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The pathogenesis of central nervous system manifestations of systemic lupus erythematosus.

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THE PATHOGENESIS OF CENTRAL NERVOUS SYSTEM
MANIFESTATIONS OF SYSTEMIC LUPUS ERYTHEMATOSUS
NATHAN J. ZVAIFLER and HARRY G. BLUESTEIN
S t u d i e s o f c e n t r a l nervous system (CNS) d i s e a s e i n
s y s t e m i c l u p u s erythematosus (SLE) a r e i n t h e i r i n f a n c y . They have been hampered b y a l a c k o f d i a g n o s t i c
c r i t e r i a , t h e absence o f d e f i n i t i v e l a b o r a t o r y t e s t s ,
and t h e i n a c c e s s i b i l i t y o f b r a i n t i s s u e s f o r s t u d y
d u r i n g l i f e . The s i t u a t i o n i s analogous t o o u r unders t a n d i n g o f l u p u s n e p h r i t i s , i n i t s v a r i o u s forms,
t h r e e decades ago.
However, even a t t h i s e a r l y s t a g e
i n t h e s t u d y o f CNS SLE, i t seems u n l i k e l y t h a t a
s i n g l e p a t h o g e n e t i c p r o c e s s w i l l be found t o e x p l a i n
a l l t h e c l i n i c a l f e a t u r e s . Thus, f o c a l v a s c u l a r e v e n t s
may be r e s p o n s i b l e f o r s t r o k e s , c r a n i a l n e u r o p a t h i e s ,
o r t r a n s v e r s e m y e l i t i s , b u t t h e y a r e l e s s l i k e l y t o be
t h e cause o f o r g a n i c mental syndromes, e n c e p h a l o p a t h i c
p i c t u r e s , psychoses, o r chorea.
Also, i n r e c o g n i t i o n
o f t h e f a c t t h a t t h e s e more d i f f u s e c e r e b r a l syndromes
a r e o f t e n t r a n s i e n t o r r e v e r s i b l e , i t seems u n l i k e l y
t h a t b r a i n c e l l d e a t h i s r e s p o n s i b l e . R a t h e r we would
a n t i c i p a t e t h a t these manifestations w i l l r e s u l t from
processes t h a t i n t e r f e r e w i t h e l e c t r i c a l i m p u l s e s o r
neurotransmitters.
Postmortem e x a m i n a t i o n o f t h e b r a i n s o f p a t i e n t s
d y i n g w i t h SLE have, i n g e n e r a l , been l i m i t e d t o l i g h t
microscopy. The two l a r g e s t s t u d i e s , a l t h o u g h s e p a r a t ed by more t h a n t e n years, a r e r e m a r k a b l y s i m i l a r
(1,Z).
They found t h a t i n f l a m m a t o r y c e l l i n f i l t r a t e s
and f i b r i n o i d n e c r o s i s o f t h e w a l l s o f s m a l l and medium
s i z e d a r t e r i e s , so t y p i c a l i n t h e k i d n e y and o t h e r
s y s t e m i c l e s i o n s o f SLE, a r e o n l y o c c a s i o n a l l y seen i n
the brain.
More o f t e n , t h e r e were d e g e n e r a t i v e and
p r o l i f e r a t i v e changes i n s m a l l v e s s e l s , s i m i l a r t o
t h o s e of h y p e r t e n s i v e encephal o p a t h y and t h r a n b o t i c
thrombocytopenic purpura. S c a t t e r e d a b o u t t h e c e r e b r a l
c o r t e x were m i c r o i n f a r c t s and g l i o s i s around s m a l l
blood vessels.
A f f e c t e d a r t e r i o l e s showed t h i c k e n i n g
Fran t h e D i v i s i o n o f Rheumatology, Department o f
Medicine, U n i v e r s i t y o f C a l i f o r n i a School o f Medicine,
San Diego. C a l i f o r n i a
Supported i n p a r t by Research Grant 80-000109 fran
t h e State o f C a l i f o r n i a , Department o f Health Services;
U.S. Public Health Service Grants AM-14916, AM-07062.
AM-30036; Kroc Foundation and A r t h r i t i s Foundation
C l i n i c a l Center Grant.
