e cificity
b etw een th e intestin al (IN T ), hepatoin testinal (H I)
and hep atosp lenic (H S) clin ical groups. Cercariacidal
(so -c a lle d “ leth a l”) an tib od y le v e ls are h igh er in
p atien ts w ith h ep a to sp len ism 9 25. W estern b lot
a n a ly sis o f sera from IN T and H S patients in dicate
that m em bers o f both group s exp ressed very h igh
le v e ls o f h etero gen eity o f their an tib od y resp on ses,
but for IN T patients there is a m ajor antigen o f
approxim ately 31 k D a that is reco g n ized b y 82 % o f
the group and b y o n ly 13 % o f HS in d iv id u a ls. In
contrast, sera from all HS patients reco g n ized 14
k D a and 66 k D a antig ens. T h e 14 k D a m o le c u le w as
also seen b y sera o f 2 5 % o f IN T p atients but the
latter w as u n recogniz ed by sera o f any o f the IN T
patients a ssayed 19. R ecen tly , it w a s seen that the
IgG response to adult w o rm an tig en s w as d istin ct
and sig n ifica n tly h ig h er in H S patients than in those
in IN T and H I clin ical grou p s64. It has a lso been
reported that le v e ls o f IgM (but n ot IgG )
anti-Sm W 68 correlate in v ersely w ith th e in ten sity o f
in fection 44.
A n tib od y cla ss and su b class su d ies741 indica te
the in v o lv em en t o f m u ltip le sc h isto so m e -sp e c ific
and n o n -s p e c ific im m u n o g lo b u lin is o ty p e s in
different in fectio n co n d itio n s. H ig h IgG 4 le v e ls are
often rem arkable, as are IgE le v e ls . Iso ty p ic
regulation w ith the duration o f in fectio n and its
p o s s ib le r o le in r e s is t a n c e / s u s c e p t i b il it y to
rein fection , as w e ll as id io ty p ic regu lation and the
relationsh ip b etw een th e ex p re ssio n o f dom inant
id io ty p es on an ti-S E A an tib od ies and m o rbid ity are
d iscu ssed in oth er sectio n s.
F in a lly , m any in d ivid u als from areas end em ic
for sch isto so m ia sis a lso harbor m u ltip le helm in th ic
in fection s w h ich e lic it a nu m ber o f cro ss-rea ctiv e
serological responses to
S . m a n s o n i ,and vice-versa18.
T h is presents an additional com p lex ity w h ich should
be consid ered in the evalu ation o f an ti-sch isto so m e
responses in d ifferen t en d em ic areas.
I m m u n e r e s p o n s e c o r r e l a t i o n s w i t h r e s i s t a n c e t o r e i n f e c t i o n
M u ltip le e p id e m io lo g ic a l stu d ie s in m any
different en d em ic areas in d ica te that in a com m u n ity
th e prevalen ce and in ten sity o f sch isto m e in fectio n s
rise during th e first d ecad e and a h a lf o f life , and this
is fo llo w e d by a d e c lin e in both param eters. A n
A r tig o d e R e v is ã o . G a z z in e tli G , C o lle y D G . H u m a n im m u n e r e s p o n s e s d u r in g s c h is to s o m ia s is m a n s o n i. R e v is ta d a S o c ie d a d e B r a s ile ir a d e M e d ic in a T r o p ic a ! 2 5 :1 2 5 -1 3 4 , a b r- ju n , 1 9 92 .
sn ails, w a s observed sim ultaneously. B y this aproach
it has b een p o ssib le to d istin gu ish an im m une from
a su scep tib le group8. A n altern ative m ethod has
been to id en tify unin fected in div iduals liv in g in
en d em ic areas w h o w ere sto o l-n eg a tiv e, but w ere
k n o w n to h a v e reasonable le v e ls o f exp o su re to
w ater con tain in g in fected sn a ils20.
V ario u s hum oral and cellu lar responses have
been su d ied con co m m itan tly in th ese differen t
en d em ic p o p u latio n s. T h e relationsh ip betw een
in ten sities o f re-in fection fo llo w in g treatment o f
129 ch ild ren in K en ya, and variou s hum oral
resp o n ses has been studied by B utterw orth and
c o lle a g u e s8. T hey have dem onstrated high le v e ls o f
IgG a n tib od ies w h ich can m ediate eo sin o p h
il-d epen il-dent il-dam age to sch istosom u la
i n v i t r o ,and
th is a ctiv ity w a s fou nd in th e sera o f all children,
b oth su scep tib le and resistant. Further a n a lysis o f
th e se sera revea led a p o sitiv e correlation betw een
in ten sity o f re-in fection s after treatment and the
le v e ls o f IgM an tib od ies w ith sp e cificity fo r a major
3 8 k D a s c h i s t o s o m u l a r s u r f a c e a n t ig e n .
F urtherm ore, Ig M -en rich ed fractions recog n izin g
both sch istosom u la r surface and e g g antig ens not
o n ly fa ile d to m e d ia te e o s in o p h il k illin g o f
sch isto so m u la , but also block ed the k illin g that w as
m ediated b y IgG fractions from the sam e sera.
T h e s e an d o th e r d ate s u g g e s t th at b lo c k in g
a n tib od ies, in clu d in g so m e IgM and in effe ctiv e IgG
iso ty p e s, prevent the exp ressio n o f im m unity in
susceptib le child ren . A related study in Bahia (Brazil)
dem onstrated an a sso ciatio n o f resistan ce after
chem oth erapy w ith se roreactivity to a 37 kD a larval
surface an tig en 22.
A noth er antib ody resp on se against a sp ecific
ep ito p e that m ay d istin gu ish b etw een resistant/
su scep tib le in d ivid u als w a s reported in the study o f
in fected and n o n -in fected in div iduals in another
en d em ic area in B razil, D iv in o d o Traira20. It w as
sh o w n that m any o f th e subjects in th e sto o
l-n e g a tiv e , l-n o l-n -il-n fected group w ere ser o p o sitiv e to a
so lu b le adult w o rm preparation (S W A P ), despite
their h a v in g n o record o f previou s in fectio n or
treatm ent. T h e in d ivid u als in this non-in fected
(en d em ic norm al) group, w h ile indistin guishable
fr o m in f e c t e d s u b je c ts in b o th S W A P and
glu tath ion e-S -tran sferase (G S T ) resp on ses, had
sign ifican tly elevated antibody lev els to param yosin.
In ad d ition , in in feced/treated indiv iduals
anti-param yosin antibody le v e ls increased after treatment
and rem anined elevated o n ly in th o se d isp layin g
com p lete p arasitolo gical cure.
