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Early evolution of MHC polymorphism
J. theor. Biol. (1991) 150, 451-456
Early Evolution of M H C Polymorphism D. R. FORSDYKE
Departrr,'nt of Biochemistry, Queen's University, Kingston, Ontario, Canada K 7 L 3 N 6 (Received on 1 May 1990, Accepted on 3 January 1991) There is unwarranted satisfaction with the view that MHC polymorphism evolved because there was a selective advantage in having a variety of MHC proteins to bind a variety of peptide subsets for presentation to T cells. While this may, in part, explain its maintainance, polymorphism may have evolved initially to reject foreign virus "grafts". The possession of similar membranes promotes aggregation between "like" cells, but it also promotes aggregation between the ceils and viruses which retain membrane components of their previous host. The selection pressure afforded by hostile virus "grafts" would favour cells which developed polymorphic membrane components (since "like" will not aggregate with "not-like'). This polymorphism would have evolved before the appearance of multicellular organisms. Thus, the evolution of modem immune systems would have been imposed upon pre-existing polymorphic systems. A path this evolution may have taken involves the development of mechanisms for intracellular distinction between self and not-self.
1. Introduction The hypotheses that the education of potential immunologically competent cells requires both negative selection (Burnet, 1959) and positive selection (Forsdyke, 1975) have found considerable experimental support (reviewed in Schwartz, 1989). However, the relationship of these processes to the p h e n o m e n o n of MHC polymorphism is poorly understood. It is argued that, although histocompatibility antigens were first recognized through tissue grafting experiments, such grafting does not normally occur in nature. Thus, M H C polymorphism could not have evolved in response to a selection pressure generated by the need to reject foreign grafts. So we must look elsewhere for an explanation for the origin of MHC polymorphism. This view is widely disseminated in textbooks and popular science journals (Marrack & Kappler, 1986; Hopkins, 1987; Grey et al., 1989; Raft, 1989). The discovery of MHC-restricted immune responsiveness (Zinkernagel & Doherty, 1974) and the role o f M H C molecules in antigen presentation (Grey et al., 1989) provided a convenient explanation for M H C polymorphism. Extensive M H C polymorphism means that most individuals are heterozygotes. Since all potentially immunogenic peptides cannot bind to one M H C gene product (Grey et al., 1989), having two M H C gene products doubles the chance that an individual will be able to assemble a functional M H C - p e p t i d e complex ("heterozygote advantage", "overdominant selection"; Hughes & Nei, 1989). However, this factor-of-two advantage does not seem particularly compelling. A doubling of the number o f M H C loci would achieve the same result. Those of the " g r o u p selectionist" school would argue 451
0022-5193/91/120451+06 $03.00/0
© 1991 Academic Press Limited
452
D.R.
FORSDYKE
for a much greater advantage at the population level. Thus, a group which had M H C polymorphism would be likely to have at least some members who would have a M H C protein able to form a functional complex with a peptide from a virulent pathogen. However, the general validity of group selectionist arguments has been questioned (Dawkins, 1976).
2. Viruses are Grafts
There would be no need to look to explanations such as the above if graft transplantation were an "experiment of nature". Actually, such experiments have probably been going on since life first evolved. When a virus passes from one host cell to another it may transfer some of the cell membrane components of its former host. These may include MHC proteins (Hecht & Summers, 1976; Bubbers & Lilly, 1977; Gelderblom et al., 1987). Such a virus is, in essence, a graft. Individuals highly polymorphic for a membrane component transferred by the virus are likely to reject the virus "graft" as foreign, just as they would a cellular allograft. This rejection response could have evolved before the evolution of the immune response as we know it today. The membranes of the "survival machines" within which the early "replicators" (RNA, DNA) encased themselves (Dawkins, 1976), are initially likely to have been quite similar to each other. We and others have shown that, in an appropriate environment, it can be thermodynamically favourable for cells with similar surface membranes to aggregate preferentially, "like with like" (Forsdyke & Ford, 1983a, b; Armstrong, 1989). Similarly, a nucleic acid fragment (selfish gene/virus) could readily transfer by budding from its cell of origin and, enveloped in the cell membrane of its former host, aggregating with a "like" target cell (Fig. 1). In this circumstance, a cell which had evolved prototypic M H C proteins with some degree of polymorphism, would be better prepared to maintain the integrity of its own nucleic acid by preventing invasion by a foreign nucleic acid (since "like" does not aggregate with "not-like"). MHC proteins could have evolved as a defence against viruses before the evolution of multicellular organisms. The evolutionary pressure to generate extensive polymorphism would have been high, since the greater the polymorphism, the less likely would be a virus to encounter a "like" cell.