Arthritis and Rheumatism, Vol. 25, No. 7 (July 1982)
o f t h e i n t i m a l and m e d i a l c o a t s and o c c a s i o n a l l y p e r i v a s c u l a r c o l l e c t i o n s o f mononuclear c e l l s . T h i s b l a n d
v a s c u l o p a t h y i s r e m i n i s c e n t o f t h e a b n o r m a l i t i e s seen
i n t h e coronary a r t e r i e s o f various s t r a i n s o f autoimmune mice, many o f whom d e v e l o p t h r o m b o s i s and myocardial
infarction
(3,4).
Immunofluorescence and
e l e c t r o n m i c r o s c o p i c e x a m i n a t i o n o f t h o s e l e s i o n s show
immune complexes d e p o s i t e d i n t h e v e s s e l w a l l s , y e t
t h e r e i s a conspicuous absence o f an i n f l a m m a t o r y
component. I t i s i m p o r t a n t t o p o i n t o u t , however, t h a t
w h i l e m i c r o v a s c u l a r l e s i o n s can a c c o u n t f o r t h e c l i n i c a l f i n d i n g s i n some SLE p a t i e n t s , t h e r e i s o f t e n a
remarkable l a c k o f c l i n i c a l - p a t h o l o g i c c o r r e l a t i o n s .
P a t i e n t s w i t h o b v i o u s l u p u s encephalopathy may show
o n l y m i n i m a l f i n d i n g s a t postmortem e x a m i n a t i o n , w h i l e
o t h e r s w i t h no h i s t o r y o f c e r e b r a l m a n i f e s t a t i o n s
d u r i n g l i f e have c h a r a c t e r i s t i c changes. Any t h e o r y o f
p a t h o g e n e s i s must d e a l w i t h t h i s d i s c r e p a n c y .
A p p r o x i m a t e l y t e n y e a r s ago, A t k i n s e t a1 ( 5 )
observed immunoglobulins i n t h e c h o r o i d p l e x i o f two
p a t i e n t s who had CNS m a n i f e s t a t i o n s o f SLE d u r i n g l i f e .
I t was suggested t h a t t h e p a t i e n t s ' symptoms m i g h t be
e x p l a i n e d b y a1 t e r a t i o n s i n c h o r o i d a l f u n c t i o n induced
by immune complexes.
Subsequently, i t has been found
t h a t c h o r o i d a l d e p o s i t s o f immunoreactants a r e a regul a r f e a t u r e of SLE--with o r w i t h o u t a h i s t o r y o f CNS
d i s e a s e - - a n d a r e o f t e n seen i n o t h e r d i s e a s e s w i t h
immune complex-mediated v a s c u l a r i n j u r y (6-8).
Likewise, s u b e n d o t h e l i a l d e p o s i t s i n c h o r o i d a l v e s s e l s a r e
a f e a t u r e o f n a t u r a l l y o c c u r r i n g (9,lO) o r e x p e r i m e n t a l
immune complex d i s e a s e s o f r o d e n t s and r a b b i t s (11,lZ).
These o b s e r v a t i o n s p r o b a b l y r e f l e c t t h e f a c t t h a t t h e
c h o r o i d a l c a p i l l a r i e s , w i t h t h e i r open f e n e s t r a t i o n s
so r e m i n i s c e n t of t h e v e s s e l s o f t h e glomerulus, a l l o w
t h e passage of immune complexes from t h e c i r c u l a t i o n
i n t o t h e i n t e r s t i t u m o f t h e c h o r o i d p l e x u s , where t h e y
a r e r e t a i n e d b y c e l l s b e a r i n g Fc r e c e p t o r s (13).
The
p h y s i o l o g i c consequences o f such d e p o s i t s a r e unknown,
b u t i t seems t h a t t h e y a r e n o t s u f f i c i e n t t o e x p l a i n
t h e CNS m a n i f e s t a t i o n s o f SLE.
R e c e n t l y , t h e r e has been c o n s i d e r a b l e i n t e r e s t i n
a n t i b o d i e s t h a t r e a c t w i t h b r a i n ( T a b l e 1).