A recent study su g g ests that sig n ific a n t degree
o f protective im m unity against
S . h a e m a t o b i u min fection also gradually d e v e lo p s in a com m u n ity in
the Gam bia38. A n a ly sis o f sera o f these patients
in dicates that the IgE antib ody le v e ls (an iso ty p e
w h ich participates in sev eral reported
i n v i t r oanti
parasite effecto r m echanism s) w ere high er in adults,
and the le v e ls o f IgG 4 an tib od ies against w o rm an
eg g antigen s (a potential b lo ck in g iso ty p e) w ere
h igh est in the 1 0-14 year-old group . R e-in fectio n
stu d ies in th is co m m u n ity have su pported the
hypothesi s that the gradual d evelopm ent o f im m unity
to in fectio n m ay in part depen d on pathw ays
in v o lv in g I g E /lg G 4 rations, w ith th e Ig E m ediatin g
(or correlating w ith ) resistan ce, and h ig h le v e ls o f
IgG 4 antib odies b lo ck in g these m echanism s in
y ou n ger patients.
P B M C r e s p o n s e s to d i f f e r e n t a n t ig e n
preparations have also b een associated w ith the
presence or ab sen ce o f re-in fectio n after treatm ent.
In a study o f re-in fection after treatm ent in 18
E gyptian patients, th o se w h o becam e re-in fected
w ere sim ila r to those w h o did n ot, in term s o f their
pretreatm ent in ten sities o f in fectio n or lo ca tio n s o f
their h ou seh old s in relationship to w ater contact
sites. H ow ev er, th ey did d iffe r in their m o st recent
P B M C resp on ses, prior to their re-in fectio n s. T h o se
patients w h o faile d to b eco m e re-in fected sh o w ed
increased responses to S E A , C A P and S W A P
antig ens after treatm ent and th ese le v e ls rem ained
h igh throughout the study p erio d 13. A p o ssib ly
related observation is the fin d in g o f h igh P B M C
responses to S W A P , C E R C , and e sp ecia lly S E A , o f
essen tially all pu tatively resistant, en d em ic norm als
liv in g in the three c o n se c u tiv e ly studied en d em ic
areas o f D iv in o d o Traira, Siq ueira and Bernardo
(B razil) (G G azzin elli: w o rk in p ro g ress). T h is is in
shap contrast to m ost o f th o se in th e in fected g ro u p ,
w h o generally presen t a m uch lo w e r resp on se to
S E A 1314 15.
I m m u n e r e s p o n s e c o r r e l a t i o n s w i t h m o r b i d i t y
Perhaps th e m ost studied asp ect o f hum an
im m u ne resp on ses d uring
sc h isto so m ia sis are
A r tig o d e R e v is ã o . G a z zin e lli G , C o lle y D G . H u m a n im m u n e r e s p o n s e s d u r in g s c h is to s o m ia s is m a n so n i. R e v is ta d a S o c ie d a d e B r a s ile ir a d e M e d ic in a T r o p ic a 1 2 5 : 1 2 5 -1 3 4 , a b r- ju n , 1992 .
B ased on stu d ies in m any d ifferent en d em ic areas,
the general interpretation o f such studies is that
a lth ou gh w o rm burden is seen to correlate w ith
se v e r ity o f d ise a s e in a u top sy stu d ie s10, th is
correla tion is n ot ab solu te, and the intensity o f a
p atien t’s im m u n e resp on se to certain antig ens o f the
parasite m ay contrib u te to the overall ou tcom e o f
that a p atien t’s d isea se. M u ltip le d ifferen ces occur
b etw een the im m u n e cap ab ilities o f IN T and HS
p atien ts, but an im portant consid eration is the
ex ten t o f th e p a tien t’s d isease. In geral, studies on
h o s p i t a l i z e d H S p a t ie n t s ( w h o a r e o f t e n
d ecom p en sated and h osp italized for sp len ectom y
and hem odynam ic surgery for hypertension) discover
patients in an an ergic state, w ith altered T cell
subset p o p u la tion s16 and very low -to-n on -respon si ve
im m une sy stem s13. H ow ever, a very different picture
is o b served w h en fie ld cases o f am bulatory HS
p atients are stu d ie d 15 26. H ere on usu ally finds that
t h e s e H S p a t ie n t s a re h y p e r - r e s p o n s iv e to
s c h is t o s o m a l a n t ig e n s , e s p e c ia lly S E A , and
e sp e c ia lly in contrast to th o se (w ith apparently w ell
regulated im m u ne response) IN T p atients15 6S.
R ecen tly , it has been seen that sev ere in fectio n is
associa ted w ith a h igh er frequence o f dem onstrable
resp on ses to fractionated S W A P by T cell W estern
a ssa y s5. A ls o , HS patients P B M C respond to T cell
W estern antigen fractions in the lo w er m olecular
w e ig h t range ( < 2 1 k D a) than do th o se o f INT
patients. A s w ith E lln er et al26 and H afez, et al37 in
sc h isto so m ia sis m ansoni patients, in sh isto som iasis
ja p o n ic a , Ohta et al55 noted few er lo w responders to
a d u lt w o r m e x t r a c ts in an HS g r o u p than
asy m p tom atic patients.
A num ber o f oth er im m u n olog ical parameters
have been correlated w ith d isea se sev erity , such as
th e occurrence o f circula tin g IC in patients w ith HS
i n f e c t i o n s 30, h i g h e r l e v e l s o f a n t i- w o r m
g lyco p rotein , but n ot an ti-eg g , an tig en s in HS
patients64, and the detection o f lo w er IN F -g am m a
prod uction b y HS in d ivid u als67.
T h e im m u n o gen etics o f sc h isto so m ia sis has
been in vestig ated by several group s 1 2 3 7 40 55 63.
V ario u s d iffer en t H L A h a p lo ty p e s h a v e b een
associated w ith hep a tosp len ism , and it appears that
som e patients have an im m u nogenetic predisposition
to sev ere d isease. T here is a lso ev id e n c e that host
gen etics (alb eit not yet im m u n o g en etics) co u ld play
a ro le in hum an resista n ce/su scep tib ility issu e s3.
