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Pathophysiology of circulating immune complexes.

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PATHOPHYSIOLOGY OF CIRCULATING IMMUNE COMPLEXES
MART MANNIK
Studies i n experimental animals have shown t h a t
c i r c u l a t i n g , l a r g e - l a t t i c e d immune complexes c o n t a i n i n g
IgG a n t i b o d i e s a r e e f f e c t i v e l y removed by K u p f f e r
c e l l s . The removal of immune complexes i s a l s o i n f l u enced by t h e n a t u r e o f antigens and a n t i b o d i e s i n t h e
complexes and by t h e f u n c t i o n a l c a p a c i t y o f t h e K u p f f e r
cells.
The presence o f immune complexes i n g l o m e r u l i
may develop by d e p o s i t i o n o f c i r c u l a t i n g immune complexes o r by l o c a l formation o f antigen-antibody comp l exes.
C i r c u l a t i ng , l a r g e - l a t t i c e d complexes deposi t
i n renal g l o m e r u l i i n t h e subendothelial and mesangial
areas, whereas s u b e p i t h e l i a l d e p o s i t s o f immune complexes a r e l o c a l l y formed.
Concepts on t h e pathophysiology o f immune complexes developed i n e x p e r i mental animals w i l l h e l p t o guide t h e study o f human
immune complex diseases,
i n c l u d i n g systemic lupus
erythema tosus (SLE).
Immune complexes cause a number o f c l i n i c a l manif e s t a t i o n s i n SLE and i n o t h e r immune complex disease.
The pathogenic immune complexes a r e e i t h e r deposited
from t h e c i r c u l a t i o n o r l o c a l l y formed.
I n local
f o r m a t i o n o f immune canplexes, t h e antigens a r e p a r t o f
t h e t a r g e t organ o r u n r e l a t e d antigens a r e s e l e c t i v e l y
deposited i n t h e organ and a n t i b o d i e s fran t h e c i r c u l a t i o n r e a c t w i t h these antigens.
I n t h i s type o f
disease mechanism u s u a l l y one organ i s i n v o l v e d .
In
c o n t r a s t , when pathogenic immune complexes a r e present
i n c i r c u l a t i o n , u s u a l l y more than one organ i s i n v o l v e d
due t o t h e d e p o s i t i o n o f c i r c u l a t i n g immune canplexes.
T h i s a r t i c l e w i l l emphasize concepts, developed by
study o f experimental animals, on t h e f a t e o f c i r c u l a t i n g i m n e canplexes and t h e d e p o s i t i o n o f immune
complexes i n r e n a l g l o m e r u l i .
Improved understanding
o f t h e pathophysiology o f immune complexes i n e x p e r i mental animals w i l l p e r m i t more i n c i s i v e i n q u i r y i n t o
human diseases.
FATE OF CIRCULATING IMMUNE COMPLEXES
Many methods have been developed t o measure t h e
c o n c e n t r a t i o n o f immune complexes i n serum o r o t h e r
body f l u i d s (1,Z).
The c o n c e n t r a t i o n o f immune complexes a t any g i v e n time i n t h e c i r c u l a t i o n depends on
the r a t e o f immune complex f o r m a t i o n and on t h e r a t e o f
Arthritis and Rheumatin. V d . 25, No. 7 (July 1982)
imnune complex removal.
The r a t e o f immune complex
f o r m a t i o n i n t u r n depends on t h e r a t e o f antibody
s y n t h e s i s and t h e r a t e o f a v a i l a b i l i t y o f s p e c i f i c
antigens.
U n f o r t u n a t e l y , no i n f o r m a t i o n i s a v a i l a b l e
on t h e r a t e of immune complex f o r m a t i o n i n human d i seases o r i n murine models of lupus.
