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Interleukin-2 deficiency genes and systemic lupus erythematosus.

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838
INTERLEUKIN-2 DEFICIENCY,
GENES, AND SYSTEMIC LUPUS ERYTHEMATOSUS
NORMAN TALAL, MICHAEL J. DAUPHINEE, and DAVID WOFSY
The a b i l i t y o f androgens t o suppress and estrogens
t o a c c e l e r a t e murine lupus o f f e r s an e x p l a n a t i o n f o r
t h e marked female predominance o f systemic lupus erythematosus (SLE). New i n f o r m a t i o n i s presented on t h e
p o s s i b l e mechanisms whereby sex s t e r o i d hormones can
modulate autoimmune disease. The nonlymphoid elements
t h a t h e l p c o n t r o l immune responses, such as thymic
e p i t h e l i u m and c e l l s o f t h e r e t i c u l o e n d o t h e l i a l system,
may be i m p o r t a n t t a r g e t s i t e s f o r sex s t e r o i d hormone
action.
T h i s i s suggested by t h e presence of sex
s t e r o i d hormone r e c e p t o r s on thymic e p i t h e l i u m , and by
t h e a b i l i t y o f sex s t e r o i d hormones t o i n f l u e n c e t h e
clearance o f p a r t i c u l a t e immune complexes.
A l l autoimmune s u s c e p t i b l e mice have a d e f i c i e n c y
o f I n t e r l e u k i n - 2 ( I L - 2 ) , a l s o known as T C e l l Growth
Factor.
I n two s t r a i n s (MRL and C57BL6), t h i s I L - 2
d e f i c i e n c y i s associated w i t h t h e presence o f t h e l p r
gene which i s r e s p o n s i b l e f o r autoimmunity and lymphop r o l i f e r a t i o n . Both MRL-lpr and C57BL6-lpr mice have a
decreased c a p a c i t y t o produce and respond t o IL-2. The
a b i l i t y o f androgen t o a m e l i o r a t e autoimmune disease i n
NZB/NZW F (B/W) mice i s a s s o c i a t e d w i t h maintenance o f
IL-2 a c t k i t y .
These r e s u l t s suggest t h a t I L - 2 i s an
i m p o r t a n t immunoregulatory molecule whose d e f i c i e n c y
may l e a d t o disturbances i n immunologic c o n t r o l mechanisms and perhaps t o immunoregulatory diseases such as
SLE.
SEX STEROID HORMONES
sex
Our l a b o r a t o r y became i n t e r e s t e d i n t h e r o l e o f
f a c t o r s i n autoimmune disease through s t u d i e s
Section o f Immunology and A r t h r i t i s Veterans Administ r a t i o n Medical Center and Department o f Medicine, Univers i t y o f California San Francisco, California
This work was supported by the Veterans Administration,
and by grants from the National I n s t i t u t e s o f Health (AM16140 and AI-15550)
Please address r e p r i n t request t o Nonan Talal, M.D.,
Director, Division o f C l i n i c a l Immunology and A r t h r i t i s ,
Professor o f Medicine and Microbiology, VA Medical Center
and University o f Texas Health Science Center San Antonio,
TX
78229
Arthritis and Rheumatism, Vd. 25, No. 7 (July 1982)
seeking an e x p l a n a t i o n f o r t h e marked female predominance o f SLE. The fema1e:male r a t i o i n SLE can be as
h i g h as 15:l d u r i n g t h e c h i l d b e a r i n g age and decreases
t o 2 : l a f t e r menopause (1). The$e c l i n i c a l observat i o n s suggest a p o s s i b l e r o l e f o r hormonal influences.
F u r t h e r c l i n i c a l evidence suggesting an endocrine
f a c t o r i n t h e pathogenesis o f SLE comes f r a n p a t i e n t s
w i t h K l i n e f e l t e r ' s syndrome, a d i s o r d e r i n which genet i c males develop g y n e c m a s t i a , sparse body h a i r , and
a t times SLE o r myasthenia g r a v i s (2). An a b n o r m a l i t y
o f estrogen metabolism occurs i n K l i n e f e l t e r ' s syndrome
and i n SLE ( 3 ) .