Antin e u r o n a l and g l i a l a n t i b o d i e s , a n t i l y m p h o c y t e a n t i bodies which crossreact w i t h b r a i n tissue, a n t i b o d i e s
t h a t s h a r e d e t e r m i n a n t s between e r y t h r o c y t e s and b r a i n ,
and a n t i g l y c o l i p i d a n t i b o d i e s have a l l been r e c o g n i z e d
CNS MANIFESTATIONS OF SLE
863
Table 1. B r a i n r e a c t i v e a n t i bodies i n SLE serum
Spec if ic i ty
Reference
A n t i lymphocyte
A n t i neu r o n a l
A n t i g l ia1
A n t i f e t a l RBC
A n t i gang 1ioside
(GM1)
16,17
16-20
18
19
21
(14-22).
I n some r e p o r t s , t h e i r presence i s associated
w i t h a c t i v e CNS SLE, where i n o t h e r s t h e r e i s no c o r relation.
The i n t r o d u c t i o n o f a n t i b o d i e s t o various
brain constituents i n t o the v e n t r i c l e s o r cerebral
c o r t e x o f experimental animals causes convulsions,
m e n i n g i t i s , impaired memory, and motor d y s f u n c t i o n
(23-25).
Therefore, i t i s reasonable t o suggest t h a t
b r a i n r e a c t i v e a n t i b o d i e s may be r e s p o n s i b l e f o r c e r t a i n forms o f SLE CNS disease.
Three c o n d i t i o n s would appear t o be necessary f o r
them t o be pathogenetic: 1) t h e a p p r o p r i a t e a n t i b o d y
should be demonstrable i n t h e c i r c u l a t i o n p r i o r t o o r
a t t h e t i m e o f t h e appearance o f CNS symptoms; 2 ) t h e r e
should be an a l t e r a t i o n o f t h e blood b r a i n b a r r i e r
s u f f i c i e n t t o a l l o w them t o e n t e r i n t o t h e c e n t r a l
nervous system; and 3) having gained access, t h e a n t i body should be a b l e t o b i n d d i r e c t l y t o b r a i n t i s s u e s .
These p o s t u l a t e s were t e s t e d , i n p a r t , by B l u e s t e i n e t
AHCMNOIO
villus
OUHl
mus
a1 who used a s e n s i t i v e radioassay t o measure a n t i b o d y
b i n d i n g t o c u l t u r e d human neuronal c e l l s ( 2 6 ) . They
found t h a t c e r e b r o s p i n a l f l u i d (CSF) from p a t i e n t s w i t h
SLE and a c t i v e CNS disease had increased amounts o f IgG
a n t i n e u r o n a l a c t i v i t y compared w i t h t h e CSF from a
group o f SLE p a t i e n t s w i t h o u t CNS disease and approp r i a t e c o n t r o l s u b j e c t s . The a n t i n e u r o n a l a c t i v i t y was
present i n much g r e a t e r c o n c e n t r a t i o n s i n t h e CSF o f
p a t i e n t s w i t h a c t i v e n e u r o l o g i c disease than i n t h e i r
serum. The frequency and amount o f a n t i n e u r o n a l a c t i v i t y was g r e a t e r i n p a t i e n t s w i t h psychoses, organic
b r a i n syndrome, o r g e n e r a l i z e d s e i z u r e s than i n those
who presented w i t h hemiparesis o r w i t h chorea/hemiballismus.
I f a n t i b o d i e s from t h e c i r c u l a t i o n a r e responsible
f o r CNS disease, then t h e y must escape t h e c o n s t r a i n t s
o f t h e blood b r a i n b a r r i e r , which n o r m a l l y prevents
serum p r o t e i n from coming i n t o c o n t a c t w i t h c o r t i c a l
t i s s u e s ( F i g u r e 1). The i n t e g r i t y o f t h i s system i s
maintained by an i n t i m a t e a p p o s i t i o n ( t i g h t j u n c t i o n s )
o f e n d o t h e l i a l c e l l s o f small c e r e b r a l vessels and t h e
epi the1 i a l c e l l s s e p a r a t i n g t h e v e n t r i c u l a r space from
t h e c h o r o i d plexus ( 2 7 ) .
Using v a r i o u s t r a c e r s , i t has
been shown t h a t p r o t e i n movement across t h e endothelium
o f a r t h e r i o l e s , c a p i l l a r i e s , and venules occurs n o t as
a r e s u l t o f leaks i n t h e t i g h t j u n c t i o n s , b u t r a t h e r by
t r a n s f e r through t h e e n d o t h e l i a l c e l l v i a v e s i c l e
formation.
