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Phosphatidylcholine: Biochemical and clinical aspects of essential phospholipids
TIBS - June 1977
140 into a less variable framework is considered by J. D. Capra. No matter whether the germ line genes code for all or only parts of the variable domain, it is generally agreed that a strict germ line theory implies the existence of a large (probably at least 104) number of antibody genes. In contrast, an extreme somatic theory requires many fewer such genes. When methods for enumerating specific DNA sequences were developed, it was hoped that a clear experimental demonstration of the number of antibody specificity genes would be forthcoming. However, as detailed by Williamson and Fitzmaurice, there are difficulties in the application of the hybridization technique to the antibody problem (e.g. purity of nucleic acid probe, extent of cross-reaction between related but non-identical nucleic acid sequences). Nonetheless, experimental results presented by Tonegawa and Steinberg are interpreted to indicate that there are fewer genes than antibodies, although the total number of such genes cannot yet be estimated. Recently, it has been possible to show that certain genes coding for antibody combining sites are inherited, and a number of examples are discussed by Braun et al. The gene product can be identified by several methods, for example, amino acid sequence of the variable region, isoelectric focusing pattern, antigenie specificity associated with the combining site (idiotype). Data presented by Du Pasquier and Wabl on the antibody responses of isogenetic amphibia are also interpreted according to the notion that at least some antibody specificities are coded in the germ line. The great appeal of the somatic diversification view is its economy and flexibility. The DNA pool of every cell (the germ line) need not be burdened with genes coding for every possible antigen. Instead, the required diversity is generated from a relatively restricted number of germ line genes. The somatic model requires both a mechanism for generating the diversity, and a method for selecting useful responses (e.g. functional molecules). A novel possible diversifier is discussed by Baltimore and colleagues. The enzyme, terminal deoxynucleotidyl transferase, is a DNA polymerase with tissue distribution restricted to thymus and bone marrow, thereby inviting speculation that it may be involved in the generation of diversity in cells of the immune system. Such an interpretation is limited by the inability to demonstrate the enzyme in precursors of antibody forming cells (B cells), although it is easily detected in cells of the T cell lineage. Although antigen is generally thought
to play an important role in selecting the appropriate immune response, it is not usually accorded a direct role in antibody diversification. It was not always so. A central tenet of the ‘instructionist’ views that were widely held until the mid-1960s was that the antigen actually dictates the sequence and/or folding of the corresponding antibody. With the demonstration that sequence governs both folding and specificity, a direct role for antigen in antibody diversification was generally abandoned. In modified form, it has now been revived with imagination and fervor by A. J. Cunningham who provides evidence that at least some diversification occurs after, and presumably as a result of, antigenic stimulation. This notion is supported by R.K. Gershon who argues that certain T cell dependent antibodies (especially those of high affinity) appear only after antigen is given. An original compromise between somatic and germ line views is suggested by N.R. Klinman and colleagues, based on a comparison of the B cell repertoire of neonatal and adult mice. They propose that a limited amount of germ line information is expanded in a predetermined (i.e. genetically controlled and antigenindependent) manner to generate the much greater number of total specificities. It is necessary that any explanation for antibody diversification also accounts for tolerance, the failure to respond to selfantigens. This problem is addressed by P.A. Bretscher who points out that selfnonself discrimination must have evolved before GOD. A related issue, the regulation of ongoing immune responses, is considered by Adam and Weiler who present a model based on the ‘network theory’ originally proposed by N. K. Jeme (in Cellular Selection and Regulation in the Immune Response, pp. 39-48 (ed. by G. M. Edelman) Raven Press, N.Y. 1974), in which antibodies produced against the antibodies themselves (i.e. anti-idiotypes) serve the regulatory function. Although much of the material presented is inherently complex, most of the individual essays are clearly written and can be understood by anyone with some knowledge of current immunologic theoryand terminology (e.g. T and B cell, idiotype and allotype). Fulfilling the promise of the title, the book provides a timely overview of current thinking and speculation on the nature of GOD. LISA STEINER Lisa Steiner is Associate Professor in the Department of Biology at Massachusetts Institute of Technology, Cambridge, Mass. U.S.A.
