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Hepatitis B and hepatocellular particles
CURRENT TOPICS are related pathogenetically or etiologically to these two mechanisms, it is difficuh to separate the diseases of the aged from the pathogenesis or etiology of aging in general. In favor o f the i m m u n e pathogenesis o f primary aging is the evidence that dietary manipulation can alter i m m u n e fimction and dysfimction and can improve optimal functional longevity. T h e precise interaction between i m m u n e response genes, self-recognition patterns, h o r m o n a l balance, and fimctional longevity is still trader investigation. In conclusion, we propose that optimal fnnctional longevity is genetically based and controlled by a Ii)'potlletical hmgevityhomeostasis gene complex that includes immnne response genes and genes that control endocrine balance. An aheration in fimctional longevity is most likely p r o d u c e d by genetic defects, including defects in i m m u n e response genes, which lead to an imbalance between the external anti internal environment, i.e., detrimental virns-host interactions and e n d o c r i n e - i m n n m e system dysfimctions. T h e precise relationship o f various diseases to the .rate o f decline o f fimction remains obscure. References 1. Waiford. R. L.: The hnmunologic Theory of Aging. Copenhagen, Munksgaard, 1969. 2. Greenberg, L.J., and Ynnis, E.J.: Immunologicalcontrol of aging: a possible primary event. Gerontologia, 18:247-260, 1972. 3. Yunis, E. J., Stutman, O., and Good, R. A.: The thymus and immune functions in animals and man. Animal Modcls for Biomedical Research. IV. ISBN 0-30901918-4, Nat. Acad. Sci.: II1, 1971. 4. Fabris, N., anti Sorkin, E.: Relation of lyml~hoidsystem and hormones to aging. Second International Workshop on Primary hnnnmodeficiency Diseases in Man. St. I'etersburg, Florida, 1973.
HEPATITIS B AND HEPATOCELLULAR PARTICLES FEx'rox SCHAFFNER, M.D.,* A,~D MICttAEL GrRI~ER, M.D.t Viral hepatitis had been separated into two f o r m s - s e r u m hepatitis and infections hepat i t i s - b n t only on clinical and epidemiologic grounds for 30 )'ears, until B l u m b e r g and his coworkers described the association o f Australia antigen with serum hepatitis. In the enstfing years the nature o f the Australia antigen, now called hepatitis B antigen (HB Ag), Ires been the snbject of vigorous investigation. Its chemi*George Baehr l'rofessor and Acting Chairman, Department of Medicine, Mount Sinai School of Medicine of the City University of New York, New York. ?Assistant Professor of Pathology, Mount Sinai School of Medicine of the City University of New York, New York.
cal nature as a lipoprotein as well as some o f its antigenic determinants have been elucidated. It has been fotmd to be associated with three distinct particnlate forms in the sernm: a 20 nm. sphernle, a tnbnle o r r o d 20 rim. in diameter and 50 to 250 rim. in length, and a large particle described by Dane et al. as measnring 42 nm. in d i a m e t e r and consisting of a core and a shell. All have antigenic determinants in common, but the core o f the Dane particle has additional antigenic material. T h e discovery o f these particles in the serum Itas renewed interest in tile search for the hepatitis virus in liver cells. Until this time ahnost two decades o f electron microscopic exantination of the liver had proved frnitless. T h e i m m n n o fluorescence observations o f Nowoslawski and Iris g r o u p in Poland have indicated that the antigenic material is indeed in tile hepatocellular cytoplasm and nuclei, particularly in chronic hepatitis and less so in the acute phase o f the disease. Various descriptions o f nuclear and cytoplasmic particles in hepatocytes have followed, but convincing evidence that the sernm and tissue particles are related had not been forthcoming. An epidemic o f hepatitis B in a Montreal renal-dialysis nlfit provided H u a n g and his coworkers with the o p p o r t u n i t y to examine the livers o f renal transplant patients treated with immnnosnppressive drngs. T h e y fonnd numerous nnclear particles, 21 to 25 nm. in diameter, that had the same antigenic determinants as hepatitis B antigen in serum. We confirmed these observations a n d found, as did H u a n g et al., that imnmnosuppressive therapy appeared to increase the n n m b e r of particles p e r nncleus and the n n m b e r o f nuclei affected, bnt the same particles could be fonnd in some nuclei in asymptomatic carriers with minimal o r no hepatic dysfnnction. ~ In these individuals, however, rod-like cytoplasmic particles, 20 to 30 nm. in diameter, conld be seen, often appearing r o u n d because tlte platte of sectioning passed t h r o u g h rods. T h e s e rods and circnlar particles, if they are separate and distinct structures, also have antigenic determinants o f hepatitis B antigen, as shown by immunoelectron microscopy. T h e y are within lunlens o f profiles o f endoplasmic reticnlnm. Fnrthertnore, the membranes o f the endoplasmic reticnlnm s n r r o n n d i n g the rods also bind tile labeled antibody. This finding suggests that the antigenic material in tile rods is manufactured o r at least assembled at this site in the hepatocellular cytoplasm. Moreover, the endoplasmic reticuhnn o f the hepatocytes is greatly hypertrophied in cells containing many rods, a finding that can be recognized in hematoxylin and eosin stained sections by the pale eosinophilic ground-glass a p p e a r a n c e o f the cytoplasm o f some hepatocytes.