V e s i c u l a r t r a n s p o r t can be enhanced by
ischemic i n j u r y o r maneuvers such as t h e i n t r o d u c t i o n
o f h y p e r t o n i c s o l u t i o n s , p r o d u c t i o n of a c u t e hypertension,
o r l o c a l i n f u s i o n o f 5-hydroxytryptamine
( s e r o t o n i n ) (28).
The second p l a c e where antibody m i g h t e n t e r t h e
CNS i s thorugh t h e CSF/brain b a r r i e r i n t h e c h o r o i d
plexus. As shown i n F i g u r e 1, t h e c h o r o i d c a p i l l a r i e s
have l a r g e f e n e s t r a t i o n s which a1 low t h e passage o f
p r o t e i n s and, under experimental c o n d i t i o n s , immune
Studies o f SLE c e r e b r o s p i n a l f l u i d
Table 2.
Patient #
SLE w i t h o u t c l i n i c a l
CNS disease
1
2
3
4
5
6
SLE w i t h c l i n i c a l
CNS disease
1
2
3
4
5
6
7
8
CELL
Figure 1. Diagrammatic r e p r e s e n t a t i o n o f t h e blood b r a i n
b a r r i e r and t h e b l o o d CSF i n t e r f a c e .
Normals
1-14
Impa im e nt
o f CSF/blood
Q a l b ~ l O - ~ barrier
CSF IgG
mg/dl
14.8
2.4
3.4
6.4
1.8
2.6
slight
none
none
none
none
none
4.6
1.2
1.2
3.0
2.6
1.2
2.30t1.38
6.3
none
none
none
none
slight
none
none
slight
9.6
3.0
6.5
7.5
9.0
7.5
2.6
17.6
7.91k4.57
2.5
5.2
6.2
8.3
4.5
4.7
17.6
6.852.99
none (10) 2.56r1.81
s l i g h t (4)
ZVAIFLER AND BLUESTEIN
864
0.7
0
OCUNICAL CNS
DISEASE
NO CLINICAL CNS
DISEASE
0.6
0.5
s
7
c3
0.4
m
0.3
-oa
8
0
u
0
8
0.2
0
T
0.1
0.0
F i g u r e 2.
Comparison o f t h e IgG t o albumin c o n c e n t r a t i o n
r a t i o s i n c e r e b r o s p i n a l f l u i d from SLE p a t i e n t s w i t h ( 0 ) and
without ( 0 ) a c t i v e neuropsychiatric manifestations.
The
bracketed v e r t i c a l b a r r e p r e s e n t s ? SD about t h e mean o f t h e
IgG/albumin r a t i o s i n CSF from 14 non SLE donors undergoing
e l e c t i v e surgery w i t h s p i n a l anesthesia.
complexes.
However, t o g a i n access t o t h e CNS, they
s t i l l must t r a v e r s e an e p i t h e l i a l basement membrane
w i t h t i h t j u n c t i o n s . Experiments performed by Harbeck
e t a1 qll) i n d i c a t e t h a t , d u r i n g acute immune complex
disease i n t h e r a b b i t , bovine serum albumin (BSA)
anti-BSA complexes d e p o s i t i n t h e c h o r o i d and t h e
p r o t e i n c o n c e n t r a t i o n o f t h e CSF increases.
IgG and
albumin values i n t h e CSF r i s e p r o p o r t i o n a t e l y , w h i l e
t h e i r l e v e l s i n t h e serum remain constant. These data
suggest a breach i n t h e blood CSF b a r r i e r . However, i t
i s noteworthy t h a t t h e complexes deposited i n t h e
choroid plexus several days b e f o r e t h e increase i n CSF
proteins.
An a l t e r n a t i v e explanation, t h e r e f o r e , i s
t h a t t h e c h o r o i d a l d e p o s i t s were o n l y i n d i c a t o r s o f
immune complex i n j u r y and t h a t t h e p r o t e i n l e a k occurr e d i n i n j u r e d c e r e b r a l vessels.
Such s t u d i e s have p o t e n t i a l relevance t o t h e
s i t u a t i o n i n SLE.
