selective compartmental dominance

8/3/2019 Selective Compartmental Dominance

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Medical Hypotheses (1998) 50, 67-80 Harcourt Brace & Co Ltd 1998

S e le c tiv e c o m p a r t m e n t a l d o m in a n c e : a nexp lanat ion for a non in fec t ious , mul t i fac tor ia le t io l o g y fo r a cq u i re d i m m u n e d e f ic ie n c ys y n d r o m e ( A ID S ), an d a r a tio n a l e f o r o z o n et h e ra p y a n d o th e r i m m u n e m o d u l at in gt he ra p ie sF. SHALLENBERG ER1524 M ain Street, Ga rdne rvi l le, N V 89410, U SA (Tel ' . 702 782 4164; Fax: 702 782 4183)

Abst rac t - - The mos t w ide ly accepted e t i o log ica l exp lanat ion for acqu i red immune def i c iencysyndrome (A IDS) cur rent l y i nvokes an in fec t i ous model i nvo lv ing the humanimm uno def i c ien cy v i rus (HIV) . Because th i s i n fec t ious mod el has fa i led to m eet anyconven t iona l c r ite r ia for es tab l i sh ing m ic rob ia l causat ion, th i s theory s t i l l re li es on the h igh,tho ug h n ot per fect , s tat is t ical correlat ion l ink ing presence o f HIV ant ibo dies wi th p at ientsd iagnosed wi th , and a t ri sk for the syndrom e. M an y scient is ts and c l in i c ians no w do ub t theHIV theo ry , thoug h, and propose ins tead a mu l t ifac tor ia l causat ion s im i la r to that seen incancer and h ear t d isease. In ord er to discard the HIV mod el , ho we ver , i t is necessary toexp la in the h igh s ta t i st ica l cor re la t i on me nt ioned above. Recent s tud ies i nvo lv ing ce l l u larmed ia ted imm un i ty and cy tok ine mod ula t i on ma y exp la in th i s sta ti s ti ca l re la t i onsh ip w i tho utthe need to i nvoke in fec t ious causat ion, by sugges t ing cer ta in func t iona l charac ter i s ti cs andfeedback loops in the immune sys tem which the author ca l l s se lec t i ve compar tmenta ldom i nanc e ( S CD). S CD p r ov ides a m ode l i n wh i c h c h r on i c dom i nanc e o f the h um o r a li m m u ne c om par tm e n t s ec ondar y t o c h r on ic h i gh -dos e an t i gen ic c ha l lenge r es u lt s i n c h ron i csuppress ion o f the ce l lu lar imm un e com par tm ent . Th is mod el pred ic ts that even HIV-negat i veme mb ers o f the r isk gro up s are suscept ib le to AIDS, ass igns no special causal ro le for HIV inA IDS, and sugges ts a ra t i ona l course o f n ontox i c thera py that can po tent ia l l y reverse cases inthe ear l ier s tages.I n t r o d u c t i o nT h e acq u i r ed i m m u n e d e f i c i en cy s y n d r o m e ( A I D S )of f ic ia l ly inc ludes 25 d i f f er en t conven t iona l d i seases

t h a t a re d i ag n o s ed a s ' A I D S ' w h e n t h ey p re s en t inp a t i en t s w h o a r e p o s i t i v e f o r H I V an t i b o d i e s an dh av e an i n v e r t ed C D 4 / C D 8 r a t i o . T h e m o s t w i d e l yaccep t ed e t i o l o g i ca l ex p lan a t i o n f o r A I D S cu r r en tl yDate received 16 April 1996Date accepted 24 October 1996 67


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68 M E D I C A L H Y P O T H E S E S

i n v o k e s a n i n f e c t i o u s m o d e l i n v o l v i n g t h e h u m a ni m m u n o d e f i c i e n c y v i r u s ( H I V ) . B e c a u s e t h i s i n f e c -t i o u s m o d e l h a s f a i l e d t o m e e t K o c h ' s p o s t u l a t e sand o ther d i rec t c r i t e r i a for es t ab l i sh ing microbia lcausa t ion , the major suppor t for th i s theory i s thehigh , tho ugh not pe r fec t , s t a t i st i ca l cor re la t ion link ingA I D S a n d r i sk o f A I D S w i t h H I V a n t i b o d y - p o s i t iv i t y ,A I D S w i t h l e u k o p e n i a o f a c la s s o f i m m u n e c e l l s ( T 4 )tha t HIV infec t s , and AIDS p a t i en t s wi th each o ther .However , H1V does not k i l l ce l l s in cu l ture , i tt ransmi t s s exua l ly and parente ra l ly only wi th grea td i f f i cu l ty , i t in fec t s only 1 in 5- 10 x 103 ce l l s, and i spresent only in t race concent ra t ions in the averageAIDS pa t i en t (1-6) . In addi t ion , HIV pos i t iv i ty i s nom o r e p r e v a l e n t a m o n g A I D S p a t i e n t s t h a n p o s i t i v i t yf o r m a n y o t h e r l a t e n t v i r u s e s , a n d A I D S r e m a i n sa b o u t 9 7 % c o n f i n e d t o t h e o r i g in a l r is k g r o u p s ( 7 - 1 0 ) .F u r t h e r m o r e , A I D S o c c u r s e v e n i n H I V - n e g a t i v e i n d i -v i d u a l s ( 1 1 - 1 3 ) . L a s t l y , t h e e r a d i c a t i o n o f H I V b yant iv i ra l medica t ion fa i l s to a l t e r the u l t imate pro-g r e s si o n o f t h e s y n d r o m e . F o r t h e s e a n d o t h e r r e a so n s ,m a n y s c i e n t i s t s a n d c l i n i c i a n s n o w d o u b t t h e H I Vt h e o r y ( 1 4 - 1 6 ) , a n d p r o p o s e i n s t e a d a n o n c o n t a g i o u s ,mul t i fac tor i a l causa t ion s imi la r to tha t s een in cancerand hea r t d i s ease .The mul t i fac tor i a l v iew recognizes the fac t tha t theH I V - A I D S c o r r e l a ti o n is n o b e t t e r t h a n t h e s t at is ti c a lc o r r e l a t i o n s l i n k i n g A I D S w i t h l o n g - t e r m c h r o n i cimmune s t imula t ion as soc ia ted wi th in t ravenous druguse ( IVDU), mul t ip le t rans fus ions , s emina l inocula -t ion , mu l t ip le bac te r i a l in fec t ions , pa ras it i c infec t ions ,t o x i c b o w e l s y n d r o m e s , a n d d r u g s ( 1 7 ) . H o w e v e r ,i n o r d e r t o d i s c a r d t h e H I V m o d e l , i t i s n e c e s s a r yto present a mode l tha t expla ins how the s t a t i s t i ca lc o r r e l a t i o n s b e t w e e n H I V s e r o p o s i t i v i t y a n d t h es u b s e q u e n t d e v e l o p m e n t o f A I D S c a n o c c u r w i t h o u tinvoking causa t ion . In th i s paper the au thor present ss u c h a m o d e l , w h i c h h e c a l ls s e l e c t i v e c o m p a r t m e n t a ld o m i n a n c e ( S C D ) . T h e S C D m o d e l p r e d i c t s t h a t t h ep r i m a r y e t i o l o g ic a l e v e n t in t h e d e v e l o p m e n t o f A I D Si s a f a i lu r e o f a n a d e q u a t e c e l l u l a r m e d i a t e d i m m u n er e s p o n s e w h i c h i s a t t r i b u t e d t o t h e s u m m a t i o n o fvar ious c l in ica l and l i fes ty le fac tors . Thi s c ondi t ionthen resu l t s in an inc rease in ex t race l lu la r an t igenwhich wi l l i n turn ac t iva te the humora l response .T h e a c t i v a t e d h u m o r a l r e s p o n s e i n d u c e s c y t o k i n e stha t exer t a nega t ive fe edba ck to the ce l lu la r media tedresponse (18 ,19) , thus resu l t ing in even fur the r sup-pres s ion o f the ce l lu la r sys tem. Thi s c rea tes a v ic iouscyc le which resu l t s in the progres s ive de te r iora t iono f t h e c e l l u l a r s y s te m i n t h e f a c e o f a h y p e r - a c t i v a t e dh u m o r a l s y s t e m s o w e l l d e s c r i b e d a s a h a l l m a r ko f A I D S . T h e p r o g r e s s i v e l o s s o f c e l l - m e d i a t e di m m u n i t y ( C M I ) o c c u r s a s a c o n s e q u e n c e o f t h ei n h i b i to r y e f f e c t o f c y t o k i n e s t h a t a r e r e l e a s e d w h e n

a n t i b o d y - m e d i a t e d i m m u n i t y ( A M I ) i s c h r o n i c a l l ya c t iv a t e d . S C D e x p l a i n s h o w H I V s e r o p o s it i v it y m a yb e n o t h i n g m o r e t h a n a n e x c e l l e n t b u t a r b i t r a r ym a r k e r f o r t h o s e i n d i v i d u a l s w h o f o r t h e r e a s o n sm e n t i o n e d a b o v e a r e i n a s ta t e o f c h r o n i c A M Iac t iva t ion .

Selective compartmental dominanceCompartmentalT h e i m m u n e s y s t e m i s e s s e n t i a l l y c h a r g e d w i t h t w of u n c t io n s : f ir s t t o d i s c r im i n a t e ' s e l f f r o m ' n o n - s e l f 'a n d s e c o n d t o e l i m i n a t e t h o s e m o l e c u l e s a n d c e l ls t h a ta r e d e t e rm i n e d t o b e ' n o n - s e l f ' . I n o r d e r to a c c o m -p l i s h t h e s e t a s k s t h e h u m a n o r g a n i s m h a s e v o l v e ds e v e r a l k n o w n s y s t e m s w h i c h h a v e d i s ti n c t f u n ct i o n s.T h e w o r d ' c o m p a r t m e n t a l ' i n S C D r e f e r s t o t w o o ft h e s e s y s t e m s o r c o m p a r t m e n t s : t h e c e l l u l a r c o m p a r t -m e n t k n o w n a s c e l l u l a r m e d i a t e d i m m u n i t y ( C M I ) ,a n d t h e h u m o r a l c o m p a r t m e n t k n o w n a s a n t i b o d y -m e d i a t e d i m m u n i t y ( A M I ) . T h e c e l lu l a r c o m p a r t m e n ti s so named because i t uses ce l l s to des t roy pr imar i lyin t race l lu la r an t igens and o ther ce l l s . Thi s i s ind i s t i n c t i o n t o t h e h u m o r a l c o m p a r t m e n t w h i c h u s e sant ibodies to des t roy ex t race l lu la r an t igens . Thus i ti s t h e s o l e d e d i c a t e d f u n c t i o n o f C M I t o r e s p o n d t oand e radica te an t igens tha t a re in t race l lu la r because ,a l t h o u g h A M I m a y b e a b l e t o l i m i t t h e p r o p a g a t i o nof in t race l lu la r infec t ions , i t cannot in fac t e l imina tet h e m . S i m i l ar l y , it i s th e f u n c t i o n o f A M I t o r e s p o n dto and e radica te an t igens tha t a re ex t race l lu la r (20) .I n a l l b u t t h e m o s t t e r m i n a l o f A I D S p a t ie n t sthe an t ibody response i s h ighly ac t ive , main ta in inge l e v a t e d l e v e ls o f a n t i b o d i e s n o t ju s t f o r H I V b u tf o r m a n y o t h e r m i c r o b e s , a n d t h e c e l l u l a r r e s p o n s ei s suppres sed , pe rmi t t ing the expres s ion of a va r i e tyof in t race l lu la r infec t ions , inc luding HIV, Eps te in-B a r r v i r u s ( E B V ) , c y t o m e g a l o v i r u s ( C M V ) , m y c o -b a c t e r i u m , p n e u m o c y s t i s , a n d o t h e r s . T h u s , i n t h e s epa t i en t s the re i s a charac te r i s ti c hyp ofun c t ion of theC M I i n t h e f a c e o f a h y p e r f u n c t i o n i n g A M I r e s p o n s e(21 ,22) .SelectiveFigure 1 shows a d iagram tha t of fe rs a s impl i f i edo v e r v i e w o f w h a t m a y t r a n s p i r e i n t h e r e c o g n i t i o na n d e l i m i n a t io n p h a s e s o f t h e s e t w o c o m p a r t m e n t s o ft h e i m m u n e s y s t e m . T h e p r o c e s s s t a r t s w i t h t h e r e -c o g n i t i o n o f t h e a n t i g e n b y t h e a n t i g e n - p r e s e n t i n gc e l l ( A P C ) . T h e S C D m o d e l h y p o t h e s i z e s t h a t t h eA P C t h e n p r o c e s s e s t h e a n t i g e n i n s u c h a w a y t h a tu n d e r t h e i n f l u e n c e o f i n t e rl e u k i n - 1 ( I L - 1 ) a n d t u m o rn e c r o s i s f a c t o r ( T N F ) i t p r e d o m i n a n t l y s t i m u l a t e s