3. Multicellularity Provokes Acceleration of the Arms Race
However, multicellular organisms, each cell of which would bear "like" polymorphic antigens, would provide a fertile soil for viruses to spread between cells. Thus, the evolution of the multicellular state should be accompanied by a strong pressure for the evolution of immune systems. This evolution would be imposed upon, and might incorporate and adapt, a pre-existing polymorphic M H C system. As long as they d e p e n d e d upon the like-with-like mechanism to associate with their target cell membrane, virus envelopes would have been indistinguishable from self. However, at an early stage of their evolution, balked by the development of
MHC
POLYMORPHISM
453
(a)
(b)
(c)
(d)
FIG. 1. Early evolution of virus-cell interactions. (a) A virus enveloped in the membrane of its former host is able to bind to a "like" target cell possessing similar membrane characteristics. Host and virus genomes are represented by wavy lines. The rectangle in the host genome represents a gene encoding a minor host surface component. The latter is represented by open boxes embedded in the membrane with "caps" pointing to the exterior. (b) Polymorphism of membrane components (represented on the left by closed boxes and on the right by closed boxes with caps) prevents viral attachment by the tow affinity like-with-like mechanism. (c) A virus incorporates the host gene encoding the minor membrane component and directs increased synthesis of this component. This permits low efficiency encounters with its target cell by the like-with-like mechanism, (d) Mutation of the viral copy of the host gene (shaded rectangle) to generate a surface ligand with high affinity for the target cell receptor. M H C - p o l y m o r p h i s m , viruses w o u l d have d e v e l o p e d specific coat p r o t e i n s c a p a b l e o f r e c o g n i z i n g n o n - p o l y m o r p h i c host cell surface p r o t e i n s as receptors for virus a t t a c h m e n t . Steps in d e v e l o p i n g this capacity m i g h t have i n c l u d e d , (i) i n c o r p o r a t i o n o f a copy o f the host gene e n c o d i n g the n o n - p o l y m o r p h i c p r o t e i n into the virus g e n o m e , a n d (ii) m u t a t i o n o f the latter to increase the affinity o f b i n d i n g of the g e n e p r o d u c t with the e x t r a c e l l u l a r d o m a i n o f the host-ceU surface d e t e r m i n a n t (Fig. 1). T h u s , the p r e - e x i s t i n g like-with-like affinity o f host m o l e c u l e s p r e s e n t i n g n o n - p o l y m o r p h i c surface d e t e r m i n a n t s w o u l d have b e e n e n h a n c e d by m u t a t i o n s o f the viral copy of the s a m e gene. The virus coat p r o t e i n i i g a n d a n d its host cell r e c e p t o r w o u l d have e v o l v e d from a c o m m o n source, a p r o t o t y p i c n o n - p o l y m o r p h i c host cell receptor. I n e n t e r i n g a n " a r m s r a c e " with its host ( D a w k i n s , 1976), the
454
D. R, F O R S D Y K E
virus would have "shown its colours" (i.e. acquired a virus-specific surface protein), thus paving the way for specific recognition by a prototypic host immune system. Initially this might have taken the form of the release of soluble decoy receptors from target cells (Ehrlich, 1900). With tissue differentiation, certain cells would specialize in generating decoy receptors. A local tendency to hypermutate would generate a decoy receptor (prototypic antibody) repertoire which might protect organisms against a range of viruses. This would require the coevolution of extracellular mechanisms for distinguishing self from not-self, as discussed previously (Forsdyke, 1968, 1969, 1975). In such a frame-work the immune system as we know it today could have evolved. 4. Simplicity Precedes Complexity. Positive Selection
It is possible that one prototypic antibody locus (with multiple V region genes) would have had the opportunity to develop evolutionarily before duplication to generate other loci. A simple model has been considered elsewhere, perhaps corresponding to an organism which once existed (or may even still exist). The model organism had a single hypervariable locus and could have mounted both cellmediated and humoral immune responses (Forsdyke, 1968, 1969, 1975). The model proposed that enhanced immunological reactivity against "near-self" MHC antigens ("alloaggression") is not encoded in the germ line as suggested by Jerne (1971), but requires a phase of positive selection of the immunological repertoire (Forsdyke, 1975). MHC proteins and other membrane components (Bluestone et al., 1988; Porcelli et al., 1989; Vidovik et al., 1989) would play a major role in the shaping of this repertoire. It was also pointed out that expanded clones of anti-near-self immunologically competent cells would present a barrier opposing the progressive mutation of molecules of a pathogen towards forms indistinguishable from host molecules ("molecular mimicry"). 5. lntracellular Distinction between Self and Not-self