R E S U M O
O e s tu d o d a r e s p o s ta im u n e d e p a c ie n te s c o m e s q u i s t o s s o m o s e p r o g r i d e e m f u n ç ã o d o a v a n ç o te c n o ló g ic o , a p e s a r d a s d ific u ld a d e s d e m a n ip u la ç ã o in v iv o d e s te c o m p le x o s is te m a p a r a s ita - h o s p e d e ir o . A ê n fa s e n o s e s tu d o s te m s id o m a is fr e q ü e n te m e n te d ir ig id a p a r a c o m p a r a ç õ e s e n tr e g r u p o s c a r a c te r ís tic o s d e in d iv íd u o s, ta is c o m o in fe c ta d o /n ã o in fe c ta d o , r e in fe c ta d o / n ã o re in fe c ta d o , a s s in to m á tic o /h e p a to - e s p lê n ic o , c o m in te n s id a d e d e in fe c ç ã o a lta /b a ix a , e tc . B a s e a d o n e s s a s c o m p a r a ç õ e s te m -s e o b tid o in fo r m a ç õ e s q u e p e r m ite m c o n j e c t u r a s r a z o á v e i s c o m r e l a ç ã o à r e g u l a ç ã o im u n o ló g ic a , s u s c e p tib ilid a d e e r e s is tê n c ia e a té m e s m o c o n s id e r a ç õ e s s ô b r e m e c a n is m o s , q u e tê m s id o m a is a p r o p r ia d a m e n te a n a lis a d o s , e n tr e ta n to , e m s is te m a s e x p e r im e n ta is . T ais e s tu d o s tê m c o m o fin a l id a d e a c o m p re e n sã o d a s c a m a s e e v e n to s q u e le va m à m o r b id a d e e a o d e s e n v o lv im e n to d e u m a v a c in a h u m a n a a n ti-e s q u is to so m a .
P a la v r a s -c h a v e s : E s q u is to s o m ía s e . R e s p o s ta im u n e . Im u n o - re g u la ç ã o .
R E FE R E N C E S
1 . A b d e l - S a l a m E , A b d e l - K h a l i h A , A b d e l - M e g u i d A ,
B a r a k u t W , M a h m o n d A A . A s s o c i a t i o n o f H L A
c l a s s I a n t i g e n s ( A l , B 5 , B 8 a n d C W 2 ) w i t h d i s e a s e
m a n i f e s t a t i o n s a n d i n f e c t io n i n h u m a n s c h i s t o s o m i a s i s
m a n s o n i in E g y p t . T i s s u e A n t i g e n s 2 7 : 1 4 2 - 1 4 6 ,
1 9 8 6 .
2 . A b d e l - S a l a m E , I s h a a c S , M a h m o u d A A F .
H i s t o c o m p a t i b i l i t y - l i n k e d s u s c e p t i b i l i t y f o r
h e p a t o s p l e n o m e g a l y in h u m a n s c h i s t o s o m i a s i s .
J o u r n a l o f I m m u n o l o g y 1 2 3 : 1 8 2 9 - 1 8 3 1 , 1 9 7 9 .
3 . A b e l L , D e m e n a i s F , P r a t a A , S o u z a A E , D e s s e i n
A . E v i d e n c e f o r t h e s e g r e g a t i o n o f a m a j o r g e n e in
h u m a n s u s c e p t i b i l i t y / r e s i s t a n c e t o i n f e c t i o n b y S c h is to s o m a m a n s o n i. A m e r i c a n J o u r n a l o f
H u m a n G e n e t i c s 4 8 : 9 5 9 - 9 7 0 , 1 9 9 1 .
4 . A lv e s - B r i t o C F , S i m p s o n A J G , B a h i a - O l i v e i r a L M C ,
R a b e l l o A L T , R o c h a R S , L a m b e r t u c c i J R , G a z z i n e l l i
G , K a t z N , C o r r e a - O l i v e i r a R . A n a l y s i s o f a n t i - K L H
a n t i b o d y in B r a z i l i a n s s u p p o r t s it s u s e f o r t h e
d i a g n o s i s o f a c u t e s c h i s t o s o m i a s i s m a n s o n i .
T r a n s a c t i o n s o f T h e R o y a l S o c i e t y o f T r o p i c a l
A r tig o d e R e v is ã o . G a z zin e lli G , C o lle y D G . H u m a n im m u n e r e s p o n s e s d u r in g s c h is to s o m ia s is m a n s o n i. R e v is ta d a S o c ie d a d e B r a s ile ir a d e M e d ic in a T r o p ic a l 2 5 :1 2 5 -1 3 4 , a b r- ju n , 1 9 92 .
5 . B a h i a - O l i v e i r a L M G , G a z z i n e l l i G , E l o i - S a n t o s
S M , C u n h a - M e l o J R , A l v e s - O l i v e i r a L F , S i l v e i r a
A M S , V i a n a I R C , C a r m o J , S o u z a A , C o r r e a -
O l i v e i r a R . D i f f e r e n t i a l c e l l u l a r r e a c t i v i t y t o a d u l t
w o r m a n t i g e n s o f p a t i e n t s w i t h d i f f e r e n t c l i n i c a l f o r m s o f s c h i s t o s o m i a s i s m a n s o n i . T r a n s a c t i o n s o f
t h e R o y a l S o c i e t y o f T r o p i c a l M e d i c i n e a n d H y g i e n e
8 6 : 5 7 - 6 1 , 1 9 9 2 .
6 . B a r s o u m I S , G a m i l F M , A l - K h a f i f M A , R a m z y R M ,
E l A l a m y M A , C o l l e y D G . I m m u n e r e s p o n s e s a n d
i m m u n o r e g u l a t i o n d u r i n g h u m a n s c h i s t o s o m i a s i s in
E g y p t . I . E f f e c t o f t r e a t m e n t o n in v i t r o r e s p o n s i v e n e s s . T h e A m e r i c a n J o u r n a l o f T r o p i c a l
M e d i c i n e a n d H y g i e n e 3 1 : 1 1 8 1 - 1 1 8 7 , 1 9 8 2 .
7 . B o c t o r F N , P e t e r J B . l g G s u b c l a s s e s in h u m a n
c h r o n i c s c h i s t o s o m i a s i s : o v e r - p r o d u c t i o n o f
s c c h i s t o s o m e - s p e c i f i c a n d n o n - s p e c i f i c I g G 4 .
C l i n i c a l a n d E x p e r i m e n t a l I m m u n o l o g y 8 2 : 5 7 4 -
5 7 8 , 1 9 8 9 .
8 . B u t t e r w o r t h A E , C o r b e t t E L , D u n n e D W , F u l f o r d
A J C , K i m a n i G , G a c h u h i R K , K l u m p p R , M b u g i i a
G , O u m a J H , A r a p S i o n g o k R K , S t u r r o c k R F .