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It is t e t n p t i n g to speculate that the n u c l e a r spherical particles are virions without coat a n d that the rods in tile e n d o p l a s m i c r e t i c u l u m are viral coat m a d e by the host hepatocytes. A f n r t h e r e x t r a p o l a t i o n m a d e b)" H n a u g a n d his coworkers in this issue oflluman Pathologq." leads to the conclusion that D a n e particles in tile s e r u m are complete viral assemblies o f core a n d coat, a n d that rods in the serttnl are derived from the bepatocellular cytoplasmic rods. T h e rods in t u r n break into the small 20 nm. particles in the s e r u n t or, p e r h a p s to some extent, even in hepatocytes. T h e difference between rods a n d the small spherical particles may be related to the d e g r e e o f twisting o f the chains o f p r o t e i n that constitute the h o s t - p r o d u c e d viral coat material, z M a n y u n a n s w e r e d questions r e m a i n . T i l e m e c l m n i s m b)" which tile virus injtn'es the cell is u n k n o w n , as is the a p p e a r a n c e o f the virus in the i n j u r e d o r d y i n g cell. Moreover, the role o f i m m u n o s u p p r e s s i o n in m a k i n g n u c l e a r particles visible requires elucidation as does the r01e o f tile rods. T i l e latter has practical significance, because the coat material, if i n d e e d
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that is what rods are, may protect the host first b)" c o v e r i n g the i n j u r i o u s core a n d second by s t i m u l a t i n g tile i m m u n e m e c l m n i s m o f tile host. s Proof is n e e d e d tlmt rods alone o r the small r o u n d particles derived f r o m t h e m are not infectious. Such i n f o r m a t i o n must be obtained in a n i m a l s or tissue cultures by techniques that r e m a i n to be perfected. T h e decade o f the 1970's will almost surely b r i n g the answers to most o f these questions a n d with thenL it is to be hoped, control of a d a n g e r o u s a n d costly disease. References 1. (;erber, M. A., 1ladzi)annis, S., Vissoulis,C., Schaffner, F., Paronetto, F., and l'opper, tl.: tlepatitis B antigen: nature and distribution of c)toplasmic antigen in hepatoc)'tes of carriers, l'roc. Soc. Exp. Biol. Med. In press. 2. Ilirsclmmn, S. Z., Vernace, S., and Schaffner, F.: Morphologic studies of Australia antigen: structural changes due to varying conditions of pit and ionic strength. J. Infect. Dis. In press, 3. Popper, tl., and Mackay, I. R.: Relation between Australia antigen and autoimmuue hepatitis. Lancet, 1:1161116-t, 1972.
HEPATITIS B AND HEPATOCELLULAR PARTICLES FEx'rox SCHAFFNER, M.D.,* A,~D MICttAEL GrRI~ER, M.D.t Viral hepatitis had been separated into two f o r m s - s e r u m hepatitis and infections hepat i t i s - b n t only on clinical and epidemiologic grounds for 30 )'ears, until B l u m b e r g and his coworkers described the association o f Australia antigen with serum hepatitis. In the enstfing years the nature o f the Australia antigen, now called hepatitis B antigen (HB Ag), Ires been the snbject of vigorous investigation. Its chemi*George Baehr l'rofessor and Acting Chairman, Department of Medicine, Mount Sinai School of Medicine of the City University of New York, New York. ?Assistant Professor of Pathology, Mount Sinai School of Medicine of the City University of New York, New York.