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SELECTIVE COMPARTMENTAL DOMINANCE 69

e i t h e r t h e a c t i v i ty o f t h e C D 4 - T H 1 c l as s o f h e l p e rc e l ls ( C M I ) o r t h e C D 4 - T H 2 c l a ss ( A M I ) . I n t h e c a s eof an t igens tha t : (a ) present as a smal l inoculumand/or a s lowly v i ru len t organi sm, or (b) a re in t ra -ce l lu la r or ce l lu la r an t igens , i t i s p roposed tha t theA P C w o u l d s e l e c t i v e l y s t i m u l a t e t h e C D 4 - T H 1 c e l ll in e . S u c h w o u l d b e t h e c a s e , f o r e x a m p l e , w i t h f u n g a linfec t ions , pro tozoa l infec t ions , v i ra l in fec t ions ,ce r t a in bac te r i a l in fec t ions , and neoplas t i c ce l l s .The fac t tha t smal l inocula s e lec t ive ly ac t iva te anda r e s u b s e q u e n t ly d e s t r o y e d b y C M I w i t h o u t e v o k i n ga n A M I r e s p o n s e e x p l a i n s h o w p a t i e n t s w h o a r ei n f e c t e d w i t h H I V a n d o t h e r i n f e c t i o u s a g e n t s m a yr e m a i n a n t i b o d y - n e g a t i v e f o r t h o s e a g e n t s ( 2 3 , 2 4 ).In the case of an t igens tha t : (a ) present as a l a rgei n o c u l u m a n d / o r a r e r a p i d l y v i r u le n t , o r ( b ) a r e n o n -infec t ious ex t race l lu la r an t igens such as pol l ens ,pe t rochemica l s , d rugs , e t c . , o r (c ) a re pa ras i t e s (2) , i ti s p roposed tha t the APC se lec t ive ly s t imula tes theC D 4 - T H 2 c e l l l i n e . T h i s p r o p o s e d d i s c r i m i n a t i n gf u n c t i o n o f th e A P C i s a fu n d a m e n t a l c o n c e p t o f S C Dwi th imp or tan t impl ica t ions , and i s re fe r red to byt h e w o r d ' s e l e c ti v e ' i n S C D . O n c e e i t h e r t h e C D 4 -T H 1 o r t h e C D 4 - T H 2 h e l p e r c e l l s a r e a c t i v a t e d a n ds t imula ted by the APC according to th i s c r i t e r i a ,t h e y t h e n b e g i n t o f u r t h e r s t i m u l a t e t h e r e s t o f t h ec o m p a r t m e n t . I n t h e c a s e o f t h e c e l lu l a r c o m p a r t m e n t ,CD4-TH1 ce l l s s t a r t s ec re t ing the cy tokines in te r -l e u k i n - 2 ( I L - 2 ) a n d g a m m a - i n t e r f e r o n ( g - I F N ) . I L - 2s t imula tes and regula tes the func t ion of the CD8c y t o t o x i c c e ll s ( C D 8 - C T ) w h i c h a r e s p e c i fi c , a n dw h i c h t h e n c o m m e n c e t o d e s t r o y t h e a n ti g e n t h a t w a so r i g i n a l l y p r o c e s s e d b y t h e A P C . L i k e w i s e , g - I F Ns t imula tes the func t ion of the na tura l k i l l e r l ineof ce l l s (NK) , and in th i s way s t imula tes the inna tei m m u n e s y s t e m ( 1 8 - 2 0 ) . B o t h t h e C D 8 - C T a n d t h eN K c e l l s , a l t h o u g h t h e y e x h i b i t m a n y d i f f e r e n c e s ,share in com m on the ab i l i ty to be c ida l to ac tua l ce ll s ,and a re thus ab le to des t roy neoplas t i c ce l l s and ce l l stha t a re infec ted wi th in t race l lu la r v i rus . Thi s i s ind i s ti n c t io n t o t h e a n t i b o d i e s p r o d u c e d b y t h e h u m o r a lc o m p a r t m e n t w h i c h a r e o n l y c a p a b l e o f d e s t r o y i n gext race l lu la r an t igens , and thus cannot e rad ica te v i ra linfec t ions (1) . S imi la r ly , in the case of the humo ra lcompar tm ent , ac t iva ted CD4-T H2 ce l l s begin to s ec re tethe cy tokines in te r l eukin-4 ( IL-4) and in te r l eukin-10( IL-10) . IL-4 in turn s t imula tes and regula tes theB - c e l l s w h i c h u l t i m a t e l y r e s u l t i n t h e p r o d u c t i o n o fant ibodies , which a re spec i f i c and which wi l l t hendes t roy the an t igen tha t was or ig ina l ly proces sed b y theA P C ( 1 8 - 2 0 ) . T h u s t h e c o n c e p t o f s e l e c ti v i ty , r e f e r -r ing to the pre fe rent i a l s t imula t ion o f e i the r the ce l lu la ro r t h e h u m o r a l c o m p a r t m e n t d e p e n d i n g o n t h e t y p e o fant igen , i s cent ra l to SCD. T here i s ample ev idenc e tosugges t tha t th i s type o f s e lec t iv i ty in fac t occurs .

Dominance

T h e w o r d ' d o m i n a n c e ' i n S C D r e f e r s t o t h e c r o s s -regula t ing charac te r i s t i c s of those cy tokines whichare s e lec t ive ly s ec re ted in the ac t iva t ion of one com-p a r t m e n t a n d s i m u l t a n e o u s l y e x e r t a s u p p r e s s i v ea c t i o n o n t h e o t h e r c o m p a r t m e n t . T h u s o n c e t h eCD 4-TH 1 ce l l l i ne i s s e l ec t ive ly s t imula ted andb e g i n s t o s e c r e t e g - I F N a n d I L - 2 , t h e s e c y t o k i n e sn o t o n l y f u n c t i o n t o f u r t h e r p r o li f e r a te C M I b u t a l s oe x e r t a n e g a t iv e o r d o w n r e g u l a t in g e f f e c t o n C D 4 -T H 2 c e l l s (F i g . 1 ). L i k e w i se , o n c e t h e C D 4 - T H 2 c e l ll ine i s s t imula ted and begins to s ec re te IL-4 and IL-l 0 , t h e s e c y t o k i n e s n o t o n l y p e r f o r m t h e i r a c t iv a t i n gf u n c t i o n s o n A M I b u t a l s o e x e r t a n e g a t iv e o r d o w n -regula t ing e f fec t on C D4-T H1 ce l l l i nes (F ig . 1)( 1 8 , 1 9 ) . T h i s e x p l a i n s w h y h i g h a n t i b o d y l e v e l sc o r r e l a te n e g a t i v e ly w i t h C M I r e s p o n s e ( 2 5 - 2 7 ) . I t isp o s t u l a te d t h a t t h i s n e g a t i v e f e e d b a c k s y s t e m o c c u r si n o r d e r t o m a i n t a i n p r e f e r e n t i a l a c t i v a t i o n o f o n ec o m p a r t m e n t o f t h e im m u n e s y s t e m o v e r th e o t h e r inorde r to have a m ore e f f i c i en t to ta l response . As th i sc o o r d i n a t e d d a n c e p r o g r e s s e s , d o m i n a n c e b e t w e e nt h e t w o c o m p a r t m e n t s c a n s w i t c h b a c k a n d f o r t h a sant igen concent ra t ions f luc tua te . For example , a l a rgei n o c u l u m o f v i r u s m a y f i r s t s e l e c t i v e l y s t i m u l a t ea n A M I r e s p o n s e , a n d t h e n w h e n t h e a n t i g e n c o n c e n -t ra t ion fa l l s , s e l ec t ive ly s t imula tes a CMI response .The SCD mode l sugges t s many o ther in te res t ingscenar ios . For example , a smal l inoculum of a v i rust h a t w o u l d n o r m a l l y s e l e c t i v e l y e l i c it a C M I r e s p o n s ec o u l d i n s t ea d t r i g g e r an A M I r e s p o n s e i f th e A M Ic o m p a r t m e n t w a s a l r e a d y a c t i v a t e d b y a c h r o n i cp a r a s it i c i n f e c t io n a n d w a s h e n c e t h e d o m i n a n tc o m p a r t m e n t .S i n c e t h e c e l l u l a r c o m p a r t m e n t i s t h e s e l e c t i v e l ya c t i v a t e d c o m p a r t m e n t i n t h e c a s e o f s m a l l i n o c u l a(23 ,24 ,28-30) , i t i s reasonable to as sume tha t th i sc o m p a r t m e n t s e r v e s a s t h e p r i m a r y o r f i r s t l i n e a r mo f t h e im m u n e r e s p o n s e , a n d t h a t i n n o r m a l h o m e o -s t a t i c c o n d i t i o n s i t e x e r t s a p r i m a r y d o m i n a n c e o v e rA M I . T h e r e i s c l i n i c a l a n d e x p e r i m e n t a l e v i d e n c eto suppor t th i s s t a t ement (23 ,29 ,31-33) . Impl ic i t ,h o w e v e r , i n t h e c r o s s - r e g u l a t i n g c o n c e p t o f d o m i -n a n c e i s t h a t w h e n t h e h u m o r a l c o m p a r t m e n tb e c o m e s a c t i v a t e d a c c o r d i n g t o t h e c r i t e r i a g i v e nabove , i t w i l l s ec re te cy tokines tha t wi l l suppres st h e c e l l u l a r c o m p a r t m e n t ( 2 6 , 2 7 , 3 0 , 3 4 ) . S h o u l d t h ea n t i g e n e x p o s u r e b e s u f f i c i e n t l y e x c e s s i v e a n d / o rm a i n t a i n e d f o r a l o n g e n o u g h t im e , a s w i t c h in g f r o ma p h y s i o l o g i c a l C D 4 - T H 1 C M I d o m i n a n c e t o ap a t h o l o g i c a l C D 4 - T H 2 A M I d o m i n a n c e m a y o c c u r( 1 8 , 1 9 ) . I n d e e d , t h e S C D m o d e l s u g g e s t s t h a t w h e nt h i s s w i t c h i n g p h e n o m e n o n o c c u r s , w h i c h I w i l ld e s i g n a te a s ' p h a s e o n e ' o f t h e s y n d r o m e , i t m a y v e r y


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7 0 M E D I C A L H Y P O T H E S E S

1. Sm all inoculum and/or slowlyvirulent virus and bacterium.2. Fungus3. Protozoa4. Neoplasia

TN F1L-1

1. Large inoculum and /or rapidlyvirulent virus and bacterium2. N oninfectious antigen3. Parasite

TN FIL-1

Activate NK cells;Inhibit cancercell replic ation ; ,11Inhibit intracellularviral replication

gamma-IFN

IL-2

Kills infected cells and hencecontrols replication of virus

IL-4, IL-10negative feedbackIL-2, gamma-IFNnegative feedback

IL-4

Antibodies and CIC1) Inhibit Recep tors2) Kill free virus3) Interfere with APC functionFig. 1 Outline of the interregulatory relationships between the cellular and the humoral compartments of the imm unesystem.

l i k e l y b e t h e s i n g l e , i n i t i a t i n g e v e n t i n a c a s c a d eo f p a t h o g e n i c e v e n t s l e a d i n g t o t h e f u l l e x p r e s s i o no f A I D S ( F i g . 2 ) .