I m m u n i t y a n d m o r b i d i t y in h u m a n s c h i s t o s o m i a s i s . In : M c A d a m K P W J ( e d ) N e w S t r a t e g i e s in P a r a s i t o l o g y . C h u r c h i l l - L i v i n g s t o n e , L o n d o n p . 1 9 3 -
2 1 0 , 1 9 8 9 .
9 . C a p r o n M , C a m u s D , C a r l i e r Y , F i g u e i r e d o J F M ,
C a p r o n A . I m m u n o l o g i c a l s t u d i e s in h u m a n
s c h i s t o s o m i a s i s . I I . A n t i b o d i e s c y t o t o x i c f o r S c h is to s o m a m a n s o n i s c h i s t o s o m u l e s . T h e A m e r i c a n J o u r n a l o f T r o p i c a l M e d i c i n e a n d H y g i e n e 2 6 : 2 4 8 -
2 5 3 , 1 9 7 7 .
1 0 . C h e e v e r A W . A q u a n t i t a t i v e p o s t-m o r te m s t u d y o f s c h i s t o s o m i a s i s m a n s o n i i n m a n . T h e A m e r i c a n
J o u r n a l o f T r o p i c a l M e d i c i n e a n d H y g i e n e 1 7 : 3 8 -
6 4 , 1 9 6 8 .
1 1 . C l a r k e V V . E v i d e n c e o f t h e d e v e l o p m e n t in m a n o f
a c q u i r e d r e s i s t a n c e to i n f e c t i o n o f s c h i s t o s o m a s p p .
C e n t r a l A f r i c a J o u r n a l o f M e d i c i n e 1 2 ( S u p p l . I) :
1-3 0 , 1 9 6 6 .
1 2 . C o l l e y D G . D y n a m i c s o f t h e h u m a n i m m u n e r e s p o n s e
t o s c h s i s t o s o m e s . In: M a h m o u d A A F f e d ) B a i l l i e r e ’s C l i n i c a l T r o p i c a l M e d i c i n e a n d C o m m u n i c a b l e
D i s e a s e s , V o l . 2 , S c h i s t o s o m i a s i s , B a i l l i e r e - T i n d a l l ,
L o n d o n 3 1 5 - 3 3 2 , 1 9 8 7 .
1 3 . C o l l e y D G , B a r s o u m I S , D a h a w i H S S , G a m il F ,
H a b i b M , E l A l a m y M A . I m m u n e r e s p o n s e s a n d
i m m u n o r e g u l a t i o n in r e l a t i o n to S c h i s t o s o m i a s i s in
E g y p t . I I I . I m m u n i t y a n d l o n g i t u d i n a l s t u d i e s o f in v itr o r e s p o n s i v e n e s s a f t e r t r e a t m e n t . T r a n s a c t i o n s o f T h e R o y a l S o c i e t y T r o p i c a l M e d i c i n e a n d H y g i e n e
8 0 : 9 5 2 - 9 5 7 , 1 9 8 6 .
1 4 . C o l l e y D G , C o o k J R , F r e e m a n J r G L , B a r t h o l o m e w
R K , J o r d a n P . I m m u n e r e s p o n s e s d u r i n g h u m a n
s c h i s t o s o m i a s i s m a n s o n i . I. In v itro l y m p h o c y t e
b l a s t o g é n i e r e s p o n s e s t o h e t e r o g e n e o u s a n t i g e n i c
p r e p a r a t i o n f r o m s c h i s t o s o m e e g g s , w o r m s a n d
c e r c a r i a e . I n t e r n a t i o n a l A r c h i v e s o f A l l e r g y a n d
A p p l i e d I m m u n o l o g y 5 3 : 4 2 0 - 4 4 3 , 1 9 7 7 .
1 5 . C o l l e y D G , G a r c i a A A , L a m b e r t u c c i J R , P a r r a J C , K a t z N , R o c h a R S , G a z z i n e l l i G . I m m u n e r e s p o n s e s
d u r i n g h u m a n s c h i s t o s o m i a s i s . X I I D i f f e r e n t i a l r e s p o n s i v e n e s s i n p a t i e n t s w i t h h e p a t o s p l e n i c
d i s e a s e . T h e A m e r i c a n J o u r n a l o f T r o p i c a l M e d i c i n e a n d H y g i e n e 3 5 : 7 9 3 - 8 0 2 , 1 9 8 6 .
1 6 . C o l l e y D G , K a t z N , R o c h a R S , A b r a n t e s W , d a
S i l v a A L , G a z z i n e l l i G . I m m u n e r e s p o n s e s d u r i n g
h u m a n s c h i s t o s o m i a s i s m a n s o n i . I X . T l y m p h o c y t e
s u b s e t a n a l y s i s b y m o n o c l o n a l a n t i b o d i e s i n
h e p a t o s p l e n i c d i s e a s e . S c a n d i n a v i a n J o u r n a l o f I m m u n o l o g y 1 7 : 2 9 7 - 3 0 1 , 1 9 8 3 .
1 7 . C o l l e y D G , M o n t e s a n o M A , P o w e l l M R , E l o i -
S a n t o s S M , P a r r a J C , G o e s A M , D o u g h t y B L
C o r r e a - O l i v e i r a R , R o c h a R S , G a z z i n e l l i G . I d i o t y p e
n e t w o r k s in s c h i s t o s o m i a s i s . In: M c A d a m K P W J ( e d ) N e w s t r a t e g i e s in P a r a s i t o l o g y , C h u r c h i l l -
L i v i n g s t o n e , L o n d o n p . 1 7 9 - 1 9 0 , 1 9 8 9 .
1 8 . C o r r e a - O l i v e i r a , R , D u s s e L M S , V i a n a l R C , C o l l e y
D G , C a r v a l h o O S , G a z z i n e l l i G . H u m a n a n t i b o d y
r e s p o n s e s a g a i n s t s c h i s t o s o m a l a n t i g e n s . I. A n ti b o d i e s
f r o m p a t ie n t s w it h a n c y l o s t o m a , A s c a r is lu m b ric o id e s o r S c h is to s o m a m a n s o n i i n f e c t i o n s r e a c t w i t h s c h i s t o s o m e a n t i g e n s . T h e A m e r i c a n J o u r n a l o f
T r o p i c a l M e d i c i n e a n d H y g i e n e 3 8 : 3 4 8 - 3 5 5 , 1 9 8 8 .
