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Interferon production in patients with systemic lupus erythematosus.

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INTERFERON PRODUCTION IN PATIENTS
WITH SYSTEMIC LUPUS ERYTHEMATOSUS
ROBERT M. FRIEDMAN, OLlVlA PREBLE, ROBERTA BLACK, and SHARON HARRELL
Many p a t i e n t s w i t h systemic lupus erythematosus
(SLE) produce l a r g e q u a n t i t i e s o f i n t e r f e r o n (1). O f
47 p a t i e n t s i n our study w i t h c l i n i c a l l y a c t i v e SLE, 22
o r 47% were found t o have s i g n i f i c a n t t i t e r s o f c i r c u l a t i n g i n t e r f e r o n , ranging from e i g h t t o 128 i n t e r n a t i o n a l u n i t s per m l o f serum.
These t i t e r s a r e
comparable t o those found i n p a t i e n t s w i t h acute v i r e mia o r undergoing treatment w i t h 10 m i l l i o n u n i t s p e r
day o f exogenous i n t e r f e r o n .
The assay used t o d e t e c t
i n t e r g e r o n w i l l r e g i s t e r as p o s i t i v e w i t h 0.05 p gms
(10- M) o f i n t e r f e r o n .
I n a d d i t i o n , o f 19 p a t i e n t s
w i t h c l i n i c a l l y i n a c t i v e SLE, 32% had s i g n i f i c a n t
t i t e r s o f i n t e r f e r o n r a n g i n g from e i g h t t o 64 i n t e r n a t i o n a l u n i t s , and f o u r o f 16 p a t i e n t s wth rheumatoid
a r t h r i t i s (25%) a l s o had t i t e r s o f i n t e r f e r o n ranging
from e i g h t t o 64 u n i t s .
I n c o n t r a s t , none o f t h e 17
c l i n i c a l l y normal c o n t r o l s had s i g n i f i c a n t l e v e l s o f
c i r c u l a t i n g i n t e r f e r o n ( t i t e r s 5 4 u n i t s / ml).
I n o r d e r t o examine whether t h e l e v e l s o f i n t e r f e r o n c o r r e l a t e d w i t h t h e a c t i v i t y o f t h e disease, s i x
p a t i e n t s were s t u d i e d d u r i n g i n t e r v a l s o f a c t i v e and
i n a c t i v e disease.
I n a l l cases t h e i n t e r f e r o n t i t e r
d u r i n g t h e a c t i v e phase o f t h e disease was s i g n i f i c a n t l y h i g h e r than d u r i n g quiescent disease.
Several types o f human i n t e r f e r o n have been des c r i b e d (Table 1). Alpha i n t e r f e r o n i s t h e p r i n c i p l e
product when b u f f y c o a t w h i t e c e l l s a r e s t i m u l a t e d w i t h
a virus.
It i s a l s o produced by n a t u r a l k i l l e r (NK)
c e l l s exposed t o f o r e i g n c e l l s .
I n a d d i t i o n , alpha
i n t e r f e r o n i s produced i n response t o endotoxin, bact e r i a , and several o t h e r i n d u c e r molecules.
Beta
i n t e r f e r o n i s t h e p r i n c i p l e product induced when f i b r o b l a s t s produce i n t e r f e r o n f o l l o w i n g s t i m u l a t i o n w i t h
double stranded RNA (dsRNA) o r a f t e r v i r u s i n f e c t i o n .
Gamma i n t e r f e r o n i s a lynphokine produced by lymphoc y t e s i n response t o mitogens o r t o antigens t o which
t h e lymphocytes have been p r e v i o u s l y exposed ( 2 ) .
Alpha i n t e r f e r o n s have molecular weights o f about
19,000, a r e s t a b l e a t pH 2, and a r e n o t species specif i c ; t h a t i s , t h e y induce an a n t i v i r a l s t a t e n o t o n l y
i n human c e l l s b u t a l s o i n bovine, p o r c i n e and o t h e r
c e l l types.
Cloning o f t h e genes f o r human alpha
i n t e r f e r o n has shown t h a t a t l e a s t 12 d i s t i n c t g e n e t i c
l o c i f o r t h i s i n t e r f e r o n e x i s t . Beta i n t e r f e r o n s a r e
a l s o s t a b l e a t pH 2 and have a molecular weight o f
about 23,000.