S e le c ti v e c o m p a r t m e n t a l d o m i n a n c e a n d A I D SI n t h e ir e x c e l l e n t r e v i e w o f t h e i m m u n e s y s t e md y s r e g u l a ti o n fo u n d i n A I D S , E d e l m a n a n d Z o l l a -P a z n e r s t a t e , ' D e s p i t e o u r l i m i t e d k n o w l e d g e , t h e r ei s e v i d e n c e th a t s u p p r e s s o r m e c h a n i s m s , v i a n o r m a l

r e g U l a to r y o r a b n o r m a l p a t h w a y s , p l a y a r o l e i n t h ei m m u n e d y s f u n c t i o n s s e e n in H I V i n f e c t i o n a n dA I D S ' . T h e s e r e s e a r c h e r s c a l l f o r a n e ti o l o g i c a lh y p o t h e s i s t h a t i n v o l v e s n o r m a l r e g u l a t o r y m e c h a -n i s m s i n r e s p o n s e t o i m m u n e s t i m u l a t i o n t o a c c o u n tf o r th e d e v e l o p m e n t o f a b n o r m a l i m m u n e f u n c t io ni n A I D S ( 3 5 ). S C D o f f e r s s u c h a h y p o t h e s i s .

U s i n g t h is m o d e l , t h e e r o s i o n o f i m m u n i t y s e e ni n A I D S c a n b e p o s t u l a t e d to o c c u r i n t h r e e p h a s e s( F i g . 2 ) . I n ' p h a s e o n e ' , a s a r e s u l t o f f a c t o r s w h i c he i t h e r d i r e c t l y s u p p r e s s C M I a n d / o r s e l e c t i v e l y s ti m u -


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S E L ~ C OM PA RT ME NT AL D OM IN AN CE 71

l a te A M I s e c o n d a r y t o t h e c h r o n i c a n ti g e n i c e x p o s u r es o c o m m o n l y f o u n d i n ' A I D S r i s k ' c o n d i t i o n s a n dl i fe s t y le s , h o m e o s t a t i c d o m i n a n c e s w i t c h e s f r o m C M It o A M I v i a n o r m a l r e g u l a t o r y p a t h w a y s . I n t h i ss t age , pa t i en t s wi l l be c l in ica l ly hea l thy , wi l l haven o r m a l C D 4 / C D 8 v a l u e s , m a y o r m a y n o t b e H I Vs e r o p o s i t i v e , w i l l h a v e e l e v a t e d i m m u n o g l o b u l i n s ,a n d w i l l h a v e a b n o r m a l C M I f u n c t i o n a s s a y s . T h eh a l l m a r k o f ' p h a s e t w o ' i s p r e s e n c e o f a n t ib o d i e sa g a i n st h o s t l y m p h o c y t e s . A g a i n t h e ' A I D S r i s k 'c o n d i t i o n s a n d l i f e s t y l e s e x p o s e p e r s o n s t o o t h e rp e o p l e ' s l y m p h o c y t e s v i a s h a r e d n e e d l e s , r e c t a l i n -semina t ion , t rans fus ions , or unt rea ted dr inking wate r ,a l l o f w h i c h a r e a s so c i a t e d w i th t h e d e v e l o p m e n to f l y m p h o t o x i c a u t o i m m u n i t y ( 3 6 ) . I t is i n s t a g e t w ot h a t t h e p h e n o m e n o n o f i n v e r t e d C D 4 / C D 8 r a t i ooccurs and c l in ica l d i s ease deve lops . The progres s ivel o s s o f T 4 c e l l s, a n d o t h e r a b n o r m a l it i e s, m a y e v e n -t u a l ly l e a d t o c o m p l e t e f a i l u re o f b o t h C M I a n d A M I ,w h i c h c o n s t i t u t e s ' p h a s e t h r e e ' . S C D p r e d i c t s t h a tpa t i en t s in phase one , and poss ib ly in phase two, a rei n a r e v e r s i b le p h a s e o f t h e s y n d r o m e .The in i t i a l pa thologica l event es t ab l i sh ing the f i r s tp h a s e o f A I D S i s t h e s w i t c h in g o f h o m e o s t a t i c d o m i -n a n c e f r o m C M I t o A M I a s d e s c r i b e d b y C l e r i c ia n d S h e r a n d c o w o r k e r s ( 1 8 , 1 9 ) . E v i d e n c e t h a t t h i si s w h a t a c t u a l l y o c c u r s is p r o v i d e d b y s tu d i e s d e m o n -s t r a t i n g t h a t p e r i p h e r a l m o n o n u c l e a r b l o o d c e l l s( P M B C s ) f r o m p a t i e n t s w h o g o o n t o d e v e l o p A I D Sp r o d u c e i n a d e q u a t e a m o u n t s o f I L - 2 a n d g - I F N , a n dt h a t t h i s o c c u r s b e f o r e a n y r e d u c t i o n i n a b s o l u t ec o u n t s o f T 4 c e l l s ( 3 7 - 3 9 ) . F u r t h e r e v i d e n c e t h a t a nA M I d o m i n a n c e i s o c c u rr i n g is p r o v i d e d b y E d e l m a na n d Z o l l a - P a z n e r , w h o p o i n t o u t t h a t B c e l l s f r o mA I D S p a t i e n t s s p o n t a n e o u s l y s y n t h e s i z e i n c r e a s e dl e v e l s o f I g G , a n d t h a t t h i s m a y b e a t t r i b u t e d t o' a b n o r m a l i m m u n o r e g u l a t o r y c i r c u i t s t h a t f a i l t odown regula te these ce l l s ' (35) . Fur the rmore , th i se x c e s s i v e I g G p r o d u c t i o n i s p o s i t i v e l y c o r r e l a t e dw i t h t he d e c r e a s e d C D 4 / C D 8 r a ti o c o m m o n l y f o u n din the pe r iphera l b lood of pa t i en t s in the ea r ly s t ageso f A I D S ( 4 0 ) . T h e S C D m o d e l s u p p o s e s th a t t h er e a s o n t h e s e B c e l ls a r e n o t d o w n r e g u l a t e d i s b e c a u s eo f i n s u f f i c i e n t l e v e l s o f I L - 2 a n d g - I F N . T h e r e g u -l a t o r y i m b a l a n c e f o u n d i n p h a s e o n e o f t h e S C Dt h e o r y o f f e r s a n e t i o l o g i c a l e x p l a n a t i o n f o r A I D Stha t i s mul t i fac tor i a l , and tho ugh i t i nc ludes infec t ionsa s a l i k e l y c o f a c t o r b e c a u s e o f t h e i r p r o n o u n c e d a n t i -genic i ty , does not s t r i c t ly requi re the presence ofe i t h e r a s p e c i f i c i n f e c t io u s a g e n t o r i n d e e d e v e n i n f e c -t i o n s i n g e n e r a l . W h y a n d h o w c o u l d t h i s i m b a l a n c eo c c u r ? T h e m o s t o b v i o u s a n d l o g i c a l a s s u m p t i o n i stha t i t i s a resu l t o f fac tors tha t e i the r suppres sC M I a c t i v a t i o n o r s t i m u l a t e A M I a c t i v a t i o n . T h e s eare l i s ted in Tables 1 and 2 . N ote tha t the re a re s evera l

Tab le 1 Factors that suppress CM ISperm alloantigens: male--malesexRecreationaldrugs: am yl nitrite, cocaine,opiates, alcohol,marijuanaCorticosteroidsTransfusionsHemophiliacsHistiocyticor lympho reticular ance r e.g. Hod gkin's, ymphoma,multiple myelom a,etc.)ThymicdamagePharmacologicalagents: anesthetics,antibiotics, antivirals, AZ T,tranquilizersMalnutritionMalabsorption (e.g. ga y bowel syndrom e')Sickle cell diseaseAge: elderlyand premature nfantsStressHeav y metals (esp. Hg, Ni, Pb)Viral infections

Ta ble 2 Factors that stimulate AM ISperm: male-m alesexIV drug useRoot canals and oth eroccult nfectionsHemophiliaMu ltiple infectionsVaccinesParasitesMycotoxinsTransfusions

f a c t o r s w h i c h r e s u l t i n b o t h a s u p p r e s s i o n o f C M Ia n d a n a c t iv a t i o n o f A M I . A c o n s i d e r a t io n o f t h e s ef a c t o r s p r o v i d e s a m p l e e x p l a n a t i o n f o r w h y t h i sd i s e as e s y n d r o m e h a s s u c h a s t ro n g p r o p e n s i t y f o r t h ef o u r m a j o r r i s k g ro u p s : h o m o s e x u a l m e n , i n t r a v e n o u sdrug use rs , hemo phi l i acs , and t rans fus ion rec ip ien t s .Homosexual menM a r k e d d y s f u n c t i o n o f t h e C M I h a s b e e n s h o w ni n 4 0 % o f 1 1 7 h e a l t h y h o m o s e x u a l m e n ( 4 1 ) . T h u s ,h o m o s e x u a l m e n a s a g r o u p a r e a t g r e a t r i s k f o rd e v e l o p i n g t h e p r e c i s e i m m u n e d y s r e g u l a t i o n f o u n di n p h a s e o n e . W h y ? M a l e h o m o s e x u a l s e x u a l p r a c -t i c e s c a u s e s p e r m r e c i p i e n t s t o d e v e l o p a n t i b o d i e stha t c ros s - reac t wi th an t igens on the sur face of Tl y m p h o c y t e s , w h i c h a r e l i k e l y t o r e s u l t i n C D 4d y s r e g u l a t i o n a n d / o r d e s t r u c t i o n ( 4 2 , 4 3 ) . I n o t h e rs t u di e s a l a rg e p r o p o r t i o n o f h e a l t h y h o m o s e x u a l m e nw e r e f o u n d t o h a v e r e d u c e d C D 4 / C D 8 r a t i o s a n dd e c r e a s e d C D 4 n u m b e r s c o m p a r e d w i t h h e t e r o s e x u a lc o n t r o l s . T h e s e f i n d i n g s c o r r e l a t e w i t h t h e n u m b e ro f s e x u a l e n c o u n t e r s a n d p r o m i s c u i t y , a n d h e n c e w i t h