The r a t e o f
removal o f immune complexes from c i r c u l a t i o n i n t u r n
depends on t h e removal o f immune complexes by t h e
mononuclear phagocytes system (MPS), f o r m e r l y c a l l e d
t h e r e t i c u l o e n d o t h e l i a l system, and on t h e d e p o s i t i o n
of t h e complexes i n t i s s u e s . I n experimental models o f
acute and c h r o n i c serum sickness a very small proport i o n of the i n j e c t e d a n t i g e n was deposited i n renal
glomeruli (3).
During these s t u d i e s c o n s i d e r a b l e
q u a n t i t y o f t h e I n j e c t e d a n t i g e n was taken up by t h e
MPS.
The f a t e o f c i r c u l a t i n g immune complexes has been
examined by i n j e c t i o n o f preformed immune complexes,
prepared w i t h IgG c l a s s o f a n t i b o d i e s . These i n v e s t i g a t i o n s have shown t h a t t h e removal o f c i r c u l a t i n g
imnune complexes by t h e MPS depends on t h e l a t t i c e o f
imnune complexes, t h e s t a t u s o f t h e MPS, t h e n a t u r e o f
antigens i n t h e complexes, and t h e c h a r a c t e r i s t i c s o f
t h e a n t i b o d i e s i n immune complexes.
The l a t t i c e o f immne complexes i s d e f i n e d as t h e
number o f a n t i g e n (Ag) and number o f a n t i b o d y (Ab)
molecules i n a g i v e n complex. When m i x t u r e s o f l a r g e
l a t t i c e d complexes, d e f i n e d as c o n t a i n i n g more t h a n two
antibody molecules, and small l a t t i c e d complexes,
d e f i n e d as c o n t a i n i n g one o r two a n t i b o d y molecules,
were i n j e c t e d i n t o mice ( 4 ) . r a b b i t s ( 5 ) o r monkeys
(6), t h e l a r g e l a t t i c e d complexes were removed r e l a t i v e l y q u i c k l y and t h e s m a l l l a t t i c e d complexes pers i s t e d longer i n c i r c u l a t i o n .
The disappearance o f
l a r g e l a t t i c e d complexes ( g r e a t e r than Ag Ab ) a f t e r
t h e i n i t i a l e x t r a v a s a t i o n was b e s t desc?ib$d by a
s i n g l e exponential component. The disappearance o f t h e
small l a t t i c e d complexes (Ag Ab
Ag Ab o r Ag Ab ) was
b e s t described by two e x p o n 2 n t f i l c&np&nents,'reflecti n g equ i1 ibra t i o n be tween intravascu l a r and extravascul a r spaces and catabolism.
As i n c r e a s i n g doses o f
complexes were i n j e c t e d , t h e c l e a r a n c e v e l o c i t y o f
l a r g e - l a t t i c e d complexes and t h e s p e c i f i c h e p a t i c
uptake o f these m a t e r i a l s reached a plateau, suggesting
s a t u r a t i o n o f t h e MPS w i t h l a r g e - l a t t i c e d complexes
(7).
D i r e c t evidence f o r a r e d u c t i o n o f Fc and C3
MANNIK
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F i g u r e 1. S p e c i f i c uptake o f imnune complexes by t h e l i v e r
and spleen i n mice.
A t t i m e z e r o micel%re
injected with
i m n e canplexes prepared from HSA and
I-labeled rabbit
a n t i b o d i e s t o HSA a t 5 - f o l d a n t l g e n excess c o n t a i n i n g 5 . 0 mg
a n t i b o d i e s . M i c e were s a c r i f i c e d a t i n d i c a t e d times and t h e
s p e c i f i c h e p a t i c and s p l e n i c uptake o f i m n e complexes was
determined (expressed as ug o f antibody i n complexes p e r
organ f 1 S.D.) ( m o d i f i e d fran 1 3 ) .
r e c e p t o r s on K u p f f e r c e l l s f o l l o w i n g i n j e c t i o n o f
immune canplexes was obtained by study o f K u p f f e r c e l l s
i s o l a t e d from r a t s ( 8 ) . The r o l e o f t h e l a t t i c e on t h e
f a t e o f c i r c u l a t i n g immune complexes was confirmed w i t h
antigen-antibody complexes o f known composition, s t a b i l i z e d by c o v a l e n t bonds (9-11).
