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Immunopathology of the membrane attack complex in systemic lupus erythematosus nephritis.

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IMMUNOPATHOLOGY OF THE MEMBRANE ATTACK COMPLEX IN
SYSTEMIC LUPUS ERYTHEMATOSUS NEPHRITIS
GREGORY BIESECKER and DAVID KOFFLER
Immune complexes d e p o s i t e d i n t h e k i d n e y s o f
p a t i e n t s w i t h s y s t e m i c l u p u s e r y t h e m a t o s u s (SLE) appear
t o p l a y an i m p o r t a n t r o l e i n t h e p a t h o g e n e s i s o f g l o merulonephritis (1-4).
To assess t h e r o l e o f t h e
membrane a t t a c k complex (MAC) o f complement i n m e d i a t i n g t i s s u e damage, t h e d i s t r i b u t i o n o f t h e MAC was
i n v e s t i g a t e d i n 22 k i d n e y s f r o m p a t i e n t s m a n i f e s t i n g
SLE n e p h r i t i s , u t i l i z i n g a n t i s e r a s p e c i f i c f o r MAC
n e o a n t i g e n i c d e t e r m i n a n t s and C 9 ( 5 ) .
The MAC was
d e t e c t e d i n b o t h g l o m e r u l i and i n t h e r e g i o n o f p e r i t u b u l a r basement membranes o f k i d n e y s w i t h m o r p h o l o g i c
e v i d e n c e o f SLE n e p h r i t i s , s u g g e s t i n g t h a t t h e MAC
i n t e r a c t s w i t h s i t e s on r e n a l basement membranes and
may f u n c t i o n i n v i v o as a d i r e c t m e d i a t o r o f nephrot o x ic it y .
The MAC was demonstrated i n c o n j u n c t i o n w i t h IgG
and C3 i n g l o m e r u l i o f n e p h r i t i c k i d n e y s . The c o m p l e t e
spectrum o f SLE k i d n e y d i s e a s e , r a n g i n g f r o m mesangial
nephropathy t o f o c a l and d i f f u s e p r o l i f e r a t i v e and
membranous g l o m e r u l o n e p h r i t i s , showed a s i m i l a r p a t t e r n
o f MAC and immune complex l o c a l i z a t i o n . Kidneys c l a s s i f i e d as f o c a l p r o l i f e r a t i v e g l o m e r u l o n e p h r i t i s r e v e a l e d segmental
immunofluorescence i n d i c a t i v e o f
immune complex d e p o s i t s w i t h i n mesangial a r e a s and
Frm t h e Department o f Pathology, Laboratory
Medicine, Hahnemann Medical College and Hospital,
Philadelphia, PA; and The Rockefeller U n i v e r s i t y ,
New York, NY.
This i n v e s t i g a t i o n was supported by United
States Public Health Service Grants AM21789 and
AM21715, and by Pennsylvania State Department of
Health.
Send r e p r i n t requests t o David K o f f l e r , M.D.,
Hahnemann Medical College b Hospital, 230 N. Broad
Street, Philadelphia, PA 19102.
Arthritis and Rheumatism, Vol. 25, No. 7 (July 1982)
c a p i l l a r y walls (Figure I A ) .
The c h a r a c t e r i s t i c p a t t e r n was comprised o f g r a n u l a r o r i r r e g u l a r aggregates
c o n t a i n i n g IgG, C3, and C l q w i t h l e s s e r amounts o f IgM.
K i d n e y s w i t h moderate t o s e v e r e d i f f u s e p r o l i f e r a t i v e
g l o m e r u l o n e p h r i t i s e x h i b i t e d b r i g h t e r immunofluorescence s t a i n i n g r e a c t i o n s , c o n s i s t i n g o f d i f f u s e , conf l u e n t aggregates w i t h a glomerular d i s t r i b u t i o n simil a r t o t h a t o f focal p r o l i f e r a t i v e glomerulonephritis
Immunofluorescence l o c a l i z a t i o n o f t h e
(Figure 2A).
MAC r e v e a l e d more d i s c r e t e d e p o s i t s o f l e s s e r i n t e n s i t y
f o r both types o f glomerulonephritis (Figures 1B & 28).
The MAC, IgG, C l q and C 3 w e r e p r e s e n t i n a s i m i l a r
distribution,
most c l e a r l y demonstrated i n k i d n e y s
showing membranous nephropathy.