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72 MEDICALHYPOTHESESt h e d e g r e e o f e x p o s u r e t o s p e r m a n d s e m e n ( 4 1 ) .T y p i c a l l y , t h i s c o n s e q u e n c e o f s p e r m e x p o s u r e h a sb e e n t h o u g h t t o b e l i m i te d t o a n a l c o n t a c t, b u t s i m i l a rr e a c t i o n s m i g h t a l s o b e f o u n d w i t h o r a l c o n t a c t i na pe rson wi th pe r iodonta l , e sophagea l , o r gas t r i cd i sease . Fur the rmore , the chronic an t ibody s t imula -t i o n c h a r a c t e r i z e d b y p h a s e o n e i s w e l l d o c u m e n t e di n h o m o s e x u a l m e n n o t o n l y s e c o n d a r y t o m u l t i p l esexua l ly t ransmi t t ed d i seases but a l so as a responset o s p e r m e x p o s u r e a n d t o t h e l e u k o c y t e s f o u n d i ns e m e n ( 4 2 ,4 4 ) . A n a l i n t e rc o u r s e , e v e n w h e n p r a c t i c e dw i t h a c o n d o m , a n d o t h e r f o r m s o f a n a l p e n e t r a t i o nwi l l f requent ly resu l t i n l ace ra t ion of the rec ta lm u c o s a , a l l o w i n g a t r a n s i e n t b a c t e r e m i a w h i c h w i l lac t iva te AM I (45) .I t i s in t e res t ing to note tha t , on the o ther hand,w o m e n e x p o s e d t o s p e rm , e v e n r e c t a l ly , s e e m t o h a v ea na tura l pro tec t ion aga ins t these event s , which w oulds e r v e t o p a r t i a l l y e x p l a i n t h e g r e a t p r e p o n d e r a n c eof th i s d i sease in me n (46) . Wi th th i s in mind , then ,i t i s no t surpr i s ing tha t s tudies have shown tha t am a j o r i t y o f a s y m p t o m a t i c , h e a l t h y h o m o s e x u a l m e nh a v e b e e n s h o w n t o h a v e e l e v a t e d c i r c u la t in g i m m u n ec o m p l e x ( C I C l e v e l s ) ( 4 7 - 5 1 ) , d e c r e a s e d P M B C r e -s p o n s e t o m i t o g e n s ( 5 2 ) , a n d o t h e r e v i d e n c e o f p h a s eo n e i m m u n e d y s r e g u l a t i o n ( 4 1 ) . L i k e w i s e , r e s p o n -s iveness to top ica l d in i t rochlorbenz ine (DNCB),which i s an accu ra te way to as ses s func t ion of theC M I , i s d e c r e a s e d in a l a r g e p e r c e n t a g e o f o t h e r w i s eh e a l t h y h o m o s e x u a l m e n ( 5 3 ) . S i n c e A I D S i s c h a r a c -t e r i z e d b y a h y p e r a c t i v a t i o n o f B - c e l l f u n c t i o n i nthe ea r ly s t ages (35) , i t i s qu i t e l ike ly tha t s implyf r o m s e x u a l p r a c t i c e s a l o n e , m a n y h o m o s e x u a l m e na r e in p h a s e o n e o f A I D S . A d d t o t h is t h e f a c tt h a t h o m o s e x u a l m e n a s a g r o u p h a v e a m u c h h i g h e rt h a n a v e r a g e i n c i d e n c e o f p r o m i s c u i ty , s e x u a l l y t r a n s-mi t t ed d i seases , pa ras i t i c infec t ions , malabsorp t ionf r o m ' g a y b o w e l s y n d r o m e ' , v i r a l i n f e c t i o n s , u s e o fant ib io t i cs , and use of rec rea t iona l drugs , i t i s no tsurpr i s ing tha t , ou t s ide of the th i rd wor ld , AIDS i sa l m o s t c o m p l e t e l y l im i t e d t o t h i s g r o u p .

Intravenous drug users (IVDUs)T h e r e i s a s u b s t an t ia l a m o u n t o f e v i d e n c e t h at I V D U sh a v e m a r k e d i m m u n e s y s t e m d y s r e g u l a t i o n , l e a v i n gthem a t r i sk for infec t ions by agent s tha t a re non-p a t h o g e n i c f o r t h e g e n e r a l p o p u l a t i o n . T h e s e a b n o r -m a l i t i e s a r e c o m m o n l y f o u n d i n u s e r s o f c o c a i n e ,opia tes , and amyl n i t r i t e . Phase one depres s ion ofC M I w i t h h y p e r a c t i v a t io n o f A M I i s w e l l d o c u m e n t e di n t h i s g r o u p ( 5 4 - 5 9 ) . T h e o v e r w h e l m i n g a n t i g e n i cexposure incur red as a resu l t o f i l l i c i t d rug con-tamina t ion expla ins the h igh inc idence of c i rcu la t ingi m m u n e c o m p l e x ( C I C ) f o r m a t i o n , as w e l l a s th e h i g h

i n c i d e n c e o f a u t o i m m u n e a b n o r m a l i t i e s i n I V D U s( 5 9 ). I V D U s a l s o a r e w e l l d o c u m e n t e d t o b e a t h i g hr i sk f o r v a r i o u s v i r a l i n f ec t i o n s w h i c h a r e t h e m s e l v e si m m u n o s u p p r e s s i v e ( 6 0 ) . F u r t h e r m o r e , m a l n u t r i t i o ni s a c o m m o n f i n d i n g i n I V D U s . T h u s t h e r e i s s u f f i -c i e n t d a t a t o c o n c l u d e t h a t a n I V D U i s l i k e l y t o b ei n t h e f i rs t p h a s e o f A I D S b a s e d o n t h e s e f a c to r sa lone .HemophiliacsI m m u n e s y s t e m d y s r e g u l a t i o n i s c o m m o n i n h e m o -phi l i a . Pe rhaps one of the mos t in te res t ing f indingsi n h e m o p h i l i a i s t h e i n c i d e n c e o f ' i d i o p a t h i c C D 4 +T - l y m p h o c y t o p e n i a ' ( I C L ) . I C L i s t h e d e s i g n a t i o ng i v e n t o c a s e s o f A I D S w h i c h a r e H I V s e r o n e g a ti v e .I n a n 1 9 8 5 s t u d y o f p e o p l e w h o h a v e r e c e i v e d b l o o dc o m p o n e n t s , c l o tt i n g f a c to r , o r b o t h , i t w a s d i s c o v e r e dt h a t t h e i n c id e n c e o f I C L i n h e m o p h i l i a c s w a s t h es a m e r e g a r d l e ss o f w h e t h e r o r n o t t h e y w e r e e x p o s e dto c lo t t ing fac tor . Thi s f ind ing ' sugges t s tha t in th i sc a s e t h e p r o b l e m m a y b e r e l a t e d t o h e m o p h i l i a it s el f ,a n d n o t t o a n i n f e c t i o u s a g e n t ' , o r p e r h a p s e v e nc l o t ti n g f a c t o r e x p o s u r e . A c c o r d i n g t o J a m e s C u r r a n ,h e a d o f th e C e n t e r s f o r D i s e a s e C o n t r o l ' s H I V / A I D Sp r o g r a m , ' I ' v e s e e n n o e v i d e n c e s o f a r t h a t t h es y n d r o m e o r s y n d r o m e s [ I C L ] a r e t r a n s m i t t e d b y a nagent , l e t a lone an agent tha t i s b lood borne or i ss p r e a d t h r o u g h t h e b l o o d s u p p l y ' . ' I t h a s t o b e c o n -f i rme d but [ th is da ta ] sugges t s i t ' s som eth ing re la t edt o h e m o p h i l i a ' ( 6 1 ) . T h e r e i s n o d o u b t t h a t h e m o -p h i l ia c s a r e s u b j e c t t o i m m u n e s y s t e m d y s r e g u l a t i o nr e s u l t i n g i n s u p p r e s s i o n o f C M I a c t i v a t i o n e v e n i nt h e a b s e n c e o f H I V . I n o n e s t u d y , H I V - s e r o n e g a t i v eh e m o p h i l i a c s h a d a 2 5 % l o w e r h e l p e r / s u p p r e s s o rT - c e l l r a t i o t h a n c o n t r o l s . R e s p o n s e t o m i t o g e n s ,i n c l u d i n g p h y t o h e m a g g l u t i n i n ( P H A ) w h i c h i s s p e -c i f i c f o r T - c e l l f u n c t i o n , w a s a l s o a s m u c h a s 5 0 %l o w e r t h a n t h a t o f c o n t r o l s . I n a d d i t i o n , o f t h e8 5 h e m o p h i l i a c s s t u d i e d , 5 0 % w e r e f o u n d t o b ec o m p l e t e l y a n e r g i c , c o m p a r e d w i t h c o n t r o l s w h o s erespon ses were a l l w i th in normal l imi t s . Fur the r , 67%o f t h e h e m o p h i l i ac s t e s t e d h a d s e r o l o g i c e v i d e n c eo f E B V r e a c t iv a t i o n s y n d r o m e ( 6 2 , 6 3 ) .S ince i t i s w ide ly accepted tha t ind iv idua l s wi thchronic an t igenic s t imula t ion (e .g . b lood produc tt h e r a p y ) o f t e n e x h i b i t i m m u n o l o g i c a l a b n o r m a l i t i e s( 6 4 ) , m a n y r e s e a r c h e r s h a v e c o n c l u d e d t h a t t h ea b n o r m a l i t i e s n o t e d i n h e m o p h i l i a c s a r e p u r e l y a n ds i m p l y t h e r e s u l t o f e x p o s u r e t o f a c t o r V I / I . I n d e e d ,m a n y h e m o p h i l i a c s w i t h th e s e i m m u n e a b n o r m a l i t i esh a v e b e e n s u b j e c t e d t o r e p e a t e d u s e o f f a c t o r V I I Ic o n c e n t r a t e b u t m a n y h a v e n o t , w h i c h l e a d s t o t h eq u e s t i o n o f w h e t h e r o r n o t t h e r e a r e i m m u n e s y s t e mi r regula r i t i e s as soc ia ted wi th hemophi l i a i t s e l f even