The 1 i v e r accounted f o r t h e overwhelming m a j o r i t y
o f removal o f c i r c u l a t i n g l a r g e - l a t t i c e d complexes i n
mice, r a b b i t s , and monkeys (4,6,12,13).
Figure 1
i l l u s t r a t e s t h e s p e c i f i c uptake o f immune complexes by
t h e l i v e r and t h e spleen i n mice a f t e r i n j e c t i o n o f a
s a t u r a t i n g dose o f s o l u b l e immune complexes.
The
h e p a t i c uptake o f complexes occurs p r i n c i p a l l y by t h e
K u p f f e r c e l l s v i a c e l l s u r f a c e r e c e p t o r s ( 1 4 ) ; these
c e l l s a r e d e r i v e d from monocytes (15). K u p f f e r c e l l s
a r e u n i q u e l y s u i t e d f o r removal o f c i r c u l a t i n g materi a l s s i n c e these c e l l s a r e n o t covered by e n d o t h e l i a l
c e l l s i n hepatic s i n u s o i d s and a r e thus exposed t o
c i r c u l a t i n g substances (16).
It i s o f i n t e r e s t t h a t
hepatocytes may a l s o p a r t i c i p a t e i n t h e removal o f
c i r c u l a t i n g immune complexes (17).
P a r t i c u l a t e immune complexes, f o r example r e d
blood c e l l s s e n s i t i z e d t o a p p r o p r i a t e degree w i t h IgG
c l a s s o f antibodies, a r e p r e f e r e n t i a l l y removed by t h e
spleen (18), i n c o n t r a s t t o s o l u b l e immune complexes.
Red blood c e l l s , s e n s i t i z e d w i t h IgG c l a s s o f a n t i bodies, have been employed i n humans t o seek evidence
f o r an a b n o r m a l i t y o r d e f e c t i n t h e clearance o f c i r c u l a t i n g immune complexes. As compared t o normals, t h e
clearance o f these c e l l s was prolonged i n p a t i e n t s w i t h
SLE due t o decreased s p l e n i c uptake (19):
It i s not
y e t c e r t a i n i f t h e clearance o f s e n s i t i z e d r e d c e l l s by
t h e spleen i n SLE and c e r t a i n o t h e r immune complex
diseases r e p r e s e n t s a decrease i n t h e clearance o f
s o l u b l e immune complexes o r an a b n o r m a l i t y c o n f i n e d t o
t h e spleen.
O f n o t e i s t h a t i n p r o t e i n u r i c mice i n f e c t e d w i t h t h e lymphocytic c h o r i o m e n i n g i t i s v i r u s t h e
clearance o f aggregated IgG was decreased (ZO), whereas
i n female F1 h y b r i d s o f NZB and NZW mice t h e clearance
and h e p a t i c uptake o f model immune canplexes was n o t
impaired ( 2 1 ) . The reasons f o r these d i f f e r e n c e s have
n o t y e t been e l u c i d a t e d .
The n a t u r e o f antigens i n immune complexes can
a l t e r t h e f a t e o f c i r c u l a t i n g immune complexes i n
a d d i t i o n t o t h e i n f l u e n c e o f l a t t i c e . Several examples
f o r t h i s have been recorded. When a human IgM (Waldenstrijm m a c r o g l o b u l i n ) was used as an a n t i g e n f o r r a b b i t
a n t i b o d i e s , s m a l l - l a t t i c e d immune complexes made w i t h
t h e 75 s u b u n i t o f t h i s p r o t e i n were removed q u i c k l y
from c i r c u l a t i o n , whereas s i m i l a r complexes made w i t h
the i n t a c t p r o t e i n persisted i n c i r c u l a t i o n (5).
Single-stranded DNA alone, i n j e c t e d i n t o n o r m 1 mice,
was removed from c i r c u l a t i o n f a s t e r than l a r g e - l a t t i c e d
immune complexes ( 2 2 ) .