1 9 . C o r r e a - O l i v e i r a R , O l i v e i r a G C , G o l g h e r D B , V i a n a
J R C , C o l l e y D G , C a r v a l h o O S , R o c h a R S , K a t z N ,
G a z z i n e l l i G . A n a l y s i s o f a n t i b o d y r e s p o n s e s o f S c h is to s o m a m a n s o n i - in f c c t e d p a t i e n t s a g a i n s t s c h i s t o s o m a l a n t i g e n s . M e m ó r i a s d o I n s t i t u t o
O s w a l d o C r u z 8 2 ( S u p p l I V ) : 1 7 9 - 1 8 1 , 1 9 8 7 .
2 0 . C o r r e a - O l i v e i r a R , P e a r c e E J , O l i v e i r a G C , G o l g h e r
D B , K a t z N , B a h i a L G , C a r v a l h o O S , G a z z i n e l l i G .
T h e h u m a n i m m u n e r e s p o n s e to d e f i n e d i m m u n o g e n s
o f S c h is to s o m a m a n so n i: e l e v a t e d a n t i b o d y l e v e l s to p a r a m y o s i n in s t o o l - n e g a t i v e i n d i v i d u a l s f r o m tw o
e n d e m i c a r e a s i n B r a z i l . T r a n s a c t i o n s o f t h e R o y a l
S o c i e t y o f T r o p i c a l M e d i c i n e a n d H y g i e n e 8 3 : 1 2 0 5 - 1 2 0 9 , 1 9 8 9 .
2 1 . D a b e s T M P , G a r c i a A A , C o l l e y D G , R a m a l h o -
P i n t o F J . L y m p h o k i n e p r o d u c t i o n b y b l o o d o r
s p l e e n m o n o n u c l e a r c e l l s f r o m p a t i e n t s w i t h
s c h i s t o s o m i a s i s m a n s o n i . T h e A m e r i c a n J o u r n a l o f
T r o p i c a l M e d i c i n e a n d H y g i e n e 4 0 : 2 7 3 - 2 8 1 , 1 9 8 9 .
2 2 . D e s s e i n A J , B e g l e y M , D e m e a r e C , C a i l o l D , F u e r i
J , G a l v ã o d o s R e i s M , A n d r a d e Z , P r a t a A , B i n a J C .
H u m a n r e s i s t a n c e t o S c h is t o s o m a m a n s o n i is a s s o c i a t e d w i t h I g G r e a c t i v i t y t o a 3 7 - k D a l a r v a l
s u r f a c e a n t i g e n . J o u r n a l o f I m m u n o l o g y 1 4 0 : 2 7 2 7 -
2 7 3 6 , 1 9 8 8 .
A r tig o d e R e v is ã o . G a z zin e lli G , C o lle y D G . H u m a n im m u n e r e s p o n s e s d u r in g s c h is to s o m ia s is m a n s o n i. R e v is ta d a S o c ie d a d e B r a s ile ir a d e M e d ic in a T r o p ic a l 2 5 :1 2 5 -1 3 4 , a b r- ju n , 1 9 92 .
C , C o l l e y D G , G a z z i n e l l i G . A n t i - i d i o t y p i c T c e l l s i n h u m a n s c h i s t o s o m i a s i s . I m m u n o l o g i c a l
I n v e s t i g a t i o n 1 8 : 3 7 3 - 3 8 8 , 1 9 8 9 .
2 4 . D u n n e D W , G r a b o w s k a A M , F u l f o r d A J C ,
B u t t e r w o r t h A E , S t u r r o c k R F , K o e c h D , O u m a J H .
H u m a n a n t i b o d y r e s p o n s e s t o S c h i s t o s o m a m a n s o n i :
t h e i n f l u e n c e o f e p i t o p e s s h a r e d b e t w e e n d i f f e r e n t
l i f e c y l c l e s t a g e s o n t h e r e s p o n s e t o t h e
s e h i s t o s o m u l u m . E u r o p e a n J o u r n a l o f I m m u n o l o g y
1 8 : 1 2 3 - 1 3 1 , 1 9 8 8 .
2 5 . D u s s e L M S . E s t u d o d a a t i v i d a d e c i t o t ó x i c a d e s o r o s d e p a c i e n t e s i n f e c t a d o s c o m S . m a n s o n i c o n t r a e s q u i s t o s s o m u l o s i n v i t r o . T e s e d e m e s t r a d o , F u n d a ç ã o O s w a l d o C r u z , R i o d e J a n e i r o , 1 9 8 6 .
2 6 . E l l n e r J J , O l d s G R , O s m a n G S , E l K h o l y A ,
M a h m o u d A A F . D i c h o t o m i e s in t h e r e a c t i v i t y to
w o r m a n t i g e n i n h u m a n s c h i s t o s o m i a s i s m a n s o n i .
J o u r n a l o f I m m u n o l o g y 1 2 6 : 3 0 9 - 3 1 2 , 1 9 8 1 .
2 7 . E l o i - S a n t o s S M , N o v a t o - S i l v a E , M a s e l i V M ,
G a z z i n e l l i G , C o l l e y D G , C o r r e a - O l i v e i r a R . I d io ty p e s e n s i t i z a t i o n i n u t e r o o f c h i l d r e n b o m to m o t h e r s
w i t h s c h i s t o s o m i a s i s o r C h a g a s ’ d i s e a s e . J o u r n a l o f
C l i n i c a l I n v e s t i g a t i o n 8 4 : 1 0 2 8 - 1 0 3 1 , 1 9 8 9 .
2 8 . E v e r n g a r d B , H a m m a r s t r o m L , S m i t h C I E ,
J o h a n s s o n S G O , L i n d e r E . S u b c l a s s d i s t r i b u t i o n
a n d I g E r e s p o n s e s a f t e r t r e a t m e n t i n h u m a n s c h i s t o s o m i a s i s . C l i n i c a l a n d E x p e r i m e n t a l
I m m u n o l o g y 7 3 : 3 8 3 - 3 8 8 , 1 9 8 8 .
2 9 . F e l d m e i e r H , G a s t l G A , P o g g e n s e e U , K o r t m a n n C ,
D a f f a l l a A A , P e t e r H H . R e l a t i o n s h i p b e t w e e n
i n t e n s i t y o f i n f e c t i o n a n d i m m u n o m o d u l a t i o n in
h u m a n s c h i s t o s o m i a s i s . I . L y m p h o c y t e
s u b p o p u l a t i o n s a n d s p e c i f i c a n t i b o d y r e s p o n s e s .
C l i n i c a l a n d E x p e r i m e n t a l I m m u n o l o g y 6 0 : 2 2 5 -
2 2 3 , 1 9 8 5 .
3 0 . G a l v ã o - C a s t r o B , B i n a J C , P r a t a A , L a m b e r t P H .