We undertook a s e r i e s o f i n v e s t i g a t i o n s i n B/W
mice t o study t h e e f f e c t s o f sex s t e r o i d hormones on
autoimmune disease.
These mice develop a lupus l i k e
syndrome c h a r a c t e r i z e d by t h e f o r m a t i o n o f a n t i b o d i e s
t o n u c l e i c acids, immune complex g l o m e r u l o n e p h r i t i s and
death from uremia.
Female mice develop t h i s i l l n e s s
several months e a r l i e r than males. Our studies, w e l l
r e p o r t e d i n t h e l i t e r a t u r e ( 4 - 6 ) , c l e a r l y demonstrate
t h a t androgens suppress and estrogens a c c e l e r a t e murine
SLE. These a c t i o n s o f sex s t e r o i d hormones were shown
by f o l l o w i n g several disease parameters i n c l u d i n g
autoantibody l e v e l s , immune complex d e p o s i t s i n t h e
kidney, and s u r v i v a l . The a b i l i t y o f male hormone t o
prolong s u r v i v a l was observed even i n o l d e r mice w i t h
a l r e a d y e s t a b l i s h e d disease ( 6 ) .
I n more r e c e n t years, we have concentrated o u r
e f f o r t s on d e f i n i n g t h e mechanisms by which sex s t e r o i d
hormones modulate murine lupus.
Because immunologic
r e a c t i v i t y i n general i s g r e a t e r i n females than i n
males ( 7 ) , b o t h f o r humns and f o r mice, we have f e l t
frm t h e beginning t h a t t h e sex hormone e f f e c t s i n B/W
mice r e p r e s e n t p h y s i o l o g i c a c t i o n s o f hormones m a n i f e s t
on an a b e r r a n t system o f d i s o r d e r e d immunologic regulation.
I n c o l l a b o r a t i o n w i t h D r . P K S i i t e r i , t h e thymus
glands o f B/W and o t h e r murine s t r a i n s were s t u d i e d f o r
t h e presence o f c l a s s i c a l sex s t e r o i d hormone receptors.
We observed estrogen r e c e p t o r - l i k e b i n d i n g i n
t h e cytoplasm prepared from thymus glands obtained from
b o t h male and female mice o f several s t r a i n s i n c l u d i n g
Balb/c, C57BL, NZB, NZW and B/W (8)_10The $served
b i n d i n g was o f h i g h a f f i n i t y (K = 10
10- M) and
low c a p a c i t y and was s p e c i f i c , a!? i s c h a r a c t e r i s t i c o f
receptor binding.
Furthermore, e s t r a d i o l b i n d i n g was
i n h i b i t e d by d i e t h y l s t i l b e s t r o l b u t n o t by dihydro-
-
IL-2, GENES, AND SLE
839
5c
I NTERLEUKINS
MRL- t/+
MRL- Ipr
I 1
1'2
I
I 4
I
I
I8
1:16
I L - 2 DILUTION
I
1:32
1
1:64
The i n t e r l e u k i n s a r e p o l y p e t i d e products o f mature
o r immature lymphocytes o r macrophages t h a t c o n t r o l
immune r e a c t i v i t y .
As such, they may be considered
immune system hormones.
We have r e c e n t l y become i n t e r e s t e d i n IL-2.
IL-2 i s a lymphokine produced by
mitogen o r a n t i g e n s t i m u l a t e d T c e l l s (12).
I L - 2 has
It
s i g n i f i c a n t T c e l l r e g u l a t o r y f u n c t i o n (13-15).
s t i m u l a t e s thymocyte p r o l i f e r a t i o n , provides h e l p e r
a c t i v i t y f o r a n t i b o d y production,
f a c i l i t a t e s the
i n d u c t i o n o f c y t o t o x i c T c e l l s , and promotes t h e prol i f e r a t i o n o f h e l p e r and c y t o t o x i c T lymphocytes i n
long term c u l t u r e .
We f i n d a d e f i c i e n c y o f I L - 2 i n
several autoimmune s u s c e p t i b l e s t r a i n s o f mice. I n two
s t r a i n s (MRL and C57BL6), t h i s d e f i c i e n c y i s associated
w i t h the presence o f an autoimmune gene c a l l e d l p r
(16).