Immune complexes w i t h t h i s
a n t i g e n were a l s o r a p i d l y removed from c i r c u l a t i o n
(23).
A s i a l o p r o t e i n s a r e r a p i d l y removed from c i r c u l a t i o n by hepatocytes due t o t h e i n t e r a c t i o n w i t h
galactose receptors.
Interestingly,
small-latticed
immune complexes made w i t h asialo-orosomucoid and a n t i bodies t o orosomucoid were removed from c i r c u l a t i o n by
hepatocytes and n o t by K u p f f e r c e l l s , whereas l a r g e l a t t i c e d complexes made w i t h t h e same antigens and
a n t i b o d i e s were taken up by b o t h K u p f f e r c e l l s and
hepatocytes (24).
4-azido-2-nitrophenyl
human serum
albumin (NAP-HSA) i s an a n t i g e n u s e f u l f o r forming
c o v a l e n t l y c r o s s l i n k e d immune complexes, u t i l i z i n g t h e
haptenic group t o combine w i t h t h e antibody as w e l l as
t o form a c o v a l e n t bond between t h e a n t i g e n and t h e
antibody.
Monomeric NAP-HSA p r e p a r a t i o n s w i t h h i g h
hapten d e n s i t y were q u i c k l y removed from c i r c u l a t i o n by
t h e l i v e r , whereas p r e p a r a t i o n s w i t h low hapten d e n s i t y
p e r s i s t e d i n c i r c u l a t i o n (25).
When Ag Abl complexes
were prepared w i t h NAP ,jHSA and NA+
HSA, t h e
complexes w i t h t h e l a t t d r ' a n t i g e n were &died
faster
from t h e c i r c u l a t i o n than t h e complexes w i t h t h e
NAP
-HSA. even though t h e l a t t i c e f o r m a t i o n i n t h e
two7P%eparations was comparable (11). These examples
serve t o emphasize t h a t t h e n a t u r e o f a n t i g e n i n immune
complexes can a l t e r t h e f a t e o f c i r c u l a t i n g immune
complexes.
I n SLE and i n o t h e r human immune complex
diseases no i n f o r m a t i o n i s a v a i l a b l e on t h e r o l e o f
s p e c i f i c antigens on t h e f a t e o f c i r c u l a t i n g immune
complexes.
The n a t u r e of a n t i b o d i e s i n i n u n e complexes
i n f l u e n c e s t h e f a t e o f c i r c u l a t i n g immune complexes.
If t h e a n t i b o d i e s i n complexes a r e i n e f f e c t i v e i n
i n t e r a c t i n g w i t h Fc r e c e p t o r s on K u p f f e r c e l l s , then
l a r g e - l a t t i c e d complexes can be expected t o p e r s i s t
l o n g e r i n c i r c u l a t i o n . T h i s was e x p e r i m e n t a l l y demons t r a t e d by u s i n g IgG w i t h reduced and a l k y l a t e d i n t e r chain d i s u l f i d e bonds t h a t rendered t h e i n t e r a c t i o n
w i t h Fc r e c e p t o r s i n e f f e c t i v e .
As a r e s u l t t h e l a r g e l a t t i c e d complexes p e r s i s t e d l o n g e r i n c i r c u l a t i o n due
t o decreased h e p a t i c uptake (4.5.12)
and caused i n creased glomerular d e p o s i t i o n (26). R e l a t i v e l y l i t t l e
work has been done w i t h immune complexes c o n t a i n i n g
a n t i b o d i e s of t h e IgA o r I g f l classes o f immunoglobul i n s . Complexes made w i t h mouse IgA deposited i n renal
g l o m e r u l i i n a mesangial p a t t e r n ( 2 7 ) .
Furthermore,
hepatocytes through i n t e r a c t i o n w i t h t h e s e c r e t o r y
component were thought t o c o n t r i b u t e t o removal o f
c i r c u l a t i n g immune complexes c o n t a i n i n g IgA (28).