C o r r e l a t i o n o f c i r c u l a t i n g i m m u n e c o m p l e x e s a n d
c o m p l e m e n t b r e a k d o w n p r o d u c t s w i t h t h e s e v e r i t y
o f t h e d i s e a s e in h u m a n s c h i s t o s o m i a s i s . T h e
A m e r i c a n J o u r n a l o f T r o p i c a l M e d i c i n e a n d H y g i e n e
3 0 : 1 2 3 8 - 1 2 4 6 , 1 9 8 1 .
3 1 . G a s t l G A , F e l d m e i e r H , D o e h i n g E , K o r t m a n n C ,
D a f f a l l a A A , P e t e r H H . N u m e r i c a l a n d f u n c t i o n a l
a l t e r a t i o n s o f l y m p h o c y t e s in h u m a n s c h i s t o s o m i a s i s .
S c a n d i n a v i a n J o u r n a l o f I m m u n o l o g y 1 9 : 4 6 9 - 4 7 9 ,
1 9 8 4 .
3 2 . G a z z i n e l l i G , K a t z N , R o c h a R S , C o l l e y D G .
I m m u n e r e s p o n s e s d u r i n g h u m a n s c h i s t o s o m i a s i s
m a n s o n i . V I I I . D i f f e r e n t i a l i n v i t r o c e l l u l a r r e s p o n s i v e n e s s t o a d u l t w o r m a n d s c h i s t o s o m u l a r
t e g u m e n t a l p r e p a r a t i o n s . T h e A m e r i c a n J o u r n a l o f
T r o p i c a l M e d i c i n e a n d H y g i e n e 3 2 : 3 2 6 - 3 3 3 , 1 9 8 3 .
3 3 . G a z z i n e l l i G , K a t z N , R o c h a R S , C o l l e y D G .
I m m u n e r e s p o n s e d u r i n g s c h i s t o s o m i a s i s m a n s o n i .
X . P r o d u c t i o n a n d s t a n d a r t i z a t i o n o f a n a n t i g e n
-i n d u c e d m -i t o g e n -i c a c t -i v -i t y b y p e r -i p h e r a l b l o o d
m o n o n u c l e a r c e l l s f r o m t r e a t e d b u t n o t a c t i v e c a n s
o f s c h i s t o s o m i a n s i s . J o u r n a l o f I m m u n o l o g y 1 3 0 :
2 8 9 1 - 2 8 9 5 , 1 9 8 3 .
3 4 . G a z z i n e l l i G , L a m b e r t u c c i J R , K a t z N , R o c h a R S ,
L i m a M S , C o l l e y D G . I m m u n e r e s p o n s e s d u r i n g h u m a n s c h i s t o s o m i a s i s m a n s o n i . X I . I m m u n o l o g i c a l
s t a t u s o f p a t i e n t s w i t h a c u t e i n f e c t i o n s a n d a f t e r
t r e a t m e n t . J o u r n a l o f I m m u n o l o g y 1 3 5 : 2 1 2 1 - 2 1 2 7 ,
1 9 8 5 .
3 5 . G a z z i n e l l i G , M o n t e s a n o M A , C o r r e a - O l i v e i r a R ,
L i m a M S , K a t z N , R o c h a R S , C o l l e y D G . I m m u n e
r e s p o n s e i n d i f f e r e n t c l i n i c a l g r o u p s o f
s c h i s t o s o m i a s i s p a t i e n t s . M e m ó r i a s d o I n s t i t u t o
O s w a l d o C r u z 8 2 ( S u p l I V ) : 9 5 - 1 0 0 , 1 9 8 7 .
3 6 . G o e s A M , G a z z i n e l l i G , R o c h a R , K a t z N , D o u g h t y
B L . G r a n u l o m a t o u s h y p e r s e n s i t i v i t y t o S c h i s t o s o m a
m a n s o n ie g g a n t i g e n s in h u m a n s c h i s t o s o m i a s i s . I l l .
I n v i t r o g r a n u l o m a m o d u l a t i o n i n d u c e d b y i m m u n e c o m p l e x e s . T h e A m e r i c a n J o u r n a l o f T r o p i c a l
M e d i c i n e a n d H y g i e n e 4 4 : 4 3 4 - 4 4 3 , 1 9 9 1 .
3 7 . H a f e z M , H a s s a n S A , E l - T a h a n H , E l - S h e n n a w y F ,
K h a s h a b a M , A l - T o n b a r y Y , E l - M o r s i Z , E l - S a l l a b
S H , E I - D e s o k y I , E l - S h a z l y A , E t e b a S .
I m m u n o g e n e t i c s u s c e p t i b i l i t y f o r p o s t - s c h i s t o s o m a l
h e p a t i c f i b r o s i s . T h e A m e r i c a n J o u r n a l o f T r o p i c a l
M e d i c i n e a n d H y g i e n e 4 4 : 4 2 4 - 4 3 3 , 1 9 9 1 .
3 8 . H a g a n P , B l u m e n t h a l U J , D u n n D , S i m p s o n A J G ,
W i l k i n s H A . H u m a n I g E , I g G 4 a n d r e s i s t a n c e to
r e i n f e c t i o n w i t h S c h i s t o s o m a h a e m a t o b i u m . N a t u r e 3 4 9 : 2 4 3 - 2 4 5 , 1 9 9 1 .
3 9 . H e n d e r s o n G S , C o n a r y J T , S u m m a r M , M c C u r l e y
T L , C o l l e y D G . I n v i v o m o l e c u l a r a n a l y s i s o f l y m p h o k i n e s i n v o l v e d in t h e m u r i n e i m m u n e r e s p o n s e
d u r i n g S c h i s t o s o m a m a n s o n ii n f e c t i o n . I. I L - 4 , n o t I L - 2 m R N A , is a b u n d a n t i n t h e g r a n u l o m a t o u s
l i v e r s , m e s e n t e r i c l y m p h n o d e s , a n d s p l e e n s o f
i n f e c t e d m i c e . J o u r n a l o f I m m u n o l o g y 1 4 7 : 9 9 2 -
9 9 7 , 1 9 9 1 .
4 0 . H i r a y a m a K , M a t s u s h i t a S , K i k u c h i I , I u c h i M , O h t a
N , S a s a z u k i T . H L A - D Q is e p i s t a t i c t o H L A - D R in
c o n t r o l l i n g t h e i m m u n e r e s p o n s e t o s c h i s t o s o m a l
a n t i g e n in h u m a n s . N a t u r e 3 2 7 : 4 2 6 - 4 3 0 , 1 9 8 7 .