I n some r e p o r t s , t h e r e a r e c l i n i c a l
and l a b o r a t o r y f i n d i n g s c o n s i s t e n t w i t h t h e p i c t u r e o f
immune complex induced acute v a s c u l a r i n j u r y . C l i n i c a l l y , an a s s o c i a t i o n has been noted between CNS manif e s t a t i o n s and dermal v a s c u l i t i s , a r t e r i t i s , and thrombocytopenia
(17,29).
Hypocomplementemia and h i g h
t i t e r s o f a n t i b o d y t o DNA have a l s o been c o r r e l a t e d
(30). It i s important t o p o i n t out, however, t h a t t h i s
While no s i n g l e
i s n o t a u n i v e r s a l experience (31).
CSF a b n o r m a l i t y i s d i a g n o s t i c o f SLE b r a i n involvement,
i t does appear t h a t t h e r e i s a more f r e q u e n t e l e v a t i o n
o f IgG, depression o f t h e f o u r t h component o f complement, and demonstration o f a n t i b o d i e s t o DNA i n these
p a t i e n t s (32-34). Likewise, although t h e r e i s n o t
complete agreement on t h e usefulness o f n o n i n v a s i v e
d i a g n o s t i c procedures, i t has been claimed t h a t abnorm a l i t i e s found by s e r i a l b r a i n scans (35), c r a n i a l
computerized tomography (34$7), and t h e measurement o f
c e r e b r a l blood f l o w w i t h
0 (38) a r e a l l c o n s i s t e n t
w i t h t h e changes i n t h e c e r e b r a l vasculature.
The a n t i n e u r o n a l a n t i b o d y and increased IgG found
i n t h e CSF need n o t be d e r i v e d from t h e c i r c u l a t i o n ;
t h e y c o u l d r e f l e c t l o c a l p r o t e i n synthesis. A number
o f analyses have been developed f o r determining t h e
source o f t h e p r o t e i n .
In p r i n c i p l e , i f t h e r e i s a
l e a k i n t h e blood b r a i n b a r r i e r , then i n d i v i d u a l prot e i n s such as albumin and IgG should e n t e r t h e CSF i n
p a r a l l e l , and t h e i r c o n c e n t r a t i o n s i n CSF should be
p r o p o r t i o n a l t o t h e i r serum l e v e l s . With l o c a l a n t i body synthesis, however, measurement o f t h e concentrat i o n o f these p r o t e i n s i n simultaneously obtained serum
and CSF samples w i l l show a d i s p r o p o r t i o n a t e i n c r e a s e
i n IgG (39). These p r i n c i p l e s have been a p p l i e d most
o f t e n i n s t u d i e s o f m u l t i p l e s c l e r o s i s and subacute
s c l e r o s i n g panencephalitis, diseases associated w i t h
l o c a l a n t i b o d y s y n t h e s i s (40,41). The a p p l i c a t i o n o f
these techniques t o a group o f SLE p a t i e n t s w i t h and
w i t h o u t c l i n i c a l CNS disease a r e shown i n Table 2. As
a n t i c i p a t e d , t h e mean value f o r CSF IgG i n those w i t h
CNS m a n i f e s t a t i o n s was s i g n i f i c a n t l y h i g h e r (p=0.014)
than those w i t h o u t apparent c l i n i c a l CNS disease,
although t h e r e were o v e r l a p p i n g i n d i v i d u a l values.
A n a l y s i s o f t h e r a t i o o f t h e c o n c e n t r a t i o n o f albumin
i n CSF and serum ( Q a l b ) suggested t h a t t h e r e was no
impairment o f t h e CSF/blood b a r r i e r . When t h e concent r a t i o n r a t i o s o f IgG t o albumin i n CSF were measured
i n t h e two groups ( F i g u r e 2), t h e r a t i o s i n 6/8 pat i e n t s w i t h c l i n i c a l CNS disease was a t l e a s t two
standard d e v i a t i o n s above t h e normal value, w h i l e a l l
o f those w i t h o u t CNS disease had normal IgG/albumin
r a t i o s . The increased r a t i o , which r e f l e c t s a g r e a t e r
than a n t i c i p a t e d amount o f IgG, favors t h e i n t e r p r e t a t i o n o f l o c a l p r o d u c t i o n o f antibody i n these p a t i e n t s .