CIRCULATING IMMUNE COMPLEXES
GLOMERULAR DEPOSITION OF IMMUNE COMPLEXES
About 80% of g l o m e r u l o n e p h r i t i s i n humans appears
t o be caused by immunologic mechanisms (29).
The
presence o f immune complexes i n g l o m e r u l i can r e s u l t
from a t l e a s t two mechanisms. F i r s t , immune complexes
may d e p o s i t i n g l o m e r u l i from t h e c i r c u l a t i o n . Second,
a n t i b o d i e s can combine w i t h a n t i g e n s i n g l o m e r l i thus
l e a d i n g t o presence o f immune complexes by l o c a l format i o n (30). T h i s mechanism can be subdivided i n t o l o c a l
immune complex formation due t o a n t i b o d i e s combining
w i t h s t r u c t u r a l a n t i g e n s i n t h e g l o m e r u l i and l o c a l
immne complex f o r m a t i o n due t o a n t i b o d i e s combining
w i t h p l a n t e d antigens.
Goodpasture's syndrome i s an
example o f l o c a l immune complex formation due t o a n t i bodies combining w i t h s t r u c t u r a l a n t i g e n s i n the g l o merular basement membrane, l e a d i n g t o d i f f u s e presence
of deposited immunoglobulins.
Several experimental
examples e x i s t f o r l o c a l immune complex f o r m a t i o n due
t o p l a n t e d antigens.
I n t r a v e n o u s l y administered aggregated IgG o r aggregated albumin deposited i n t h e
mesangial area, and i f a n t i b o d i e s t o t h e deposited
p r o t e i n s were i n j e c t e d , an acute inflammatory response
ensued i n t h e mesangial area o f t h e glomerulus (31).
Concanavalin A bound t o t h e g l o m e r u l a r c a p i l l a r y w a l l
and when a n t i b o d i e s were i n j e c t e d , lumpy-bumpy d e p o s i t s
o f immune complexes were observed (32).
Furthermore,
t h e s u b e p i t h e l i a l d e p o s i t s o f immune complexes i n
models o f membranous g l o m e r u l o n e p h r i t i s appear t o be
generated by l o c a l f o r m a t i o n r a t h e r than by passsage o f
c i r c u l a t i n g imnune complexes through t h e glomerular
basement membrane (30).
Evidence f o r t h i s event was
marshalled i n r a t s w i t h t h e FxlA antigen, d e r i v e d from
t h e brush border o f proximal t u b u l e s (33) and w i t h
i n t e r m i t t e n t p e r f u s i o n o f bovine serum albumin and
a n t i b o d i e s t o t h i s p r o t e i n (34).
Furthermore, s i n c e
t h e glomerular basement membrane has f i x e d n e g a t i v e
charges, i n t r a v e n o u s l y i n j e c t e d , p o s i t i v e l y charged
( c a t i o n i c ) molecules l o c a l i z e d t o i t by e l e c t r o s t a t i c
bonds and served as p l a n t e d antigens, as demonstrated
w i t h c a t i o n i c f e r r i t i n (35).
The above examples o f
l o c a l immune complex f o r m a t i o n i n g l o m e r u l i serve t o
emphasize t h a t n o t a l l lumpy-bumpy d e p o s i t s o f immune
complexes a r e deposited from c i r c u l a t i o n .
I n c h r o n i c serum sickness models o f glomerulon e p h r i t i s s u b e n d o t h e l i a l , mesangial and s u b e p i t h e l i a l
d e p o s i t s o f immune complexes have been observed. These
were thought t o a r i s e by d e p o s i t i o n o f c i r c u l a t i n g
imrmne complexes.
The i n j e c t i o n o f preformed immune
complexes i n t o u n i m w n i z e d animals showed, however,
t h a t c i r c u l a t i n g complexes deposited i n t h e subendot h e l i a l area a d j a c e n t t o t h e mesangimum and i n t h e
mesangial area.