4 1 . J a s s i m A , H a s s a n K , C a t t y D . A n t i b o d y i s o t y p e s in
h u m a n s c h i s t o s o m i a s i s m a n s o n i . P a r a s i t e
I m m u n o l o g y 9 : 6 2 7 - 6 5 0 , 1 9 8 7 .
4 2 . K a n a m u r a H Y , H o s h i n o - S h i m i z u S . C a m a r g o M E ,
d a S i l v a L C . C l a s s s p e c i f i c a n t i b o d i e s a n d f l u o r e s c e n t
s t a i n i n g p a t t e r n s in a c u t e a n d c h r o n i c f o r m s o f
s c h i s t o s o m i a s i s m a n s o n i . T h e A m e r i c a n J o u r n a l o f
T r o p i c a l M e d i c i n e a n d H y g i e n e 2 8 : 2 4 2 - 2 4 8 , 1 9 7 9 .
4 3 . K h a f i l e J , D u n n e D W , R i c h a r d s o n B A , M a z z a G ,
T h o m e K J I , C a p r o n A , B u t t e r w o r t h A E . F u n c t i o n a l
r o l e o f h u m a n I g G s u b c l a s s e s in e o s i n o p h i l - m e d i a t e d
A r tig o d e R e v is ã o . G a z zin e lli G , C o lle y D G . H u m a n im m u n e r e s p o n s e s d u r in g s c h is to s o m ia s is m a n s o n i. R e v is ta d a S o c ie d a d e B r a s ile ir a d e M e d ic in a T r o p ic a l 2 5 :1 2 5 -1 3 4 , a b r- ju n , 1 9 92 .
J o u r n a l o f I m m u n o l o g y 1 4 2 : 4 4 2 2 - 4 4 2 7 , 1 9 8 9 .
4 4 . K i n g C H , E l I b i a r y S , E l N a w a w i M , S a w y e r J ,
G r i f f i n A , E l H a w e y A , M a h m o u d A A F . I n t e n s i t y
o f S c h i s t o s o m a m a n s o n i i n f e c t i o n i n a h u m a n p o p u l a t i o n is i n v e r s e l y c o r r e l a t e d w i t h a n t i b o d y r e s p o n s e t o S m W 6 8 , a p r o t e c t i v e p a r a s i t e a n t i g e n .
J o u r n a l o f I n f e c t i o u s D i s e a s e 1 6 0 : 6 8 6 - 6 9 1 , 1 9 8 9 . 4 5 . K l o e t z e l K , d a S i l v a J R . S c h i s t o s o m i a s i s m a n s o n i
a c q u i r e d i n a d u l t h o o d : b e h a v i o u r o f e g g c o u n t s a n d
t h e i n t r a d e r m a l t e s t . T h e A m e r i c a n J o u m a l o f T r o p i c a l
M e d i c i n e a n d H y g i e n e 1 6 : 1 6 7 - 1 6 9 , 1 9 6 7 .
4 6 . L i m a M S , G a z z i n e l l i G , R o c h a R S , K a t z N , C o ll e y D G . D e m o n s t r a t i o n o f L e u k o c y t e I n h i b i t o r y F a c t o r
( L I F ) i n h u m a n s c h i s t o s o m i a s i s m a n s o n i a n d its
e v a l u a t i o n f r o m p a t i e n t s i n a n e n d e m i c s e t t i n g .
C l i n i c a l I m m u n o l o g y a n d I m m u n o p a t h o l o g y 3 7 :
3 5 1 - 3 5 9 , 1 9 8 5 .
4 7 . L u n d e M N , O t t e s e n E A , C h e e v e r A W . S e r o l o g i c a l
d i f f e r e n c e s b e t w e e n a c u t e a n d c h r o n i c
s c h i s t o s o m i a s i s m a n s o n i d e t e c t e d b y e n z y m e - l i n k e d i m m u n o a b s o r b a n t a s s a y ( E L I S A ) . T h e A m e r i c a n
J o u r n a l o f T r o p i c a l M e d i c i n e a n d H y g i e n e 2 8 : 8 7 -
9 1 , 1 9 7 9 .
4 8 . M a n s o u r M M , O m e r A l i P , F a r i d Z , S i m p s o n A J G ,
W o o d y J W . S e r o l o g i c a l d i f f e r e n t i a t i o n o f a c u t e a n d
c h r o n i c s c h i s t o s o m i a s i s m a n s o n i b y a n t i b o d y
r e s p o n s e s t o k e y h o l e l i m p e t h e m o c y a n i n . T h e
A m e r i c a n J o u r n a l o f T r o p i c a l M e d i c i n e a n d
H y g i e n e 4 1 : 3 3 8 - 3 4 4 , 1 9 8 9 .
4 9 . M o n t e s a n o M A , F r e e m a n G L , G a z z i n e l l i G , C o ll e y
D G . R e c o g n i t i o n b y m o n o c l o n a l a n t i - i d i o t y p i c
a n t i b o d i e s o f s e v e r a l i d i o t y p e s o n a m o n o c l o n a l a n t i
s o l u b l e s c h i s t o s o m a l e g g a n t i g e n a n t i b o d y a n d a n t i
s o l u b l e s c h i s t o s o m a l e g g a n t i g e n a n t i b o d i e s f r o m
p a t i e n t s w i t h d i f f e r e n t c l i n i c a l f o r m s o f i n f e c t i o n .
J o u r n a l o f I m m u n o l o g y 1 4 5 : 3 0 9 5 - 3 0 9 9 , 1 9 9 0 .
5 0 . M o n t e s a n o M A , F r e e m a n J r G L , G a z z i n e l l i G ,
C o l l e y D G . E x p r e s s i o n o f c r o s s - r e a c t i v e , s h a r e d
i d i o t y p e s o n a n t i - S E A a n t i b o d i e s f r o m h u m a n s m i c e
w i t h s c h i s t o s o m i a s i s . J o u r n a l o f I m m u n o l o g y 1 4 5 :
1 0 0 2 - 1 0 0 8 , 1 9 9 0 .
5 1 . M o n t e s a n o M A , L i m a M S , C o r r e a - O l i v e i r a R ,
G a z z i n e l l i G , C o l l e y D G , X V I . I d i o t y p i c d i f f e r e n c e s
i n a n t i b o d y p r e p a r a t i o n s f r o m p a t i e n t s w i t h d i f f e r e n t
c l i n i c a l f o r m s o f i n f e c t i o n . J o u r n a l o f I m m u n o l o g y
1 4 2 : 2 5 0 1 - 2 5 0 6 , 1 9 8 9 .