I n CSF, t h e f i n d i n g t h a t immunoglobulins a r e
r e s t r i c t e d i n t h e i r e l e c t r o p h o r e t i c m o b i l i t y has been
used as another i n d i c a t o r o f l o c a l antibody production,
s i n c e i t i m p l i e s t h a t most o f t h e IgG i s d e r i v e d from a
l i m i t e d number o f plasma c e l l clones.
Oligoclonal
banding i s t y p i c a l l y found i n p a t i e n t s w i t h m u l t i p l e
Table 3. Comparison between c e r e b r o s p i n a l f l u i d and
serum IgG a n t i n e u r o n a l b i n d i n g i n SLE
Antineuronal bindinq
Patients
Fluid
Direct
Direct/Ug IgG
C e n t r a l nervous
system
Cerebrospinal
fluid
serum
9482234
274 1t993
568r177
70t31
Noncentral
nervous
system
Cerebrospinal
fluid
serum
182t66
2736i1502
138+- 114
64r44
CNS MANIFESTATIONS OF SLE
865
F i g u r e 3.
Immunofluorescent s t a i n i n g o f c e l l s i n t h e c e r e b r a l c o r t e x . T i s s u e o b t a i n e d postmortem from a young woman w i t h a c t i v e
l u p u s r e l a t e d o r g a n i c b r a i n syndrome: a ) photomicrograph o f a n t i - I g M immunfluorescence. Note t h e c l u s t e r i n g o f b r i g h t s t a i n i n g
c e l l s w i t h a " r i n g " p a t t e r n c l u s t e r i n g around b l o o d v e s s e l s ; b) photomicrograph o f a n t i - I g G immunofluorescence. B r i g h t s t a i n i n g
c e l l s a r e found f u r t h e r away f r o m t h e b l o o d vessels o u t t o t h e p e r i p h e r y o f t h e f i e l d .
s c l e r o s i s who have h i g h IgG i n d i c e s ( 4 0 ) .
We have
analyzed SLE CSF from p a t i e n t s w i t h a c t i v e CNS disease
and increased IgG c o n c e n t r a t i o n and have been unable t o
demonstrate
restricted
electrophoretic
migration.
Moreover, we a r e impressed by t h e p a u c i t y o f p a t h o l o g i c
s t u d i e s showing immunocmpetent c e l l s i n t h e b r a i n
t i s s u e s o f p a t i e n t s dying w i t h a c t i v e SLE CNS disease.
Therefore, we have sought an a l t e r n a t i v e e x p l a n a t i o n t o
l o c a l p r o d u c t i o n t o account f o r t h e s p e c i f i c accumulat i o n o f immunoglobulin i n t h e CSF o f SLE p a t i e n t s w i t h
CNS disease.
I t i s reasonable t o suggest t h a t i f c i r c u l a t i n g
a n t i b o d i e s d i r e c t e d a g a i n s t neuronal antigens gained
access t o t h e CNS, they c o u l d be concentrated l o c a l l y
as a r e s u l t o f a b s o r p t i o n and subsequent shedding from
neuronal t i s s u e s . Some support f o r t h i s concept comes
from measurements o f t h e s p e c i f i c a c t i v i t y o f a n t i neuronal a n t i b o d i e s i n blood and CSF o f p a t i e n t s w i t h
and w i t h o u t CNS disease. Table 3 shows t h a t t h e amount
o f antineuronal antibody b i n d i n g per microgram o f IgG
i s s i m i l a r i n t h e serum o f both groups o f p a t i e n t s , b u t
t h e s p e c i f i c a c t i v i t y o f the CSF IgG i n t h e presence o f
CNS disease i s more than t w i c e t h a t o f CSF IgG w i t h o u t
c e r e b r a l m a n i f e s t a t i o n s . The b i n d i n g o f a n t i b o d i e s t o
neuronal c e l l membranes i n b r a i n t i s s u e obtained postmortem from a young woman w i t h severe SLE organic
psychosis i s demonstrated i n F i g u r e 3.
Both IgG and
IgPl a n t i b o d i e s r i n g neuronal c e l l s . The i n t e n s i t y o f
t h e membrane immunofluorescence i s p r o p o r t i o n a l t o t h e
d i s t a n c e from t h e c e r e b r a l vessels. L i g h t microscopy
revealed m i c r o i n f a r c t i o n s and p e r i vascul a r g l io s i s b u t
n o t active cerebral v a s c u l i t i s .