No d e p o s i t s were found i n t h e sube p i t h e l i a l area.
These experiments were performed i n
mice, u s i n g r a b b i t IgG a n t i b o d i e s t o bovine serum
albumin (36), t o human serum albumin (26), o r t o
DNP-bovine serum albumin (37).
Furthermore, several
experiments i n d i c a t e d t h a t o n l y l a r g e - l a t t i c e d immune
complexes ( g r e a t e r than Ag Ab ) deposited i n t h e sube n d o t h e l i a l and mesangial a$ea!s.
F i r s t , when m i x t u r e s
o f l a r g e - l a t t i c e d and s m a l l - l a t t i c e d complexes were
i n j e c t e d i n t o mice, g l o m e r u l a r d e p o s i t i o n o f t h e complexes progressed o n l y w h i l e l a r g e - l a t t i c e d complexes
remained i n c i r c u l a t i o n (26). Second, when o n l y smalll a t t i c e d complexes were i n j e c t e d i n t o mice, prepared a t
5 0 - f o l d a n t i g e n excess, no glomerular d e p o s i t s developed during t h e f o u r day experiments (38, Haakenstad,
S t r i k e r , Mannik
unpublished observations).
Third,
-
785
when preformed, l a r g e - l a t t i c e d immune complexes were
allowed t o d e p o s i t i n g l o m e r u l i by p r i o r i n j e c t i o n , t h e
a d m i n i s t r a t i o n o f a l a r g e excess o f a n t i g e n r e s u l t e d i n
complete r e l e a s e of e x t r a c e l l u l a r g l o m e r u l a r immune
complexes, presumably by conversion o f l a r g e - l a t t i c e d
t o s m a l l - l a t t i c e d immune complexes (39).
Collectively
these experiments i n d i c a t e t h a t t h e l a t t i c e o f immune
complexes has a s i g n i f i c a n t r o l e i n depositon o f complexes i n g l o m e r u l i . The l a t t i c e o f complexes i s n o t
o n l y i n f l u e n c e d by t h e degree o f a n t i g e n excess, b u t
a l s o by a n t i g e n valence, t h e a v i d i t y between t h e a n t i gens and a n t i b o d i e s and t h e a b s o l u t e c o n c e n t r a t i o n o f
t h e i nt e rac t a nt s
The r o l e of antigen-antibody a v i d i t y i n d e p o s i t i o n
of immune complexes i n g l o m e r u l i has been o f considerable interest.
The i n j e c t i o n o f preformed immune
complexes made w i t h h i g h a v i d i t y o r w i t h low a v i d i t y
a n t i b o d i e s i n d i c a t e d t h a t t h e former deposited predomi n a n t l y i n t h e mesangium and t h e l a t t e r i n t h e sube p i t h e l i a l area (40, 41). O f n o t e i s t h a t b o t h s e t s o f
these complexes were prepared a t 80-fold a n t i g e n excess
from ovalbumin and r a b b i t a n t i b o d i e s t o ovalbumin, and
then i n j e c t e d r e p e a t e d l y i n t o mice. The d i f f e r e n c e i n
t h e l o c a l i z a t i o n was a t t r i b u t e d t o t h e a v i d i t y o f
a n t i b o d i e s . Several points, however, suggest 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 these experiments. The complexes
prepared a t 8 0 - f o l d ovalbumin excess must have been
small l a t t i c e d complexes, d i f f e r i n g between t h e h i g h
a v i d i t y and low a v i d i t y complexes m a i n l y i n t h e a b i l i t y
t o d i s s o c i a t e i n t o f r e e a n t i g e n and f r e e antibody.
Free ovalbumin w i t h m o l e c u l a r w e i g h t o f 40,000 was
q u i c k l y removed from c i r c u l a t i o n so t h a t by 10 minutes
l e s s than h a l f o f t h e i n j e c t e d m a t e r i a l remained i n
c i r c u l a t i o n (M. Mannik
unpublished observations).