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S E L E C TI V E C O M P A R T M E N T A L D O M I N A N C E 7 3i n t h e a b s e n c e o f f a c t o r V I I I e x p o s u r e . S e v e r a l p u b l i-c a ti o n s h a v e r e p o r te d l o w n u m b e r s o f C D 4 l y m p h o -c y t e s e v e n i n u n c o m p l i c a t e d h e m o p h i l i a ( 6 5 - 6 7 ) .A l s o , w h e r e a s t h e r i s k o f A I D S i n h e m o p h i l i a i s' r e a d i ly p r e d i c t e d ' b y t h e e x t e n t o f t h e C D 4 d e p l e t i o n( 6 8 ), M a h i r e t a l c o n c l u d e d t h a t t h i s C D 4 d e c r e a s ew a s u n r e l a t e d t o w h e t h e r t h e l a s t d o s e o f f a c t o r V I I Iw a s f r o m 2 w e e k s t o 5 y e a r s b e f o r e t h e s u b j ec t s w e r etes t ed (69) . In the i r paper , J in e t a l s t a t ed tha t , 'R ecen teviden ce , sugges t s tha t a t leas t some of thesei m m u n o l o g i c a b n o r m a l it i e s m a y b e p r e s e n t in p a t i e n tsw h o h a v e r e c e i v e d l i t t l e o r n o f a c t o r r e p l a c e m e n tt h e r a p y ' . F o r e x a m p l e , u n t r e a t e d h e m o p h i l i a c s h a v ed e c r e a s e d N K a c t i v i t y w h i c h s u g g e s t s a f u n c t i o n a ld e f e c t i n N K c e l l l y r i c c a p a b i l i t y . T h e y a l s o h a v ei n c r e a s e d I g G l e v e l s , i n c r e a s e d C D 8 c o u n t s , a n ddecreased he lper / suppres sor ra t ios (70) .R e g a r d l e s s o f w h e t h e r o r n o t h e m o p h i l i a c s h a v ei n h e r e n t i m m u n e s y s t e m c o m p r o m i s e , i t i s c l e a rt h a t e x p o s u r e t o b l o o d a n d b l o o d c o m p o n e n t s d o e sr e s u lt i n i m m u n e s y s t e m a b n o r m a l i ti e s . M a d h o k e t a l.e x a m i n e d C M I f u n c t i o n i n 2 9 h e m o p h i l i a c s a n dd i s c o v e r e d t h a t 1 0 0 % o f t h e m h a d a r e s p o n s e b e l o wt h e n o r m a l m e d i a n , a n d 6 5 % d e m o n s t r a t e d a m a r k e dd y s f u n c t i o n . T h e s e r e s u l t s w e r e e q u a l l y n o t e d i nb o t h H I V - s e r o p o s i t i v e a n d s e r o n e g a t i v e p a t i e n t s .In the s e ronega t ive pa t i en t s , t he re was an inverser e l a t i o n s h i p b e t w e e n e x p o s u r e t o c l o t t i n g f a c t o r a n dskin response to in t radermal an t igenic cha l l enge . Theauthors conc lude tha t , 'Thi s s tudy shows tha t c lo t t ingf a c t o r c o n c e n t r a t e i m p a i r s t h e C M I r e s p o n s e t o an e w a n t i g e n i n th e a b s e n c e o f i n f e c t i o n w i t h H I V '( 7 1 ) . T o f u r t h e r t h i s c o n c e p t , i t h a s b e e n d i s c o v e r e dt h a t w h e n l y m p h o c y t e s a r e t a k e n f r o m n o r m a l s u b -j e c t s a n d a r e i n c u b a t e d w i t h f a c t o r V I I I c o n c e n t r a t et h e y h a v e a n i n h i b i t e d p r o l i f e ra t i v e r e s p o n s e t o b o t hP H A a n d c o n c a n a v a l i n A ( 6 9 ) . T h i s f in d i n g h a s l e a ds e v e r a l r e s e a r c h e r s t o h y p o t h e s i z e t h e p r e s e n c e o fa n a l l o a n t i g e n i n f a c t o r V I I I c o n c e n t r a t e w h i c h m a ybe ' a s soc ia ted wi th c l in ica l ly s igni f i cant immuno-d e f i c i e n c y i n t h e a b s e n c e o f H T L V - I I I i n f e c t i o n 'A n d , ' w e b e l i e v e t h a t t h e s e a b n o r m a l i ti e s m o r e l i k e l yr e p r e s e n t a p r e - e x i s t i n g d i s o r d e r o f i m m u n o r e g u l a -t ion ' (62 ,69) . J in e t a l s t a t ed ' I t i s sugges ted heret h a t i n d i v i d u a l s w i t h h e m o p h i l i a h a v e u n d e r l y i n gi m m u n e a b n o r m a l i t ie s t h a t a r e e x a c e r b a t e d b y c h r o n i cf a c t o r i n f u s i o n a n d t h a t a l s o m a y p r o v i d e t h e a p p r o -p r i a t e m i l i e u f o r t h e p a t h o g e n i c e x p r e s s i o n o f H I Vinfec t ion ' (70) .S o w h a t r o l e , i f a n y , d o e s H I V a p p e a r t o h a v e i n t h ep r o g r e s s i o n o f a h e m o p h i l i a c ' s a l r e a d y d y s f u n c t i o n a li m m u n e r e s p o n s e ? A c c o r d i n g t o p u b l i s h e d i n f o r m a -t i o n , a lt h o u g h t h e m a j o r i ty o f h e m o p h i l i a c s h a v e b e e ne x p o s e d t o H I V t h r o u g h t h e u s e o f b l o o d p r o d u c t s ,o n l y 6 7 o u t o f a b o u t 1 7 0 0 0 h e m o p h i l ia c s h a v e

ever deve loped AIDS (62) . Thi s i s no t a s t a t i s t i c tha tc o m p e l s o n e t o c o n c l u d e t h a t H I V i s a m a j o r e t i o -l o g i c a l f a c t o r i n t h i s s y n d r o m e . A l s o , a m o n g t r e a t e dh e m o p h i l i a c s , t h e d e g r e e o f i m m u n e s y s t e m a b n o r -m a l i t i e s r e m a i n s t h e s a m e r e g a r d l e s s o f w h e t h e rt h e y a r e s e r o p o s i t i v e o r s e r o n e g a t i v e f o r H I V ( 7 0 ) .A d d i t i o n a l ly , w h e r e a s t h e i n c i d e n c e o f H I V s e r o p o s i-t i v it y i n c r e as e s w i t h e x p o s u r e t o f a c t o r V I I I c o n c e n -t ra t e , t he inc idence of AIDS i s unre la ted to th i se x p o s u r e , a n d c o r r e l a te s o n l y w i t h a g e ( 6 2 ,6 8 ) . S i n c ei t is k n o w n t h a t i m m u n e s y s t e m f u n c t i o n d e t e r io r a t e swi th age , th i s obse rva t ion sugges t s tha t the presenceo f H I V m a y b e p u r e l y c i r c u m s t a n t i a l . B a c k i n g u pth i s as se r t ion i s the s t a t i s t i ca l f ind ing tha t pa t i en t sw h o a r e s e r o p o s i ti v e t o H I V p r o g r e s s to A I D S m u c hm o r e q u i c k l y a s t h e y b e c o m e o l d e r . I n f a c t , a m o n gH I V s e r o p o s i t i v e p e r s o n s , t h e i n c i d e n c e o f A I D Sis c lose ly t i ed to age , wi th an inc idence of 0 .83 per1 0 0 p e r s o n y e a r s i n p e r s o n s a g e d 1 - 1 7 , 5 . 6 6 p e r1 0 0 p e r s o n y e a r s i n p e r s o n s a g e d 3 4 - 5 0 , a n d 1 1 . 2 6p e r 1 0 0 p e r s o n y e a r s i n p e r s o n s o l d e r t h a n 5 0 ( 6 8 ) .Thi s hug e s t a t i st i ca l d i f fe re nce fi t s the SC D m ode lm u c h b e t t e r t h a n t h e H I V i n f e c t io u s m o d e l .H e m o p h i l i a c s a l so h a v e h i g h l e v e l s o f C I C s a s w e l la s l y m p h o t o x i c a u t o i m m u n e a n t i b o d ie s ( 7 2 ). H e m o -p h i l ia c s h a v e a h i g h i n c i d e n c e o f c h r o n i c h e p a t i ti s a n dc h r o n i c c y t o m e g a l i c i n f e c t i o n s , a n d t h e s e i n f e c t i o n si n c r e a s e t h e r a t e a t w h i c h A I D S d e v e l o p s b y a f a c t o ro f t h r e e (7 3 ) . A u t o i m m u n i t y i s f o u n d in a s m a n ya s 3 - 5 % o f h e m o p h i l i a c s , a n d i s o f te n t r e a te d w i t hd r u g s t h a t s u p p r e s s C M I ( 7 4 ) . F o r w e l l r e p o r t e dh i g h l e v e l s o f F c Y r e c e p t o r a n ti b o d y i n h e m o p h i l i a c s( 7 5 ) . T h e F c Y r e c e p t o r i s f o u n d o n l y m p h o c y t e s ,and b locking th i s receptor s t imula tes a nonspec i f i cT - c e l l s u p p r e s so r a c t i v a ti o n w h i c h w o u l d c a u s e C M Isuppres s ion (76) . A l l th i s occurs in hemophi l i acsr e g a r d l e s s o f t h e p r e s e n c e o f H I V . F u r t h e r m o r e ,e v e n w h i l e S u l l i v a n e t a l . d e m o n s t r a t e d t h e d e p r e s s e dC M I r e s p o n s e a s s o c ia t e d w i t h e x p o s u r e t o f a c t o r V I I Ic o n c e n t r a t e , t h e y a l s o n o t e d t h a t B - c e l l p r o l i fe r a t io nwas the s ame as in normal cont ro l s (62) . Thi s i sa n o t h e r f i n d in g t h a t v e r y n i c e l y f i ts t h e S C D m o d e l .C lea r ly , hemophi l i acs a re a l so a t s igni f i cant r i sk ofd e v e l o p i n g t h e C M I s u p p r e s s io n i n t h e f a c e o f A M Iac t iva t ion tha t charac te r i zes phase one .Transfusion recipientsB l o o d t r a n s f u s i o n s d e p r e s s t h e C M I . T h i s f a c t h a sb e e n e x p l o i t e d b y s u r g e o n s w h o p r e t r e a t t h e i r p a ti e n tsw i t h b l o o d t r a n s f u s i o n s b e f o r e t h e y u n d e r g o t r a n s -p l a n t p r o c e d u r e s . T h e i m m u n o s u p p r e s s i v e a c t i v i t yof the t rans fus ion resu l t s in a s igni f i cant ly reducedinc idence of gra f t re j ec t ion (77) . I t t u rns out tha t th i si m m u n o s u p p r e s s i o n i s a c c o m p a n i e d b y a n i n v e r t e d


