Monoclonal lupus autoantibodies

Abstract

The autoimmune syndrome o f systemic lupus erythema t o s u s (SLE) encompasses a d i v e r s i t y o f c l i n i c a l and immunological a b n o r t n a l i t i e s , some o f which remain as b a f f l i n g today as t h e y were twenty y e a r s ago. The d i s o r d e r should, we b e l i e v e , be regarded as a syndrome because i t may e i t h e r a r i s e spontaneously, e r u p t a f t e r exposure t o u l t r a v i o l e t l i g h t , o r develop d u r i n g t r e a tment w i t h a v a r i e t y o f drugs.I t can, moreover, v a r y i n c l i n i c a l s e v e r i t y from m i l d a r t h r a l g i a t o r a p i d l y p r o g r e s s i v e g l o m e r u l o n e p h r i t i s .A f e a t u r e commn t o a l l forms o f t h e l u p u s syndrome i s t h e presence o f a n t i b o d i e s t o one o r more c o n s t i t u e n t s o f t h e c e l l nucleus, i n c l u d i n g DNA ( e i t h e r s i n g l e strarlded DNA sDNA , double s t r a n d e d DNA dsDNA o r both), n u c l e op r o t e i n s , and h i s t o n e s . I n a d d i t i o n , o t h e r a n t i b o d i e s may a r i s e :autoimmune h e m o l y t i c anemia, thrombocytopenia, l u p u s a n t i c o a g u l a n t s , and b i o l o g i c a l l y f a l s e p o s i t i v e t e s t s f o r s y p h i l i s a r e common problems.The o r i g i n s o f l u p u s a u t o a n t i b o d i e s a r e unknown. Whether n u c l e i c a c i d s themselves p r o v i d e t h e immunizing s t i m u l u s remains e n i g m a t i c , e s p e c i a l l y because dsDNA i s a v e r y weak immunogen --even i n experimental a n i m a l s t h a t a r e g e n e t i c a l l y programmed t o produce anti-DNA a n t i b o d i e s spontaneously ( 1 ) . D e f i c i e n c i e s o f T lymphocyte f u n c t i o n , n o t a b l y t h o s e o f suppressor c e l l s , have been i m p l i c a t e d i n SLE (2). b u t t h e y l a c k t h e s p e c i f i c i t y t h a t corresponds t o t h e s p e c i f i c i t y o f l u p u s a u t o a n t i b o d i e s and t h e i r p r e d i l e c t i o n f o r n u c l e a r c o n s t i t u e n t s . Moreover, t h e presence o f i d e n t i c a l a b n o r m a l i t i e s i n some c l i n i c a l l y normal, s e r o n e g a t i v e r e l a t i v e s o f p a t i e n t s w i t h SLE ( 3 ) argues t h a t i m p a i r e d f u n c t i o n o f suppressor lymphocytes does n o t , by i t s e l f , i n s t i g a t e t h e p r o d u c t i o n o f l u p u s a u t o a n t i b o d i e s .Many o f t h e p u z z l i n g aspects o f SLE would be c l a r i f i e d by d e t a i l e d analyses o f t h e immunochemistry of l u p u s a u t o a n t i b o d i e s .Such work, however, has been hampered by t h e f o r m i d a b l e t e c h n i c a l problem o f separ a t i n g i n d i v i d u a l a n t l b o d i e s from t h e complex m i x t u r e of a n t i b o d i e s i n l u p u s serum. The i s o l a t i o n o f i n d i v idual a n t i b o d i e s i s e s s e n t i a l t o d i s t i n g u i s h t r u e speci f i c i t y from t h e c r o s s r e a c t i o n s o f m i x t u r e s o f...