For t h i s reason t h e h i g h degree o f a n t i g e n excess would
q u i c k l y be l o s t . Therefore, t h e most l i k e l y explanat i o n f o r t h e observed r e s u l t s i s t h a t w i t h r a p i d l o s s
o f excess ovalbumin t h e complexes w i t h h i g h a v i d i t y
a n t i b o d i e s were converted t o l a r g e - l a t t i c e d complexes
and l o c a l i z e d i n t h e mesangium.
On t h e o t h e r hand,
w i t h l o s s o f excess ovalbumin t h e complexes w i t h low
a v i d i t y a n t i b o d i e s were d i s s o c i a t e d i n t o f r e e a n t i g e n
and f r e e antibody, l e a v i n g f r e e a n t i b o d y i n c i r c u l a t i o n
w i t h f u r t h e r l o s s o f antigen. Repeated i n j e c t i o n s of
complexes would thus c r e a t e t h e a l t e r n a t i n g presence o f
a n t i g e n and a n t i b o d y t h a t culminated i n l o c a l f o r m a t i o n
o f immune complexes i n t h e s u b e p i t h e l i a l area. These
experiments and t h e suggested i n t e r p r e t a t i o n would
e x p l a i n one p o s s i b l e way t h a t a v i d i t y between antigens
and a n t i b o d i e s can i n f l u e n c e g l o m e r u l a r l o c a l i z a t i o n o f
immune complexes. Another way t h e a n t i b o d y a v i d i t y can
i n f l u e n c e g l o m e r u l a r l o c a l i z a t i o n o f complexes i s
through l a t t i c e formation.
For example, h i g h a v i d i t y
a n t i b o d i e s tended t o form l a r g e - l a t t i c e d complexes w i t h
m u l t i v a l e n t antigens, whereas low a v i d i t y a n t i b o d i e s
tended t o form s m a l l - l a t t i c e d complexes t h a t d i d n o t
d e p o s i t i n g l o m e r u l i (37).
The u l t r a s t r u c t u r a l sequence o f d e p o s i t i o n o f
c i r c u l a t i n g , l a r g e - l a t t i c e d immune complexes i n g l o m e r u l i i s o f some i n t e r e s t . F o l l o w i n g t h e i n j e c t i o n o f
one dose o f immune complexes, t h e e l e c t r o n dense dep o s i t s were f i r s t noted i n t h e e n d o t h e l i a l f e n e s t r a e
and s u b e n d o t h e l i a l area, p a r t i c u l a r l y a d j a c e n t t o t h e
mesangium (26).
T h i s was f o l l o w e d by development of
mesangial deposits.
When t h e l a r g e - l a t t i c e d complexes
had c l e a r e d from c i r c u l a t i o n , t h e v i s i b l e d e p o s i t s
disappeared f i r s t from t h e e n d o t h e l i a l fenestrae, t h e
s u b e n d o t h e l i a l area and e v e n t u a l l y from t h e mesangial
.
-
MANNIK
786
matrix.
The removal o f d e p o s i t s f r o m t h e mesangial
m a t r i x i n p a r t was due t o p h a g o c y t o s i s b y monocytes;
t h e r e s i d e n t mesangial c e l l s d i d n o t p h a g o c y t i z e immune
complexes (42).
It i s of n o t e t h a t t h e l a r g e - l a t t i c e d
i n j e c t e d immune complexes reached a b o u t 22 Svedberg
u n i t s as estimated by sucrose d e n s i t y g r a d i e n t u l t r a centrifugation.
These s o l u b l e complexes would n o t be
v i s u a l i z e d as e l e c t r o n dense m a t e r i a l i n g l o m e r u l i b y
t h e employed m a g n i f i c a t i o n .
Therefore, rearrangement
o f t h e immune c a n p l e x e s must o c c u r i n t h e g l o m e r u l i ,
possibly by formation o f i m n e precipitates. For t h i s
t o o c c u r i m n e complexes m u s t undergo l o c a l i n c r e a s e
i n c o n c e n t r a t i o n w i t h o u t a change i n c o n c e n t r a t i o n o f
f r e e antigen.