They tend, however, t o be much more
species s p e c i f i c - than alpha i n t e r f e r o n , and u n l i k e
alpha i n t e r f e r o n s which have l i t t l e o r no carbohydrate
Arthritis and R h e u m a h , Vd. 25, No. 7 (July 1982)
associated w i t h them, b e t a i n t e r f e r o n s a r e glycoproteins.
Cloning o f beta i n t e r f e r o n genes has i n d i c a t e d
t h a t t h e r e i s perhaps o n l y one human b e t a i n t e r f e r o n ,
a l t h o u g h very r e c e n t work suggests t h e r e may be several
types o f b e t a i n t e r f e r o n s .
Gamma i n t e r f e r o n s a r e
g l y c o p r o t e i n s t h a t a r e l a b i l e a t pH 2.
They have a
m o l e c u l a r w e i g h t o f about 25.000.
Since they have n o t
y e t been p u r i f i e d o r cloned, o u r i n f o r m a t i o n about them
i s more r e s t r i c t e d than f o r alpha o r b e t a i n t e r f e r o n s
(2).
The c l a s s i f i c a t i o n o f i n t e r f e r o n s i s based on t h e
s p e c i f i c i t y o f a n t i s e r a d i r e c t e d a g a i n s t alpha and beta
interferons (useful antisera against g a m interferon
The s p e c i f i c i t y o f t h e sera we
i s n o t y e t available).
used i n our s t u d i e s has been evaluated: t h e a n t i a l p h a
antiserum n e u t r a l i z e s o n l y alpha i n t e r f e r o n s whereas
the antibeta neutralizes only beta interferon; neither
antiserum a f f e c t s t h e t i t e r o f gamma i n t e r f e r o n . When
these a n t i s e r a were used t o c h a r a c t e r i z e t h e i n t e r f e r o n
present i n t h e serum o f SLE p a t i e n t s , we found s i g n i f i c a n t ( f o u r t o 1 2 8 - f o l d ) n e u t r a l i z a t i o n by a n t i a l p h a
i n t e r f e r o n antiserum i n 17 o f t h e 19 SLE samples t e s t ed. Only f o u r SLE i n t e r f e r o n samples were n e u t r a l i z e d
s i g n i f i c a n t l y ( f o u r - e i g h t f o l d ) by a n t i b o d y a g a i n s t
beta i n t e r f e r o n . These r e s u l t s i n d i c a t e d t h a t most o f
t h e i n t e r f e r o n a c t i v i t y i n t h e serum o f SLE p a t i e n t s
was due t o alpha i n t e r f e r o n .
To f u r t h e r support these r e s u l t s , we examined t h e
a c t i v i t y o f t h e i n t e r f e r o n fran t h e serum o f SLE pat i e n t s on bovine (MDBK) c e l l s .
For t h e e i g h t lupus
sera t e s t e d so f a r , t h e a n t i v i r a l a c t i v i t y on MDBK
c e l l s was equal t o t h e a n t i v i r a l a c t i v i t y on human
(GM-2504) c e l l s . Since t h i s i s very c h a r a c t e r i s t i c of
human alpha, b u t n o t beta, i n t e r f e r o n , t h i s experiment,
therefore, c o n f i r m s t h a t most of t h e a n t i v i r a l a c t i v i t y
i n these sera i s indeed due t o alpha i n t e r f e r o n .
The presence o f alpha i n t e r f e r o n i n t h e serum o f
SLE p a t i e n t s has several i m p l i c a t i o n s which may be of
d i a g n o s t i c o r p r o g n o s t i c importance.
The presence o f
alpha i n t e r f e r o n may a l s o bear on t h e c l i n i c a l p i c t u r e
seen i n SLE. P a t i e n t s r e c e i v i n g exogenous alpha i n t e r feron f o r treatment o f v i r a l diseases o r cancer canrnonly have fever, general malaise, muscle pain, and
alopecia. The c r y p t i c growth r e t a r d a t i o n seen i n young
p a t i e n t s w i t h SLE may r e f l e c t t h e i n h i b i t i o n o f c e l l
growth caused by i n t e r f e r o n . I n a d d i t i o n , some o f t h e
remarkable e f f e c t s o f i n t e r f e r o n on t h e immune system,
such as t h e i n h i b i t i o n o f delayed h y p e r s e n s i t i v i t y
INTERFERON PRODUCTION IN SLE
Table 1.