MRL-lpr mice spontaneously develop autoimmune
disease c h a r a c t e r i z e d by a n t i b o d i e s t o n u c l e i c acids,
immune complex g l o m e r u l o n e p h r i t i s , and death from renal
f a i l u r e (17). They have c e r t a i n unique f e a t u r e s which
make them p a r t i c u l a r l y i n t e r e s t i n g murine models f o r
SLE.
F i r s t , they develop massive g e n e r a l i z e d p e h adenopathy a s s o c i a t e d w i t h p r o l i f e r a t i o n o f L y t - 1 23 T
c e l l s . Second, t h e y e x h i b i t excessive T h e l p e r function.
F i n a l l y , a s i n g l e autosomal r e c e s s i v e gene, l p r ,
i s r e s p o n s i b l e f o r both t h e l y n l p h o p r o l i f e r a t i o n and
severe autoimmunity o f MRL-lpr mice (18).
Several
immunoregulatory a b n o r m a l i t i e s which m i g h t c o n t r i b u t e
t o autoimmunity i n MRL-lpr mice have been i d e n t i f i e d .
Figure 1. IL-2 a c t i v i t y i n culture supernatants derived from
spleen c e l l s O f 5 month old MRL-lpr (0-----0) and MRL-+/+
(@----- 0 ) . The MRL-+/+ mice are identical t o MRL-lpr mice,
but lacking the l p r gene, hence, normal IL-2 activity. Each
point represents the man value o f S i x individual mice. The
dotted l i n e shows the stimulatory effects o f Con A (10 ug/ml)
alone i n the assay.
x
t e s t o s t e r o n e (DHT), progesterone, o r c o r t i s o l . T r e a t ment o f c a s t r a t e d B/W mice w i t h e s t r a d i o l r e s u l t e d i n
t r a n s l o c a t i o n o f t h e cytoplasmic r e c e p t o r t o t h e nucleus. We a l s o found s p e c i f i c b i n d i n g o f DHT i n thymic
cytoplasm from Balbfc, NZB and B/W mice. Thus, t h e r e
appear t o be r e c e p t o r s f o r sex s t e r o i d hormones i n t h e
thymus from several s t r a i n s o f mice, both normal and
autoimmune.
The b i n d i n g a f f i n i t y and s t e r o i d s p e c i f i c i t y o f these r e c e p t o r s a r e c o n s i s t e n t w i t h t i s s u e
estrogen r e c e p t o r s found i n t h e u t e r i o f r a t s and o t h e r
species.
There i s au5oradiographic evidence f o r nuc l e a r c o n c e n t r a t i o n o f H - e s t r a d i o l i n thymic r e t i c u l a r
These r e c e p t o r s suggest t h a t sex
c e l l s of r a t s ( 9 ) .
hormones could i n f l u e n c e immune mechanism by a c t i n g on
thymic e p i t h e l i u m o r on thymocytes.
The thymus may n o t be t h e o n l y s i t e o f sex s t e r o i d
hormone a c t i o n , however. There i s evidence f o r estrogen
s t i m u l a t i o n o f t h e r e t i c u l o e n d o t h e l i a l system (10).
In
recent s t u d i e s w i t h D r . Hannah Shear, we have found
t h a t sex hormones modulate t h e clearance o f IgG and
complement coated autologous mouse e r y t h r o c y t e s i n B/W
mice (11).
Estrogen delays clearance from t h e c i r c u l a t i o n , whereas androgen promotes more r a p i d removal.
These r e s u l t s probably r e f l e c t sex s t e r o i d hormone
e f f e c t s on t h e r e t i c u l o e n d o t h e l i a l system.
z
g
86 - +/+
U
2a
0
V
z
W
-z
0
I
rn
I L - 2 DILUTION
Figure 2 .
IL-2 a c t i v i t y i n culture suprenatants derived
month old C57BL6-lpr (0-----0)
and C67BL6-+/+
mice.