Essential phospholipids Phosphatidylcholine : Biochemical and Clinical Aspects of Essential Phospholipids edited by H. Peeters, published by SpringerVerlag, Berlin, 1976. DM 38.- ($15.60) (viii+254pages) This book covers the proceedings of a symposium held at the Simon Stevin Institute in Bruges, Belgium, 15-18 November 1975, on the chemistry and biology of polyunsaturated phosphatidylcholines. These are also referred to as essential phospholipids (EPL) because they have essential fatty acids as their esters. At the symposium, particular attention was given to the prototype 1, 2-dilinoleolyl phosphatidylcholine which some of the contributors had used in drug form (EPLNattermann or Lipostabil) for pharmacokinetic studies and therapeutic trials in clinical and experimental hyperlipoproteinemias and atherosclerosis. The glossary and the introductory reviews provide a useful background for studies on the fate of orally or intravenously administered EPL and on the enzymes postulated to be involved in such processes. The other sections convey a rather optimistic outlook on EPL as effective hypolipidemic agents and ameliorators of both cholesteryl ester deposition in the arterial wall and regression of experimental atherosclerosis. In addition, the potential of EPL in the treatment of cardiovascular disorders surfaces from the studies showing that these lipids increase blood flow and decrease the capacity of platelets to aggregate. As a whole, the book, which is 248 pages long, is well organized. The 10 chapters, contributed by 36 authors, follow a logical order, and each has an informative summary. The subject index is well compiled. All of these features, plus the handsome soft cover, make this new volume a welcome addition to the literature. The book covers an area that is still in the developmental phase. Those interested in phospholipid research are likely to find these Proceedings both interesting and challenging. They are also likely to perceive that many ideas are still unsettled and that more extensive work is needed for a precise definition of the role played by EPL in biology and medicine. The editor, the authors, and the publisher deserve praise for promptly publishing useful information gathered from a timely A. M. SCANU symposium. A. M. Scanu is Professor of Biochemistry and Medicine at the University of Chicago, Chicago, Illinois, U.S.A.
140 into a less variable framework is considered by J. D. Capra. No matter whether the germ line genes code for all or only parts of the variable domain, it is generally agreed that a strict germ line theory implies the existence of a large (probably at least 104) number of antibody genes. In contrast, an extreme somatic theory requires many fewer such genes. When methods for enumerating specific DNA sequences were developed, it was hoped that a clear experimental demonstration of the number of antibody specificity genes would be forthcoming. However, as detailed by Williamson and Fitzmaurice, there are difficulties in the application of the hybridization technique to the antibody problem (e.g. purity of nucleic acid probe, extent of cross-reaction between related but non-identical nucleic acid sequences). Nonetheless, experimental results presented by Tonegawa and Steinberg are interpreted to indicate that there are fewer genes than antibodies, although the total number of such genes cannot yet be estimated. Recently, it has been possible to show that certain genes coding for antibody combining sites are inherited, and a number of examples are discussed by Braun et al. The gene product can be identified by several methods, for example, amino acid sequence of the variable region, isoelectric focusing pattern, antigenie specificity associated with the combining site (idiotype). Data presented by Du Pasquier and Wabl on the antibody responses of isogenetic amphibia are also interpreted according to the notion that at least some antibody specificities are coded in the germ line. The great appeal of the somatic diversification view is its economy and flexibility. The DNA pool of every cell (the germ line) need not be burdened with genes coding for every possible antigen. Instead, the required diversity is generated from a relatively restricted number of germ line genes. The somatic model requires both a mechanism for generating the diversity, and a method for selecting useful responses (e.g. functional molecules). A novel possible diversifier is discussed by Baltimore and colleagues. The enzyme, terminal deoxynucleotidyl transferase, is a DNA polymerase with tissue distribution restricted to thymus and bone marrow, thereby inviting speculation that it may be involved in the generation of diversity in cells of the immune system. Such an interpretation is limited by the inability to demonstrate the enzyme in precursors of antibody forming cells (B cells), although it is easily detected in cells of the T cell lineage. Although antigen is generally thought