5 2 . M o s m a n n T R , C o f f m a n R L . T h l a n d T H 2 c e l l s :
d i f f e r e n t p a t t e r n s o f l y m p h o k i n e s e c r e t i o n l e a d to
d i f f e r e n t f u n c t i o n a l p r o p e r t i e s . A n n u a l R e v i e w o f
I m m u n o l o g y 7 : 1 4 5 - 1 7 3 , 1 9 8 9 .
5 3 . N a s h T E , C h e e v e r A W , O t t e s e n E A , C o o k J A .
S c h i s t o s o m e i n f e c t i o n i n h u m a n s : p e r s p e c t i v e s a n d
r e c e n t f i n d i n g s . A n n a l s o f I n t e r n a l M e d i c i n e 9 7 :
7 4 0 - 7 5 4 , 1 9 8 2 .
5 4 . N a s h T E , G a r c i a C o y c o C , R u i z T i b e n E , N a z a r i o
-L o p e z H A , V a z q u e z G , T o r r e s - B o r g e s A .
D i f f e r e n t i a t i o n o f a c u t e a n d c h r o n i c s c h i s t o s o m i a s i s
b y a n t i b o d y r e s p o n s e s t o s p e c i f i c s c h i s t o s o m e
a n t i g e n s . T h e A m e r i c a n J o u r n a l T r o p i c a l M e d i c i n e
a n d H y g i e n e 3 2 : 7 7 6 - 7 8 4 , 1 9 8 3 .
5 5 . O h t a N , N i s h i m u r a Y K , I u c h i M , S a s a z u k i T .
I m m u n o g e n e t i c a n a l y s i s o f p a t i e n t s w i t h p o s t
s c h i s t o s o m a l l i v e r f i b r o s i s in m a n . C l i n i c a l a n d E x p e r i m e n t a l I m m u n o l o g y 4 9 : 4 9 3 - 4 9 9 , 1 9 8 2 .
5 6 . O m e r A l i P , M a n s o u r M , W o o d y L N , S m i t h e r s S R ,
S i m p s o n A J G . A n t i b o d y t o c a r b o h y d r a t e a n d
p o l y p e p t i d e e p i t o p e s o n t h e s u r f a c e o f s c h i s t o s o m u l a
o f S c h i s t o s o m a m a n s o n i i n E g y p t i a n p a t i e n t s w i t h a c u t e a n d c h r o n i c s c h i s t o s o m i a s i s . P a r a s i t o l o g y 9 8 :
4 1 7 - 4 2 4 , 1 9 8 9 .
5 7 . O t t e s e n E A . M o d u l a t i o n o f t h e h o s t r e s p o n s e in
h u m a n s c h i s t o s o m i a s i s . I . A d h e r e n t s u p r e s s o r c e l l s
t h a t i n h i b i t l y m p h o c y t e p r o l i f e r a t i o n r e s p o n s e s to
p a r a s i t e a n t i g e n s . J o u r n a l o f I m m u n o l o g y 1 2 3 :
1 6 3 9 - 1 6 4 4 , 1 9 7 9 .
5 8 . O t t e s e n E A , H i a t t R A , C h e e v e r A W , S o t o m a y o r
Z R , N e v a F A . T h e a c q u i s i t i o n a n d l o s s o f a n t i g e n -
s p e c i f i c c e l l u l a r i m m u n e r e s p o n s i v e n e s s in a c u t e
a n d c h r o n i c s c h i s t o s o m i a s i s i n m a n . C l i n i c a l a n d
E x p e r i m e n t a l I m m u n o l o g y 3 3 : 3 8 - 4 7 , 1 9 7 8 .
5 9 . P a r r a J C , L i m a M , C o l l e y T A , G a z z i n e l l i G , C o l l e y
D G . F l o w c y t o m e t r i c a n a l y s i s o f s c h i s t o s o m a l
p a t i e n t ’s l y m p h o b l a s t s s t i m u l a t e d i n v i t r o l e g s o l u b l e a n t i g e n s ( S E A ) , a n t i - S E A i d i o t y p e s a n d
s t a p h y l o c o c c a l e n t e r o t o x i n B ( S E B ) . I n : A b s t r a c t s o f I n t e r n a t i o n a l S y m p o s i u m o n S c h i s t o s o m i a s i s .
R e c i f e p . 2 0 - 2 5 , 1 9 9 1 .
6 0 . P a r r a J C , L i m a M S , G a z z i n e l l i G , C o l l e y D G . A n t i -
i d i o t y p i c T c e l l s c a n r e c o g n i z e a n d r e s p o n d t o a n t i-
S E A i d i o t y p e s d i r e c t l y . J o u r n a l o f I m m u n o l o g y
1 4 0 : 2 4 0 1 - 2 4 0 5 , 1 9 8 8 .
6 1 . P e a r c e E J , C a s p a r P , G r z y c h J M , L e w i s F A , S h e r
A . D o w n r e g u l a t i o n o f T h l c y t o k i n e p r o d u c t i o n
a c c o m p a n i e s i n d u c ti o n o f T h 2 r e s p o n s e s b y a p a r a s i t i c
h e l m i n t h , S c h i s t o s o m a m a n s o n i . J o u r n a l o f E x p e r i m e n t a l M e d i c i n e 1 7 3 : 1 5 9 - 1 6 6 , 1 9 9 1 .
6 2 . R o c k l i n R E , B r o w n A P , W a r r e n K S , P e l l e y R P ,
H o u b a V , S i o n g o k T K A , O u m a J , S t u r r o c k R F ,
B u t t e r w o r t h A E . F a c t o r s t h a t m o d i f y t h e c e l l u l a r -
i m m u n e r e s p o n s e i n p a t i e n t s i n f e c t e d b y S c h i s t o s o m a m a n s o n i .J o u r n a l o f I m m u n o l o g y 1 2 5 : 1 9 1 6 - 1 9 2 3 , 1 9 8 0 .
6 3 . S a s a z u k i T , O h t a N , K a n e o k a R , K o j i m a S .
A s s o c i a t i o n b e t w e e n a n H L A p a p l o t y p e a n d l o w
r e s p o n s i v e n e s s t o s c h i s t o s o m a l w o r m a n t i g e n in
m a n . J o u r n a l o f E x p e r i m e n t a l M e d i c i n e 1 5 2 : 3 1 4 5 -
3 1 8 5 , 1 9 8 0 .
6 4 . S i m p s o n A J G , Y i X , L i l l i w h i t t e J , O m e r A l i P ,
K e l l y C , M o t t R , S m i t h e r s S R , C o r r e a - O l i v e i r a R ,