cal nature as a lipoprotein as well as some o f its antigenic determinants have been elucidated. It has been fotmd to be associated with three distinct particnlate forms in the sernm: a 20 nm. sphernle, a tnbnle o r r o d 20 rim. in diameter and 50 to 250 rim. in length, and a large particle described by Dane et al. as measnring 42 nm. in d i a m e t e r and consisting of a core and a shell. All have antigenic determinants in common, but the core o f the Dane particle has additional antigenic material. T h e discovery o f these particles in the serum Itas renewed interest in tile search for the hepatitis virus in liver cells. Until this time ahnost two decades o f electron microscopic exantination of the liver had proved frnitless. T h e i m m n n o fluorescence observations o f Nowoslawski and Iris g r o u p in Poland have indicated that the antigenic material is indeed in tile hepatocellular cytoplasm and nuclei, particularly in chronic hepatitis and less so in the acute phase o f the disease. Various descriptions o f nuclear and cytoplasmic particles in hepatocytes have followed, but convincing evidence that the sernm and tissue particles are related had not been forthcoming. An epidemic o f hepatitis B in a Montreal renal-dialysis nlfit provided H u a n g and his coworkers with the o p p o r t u n i t y to examine the livers o f renal transplant patients treated with immnnosnppressive drngs. T h e y fonnd numerous nnclear particles, 21 to 25 nm. in diameter, that had the same antigenic determinants as hepatitis B antigen in serum. We confirmed these observations a n d found, as did H u a n g et al., that imnmnosuppressive therapy appeared to increase the n n m b e r of particles p e r nncleus and the n n m b e r o f nuclei affected, bnt the same particles could be fonnd in some nuclei in asymptomatic carriers with minimal o r no hepatic dysfnnction. ~ In these individuals, however, rod-like cytoplasmic particles, 20 to 30 nm. in diameter, conld be seen, often appearing r o u n d because tlte platte of sectioning passed t h r o u g h rods. T h e s e rods and circnlar particles, if they are separate and distinct structures, also have antigenic determinants o f hepatitis B antigen, as shown by immunoelectron microscopy. T h e y are within lunlens o f profiles o f endoplasmic reticnlnm. Fnrthertnore, the membranes o f the endoplasmic reticnlnm s n r r o n n d i n g the rods also bind tile labeled antibody. This finding suggests that the antigenic material in tile rods is manufactured o r at least assembled at this site in the hepatocellular cytoplasm. Moreover, the endoplasmic reticuhnn o f the hepatocytes is greatly hypertrophied in cells containing many rods, a finding that can be recognized in hematoxylin and eosin stained sections by the pale eosinophilic ground-glass a p p e a r a n c e o f the cytoplasm o f some hepatocytes.
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It is t e t n p t i n g to speculate that the n u c l e a r spherical particles are virions without coat a n d that the rods in tile e n d o p l a s m i c r e t i c u l u m are viral coat m a d e by the host hepatocytes. A f n r t h e r e x t r a p o l a t i o n m a d e b)" H n a u g a n d his coworkers in this issue oflluman Pathologq." leads to the conclusion that D a n e particles in tile s e r u m are complete viral assemblies o f core a n d coat, a n d that rods in the serttnl are derived from the bepatocellular cytoplasmic rods. T h e rods in t u r n break into the small 20 nm. particles in the s e r u n t or, p e r h a p s to some extent, even in hepatocytes. T h e difference between rods a n d the small spherical particles may be related to the d e g r e e o f twisting o f the chains o f p r o t e i n that constitute the h o s t - p r o d u c e d viral coat material, z M a n y u n a n s w e r e d questions r e m a i n . T i l e m e c l m n i s m b)" which tile virus injtn'es the cell is u n k n o w n , as is the a p p e a r a n c e o f the virus in the i n j u r e d o r d y i n g cell. Moreover, the role o f i m m u n o s u p p r e s s i o n in m a k i n g n u c l e a r particles visible requires elucidation as does the r01e o f tile rods. T i l e latter has practical significance, because the coat material, if i n d e e d
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that is what rods are, may protect the host first b)" c o v e r i n g the i n j u r i o u s core a n d second by s t i m u l a t i n g tile i m m u n e m e c l m n i s m o f tile host. s Proof is n e e d e d tlmt rods alone o r the small r o u n d particles derived f r o m t h e m are not infectious. Such i n f o r m a t i o n must be obtained in a n i m a l s or tissue cultures by techniques that r e m a i n to be perfected. T h e decade o f the 1970's will almost surely b r i n g the answers to most o f these questions a n d with thenL it is to be hoped, control of a d a n g e r o u s a n d costly disease. References 1. (;erber, M. A., 1ladzi)annis, S., Vissoulis,C., Schaffner, F., Paronetto, F., and l'opper, tl.: tlepatitis B antigen: nature and distribution of c)toplasmic antigen in hepatoc)'tes of carriers, l'roc. Soc. Exp. Biol. Med. In press. 2. Ilirsclmmn, S. Z., Vernace, S., and Schaffner, F.: Morphologic studies of Australia antigen: structural changes due to varying conditions of pit and ionic strength. J. Infect. Dis. In press, 3. Popper, tl., and Mackay, I. R.: Relation between Australia antigen and autoimmuue hepatitis. Lancet, 1:1161116-t, 1972.