The C57BL6-lpr mice are identical t o
C57BL6-+/+ mice, but having the l p r gene, are deficient i n
IL-2. Each l i n e represents the mean value o f I L - 2 a c t i v i t y
i n four individual mice.
from 3
(0----4)
TALAL ET AL
840
Table 1.
leukin-2
organs*
Production o f i n t e r by
murine
lymphoid
Strain
Spleen
Control
C578L6
CBA
MRL-t/t
BXSB Female
Autoimmune
C57BL6-lpr
MRL-lor
21.1
97.8
29.3
10.0
B/W
1.0
0.7
6.4
BXSB Male
0.8
Lymph node
F i g u r e 3, IL-2 a c t i v i t y was v i r t u a l l y
c o n t r o l mice b u t maintained i n t h e DHT
Such t r e a t e d mice a l s o have preserved
responses t o PHA, l e s s immune complex
prolonged s u r v i v a l .
DISCUSSI O N
10.4
208.8
52.4
20.1
4.4
0.6
4.4
2.5
*IL-2 expressed i n growth promot i o n u n i t s ( v a l u e o f one represents no growth). A l l mice were
females, except as noted, and s i x
months o f age.
To c l a r i f y t h e molecular b a s i s f o r abnormal i m munoregulation i n MRL-lpr mice, we examined t h e a b i l i t y
o f spleen c e l l s t o produce and respond t o I L - 2 ( 1 6 ) .
MRL-lpr mice had a marked d e f e c t i n I L - 2 p r o d u c t i Q n
which was present a s e a r l y as two months, p r i o r t o t h e
onset o f c l i n i c a l disease. By f i v e months o f age, t h e
d e f e c t I n IL-2 p r o d u c t i o n was v i r t u a l l y a b s o l u t e
(Figure 1). The r e d u c t i o n o f I L - 2 a c t i v i t y was independent o f t h e d u r a t i o n o f c u l t u r e o r t h e dose o f
Concanavalin A (Con A ) used t o s t i m u l a t e I L - 2 production.
The d e f e c t was n o t r e l a t e d t o suppressor c e l l s .
We suspected t h a t t h i s IL-2 d e f e c t was r e l a t e d i n
some way t o the l p r gene. To t e s t t h i s hypothesis, we
s t u d i e d C57BL6 mice i n t o which t h e l p r gene was t r a n s f e r r e d by e i g h t c y c l e s o f cross i n t e r c r o s s mating.
These C57BL6-lpr mice develop an autoimmune disease
s i m i l a r t o t h a t o f t h e MRL-lpr c h a r a c t e r i z e d by lymphadenopathy, a n t i n u c l e a r a n t i b o d i e s , and e a r l y m o r t a l ity.
L i k e MRL-lpr mice, C57BL6-lpr mice developed a
d e f e c t i n I L - 2 a c t i v i t y e a r l y i n l i f e which became
p r o g r e s s i v e l y more severe w i t h age.
Although spleen
c e l l s from two month o l d C57BL6-lpr mice produced I L - 2
n o r m a l l y i n response t o Con A, spleen c e l l s from t h r e e
month o l d mice showed a marked r e d u c t i o n i n IL-2 a c t i v i t y ( F i g u r e 2). There was v i r t u a l l y no I L - 2 a c t i v i t y
a t s i x months o f age.
Con A s t i m u l a t e d spleen c e l l s from MRL-lpr and
C57BL6-lpr mice a l s o p r o l i f e r a t e d s i g n i f i c a n t l y l e s s i n
response t o standard IL-2 p r e p a r a t i o n s than d i d spleen
c e l l s from age matched congenic c o n t r o l s , T h i s f a i l u r e
o f spleen c e l l s t o respond t o I L - 2 n o r m a l l y was n o t due
t o a b s o r p t i o n of I L - 2 by MRL-lpr spleen c e l l s .
NZB, B/W and BXSB male mice a l s o have a d e f i c i e n c y
of I L - 2 p r o d u c t i o n which can be demonstrated i n both
spleen and lymph node (Table 1). T h i s a b n o r m a l i t y
develops l a t e r i n these s t r a i n s when compared t o MRLl p r and C57BL6-lpr s t r a i n s ,
We s t u d i e d whether t h e a b i l i t y o f androgen t o
a m e l i o r a t e autoimmune disease i n B/W mice c o u l d be
associated w i t h maintenance o f I t - 2 a c t i v i t y ( 1 9 ) . DHT
was g i v e n by t h e s i l a s t i c i m p l a n t method t o female B/W
mice a t f o u r months of age. IL-2 p r o d u c t i o n by spleen
c e l l s was measured two months l a t e r .