Based on these observations, we suggest t h a t t h e
pathogenesis o f t h e d i f f u s e fotms o f SLE CNS disease
r e q u i r e s t h e coexistence o f serum a n t i b o d i e s d i r e c t e d
a g a i n s t b r a i n t i s s u e and an a l t e r a t i o n i n t h e normal
blood b r a i n b a r r i e r . N e i t h e r alone i s s u f f i c i e n t . I n
combination, they r e s u l t i n t h e antibody e n t e r i n g t h e
CNS, b i n d i n g t o neuronal c e l l s and i n t e r f e r i n g w i t h
t h e i r function.
Immune complexes a r e l i k e l y mediators
o f t h e d i s r u p t i o n o f t h e blood b r a i n b a r r i e r , but why
they produce e n d o t h e l i a l damage i n t h e absence o f a
t y p i c a l inflammatory r e a c t i o n i s n o t known. Perhaps
t h e complexes a r e unique i n composition, size, o r t h e i r
a b i l i t y t o a c t i v a t e complement.
There i s a r e c e n t
r e p o r t o f t h e a s s o c i a t i o n o f small (approximately 7 s )
complexes w i t h c e r e b r i t i s w h i l e c e r t a i n forms o f r e n a l
disease c o r r e l a t e d w i t h l a r g e (>19s) complexes ( 4 2 ) .
A l t e r n a t i v e l y , t h e small a r t e r i o l e s o f t h e b r a i n may
respond d i f f e r e n t l y t o immune i n j u r y because o f t h e i r
unique anatomy.
Ischemia o r l o c a l r e l e a s e o f vasoa c t i v e substances from p l a t e l e t s may enhance v e s i c u l a r
protein transport i n t o the brain, but the preservation
o f t h e t i g h t e n d o t h e l i a l j u n c t i o n s may prevent polymorphonuclear leukocytes from g e t t i n g a t t h e a n t i g e n
antibody deposits.
T e s t i n g t h i s hypothesis f o r t h e pathogenesis o f
t h e n e u r o p s y c h i a t r i c m a n i f e s t a t i o n s o f SLE w i l l r e q u i r e
more d e t a i l e d knowledge o f t h e v a s c u l a r l e s i o n s and t h e
neuron r e a c t i v e a n t i b o d i e s .
Presently, there i s a
p a u c i t y o f e l e c t r o n microscopic and immrnofluorescent
s t u d i e s o f t h e CNS v a s c u l a r l e s i o n s i n e i t h e r e x p e r i mental o r n a t u r a l l y o c c u r r i n g lupus. These should be
forthcoming soon.
More i n f o r m a t i o n about t h e proport i o n o f imrmnoglobulin i n t h e CSF which has s p e c i f i c
a n t i n e u r o n a l a c t i v i t y i s needed. These studies, and a
b e t t e r characterization o f the o l igoclonal i t y o f the
a n t i n e u r o n a l a n t i b o d i e s a r e c u r r e n t l y i n progress.
Furthermore, t h e unique a n t i g e n i c determinants recogn i z e d by i n d i v i d u a l a n t i n e u r o n a l a n t i b o d i e s must be
d e f i n e d and t h e i r i n f l u e n c e on b r a i n c e l l f u n c t i o n
measured. The m u l t i p l e CNS a b n o r m a l i t i e s observed i n
SLE may r e f l e c t d i f f e r e n t a n t i b o d y s p e c i f i c i t i e s i n a
manner analogous t o t h e f i n d i n g o f a n t i b o d i e s t o subt h a l a m i c and caudate n u c l e i i n p a t i e n t s w i t h v a r i o u s
forms o f chorea (13,43). I t w i l l be e s p e c i a l l y import a n t t o d e f i n e t h e r e a c t i v i t y o f a n t i b o d y e l u t e d from
b r a i n t i s s u e s o f SLE p a t i e n t s d y i n g w i t h a c t i v e CNS
disease.
Obviously, much remains t o be done, b u t t h e
technology e x i s t s t o answer these i m p o r t a n t questions.
ZVAl FLER AND BLUESTElN
866
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