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7 4 MEDICAL HYPOTHESESCD4/CD8 ra t io , and tha t a l l t h i s occurs in a dose-d e p e n d e n t m a n n e r ( 7 8 , 7 9 ) . T h e p a t i e n t s w h o r e c e i v eb l o o d t r a n s f u s i o n s a n d l a t e r g o o n t o p r o g r e s s t oA I D S a r e s m a l l i n n u m b e r , a n d a r e a l m o s t a l w a y sl i m i te d t o t h o s e w h o r e c e i v e a s m u c h a s 1 5 t o 2 0 u n i t so f b l o o d ( 8 0 ). A l t h o u g h t h e a v e r a g e t r a n s fu s i o ninvolves l e s s than f ive uni t s of b lood, pa t i en t s whol a t e r d e v e l o p A I D S r e c e i v e a n a v e r a g e o f 2 1 u n i t s(81) . Thus , these pa t i en t s a re p laced in a phaseo n e s i tu a t io n c h a r a c t e r i z e d b y a n a n t i g e n i c o v e r l o a ds t imula t ing B-ce l l p ro l i fe ra t ion in the presence ofC M I s u p p r e s s i o n . F u r t h e r m o r e , M o r g a n e t a l d e -s c r i b e d a p e r s i s t e n t l y m p h a d e n o p a t h y v e r y s i m i l a rt o p a t ie n t s i n t h e e a r l y s ta g e s o f A I D S , w h i c h h enoted in pa t i en t s subjec ted to mass ive t rans fus ions(82) . Inc identa l ly , i t should be noted th a t of pa t i en t sw h o r e c e iv e d H I V - c o n t a m i n at e d b l o o d , 4 0 % o f t h e mn e v e r b e c a m e H I V s e r o p o s i ti v e (8 1 ) . U s i n g t h e S C Dm o d e l o n e w o u l d e x p l a i n t h i s f in d i n g b y p o s t u l a t in gtha t th i s 40% apparent ly had a CMI tha t was s t ronge n o u g h t o h a n d l e t h e e x p o s u r e w i t h o u t t h e n e e dto ca l l AMI in to ac t ion . Evidence for th i s suppos i t ioni s s u p p l i e d b y t h e f a c t t h a t A I D S c a s e s f o l l o w i n gt r a n sf u s i o n s a r e e x t r e m e l y r a re i n p e r s o n s y o u n g e rt h a n 2 1 ( 1 6 ). O f c o u r s e , th e c h a n c e o f c o n t r a c t in gv a r i o u s i m m u n o s u p p r e s s i v e v i r a l i n f e c t i o n s a f t e rmass ive t rans fus ion i s inc reased , and i s l ike ly ye ta n o t h e r f a c t o r i n t h e T H 1 t o T H 2 s h i f t p o s t u l a te d t oo c c u r i n p h a s e o n e . T r a n s f u s i o n p a t ie n t s, l i k e h e m o -phi l i acs , a l so deve lop lymphotoxic an t ibodies (83) ,a n d s t u d i e s h a v e r e p e a t e d l y c o n f i r m e d t h a t a u t o -i m m u n e i m m u n o s u p p r e s s i o n o c c u r s a s a r e s u l t o ft rans fus ions (84 ,85) . Las t ly i t mus t be rememberedt h a t m a n y p a t ie n t s w h o r e c e i v e m a s s i v e t r a n sf u s i o n sare , by the ve ry na ture o f the i r need fo r the t ransfus ions,v e r y l i k e l y a l r e a d y i n a s t a t e o f i m m u n o s u p p r e s s io n .The three phases o f AID S (Fig. 2)Phase one AIDS, in th i s mode l , represent s the in i t i a ls t a g e o f t h e s y n d r o m e a n d i s c h a r a c t e r i z e d b y t h ei m m u n e s y s t e m d y s r e g u l a t i o n t h a t o c c u r s a s t h en o r m a l p h y s i o l o g i c a l d o m i n a n c e o f C M I i s r e p l a c e db y A M I d o m i n a n c e . T h e h a l lm a r k s o f th i s p h a s e a r e :( a ) n o r m a l b l o o d c o u n t s a n d r a ti o s , ( b) a s y m p t o m a t i cpa t i en t s , (c ) degrees of anergy , (d) poor responset o D N C B , ( e ) a b n o r m a l l y l o w P M B C r e s p o n s e t om i t o g e n s , a n d ( f ) e l e v a te d i m m u n o g l o b u l i n s a n d C I Cl e v e ls . P h a s e t w o i s a n a u t o i m m u n e p h a s e p o s t u l at e dt o o c c u r a s t h e u n r e s t r a i n e d A M I b e g i n s t o p r o -d u c e l y m o p h o c y t o t o x i c C I C s a n d a u t o a n t ib o d i e s . T h econcept tha t CICs p lay a ro le in the pa thogenes i so f A I D S i s n o t n e w ( 5 0 , 8 6 , 8 7 ) . I n d e e d , t h e d e g r e eo f C I C e l e v a t io n i n c r ea s e s a s l y m p h a d e n o p a t h y s y n -d r o m e p r o c e e d s t h r o u g h A R C o n t o A I D S ( 5 3 ) . I t

h a s a l s o b e e n s h o w n t h a t w h e n C I C s a r e r e m o v e dthrough p lasmapheres i s , pa t i en t s exper i enced c l in ica li m p r o v e m e n t , K a p o s i ' s s a r c o m a r e g r e s s e d , N K a c t i -v i ty inc reased , whi t e b lood ce l l s inc reased , and theC D 4 / C D 8 r a t i o i m p r o v e d ( 8 8 , 8 9 ) . T h y m i c d e s t r u c -t i o n , a c o m m o n f e a t u r e o f a d v a n c e d A I D S , c a n b e ap r e c u r s o r t o s e v e r e i m m u n o d e f i c i e n c y ( 4 8 , 9 0 - 9 2 ) ,a n d h a s b e e n d e m o n s t r a te d t o o c c u r i n c a t s s e c o n d a r yt o C I C a c t i v it y ( 9 2 ). T h i s p h a s e m a y b e f u r t h e r i n t e n -s i f i e d b y p o o r l y c o n t r o l l e d v i r a l i n f e c t i o n s w h i c hm a y b e t h e s o u r c e f o r l y m p h o c y t o t o x i c v i r a l p r o t e in s .U n b o u n d v i r a l p r o t e i n s m a y l i k e l y i n t e r a c t d i r e c t l ywi th CD4 ce l l s in a way tha t d imini shes the i r func-t i o n , a s is e v i d e n c e d b y t h e f a c t th a t d e c r e a s e d P H Aresponse cor re la t es we l l w i th v i ra l an t igenemia (34) .A l l t h i s m a y l e a d t o f u r t h e r d e f e c t i v e a n t i g e n p r e -s e n t at i o n w i t h s u b s e q u e n t d e c r e a s e in t h e C D 4 e x p a n -s ion , a s we l l a s ac tua l cy topa th ic des t ruc t ion of theCD4 ce l l l i ne (93 ,94) . The addi t iona l mani fes ta t iono f m u l t i s y s te m a u t o i m m u n e d i s e a s e i s a l s o p o s t u la t e dto occur a t th i s t ime (48 ,95) , and can expla in a grea tm a n y o f t h e o t h e r w i se p o o r l y u n d e r s to o d s y m p t o m sassoc ia ted wi th the syndrome, such as d ia r rhea ,throm boc ytop enia (96) , rashes , anemia (51) , e tc .S o n n a b e n d r e p o r t e d p o s i t i v e a n t i n u c l e a r a n t i b o d yt i t e r s in over 30% of pa t i en t s wi th AIDS (48) . Inother s tudies , au toant ibodies found in AIDS pa t i en t s 's e r a h a v e b e e n f o u n d t o i n t e r f e r e w i th v a r i o u s T c e l lfunc t ions , and a l so can l ead to the des t ruc t ion ofT - c e l l s e i th e r b y a n t i b o d y - m e d i a t e d l y s i s o r b y a n t i-b o d y - d e p e n d e n t c e l l u la r t o x i c i ty ( 9 7 - 9 9 ) . T h u s , t h ees sent i a l charac te r i s t i c s of phase two would inc lude :( a ) p r o g r e ss i v e d e c l in e i n C D 4 n u m b e r s , ( b ) r e v e r sa lo f t h e n o r m a l C D 4 / C D 8 r a ti o , ( c ) a b n o r m a l v a l u e sf o r m a n y b l o o d p a r a m e t e r s , ( d ) s i g n s a n d s y m p t o m so f a u t o i m m u n e d i s o r d e r s ( e . g . p o s i t i v e A N A t i t e r s ) ,( e ) d e c r e a s e in s e r u m c o m p l e m e n t l e v e l s, ( f ) e l ev a t e dvi ra l t i t e r s , (g) neoplas t i c d i sease , and (h) onse t ofoppor tuni s t i c infec t ions . Phase three would ident i fyt h o s e p a t i e n t s w h o , t h r o u g h t h e a b o v e m e c h a n i s m s ,h a v e f u l l y p r o g r e s s e d t o t h e m u l t i p l e o r g a n f a i l u r e sseen in end s t age d i sease which resu l t f rom ap r o f o u n d f a i l u r e o f b o t h C M I a n d A M I .The question o f the HIV-seropositivity correlationC e r t a i n ly t h e m o s t c o m p e l l i n g r e a s o n t o a s s u m e t h a tA I D S i s a n i n f e c t i o u s d i s e a s e c a u s e d b y H I V i s t h es t rong s t a t i s t i ca l cor re la t ion be tween the presence ofH I V a n t i b o d i e s a n d t h e s u b s e q u e n t d e v e l o p m e n to f t h e d i s e a s e. I n d e e d , a f t e r o v e r a d e c a d e o f f r u it l es sa t te m p t s t o d e t e r m i n e j u s t h o w H I V c a u s e s A I D S ,c o m b i n e d w i t h a f a i l u re t o e f f e c t i v e l y t r e a t t h e d i s e a sewi th a mul t ip l i c i ty of an t iv i ra l medica t ions , manysc ient is t s and c l in ic i ans a re ca l l ing for a re -eva lu a t ion


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SELECTIVECOMPARTMENTALDOMINANCE 75o f t h e H I V t h e o r y ( 1 4 - 1 6 ) . N o n e t h e l e s s , b e f o r e t h eH I V t h e o r y c a n b e r e a s o n a b l y c h a l l e n g e d , i t f i r s tb e c o m e s n e c e s s a r y t o p r o v i d e a p l a u s i b l e e x p l a n a t i o nf o r t h i s c o r r e l a t i o n w i t h o u t i n v o k i n g a c a u s e - a n d -e f fec t r e l a ti onsh ip . Se l ec t ive com par tmenta l dom nan cep r o v i d e s t h e f o l l o w i n g e x p l a n a t i o n . W h e n a n i n d i -v i d u a l w i t h a n i n t ac t C M I i s e x p o s e d t o H I V , o r a n yv i r u s f o r t h a t m a t t e r , t h e c e l l u l a r c o m p a r t m e n t i sse l ec t ive ly ac t iva t ed and des t roys t he v i rus . S imul -t a n e o u s l y , th e c e l l u l a r c o m p a r t m e n t e x e r t s a s u p p r e s -s i v e d o m i n a n c e o v e r t h e h u m o r a l c o m p a r t m e n t , a n dt h u s t h e A M I w i t h r e s p e c t t o t hi s p a r t ic u l a r e x p o s u r ei s neve r ac t iva t ed . In o the r words t he i nd iv idua lb e c o m e s i n f e c t e d w i t h t h e v i r u s b u t , i n t h e c a s e o fa n i n t a c t c e l l u l a r c o m p a r t m e n t , n e v e r g e n e r a t e s a na n t i b o d y . N o w w h a t h a p p e n s t o a n i n d i v i d u a l w h oa t t h e t im e h e i s e x p o s e d t o H I V i s a l r e a d y in p h a s eo n e o f A I D S a n d h a s t h u s d e v e l o p e d s u p p r e s s e dC M I ? I n t h i s c a s e , s i n c e th e c e l l u l a r c o m p a r t m e n t

o '~

Factors wh ich eithers t imula t e AM I and/orsuppress CM I

~ . , ~ , x ~ " / ~ x ~ Z ; ,o ~~

A M I 7 f a i l to s up p re ss x ~ C M I

1 JT H 1 t o T H 2switchCIC 'sAutoant ibodies

CD4 dest ruct ionB-cel l dest ruct ionPlatelet dest ruct ionAnemiaDecreased APC func t ion

--~ Mul t ipleOrgan Sys t em Fai l u re~ ~ Ne oplas t i c i sease~. AM I fai lure~ . ~ C M I F a il ur eF ig . 2 The t h ree phases o f AIDS.