D i f f u s e subepithel i a l
d e p o s i t s w i t h a g r a n u l a r o r w i r e l o o p appearance cont a i n e d b o t h immune complexes and t h e MAC ( F i g u r e 3 ) .
The MAC was p r e s e n t i n t h e t u b u l a r r e g i o n s as
segmental o r i r r e g u l a r t h i c k e n e d l i n e a r p e r i t u b u l a r
d e p o s i t s i n t h e 22 k i d n e y specimens s t u d i e d .
The
i n c i d e n c e o f IgG and C 3 was l o w e r , 32% and 64% respectively.
I n f l a m m a t o r y changes w i t h i n t h e i n t e r s t i t i u m
w e r e more c l o s e l y c o r r e l a t e d w i t h t u b u l a r MAC d e p o s i t s
t h a n w i t h d e p o s i t s o f e i t h e r IgG o r C 3 ( F i g u r e s 4,5,6).
No c o r r e l a t i o n was f o u n d between g l o m e r u l a r and t u b u l a r
MAC l o c a l i z a t i o n f o r i n d i v i d u a l p a t i e n t s , e x c e p t t h a t
k i d n e y s showing s e v e r e d i f f u s e p r o 1 i f e r a t i v e g l o m e r u l o n e p h r i t i s m a n i f e s t e d e x t e n s i v e d e p o s i t i o n of b o t h
p e r i t u b u l a r and g l o m e r u l a r MAC.
A t y p i c a l case o f
f o c a l p r o l i f e r a t i v e g l o m e r u l o n e p h r i t i s i s shown i n
F i g u r e 7:
IgG d e p o s i t s i n g l o m e r u l i b u t n o t i n p e r i t u b u l a r regions (Figure 7A), C 3 surrounding a small
c l u s t e r o f t u b u l e s ( F i g u r e 7B) and MAC d e p o s i t s i n t h e
p e r i t u b u l a r r e g i o n o f a l a r g e r group o f r e n a l t u b u l e s
( F i g u r e 7C).
MAC l o c a l i z a t i o n v a r i e d fran an i r r e g u l a r
l i n e a r p a t t e r n w i t h segmental a r e a s o f t h i c k e n i n g
( F i g u r e 7D), t o i r r e g u l a r , g r a n u l a r aggregates shown i n
F i g u r e 8.
Each o f t h e k i d n e y s s t u d i e d m a n i f e s t e d f o c a l o r
d i f f u s e p e r i t u b u l a r i n f i l t r a t e s , comprised p r i m a r i l y o f
mononuclear c e l l s . B o t h p r o x i m a l and d i s t a l t u b u l e s
w i t h i n i n f l a m m a t o r y a r e a s showed d e g e n e r a t i v e changes
marked b y t h i c k e n e d basement membranes as w e l l as
v a c u o l i z a t i o n and a t r o p h y o f t h e e p i t h e l i u m . The most
s e v e r e i n f l a m m a t o r y r e a c t i o n s were a s s o c i a t e d w i t h
MEMBRANE AUACK COMPLEX
877
d i f f u s e p r o l i f e r a t i v e glomerulonephritis.
Renal t i s sues showing f o c a l p r o l i f e r a t i v e g l o m e r u l o n e p h r i t i s o r
mesangial nephropathy c o n t a i n e d d i s c r e t e f o c i o f i n flammation predominantly i n t h e r e g i o n o f proximal
t u bu 1e s.
The l a c k of c o r r e l a t i o n o f p e r i t u b u l a r d e p o s i t s o f
MAC and immune complexes may be e x p l a i n e d b y one o r
more o f t h e f o l l o w i n g :
a ) t h e MAC i s i n t r i n s i c a l l y
more r e s i s t a n t t o d i g e s t i o n b y p r o t e o l y t i c enzymes t h a n
e i t h e r i m r m n o g l o b u l i n o r C3 ( 6 ) and i n s e r t i o n o f MAC
i n t o t h e p h o s p h o l i p i d membrane may e x e r t an a d d i t i o n a l
p r o t e c t i v e e f f e c t ; b ) l o c a l i z a t i o n of immune complexes
may be d i f f i c u l t because t h e y a r e masked o r n o t p r e s e n t
i n s u f f i c i e n t q u a n t i t i e s f o r d e m o n s t r a t i o n b y immunof l u o r e s c e n c e ; and, c ) t h e MAC may be d e p o s i t e d f o l l o w i n g a c t i v a t i o n of t h e a l t e r n a t i v e pathway b y immunog l o b u l i n i n d e p e n d e n t mechanisms, e.g., b a c t e r i a l endot o x i n (7), accounting f o r t h e f a i l u r e t o demonstrate
p e r i t u b u l a r IgG.