Types o f human i n t e r f e r o n
Inducers
Characteris t i c s
Alpha
be)
Viruses. f o r e i g n c e l l s
b a c t e r i a l products
Stable,
n o t species s p e c i f i c ,
sub types,
protein
Beta
(F)
dsRNA ( s y n t h e t i c o r
host),
viruses
Stable.
species s p e c i f i c .
glycoproteln
Gamma
Antigens, mitogens
Labi 1e,
a lymphokine.
glycoprotein
(T,
imwne.
type 11)
reactions, s t i m u l a t i o n o f a n t i b o d y production, and
a c t i v a t i o n o f NK c e l l s may c o n t r i b u t e t o t h e SLE syndrome.
The presence o f alpha i n t e r f e r o n may p r o v i d e
i n s i g h t i n t o t h e e t i o l o g y o f SLE. Although i t has a l s o
been r e p o r t e d t h a t NK c e l l s produce alpha i n t e r f e r o n i n
response t o f o r e i g n c e l l s o r a f t e r exposure t o b a c t e r i a
o r b a c t e r i a l products, t h e m s t p o t e n t inducers o f
alpha i n t e r f e r o n a r e viruse,s.
Our r e s u l t s may, t h e r e fore, suggest v i r a l i n f e c t i o n d u r i n g t h e course o f SLE
o r i n i t s etiology.
Several previous s t u d i e s have suggested t h a t
i n t e r f e r o n may be r e l a t e d t o r e n a l disease o r a lupus
803
l i k e disease i n mice.
I n j e c t i o n o f antimouse i n t e r feron a n t i b o d y i n t o Swiss mice i n f e c t e d a t b i r t h w i t h
lymphocytic c h o r i o m e n i n g i t i s v i r u s (LCMV), an excel l e n t
i n d u c e r o f i n t e r f e r o n i n mice, was accompanied by a
decrease i n t h e i n c i d e n c e o f g l o m e r u l o n e p h r i t i s .
Conversely, when newborn Swiss mice were t r e a t e d w i t h a
m i x t u r e o f alpha and b e t a i n t e r f e r o n , an immrne complex
type o f g l o m e r u l o n e p h r i t i s developed, which mimicked
t h a t found i n mice c h r o n i c a l l y i n f e c t e d w i t h LCMV ( 3 ) .
I n a d d i t i o n , LCMV i n f e c t i o n a c c e l e r a t e s t h e development
o f SLE i n several mouse s t r a i n s , and a d m i n i s t r a t i o n and
a d m i n i s t r a t i o n o f p o l y I ' p o l y C. a s y n t h e t i c dsRNA
i n t e r f e r o n i n d u c e r a c c e l e r a t e s t h e development o f
disease i n NZB mice.
Thus, t h e d i s c o v e r y o f alpha, and perhaps o t h e r
i n t e r f e r o n s , i n t h e serum o f SLE p a t i e n t s i s i n t r i guing.
T h i s i n t e r f e r o n may r e l a t e t o t h e e t i o l o g y
and/or t h e c l i n i c a l p i c t u r e seen i n human SLE.
REFERENCES
1.
2.
3.
Hooks JJ. Moutsopoulos HM. Geis SA. S t a h l NI, Decker
JL, N o t k i n s AL:
I m n e interferon i n the c i r c u l a t i o n
New Engl J Med
o f p a t i e n t s w i t h autoimnune disease.
301:5-8, 1979
Friedman RM: I n t e r f e r o n s , A P r i m e r . New York h London,
Academic Press, 1981. pp 17-24
Gresser I. Morel-Maroger L, V e r r o u s t P, R i v i e r e Y. G i l l o n JC: A n t i - i n t e r f e r o n g l o b u l i n i n h i b i t s t h e development o f g l o m e r u l o n e p h r i t i s i n mice i n f e c t e d a t b i r t h
w i t h lymphocytic choriomengitis virus.
Proc N a t l Acad
S c i USA 75:3413-3416. 1978
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