i s n o l o n g e r c a p a b l e o f p r o v i d i n g a d e q u a t e p r i m a r yd e f e n s e , t h e i n d i v i d u a l w i l l d e v e l o p a n a n t i b o d y t oH I V . T h u s , p o s s e s s i n g a n a n t i b o d y t o H I V m a ys i m p l y s e l e c t o u t t h o s e i n d i v i d u a l s w h o a r e a l r e a d yi n p h a s e o n e o f t h e d i s e a se s y n d r o m e d u e t o o t h e rfac to r s . Th i s a sse r t i on i s bo l s t e red by s tud ie s whichh a v e d e m o n s t r a t e d t h a t T - c e l l s i n H I V - p o s i t i v ep a t ie n t s a r e d e f e c t i v e in I L - 2 a n d g - I F N p r o d u c t i o n( 3 7 - 3 9 ) . T h i s r e a s o n i n g a l s o e x p l a i n s w h y t h em a j o r i t y o f p a t ie n t s w h o d e v e l o p A I D S h a v e h i g han t ibod y t i te r s t o a hos t o f v i ruses (16) , wh i l e a t thes a m e t i m e s h o w i n g e v i d e n c e o f C M I s u p p r e s s i o n l o n gb e f o r e a n y d e c r e a s e i n C D 4 c o u n t s ( 9 4 , 1 0 0 - 1 0 2 ) .T h i s m o d e l a l s o s e r v e s t o e x p l a i n w h y m o s t p e o p l ew h o a r e e x p o s e d to H I V n e v e r b e c o m e s e ro p o s it iv e ,w h i l e s i m u l t a n e o u s l y o f f e r i n g a n e t i o l o g i c r a t i o n a l ef o r th e m a n y c a s e s o f H I V - n e g a t i v e A I D S . F u r t h e re v i d e n c e t o s u p p o r t th i s t h e o r y i s p r o v i d e d i n s e v e r a lp u b l i s h e d r e p o r t s o f i n d i v i d u a l s w h o w e r e e x p o s e dt o H I V t h r o u g h c o n t a m i n a t e d n e e d l e p u n c t u r e s . I ne a c h c a s e t h e e x p o s u r e w a s w e l l d o c u m e n t e d , a n de v i d e n c e o f p r i m a r y i n f e c t i o n w a s d e m o n s t r a t e d b y ap o s i t i v e c e ll u l a r i m m u n e r e c a l l t o H I V a n t ig e n s . M o s to f t h e s e p e r s o n s , h o w e v e r , f a i l e d t o d e v e l o p a n t i -b o d i e s t o H I V - - p r e s u m a b l y i n d i c a t i n g t h a t , a l t h o u g ht h e y w e r e i n f e c t e d , a n t i b o d i e s w e r e n o t f o r m e d ,b e c a u s e o f a n i n t ac t a n d t h u s e f f e c t i v e p r i m a r y C M Ir e s p o n s e ( 2 3 , 2 4 ). P a t i e n ts w h o a r e H I V p o s i t i v e m a yn e v e r d e v e l o p A I D S , b u t t h o s e t h a t d o d e v e l o p t h ef u l l s y n d r o m e d o s o o n l y a f t e r m a n y y e a r s . I t h a sb e e n p o s t u l a t e d t h a t t h i s i s b e c a u s e H I V h a s a ni n c r e d i b l y lo n g l a t e n c y p e r i o d . M i g h t i t n o t b e a m o r ereasonab le exp lana t ion to sugges t t ha t t h i s i s t hel e n g t h o f t i m e t h a t i s n e e d e d f o r p h a s e o n e d i s e a s et o p r o g r e s s t o t h e p h a s e t w o a n d t h r e e s t a t e s s e e ni n A I D S ?The rea l cause(s ) o f AIDS?I f th e s i n g l e c o m m o n d e n o m i n a t o r i n t h e e a r ly p a t h o -g e n e s i s o f A I D S i s p h a s e o n e s w i t c h i n g o f C M Id o m i n a n c e f o r A M I d o m i n a n c e , t h e n i t s h o u l d b e a neasy exe rc i se t o pos tu l a t e wha t i n i t i a t i ng and p ro-m o t i n g f a c t o r s a r e n e e d e d t o e s t a b l i s h a n d m a i n t a i nth i s swi t ch . Th i s would inc lude a l l f ac to r s t ha t e i t he rd e p r e s s C M I ( T a b l e 1 ) o r s t i m u l a t e A M I ( T a b l e 2 ) .A m u l t i f a c to r i a l e t i o l o g y f o r A I D S s h o u l d b e n omore su rpr i s ing than the pos tu l a t ed mul t i f ac to r i a le t i o l o g i e s f o r c a n c e r a n d c a r d i o v a s c u l a r d i s e a s e .Kol i ad in , us ing a s t a t i s t i ca l ana lys i s , ha s been ab l eto c l ea r ly demons t ra t e t ha t t he f ac t t ha t t he ma jorr i s k g r o u p s a r e p r e d o m i n a n t l y r e p r e s e n t e d o n t h e s el i s t s (Tab le s 1 and 2 ) se rves t o exp la in t he s t a t i s -t i c a l g r o u p i n g o f t h e d i s e a s e m u c h b e t t e r t h a n t h epos tu l a t i on o f an in fec t ious agen t (17) .


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76 MEDICAL HYPOTHESES

Oz o n e t h e r a p y a n d A I D SI f th e e t i o l o g y o f A I D S c o n s i s t s o f a m u l t i p l i c i ty o ff a c t o r s a l l o f w h i c h r e s u l t i n t h e p h a s e o n e s h i f t i n gm e n t i o n e d a b o v e , t h e n t h e t h e r a p e u t i c a p p r o a c hs h o u l d b e o n e t h a t b o t h e l i m i n a t e s e x p o s u r e t o t h o s ef a c t o r s a n d f o c u s e s o n t h e r a p i e s a i m e d a t s t i m u l a t i n gC M I a n d / o r d o w u r e g u l a t i n g A M I . T o t h a t e x t e n t ,a n t i v i r a l a n d o t h e r a n t i m i c r o b i a l t r e a t m e n t s w o u l dh a v e a p r e d i c t a b l y p o s i t i v e e f f e c t d u e t o t h e i r a b i l i t yt o l o w e r a n t i g e n i c l o a d . H e n c e , i t h a s b e e n d e m o n -s t r a t e d t h a t a l o w e r e d s e r u m v i r a l l o a d i s a f i n d i n gtha t i s s ta t i s t i ca l ly as soc ia ted w i th a be t te r pa t ien to u t c o m e ( 1 0 3 , 1 0 4 ) . T h e p r o b l e m w i t h r e l y i n g e x c l u -s i v e l y o n t h i s f o r m o f t h e r a p y l i e s b o t h i n i t s i n n a t el i m i t a t io n s o n a c c o u n t o f t h e m u l t i p l i c i t y o f m i c r o b e sp r e s e n t a n d t h e d e v e l o p m e n t o f d r u g r e s is t a n c e , a n dt o a l a r g e e x t e n t o n t h e t o x i c n a t u r e o f t h e d r u g su s e d . R e s e a r c h s h o u l d i d e a l l y b e d i r e c t e d t o w a r d s al e s s t o x i c a n d m o r e b r o a d - r a n g e d a p p r o a c h . O z o n et h e r a p y i s a n e x a m p l e o f s u c h a t r e a t m e n t m o d a l i t y .

O z o n e t h e r a p y h a s b e e n u s e d i n m a n y c l i n i c a ls i t u a t i o n s o v e r t h e p a s t s i x t y y e a r s . T h e h i s t o r y o ft h i s g a s e o u s s u b s t a n c e a n d t h e m a n y w a y s t h a t i t h a sb e e n u s e d a r e w e l l d o c u m e n t e d i n l i t e r a l l y h u n d r e d so f c l i n i c a l p a p e r s . F o r a n e x t e n s i v e b i b l i o g r a p h y a n da n e x c e l l e n t o v e r v i e w o n a l l a sp e c t s o f t h e c l in i c a l u s eo f o z o n e t h e r e a d e r i s r e f e rr e d t o 'Ozone in Medicine'b y S c h i l l i n g a n d V i e b a h n ( 1 0 5 ) . O z o n e h a s b e e nu s e d e x t e n s i v e l y a s a t r e a t m e n t f o r a v a r i e t y o f v i r a ld i s o r d e rs , i n c l u d i n g h e r p e s , a c u t e h e p a t i t i s ( 1 0 6 - 1 0 8 ) ,and chr onic hepa t i t i s ( 109) . A ddi t iona l ly , i t s e f f ec -t i v e n e s s a s a t r e a t m e n t f o r A I D S h a s a l s o b e e n r e -p o r t e d ( 1 1 0 - 1 1 3 ) . F u r t h e r m o r e , n o t o n l y i s o z o n et h e r a p y a n e x t r e m e l y i n e x p e n s i v e a n d e a s y - t o -a d m i n -i s t e r f o r m o f t r e a t m e n t , b u t t h e s a f e t y o f t h i s m o d a l i t yh a s b e e n s t u d i e d a n d i s w i t h o u t p a r a l l e l ( 1 1 4 ) . I ta p p e a r s t h a t t h e o n l y d o w n s i d e t o t h i s t r e a t m e n t i st h e f a c t t h a t i t i s n o n - p a t e n t a b l e a n d h e n c e o f f e r s n or e a l f i n a n c i a l i n c e n t i v e f o r s t u d y . T o t h i s e n d , H o r s tK i e f M . D . , a p i o n e e r i n t h e u s e o f c l in i c a l o z o n e ,w h e n a s k e d w h y t h i s t r e a t m e n t i s v i r t u a l l y u n k n o w no u t s id e o f G e r m a n y , r e s p o n d e d b y s a y i n g, ' N o b o d yi n t h e p h a r m a c e u t i c a l i n d u s t r y c a n s e l l o z o n e . W h e nw e c a n f i n d a w a y t o s e l l o z o n e , I ' m s u r e t h a t o z o n ew i l l b e t h e m o s t i m p o r t a n t d r u g i n t h e w o r l d ' ( 1 1 5 ).I t i s m o s t p r o b a b l e t h a t t h e e f f i c a c y o f o z o n et h e r a p y i n a c u t e a n d c h r o n i c v i r a l d i s o r d e r s i s n o ts o m u c h a r e s u l t o f i ts p o t e n t i n v i t r o a n t i v i ra l a c t i o n( 1 1 6 , 1 1 7 ) , b u t m o r e l i k e l y s t e m s f r o m i t s a b i l i t yt o m o d u l a t e t h e p r o d u c t i o n o f c y t o k i n e s i n P M B C s .T h i s e f f e c t h a s b e e n w e l l d o c u m e n t e d b y B o c c ia n d c o w o r k e r s i n a s e r i e s o f e x p e r i m e n t a l p a p e r s( 1 1 4 , 1 1 8 - 1 2 1 ) . B o c c i h a s b e e n a b l e t o c l e a rl y d e m o n -s t r a t e t h a t w h e n e x p o s e d t o v a r i o u s c o n c e n t r a t i o n s

o f o z o n e , P M B C s r e l ea s e v a r y i n g a m o u n t s o f I L - 2 ,g - I F N , I L - 1 , I L - 6 , T N F - a l p h a , a n d G M - C S F . A d d i -t i o n a l ly , t h e v a r i o u s c o n c e n t r a t i o n s o f o z o n e t h a t a r en o t e d t o s t i m u l a t e t h e o p t i m a l p r o d u c t i o n o f t h e sec y t o k i n e s v e r y c l o s e l y a p p r o x i m a t e t h o s e t h a t h a v eb e e n e m p i r i c a l l y a r r i v e d a t o v e r t h e l a s t f i f t y y e a r ss i m p l y f r o m o b s e r v a t i o n o f t h e r e s u l t s o f c l i n i c a lt r i a l s . S i m i l a r l y , t h e d o s a g e s c h e d u l e t h a t h a s b e e nt r a d i t i o n a l l y u s e d o v e r t h e y e a r s c o r r e l a t e s w e l l w i t ht h e l e n g t h o f t i m e t h a t P M B C s c o n t i n u e t o r e l e a s ec y t o k i n e s a f t e r t h e i r e x p o s u r e t o o z o n e .