T u b u l o i n t e r s t i t i a l n e p h r i t i s (8,9) has been s t r e s sed as a p o t e n t i a l l y i m p o r t a n t f a c t o r c o n t r i b u t i n g t o
t h e d e s t r u c t i o n o f r e n a l parenchyma and t h e p r o g r e s s i o n
o f glomerulonephritis.
Tubular associated
immune
complex d e p o s i t s have been r e p o r t e d f o r two p a t i e n t s
w i t h SLE and a c u t e r e n a l f a i l u r e w i t h h i s t o l o g i c a l l y
normal g l o m e r u l i ( 1 0 ) .
Experimental studies i n d i c a t e
t h a t p e r i t u b u l a r d e p o s i t s a r e observed i n most r a b b i t s
a f f e c t e d by c h r o n i c serum s i c k n e s s d i s e a s e induced by
b o v i n e serum a l b u m i n i m m u n i z a t i o n (11) and a l s o may b e
f o u n d i n a n i m a l s immunized w i t h homologous k i d n e y
(12,13).
However, t h e u n i f o r m presence o f IgG i n t h e
experimental renal lesions b u t n o t i n t h e tubulointers t i t i a l l e s i o n s o f SLE suggests t h a t i n SLE n e p h r i t i s
s e v e r a l mechanisms may be o p e r a t i v e .
One mechanism
w i t h i m p o r t a n t t h e r a p e u t i c i m p l i c a t i o n s c o u l d be t h e
a c t i v a t i o n o f complement due t o s u b c l i n i c a l i n t e r s t i t i a l p y e l o n e p h r i t i s o c c u r r i n g i n immunosuppressed SLE
patients.
P r e l i m i n a r y s t u d i e s have demonstrated ext e n s i v e p e r i t u b u l a r d e p o s i t s o f t h e MAC i n k i d n e y s w i t h
morphol o g i c e v i d e n c e o f p y e l onephr it i s.
The MAC d e p o s i t e d i n t i s s u e may d i r e c t l y damage
Figure 2.
Diffuse p r o l i f e r a t i v e glomerulonephritis. Glomerular staining. ( A ) C 3 .
Extensive granular and lumpy
deposits s i m i l a r t o those found f o r IgG (X400). ( 6 ) MAC.
More extensive deposits than observed i n Figure lB, but less
intense staining than IgG o r C 3 (X400).
Figure 3 . Glomerular l o c a l i z a t i o n o f IgG and MAC. Membranous nephropathy. Wire loop deposits along c a p i l l a r y walls of
IgG ( A ) and MAC (B) showing a s i m i l a r d i s t r i b u t i o n (X400).
Figure 1. Focal p r o l i f e r a t i v e glomerulonephritis. Glomerul a r staining. ( A ) IgG. Segmental granular aggregates w i t h i n
c a p i l l a r y walls o f glomerular t u f t s plus extensive mesangial
deposits (arrows) (X400).
( B ) MAC.
Similar d i s t r i b u t i o n
showing more discrete deposits o f lesser i n t e n s i t y (X400).
BIESECKER AND KOFFLER
878
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Peritubular Inflammation
Figure 4 . Comparison o f the number o f tubules reacting f o r
IgG with c e l l u l a r i n f i l t r a t i o n f o r each case studied. Involved tubules graded as follows: + = ~ 2 5 % ; ++ = 25-5W ;
+++ = > 50% as determined by immnofluorescence o r l i g h t
microscopic examinatlon. Autopsy (e). Biopsy ( 0 ) .
c e l l u l a r o r basement membranes w i t h o u t t h e p a r t i c i p a t i o n o f p r o t e a s e s f r o m e i t h e r n e u t r o p h i l s o r serum.