to play an important role in selecting the appropriate immune response, it is not usually accorded a direct role in antibody diversification. It was not always so. A central tenet of the ‘instructionist’ views that were widely held until the mid-1960s was that the antigen actually dictates the sequence and/or folding of the corresponding antibody. With the demonstration that sequence governs both folding and specificity, a direct role for antigen in antibody diversification was generally abandoned. In modified form, it has now been revived with imagination and fervor by A. J. Cunningham who provides evidence that at least some diversification occurs after, and presumably as a result of, antigenic stimulation. This notion is supported by R.K. Gershon who argues that certain T cell dependent antibodies (especially those of high affinity) appear only after antigen is given. An original compromise between somatic and germ line views is suggested by N.R. Klinman and colleagues, based on a comparison of the B cell repertoire of neonatal and adult mice. They propose that a limited amount of germ line information is expanded in a predetermined (i.e. genetically controlled and antigenindependent) manner to generate the much greater number of total specificities. It is necessary that any explanation for antibody diversification also accounts for tolerance, the failure to respond to selfantigens. This problem is addressed by P.A. Bretscher who points out that selfnonself discrimination must have evolved before GOD. A related issue, the regulation of ongoing immune responses, is considered by Adam and Weiler who present a model based on the ‘network theory’ originally proposed by N. K. Jeme (in Cellular Selection and Regulation in the Immune Response, pp. 39-48 (ed. by G. M. Edelman) Raven Press, N.Y. 1974), in which antibodies produced against the antibodies themselves (i.e. anti-idiotypes) serve the regulatory function. Although much of the material presented is inherently complex, most of the individual essays are clearly written and can be understood by anyone with some knowledge of current immunologic theoryand terminology (e.g. T and B cell, idiotype and allotype). Fulfilling the promise of the title, the book provides a timely overview of current thinking and speculation on the nature of GOD. LISA STEINER Lisa Steiner is Associate Professor in the Department of Biology at Massachusetts Institute of Technology, Cambridge, Mass. U.S.A.
Essential phospholipids Phosphatidylcholine : Biochemical and Clinical Aspects of Essential Phospholipids edited by H. Peeters, published by SpringerVerlag, Berlin, 1976. DM 38.- ($15.60) (viii+254pages) This book covers the proceedings of a symposium held at the Simon Stevin Institute in Bruges, Belgium, 15-18 November 1975, on the chemistry and biology of polyunsaturated phosphatidylcholines. These are also referred to as essential phospholipids (EPL) because they have essential fatty acids as their esters. At the symposium, particular attention was given to the prototype 1, 2-dilinoleolyl phosphatidylcholine which some of the contributors had used in drug form (EPLNattermann or Lipostabil) for pharmacokinetic studies and therapeutic trials in clinical and experimental hyperlipoproteinemias and atherosclerosis. The glossary and the introductory reviews provide a useful background for studies on the fate of orally or intravenously administered EPL and on the enzymes postulated to be involved in such processes. The other sections convey a rather optimistic outlook on EPL as effective hypolipidemic agents and ameliorators of both cholesteryl ester deposition in the arterial wall and regression of experimental atherosclerosis. In addition, the potential of EPL in the treatment of cardiovascular disorders surfaces from the studies showing that these lipids increase blood flow and decrease the capacity of platelets to aggregate. As a whole, the book, which is 248 pages long, is well organized. The 10 chapters, contributed by 36 authors, follow a logical order, and each has an informative summary. The subject index is well compiled. All of these features, plus the handsome soft cover, make this new volume a welcome addition to the literature. The book covers an area that is still in the developmental phase. Those interested in phospholipid research are likely to find these Proceedings both interesting and challenging. They are also likely to perceive that many ideas are still unsettled and that more extensive work is needed for a precise definition of the role played by EPL in biology and medicine. The editor, the authors, and the publisher deserve praise for promptly publishing useful information gathered from a timely A. M. SCANU symposium. A. M. Scanu is Professor of Biochemistry and Medicine at the University of Chicago, Chicago, Illinois, U.S.A.