O z o n e t h e r a p y : ( a ) i n d u c e s i n c r e a s e d p r o d u c t i o no f t h e c y t o k i n e s IL - 2 a n d g - I F N , t he v e r y s a m ec y t o k i n e s t h a t s e l e c t i v e l y a c t i v a t e C M I ; ( b ) i n c l i n i c a ls t u d i e s h a s b e e n s h o w n t o r e d u c e t h e p r o d u c t i o no f i m m u n o g l o b u l i n s , s u g g e s t in g a d o w n r e g u l a t io n o fA M I ( 1 2 2 ) ; ( c ) h a s b e e n r e p o r t e d t o b e e f f e c t i v ei n s e v e r a l v i r a l d i s e a s e s ; a n d ( d ) h a s b e e n r e p o r t e da s b e i n g e f f e c t i v e i n p a t i e n t s w i t h A I D S . T h e s ef i n d i n g s s t r o n g l y s u g g e s t t h a t o z o n e t h e r a p y m a yh a v e t h e p o t e n t i a l to r e v e r s e t h e s w i t c h i n g p h e n o m e n ad e s c ri b e d a b o v e a s a h a l l m a r k o f p h a s e o n e o f A I D S ,a n d h e n c e r e p r e s e n t a n i n e x p e n s i v e , n o n t o x i c , a n de f f e c t i v e t re a t m e n t . F o r t h i s r e a s o n , a p i l o t s t u d yt o i n v e s t i g a t e t h e p o s s i b l e e f f e c t o f o z o n e o n t h e i nv i v o f u n c t i o n a l c h a r a c t e r i s t i cs o f C M I w a s i n i ti a te d .

F o u r s u b j e c t s w i t h a d v a n c e d A I D S w e r e t r e a t e dw i t h a c o u r s e o f o z o n e t h e r a p y a d m i n i s t e r e d i n t h ef o r m k n o w n a s m a j o r a u t o h e m o t h e r a p y . T h i s t e c h n i-q u e i n v o l v e d t h e w i t h d r a w a l o f 2 0 0 c c o f h e p a r in i z e dw h o l e b l o o d i n t o a v a c u u m b o t t l e t o w h i c h 2 0 0 c c o fa n o z o n e - o x y g e n g a s m i x t u r e a t a c o n c e n t r a t i o n o f8 0 g a m m a ( 8 0 m c g m o f o z o n e t o 1 c c o f o x y g e n ) w a sa d d e d . T h e b l o o d w a s a d m i x e d w i t h t h e o z o n e g a sm i x t u r e f o r 3 0 s e c o n d s a n d t h e n p r o m p t l y r e i n f u s e di n t o t h e p a t i e n t . T h e e n t i r e p r o c e d u r e t o o k a b o u t4 0 m i n u t e s . E a c h p a t i e n t w a s a d m i n i s t e r e d o n e t r e a t -m e n t p e r d a y f o r f r o m 5 t o 1 0 c o n s e c u t i v e d a y s .I n o r d e r t o t e s t th e e f f e c t t h a t t h e t re a t m e n t h a d o n t h ef u n c t i o n a l c h a r a c t e ri s t i cs o f C M I , a m i t o g e n r e s p o n s ep a n e l w a s p e r f o r m e d b o t h a s a b a s e l i n e a n d a f t e r t h et r e a t m e n t p e r i o d w a s o v e r . T h e r e s u l t s a r e d i s p l a y e di n T a b l e 3 .

Discuss ionA c a s e h a s b e e n m a d e f o r a m u l t i f a c t o r i a l e t i o l o g i c a lv i e w o f A I D S . I f t h i s v i e w t u r n s o u t t o b e c o r r e c t ,t h e i m p l i c a t i o n s f o r b o t h p r e v e n t i o n a n d t h e r a p y a r ee n o r m o u s . P r e v e n t i o n w o u l d t h e n t a k e o n a m u c hm o r e c o m p r e h e n s i v e a p p r o a c h t h a n i s c u r r en t l y b e i n gt a k e n . A t t e n t i o n w o u l d n o t b e r e s t r i c t e d t o a n t i -i n f e c t i o n p r e c a u t io n s , b u t i n s t e a d w o u l d a l s o c o n s i d e rp r e v e n t i n g t h e o c c u r r e n c e o f a n y o f t h e f a c t o r s t h a t


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SELECTIVECOMPARTMENTALDOMINANCETable 3 Experim ental results

7 7

Patient CD4 CD8 PHA %A CON-A %A PWN %A%/ABS. %/ABS. (NL > 77) PHA (NL > 35) CON-A (NL > 27) PWMT.B. 5/13 71/192 6.6 1"192% 1.8 1"66% 4.3 '1"297%J.M. 14/207 75/1107 45.5 1"73% 25.4 1"49% 11.1 1"4%B.K. 10/190 75/1390 18.6 'I"21% 4.0 ,1,17% 1.8 "1"72%F.L. 8/202 74/1871 5.7 ,1,30% 1.8 $38% 1.1 ,1,9%AVERAGE 9/ 15 3 73/1140 25.45 1'22% 8.25 t"41% 4.57 1"101%PHA phytohemagglutinin, CON-A concanavalin A, PWM pokeweed mitogen.

a p p e a r i n T a b l e s 1 a n d 2 . L i k e w i s e , t re a t m e n t w o u l dnot be re s t r i c t ed s imply to the admin i s t ra t ion o fan t i - in fec t ious the rap ie s , bu t would a l so focu s heav i lyo n m o d a l i ti e s t h a t m o d u l a t e th e i m m u n e s y s t e m b a c kt o w a r d s C M I d o m i n a n c e . T o t h i s e n d , it a p p e a rs t h a to z o n e t h e r a p y m a y b e h e l p f u l .

T h e s t u d y p r e s e n t e d i s o b v i o u s l y f l a w e d b y b o t hl a c k o f c o n t r o l a n d a d e q u a t e n u m b e r s , a n d i n n ow a y c a n t h e r e s u l t s b e c o n s i d e r e d c o n c l u s i v e . I tw a s u n d e r t a k e n m e r e l y t o d e t e r m i n e i f t h i s p a r t ic u l a rf o r m o f i m m u n o m o d u l a t i n g t h e r a p y c o u l d p r o d u c ethe pos i t i ve c l in i ca l and l abora to ry re su l t s t ha t t heS C D t h e o r y p r e d i c ts w o u l d o c c u r , a n d t h u s s t i m u l at efur the r i nves t iga t ion . In th i s capac i ty i t seems to hav ed o n e j u s t t h a t . T h e f a c t t h a t t h e re w a s a n a v e r a g ei n c r e a s e i n t h e i m m u n o l o g i c a l r e s p o n s e t o a l l t h r e em i t o g e n s i s c o n s i s t e n t w i t h w h a t S C D p r e d i ct s . A d d i -t i o n a ll y , a ll o f t h e p a t ie n t s w h o w e r e s y m p t o m a t i ce x p e r i e n c e d c l i n ic a l i m p r o v e m e n t , w h e r e a s n o p a t i e n te n c o u n t e r e d d e t e r i o r a t io n o f h i s c o n d i t i o n d u r i n g t h et rea tment pe r iod . Al so , no te tha t a l l o f t hese pa t i en t sw e r e i n p h a s e t w o o f t h e d i s e a s e . I f i t i s p o s s i b l et o e n h a n c e i m m u n e f u n c t i o n i n t h i s p h a s e , w h e nt h e d o m i n a n c e s w i t c h i n g p h e n o m e n a m a y i n f a c tb e i r r e v e r s i b l e , t h e n p e r h a p s e v e n g r e a t e r r e s u l t sc o u l d b e o b s e r v e d i f p h a s e o n e p a t i e n ts w e r e t r e at e d .Indeed , a con t ro l l ed t r i a l o f pa t i en t s i n bo th phasesw o u l d b e t h e m o s t a p p r o p r i a t e f o r m o f i n v es t i g at i o n .T h i s l i n e o f t h i n k i n g a l s o p r e s e n t s a n o t h e r v e r yt e m p t i n g s c e n a r io . A s s u m i n g t h a t A I D S i s n o t c a u s e db y H I V , t h e n d e m o n s t r a t in g t h e p r e s e n c e o f H I Va n t i b o d ie s m a y n o t b e t h e m o s t e f f e c t i v e w a y t os c r e e n f o r s t ag e o n e o f t h e d i s ea s e . A s u p e r i o r m e t h o do f s c r e e n i n g m a y b e t o a s s es s C M I f u n c t i o n w i t ht e s ts s u c h a s s i m p l e s k i n t e s t i n g o r w i t h t h e m i t o g e nr e s p o n s e p a n e l . N o d o u b t , g i v e n t h e f i n d i n g s i nthe l i t e ra tu re , i t cou ld be accura t e ly p red ic t ed tha t ar a t h e r la r g e s e g m e n t o f th e ' a t- r i s k g r o u p s ' w o u l d b ef o u n d t o b e f u n c t i o n i n g i n s t a g e o n e o f t h e d i s e a s e ;A n y p a t i e n t w i t h n o r m a l C D 4 / C D 8 v a l u e s i n t h ef a c e o f a b n o r m a l C M I f u n c t i o n a s s a y s , re g a r d l e s so f t h e i r H I V s t a t u s , s h o u l d b e c o n s i d e r e d i n t h e

p o t e n t i a l l y r e v e r s i b l e s t a g e o n e o f t h e d i s e a s e a n ds h o u l d b e t r e a t e d w i t h i m m u n e m o d u l a t i n g t h e r a p i e su n t i l C M I f u n c t i o n i s d e t e r m i n e d t o b e n o r m a l . T h i st r e a t m e n t s h o u l d b e r e n d e r e d w h e t h e r t h a t p a t i e n th a s a n t i b o d i e s to H I V o r n o t.

Statement o f research approva lT h e e x p e r i m e n t a l r e s e ar c h d e s c r i b e d i n t h i s p a p e r w a sa p p r o v e d a n d o v e r s e e n b y t h e I n s t i t u t i o n a l R e v i e wB o a r d o f t h e I n t e r n a t i o n a l B i o - O x i d a t i v e M e d i c i n eF o u n d a t i o n , O k l a h o m a C i t y , O K , U S A . T h e e x p e r i -m e n t a l d e s i g n , a l l r el e a s e s , a n d t h e i n f o r m e d c o n s e n tw e r e j u d g e d t o b e i n f u l l c o n f o r m i t y w i th a h i g hs t anda rd o f e th ic s .

A c k n o w l e d g e m e n tSpecial appreciation is expressed to Carole Keith at the SavittMedical Library, University of Nevada School of Medicine for allher help in the preparation of this manuscript.

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selective compartmental dominance

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