The mechanisms f o r p o s s i b l e l o c a l i n c r e a s e d c o n c e n t r a t i o n o f immune complexes a t t h e g l o m e r u l a r basement membrane a r e n o t c l e a r . The p o t e n t i a l
r o l e o f f i x e d n e g a t i v e charges on t h e basement membrane
needs t o be e x p l o r e d .
The g l o m e r u l a r f i l t r a t i o n p r o cess a l o n e s h o u l d n o t l e a d t o i n c r e a s e d l o c a l concent r a t i o n o f complexes s i n c e a l s o a n t i g e n s would be
c o n c e n t r a t e d a l o n g w i t h o t h e r macromolecules.
The
f o r m a t i o n o f t h e e l e c t r o n dense d e p o s i t s , however,
appears t o depend on i m m u n o s p e c i f i c r e a c t i o n s f o r two
reasons.
F i r s t , when immune d e p o s i t s developed i n m i c e
s i m u l t a n e o u s l y w i t h f e r r i t i n and w i t h f i b r i n o g e n as
a n t i g e n s , t h e immune d e p o s i t s were s e g r e g a t e d t o t h o s e
c o n t a i n i n g f e r r i t i n and t h o s e c o n t a i n i n g f i b r i n o g e n
w i t h o u t mixed d e p o s i t s (43).
Second, t h e e l e c t r o n
dense d e p o s i t s were r e l e a s e d b y exposure t o l a r g e
excess o f a n t i g e n (39).
Aggregated p r o t e i n s a l s o accumulate i n t h e mes a n g i a l m a t r i x and become d e p o s i t s v i s i b l e b y e l e c t r o n
microscopy, i n c l u d i n g a g g r e g a t e d albumin, a g g r e g a t e d
IgG, and a g g r e g a t e d IgM (44,45).
The mechanisms f o r
t h i s p r o c e s s a r e n o t known. b u t must r e p r e s e n t p r o cesses o t h e r t h a n i m m r n o s p e c i f i c i n t e r a c t i o n s .
I n t h e d i s c u s s e d e x p e r i m e n t a l models, u t i l i z i n g
I n t r a v e n o u s l y i n j e c t e d immune complexes o r a g g r e g a t e d
proteins, the deposits are only t r a n s i e n t l y i n t h e
s u b e n d o t h e l i a l area,
p a r t i c u l a r l y adjacent t o t h e
mesangium, and t h e mesangial d e p o s i t s p e r s i s t much
longer.
Thus, a t r a n s l o c a t i o n o f t h e d e p o s i t s appears
t o o c c u r fran s u b e n d o t h e l i a l t o mesangial a r e a b u t t h e
mechanism f o r t h i s p o s s i b l e p r o c e s s i s n o t known.
Of
i n t e r e s t i s t h a t In c h r o n l c models o f immune complex
d i s e a s e and i n human d i s e a s e s t h e s u b e n d o t h e l i a l deposits c a n be v e r y e x t e n s i v e and e x t e n d a r o u n d t h e
p e r i p h e r a l c a p i l l a r y loop. The f a i l u r e t o a c h i e v e such
e x t e n s i v e d e p o s i t s i n a c u t e e x p e r i m e n t s may i n p a r t be
due t o t h e r e l a t i v e l y s h o r t n a t u r e o f t h e experiments.
Even though s t u d i e s i n e x p e r i m e n t a l a n i m a l s have
p r o v i d e d some c o n c e p t s o f how imnune complexes f r a n
c i r c u l a t i o n d e p o s i t I n r e n a l g l o m e r u l i , much more
remains t o be l e a r n e d .
As more i n f o r m a t i o n i s obt a i n e d , u n d o u b t e d l y new approaches w i l l become a v a i l a b l e t o enhance t h e u n d e r s t a n d i n g o f human i m n e
c a n p l e x diseases, i n c l u d i n g SLE.
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