-I n v i t r o s t u d i e s have shown t h a t i n s e r t i o n o f t h e MAC
i n t o p h o s p h o l i p i d meinbranes causes p h y s i c a l d i s r u p t i o n
o f t h e membrane, c r e a t i n g membrane d e f e c t s ( 1 4 ) . These
f u n c t i o n a l o r r e a l " h o l e s " i n t h e membrane c r e a t e d b y
t h e MAC a l l o w t h e i n f l u x o f w a t e r and e x t r a c e l l u l a r
i o n s , d i s r u p t i n g normal c e l l u l a r f u n c t i o n o r l e a d i n g t o
c o l l o i d osmotic l y s i s .
In t i s s u e t h e MAC may cause
p h y s i c a l d i s r u p t i o n o f t h e plasma membrane and d i s r u p t i o n o f c e l l u l a r a r c h i t e c t u r e , as has been observed tit
t h e muscle e n d p l a t e i n m y a s t h e n i a g r a v i s ( 1 5 ) .
The f a i l u r e t o observe s i g n i f i c a n t n e u t r o p h i l
i n f i l t r a t i o n i n most forms o f human g l o m e r u l o n e p h r i t i s
s u g g e s t s t h a t o t h e r pathways c o n t r i b u t e t o t i s s u e
injury.
I n r a b b i t s , e x p e r i m e n t a l immune complex g l o m e r u l o n e p h r i t i s may p r o g r e s s d e s p i t e d e p l e t i o n o f
n e u t r o p h i l s ( 1 6 ) . I n t e r a c t i o n o f t h e MAC w i t h basement
o r c e l l u l a r membranes may be t h e common pathway f o r
m e d i a t i o n o f t i s s u e i n j u r y i n v o l v i n g b o t h immune and
nonimmune i n i t i a t e d i n f l a m m a t o r y l e s i o n s . F o r example,
t h e MAC has been demonstrated i n n e c r o t i c s k e l e t a l
muscle f i b e r s i n a v a r i e t y o f neuromuscular d i s e a s e s
(17), p o s s i b l y r e s u l t i n g from a l t e r n a t i v e complement
pathway a c t i v a t i o n b y t i s s u e breakdown p r o d u c t s l e a d i n g
t o assembly of t h e MAC. The c o r r e l a t i o n o f p e r i t u b u l a r
MAC, an a g e n t w i t h known p o t e n t i a l f o r damaging membranes, w i t h p e r i t u b u l a r i n f l a m m a t i o n suggests t h a t
t h i s complex may be a more r e l i a b l e m a r k e r f o r t i s s u e
i n j u r y t h a n IgG a n d / o r C3.
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P e r i t u b u l a r Inflammation
Figure 5. Comparison o f peritubular C3 l o c a l i z a t i o n with
c e l l u l a r i n f i l t r a t i o n f o r each case.
Involved tubules
graded as i n Figure 4.
+
++
+++
Peritubular lnflammat i o n
Figure 6 . Comparison o f peritubular MAC l o c a l i z a t i o n with
c e l l u l a r i n f i l t r a t i o n . Involved tubules graded as i n Figure
4.
MEMBRANE AlTACK COMPLEX
879
Figure 8.
Tubular l o c a l i z a t i o n o f IgG and MAC.
(A) IgG
s t a i n i n g o f i n t r a l u m i n a l casts. Note absence o f p e r i t u b u l a r
IgG (X400).
( B ) I r r e g u l a r granular aggregates of MAC surrounding tubules.
No s t a i n i n g o f i n t r a l u m i n a l casts f o r
MAC.
(X400).
D i f f u s e pro1 i f e r a t i v e glomerulonephritis.
6.
7.
8.
9.
Figure 7.
L o c a l i z a t i o n o f MAC i n t u b u l a r regions. Focal
p r o l i f e r a t i v e glomerulonephritis.
(A) IgG present i n l o meruli, but absent frm p e r i t u b u l a r regions (X150). (BY C3
present i n glomeruli and surrounding a small group o f tubul e s ( a r r o w ) ( X 1 5 0 ) . (C) Prominent p e r i t u b u l a r deposits o f
MAC (center) (X150). (D) Discontinuous, segmentally t h i c k ened deposits o f MAC i n the region o f the t u b u l a r basement
membrane (X400). Stained sections were c u t from the same
t i s s u e block.
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