As shown i n
absent i n t h e
t r e a t e d mice.
pro1 i f e r a t i v e
n e p h r i t i s and
The a b i l i t y o f sex s t e r o i d hormones t o a m e l i o r a t e
autoimrmne disease i n B/W m i c e suggested an e x p l a n a t i o n
f o r t h e marked female predominance o f SLE (4-6).
F u r t h e r evidence was p r o v i d e d by L a h i t a e t a1 (3) who
r e p o r t e d t h a t l u p u s p a t i e n t s , l i k e K l i n e f e l t e r pat i e n t s , have an a l t e r a t i o n i n e s t r o g e n metabolism which
r e s u l t s i n a hyperestrogenic i n f l u e n c e .
I t remains t o
be seen whether t h i s r o l e f o r an endocrine component i n
t h e pathogenesis o f SLE can be turned t o t h e r a p e u t i c
advantage. As r e p o r t e d i n t h i s meeting (20), t h e r e i s
some evidence t h a t lupus p a t i e n t s may b e n e f i t from
t r e a t m e n t w i t h danazol.
I t i s i n t e r e s t i n g t h a t thymic e p i t h e l i u m and
r e t i c u l o e n d o t h e l ium may be i m p o r t a n t s i t e s o f a c t i o n
f o r sex s t e r o i d hormones. These two t a r g e t tissues,
a1 though n o t themselves lymphoid, a r e enormously inf l u e n t i a l i n r e g u l a t i n g immune f u n c t i o n .
Thymic e p i t h e l i u m expresses I a a n t i g e n s which p l a y a major r o l e
i n d i r e c t i n g lymphocyte s p e c i f i c i t y and i n i n d u c i n g
helper T c e l l a c t i v i t y .
Thymic e p i t h e l i u m a l s o produces hormones which a r e i n t i m a t e l y i n v o l v e d i n p e r i pheral T c e l l d i f f e r e n t i a t i o n .
Thus, by i n f l u e n c i n g
t h e expression o f I a o r t h e p r o d u c t i o n o f thymic hormones, sex s t e r o i d s c o u l d e x e r t i n f l u e n c e on t h e immune
'"1
-.=
%
e
50L
L
P
9
i
10
r ! 5
5
'
Spleen LN
2 Month
Spleen LN
6 Month
Spleen LN
spleen LN
6 Month
+
6 Monfh
DHT
DHT
(1 Implant)
+
(2 Implants)
F i g u r e 3.
I L - 2 a c t i v i t y i n c u l t u r e supernatants d e r i v e d
from DHT implanted B/W female mice ( a l l s u r g i c a l implants
were p e r f o n e d two months b e f o r e k i l l i n g ) .
Spleen and lymph
node c e l l s from mice implanted w i t h 1 o r 2 i m p l a n t s (1.5 cm
i n l e n g t h ) produced more IL-2 t h a n non-OHT implanted sham
mice. Each group c o n s i s t e d o f a mean value from s i x o r m r e
pooled mice.
IL-2, GENES, AND SLE
response a t several l e v e l s . Likewise, immune complexes
combine w i t h lymphocyte o r mcrophage Fc receptors, f i x
complement and induce inflammatory events.
Effects o f
sex s t e r o i d hormones on immune complex clearance b y
c e l l s of t h e r e t i c u l o e n d o t h e l i a l system would a l s o have
i m p o r t a n t immu n o r egu 1a t o r y a c t i o n s ,
Our s t u d i e s on I L - 2 were undertaken i n a cont i n u i n g e f f o r t t o f i n d b e t t e r and more s p e c i f i c ways t o
r e s t o r e immunologic r e g u l a t i o n and t u r n o f f autoimmune
processes. We found a d e f i c i e n c y o f I L - 2 i n a l l autoimmune mice.
T h i s IL-2 d e f i c i e n c y , along w i t h a decreased syngeneic mixed lymphocyte response (SMLR), a r e
c m m n features o f murine lupus (21). The SMLR r e p r e sents t h e response o f l y t - 1 23- c e l l s t o I a a n t i g e n s
presented by macrophages and perhaps o t h e r non T c e l l s .
The SMLR i s decreased i n MRL-lpr b u t n o t MRL-+/+ mice,
i n BXSB male b u t n o t female mice, and i n o l d e r NZB and
B/W mice.
An analogous response (autologous MLR) i s
depressed i n many human autoimmune d i s o r d e r s i n c l u d i n g
SLE (22).
These two a b n o r m a l i t i e s (decreased I L - 2 and
decreased SMLR) a r e probably r e l a t e d because I L - 2 i s
normally produced d u r i n g t h e SMLR and a c t s t o s t i m u l a t e
proliferation.
We suspect t h a t these t w i n immune def e c t s r e f l e c t i m p o r t a n t immunoregulatory d i s t u r b a n c e s
associated w i t h autoimmunity.
The r e l a t i o n s h i p o f I L - 2 d e f i c i e n c y t o t h e l p r
gene i n two s t r a i n s which subsequently develop SLE i s
most i n t r i g u i n g .
I t suggests a r e l a t i o n s h i p between
IL-2 d e f i c i e n c y and an autosomal r e c e s s i v e gene t h a t i s
r e s p o n s i b l e f o r murine lupus. We a r e c u r r e n t l y studyi n g the nature o f t h i s relationship. I n addition, the
a b i l i t y o f androgen t o m a i n t a i n I L - 2 a c t i v i t y i n B/W
mice suggests a r e l a t i o n s h i p between t h e b e n e f i c i a l
e f f e c t s o f male hormone and T C e l l Growth Factor.
Our s t u d i e s should be seen i n t h e broad c o n t e x t o f
a f i e l d t h a t m i g h t be c a l l e d immunoendocrinology ( 2 3 ) ,
r e p r e s e n t i n g an i n t e r f a c e between t h e o t h e r w i s e separ a t e d i s c i p l i n e s o f i m u n o l ogy and endocri no1ogy.
We
have focused a t t e n t i o n on two aspects o f t h a t overlap:
1) t h e modulation o f autoimmune disease by c l a s s i c a l
sex s t e r o i d hormones, and 2) t h e r e l a t i o n s h i p o f t h e
c l a s s i c a l endocrine system t o t h e immune system.
Indeed, I L - 2 i t s e l f , being a growth f a c t o r , can be
considered an immune system "hormone".
I n t e r a c t i o n s between t h e immune and endocrine
systems a r e n o t l i m i t e d t o endocrine i n f l u e n c e s on
immnity b u t i n c l u d e immunologic modulation o f hormone
receptors, e.g.,
i n s u l i n receptors, lymphocytic regul a t i o n o f o s t e o c l a s t a c t i v i t y and bone metabolism, and
thymic a c t i v i t y as an endocrine organ. The presence o f
s t e r o i d s e n s i t i v e r e c e p t o r s i n t h e hypothalamus r a i s e s
t h e p o s s i b i l i t y t h a t neuroendocrine pathways a l s o
i n t e r a c t w i t h t h e immune sytem. Neuroendocrine influences superimposed upon t h e i m u n e and endocrine
systems would c r e a t e pathways by which t h e b r a i n c o u l d
c o n t r o l c e r t a i n immunologic f u n c t i o n s .
Evidence i s
accumulating t o support a r o l e f o r neuroendocrine
f a c t o r s i n immunity (24,25), which might account f o r
r e p o r t s r e l a t i n g s t r e s s t o t h e development o f autoimmune diseases (26).
The m u l t i f a c t o r i a l n a t u r e o f autoimmune disease
may a t times seen complicated and confusing. However,
these many f a c t o r s a l s o o f f e r o p p o r t u n i t i e s f o r new
t h e r a p e u t i c approaches based on mechanisms which,
although o u t s i d e t h e c l a s s i c a l immune system, may
nevertheless r e s t o r e immune r e g u l a t i o n and a m e l i o r a t e
disease.
84 I
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