It is argued that "there are no obvious cues to distinguish self from foreign proteins inside the cell" (Bevan, 1989). Recently it was stated that the "finding... that the transfected gene encoding influenza nucleoprotein yields MHC class-I-associated peptides on the cell surface has suggested that the transfected cell, not being an immune system, cannot know that the influenza gene is foreign" (Kourilsky & Claverie, 1989). Thus, it is envisaged that "foreign proteins have to compete with more than 10 000 species of self proteins for presentation at the cell surface" (Bevan, 1989). However, absence of evidence is not evidence of absence. Absence of a known mechanism for intracellular self/non-self distinction does not mean that such a mechanism does not exist. Indeed, the principle of intracellular self/non-self distinction was firmly established with the discovery of bacterial DNA restrictionmodification systems (Arber & Linn, 1969). A mechanism for distinction at the protein level, based on concentration-dependent (lyotropic) phase transitions, has been proposed (Forsdyke, 1985). Proteins which exceed their solubility limits in the
MHC
POLYMORPHISM
455
crowded intracellular environment will aggregate and mark themselves as different from other proteins (Marston, 1986). The synthesis and breakdown of viral proteins would not be so tightly regulated as in the case of host cell proteins. After all, the raison d'etre of a virus is to increase in number. Changes in environmental conditions (e.g. heat shock), which might favour the aggregation of self proteins, would be dealt with by special mechanisms, such as the activation of chaperonin-like proteins which would reverse aggregation (Fischer & Schmid, 1990). Having been marked as different, foreign aggregates would be degraded, first to peptides and then to amino acids. This level of coping with foreign material could be achieved by unicellular organisms. Association of foreign peptide fragments with prototypic polymorphic MHC proteins en route to the cell surface would not seem advantageous at the unicellular stage of evolution. However, in multicellular organisms, the modified, "near-self", MHC antigenic determinants so created would be recognized by host immunologically competent cells which would already have been educated, by mechanisms such as outlined previously (Forsdyke, 1975), to respond against near-self. By associating peptide fragments with MHC determinants, the organism would merely be taking advantage of the pre-existence of a large population of immunologically competent cells reactive with near-self. A cell displaying modified MHC proteins would have become labelled for destruction by immunologically competent cells or their products, a feature of considerable selective advantage for the organism. The pre-existing polymorphism of MHC proteins would increase the chance that a successful MHC-peptide complex would be formed and, in the continuing evolutionary arms race with pathogens, modifications of MHC proteins might have occurred to enhance their recognition of sets of structural features shared by many peptides. Since the critical self-vs.-non-self decision had already been made intracellularly, it would be sufficient for the peptide-MHC protein complex to be recognizable as near-self. This might involve recognition by T cell receptors both of conformational changes in MHC molecules and of features of the associated peptide. There would be no necessity for a stage in the education of immunologically competent cells in which cells reactive with complexes of MHC proteins and self-peptides derived from the organism's intracellular proteins would be eliminated (Berg et al., 1989). This would then leave open to the organism the option of destroying cells inwhich the regulation of the intracellular concentration of one of its own proteins had become disordered. 6. Positive Selection in Different Environments. Cell Lineages
Duplication of hypervariable loci and segregation of their expression to different tissue compartments would provide opportunity for exposure of different populations of potential immunologically competent cells to different spectra of antigens during the phase of positive selection. Thus, cell lineages (e.g. prototypic T and B lineages) might have arisen. This would provide the opportunity for the evolution of a division of labour. One lineage would be concerned primarily with cell-mediated responses and another lineage with humoral responses.
456
D.R.
FORSDYKE
REFERENCES ARBER, W. & LINN, S. (1969). Ann. Rev. Biochem. 38, 467-500. ARMSTRONG, P. B. (1989). Crit. Rev. Biochem. 24, 119-149. BERG, L. J., PULLEN, A. M., FAZEKAS DE ST. GROTH, B., MATH1S, D., BENO1ST, C. & DAVIS, M. M. (t989). Cell 58, 1035-1046. BEVAN, M. J. (1989). Nature, Lond. 342, 478-479. BLUESTONE, J. A., CRON, R. Q., CO'I-FERMAN, M., HOULDEN, B. A. & MATIS, L. A. (1988). J. expl. Med. 168~ 1899-1916. BUBBERS, J. E. & LILLY, F. (1977). Nature, Lond. 266, 458-459. BURNET, F. M. (1959). The CIonal Selection Theory of Acquired Immunity. Cambridge: Cambridge University Press. DAWK1NS, R. (1976). The Selfish Gene. Oxford: Oxford University Press. EHRLICH, P. (1900). Proc. 17,. Soc. B. 66, 424-435. FISCHER, G. & SCHMID, F. X. (1990). Biochemistry 29, 2205-2212. FORSDYKE, D. R. (1968). Lancet i, 281-283. FORSDYKE, D. R. (1969). J._theor. Biol. 25, 173-185. FORSDYKE, D. R. (1975). J. theor. Biol. 52, 187-198. FORSDYKE, D. R. (1985). J. theor. Biol. 115, 471-473. FORSDYKE, D. R. & FORD, P. (1983a). J. theor. Biol. 103, 467-472. FORSDYKE, D. R. & FORD, P. (1983b). Biochem. J. 214, 257-260. GELDERBLOM, H., REUPKE, H., WINKLE, T., KUNZE, R. & PAULI, G. (1987). Z. Naturforsch. 42c, 1328-1334. GREY, H. M., SET'rE, A. & BUUS, S. (1989). Sci. Am. 261, (5), 56-64. HECHT, T. T. & SUMMERS, D. F. (1976). Z Virol. 19, 833-845. HOPKINS, N. H. (1987). In: Molecular Biology of the Gene 4th edn Menlo park: Benjamin/Cummings. p. 888. HUGHES, A. L. & NEI, M. (1989). Proc. hath. Acad. Sci. U.S.A. 86, 958-962. JERNE, N. (1971). Eur. J. lmmunol. 1, 1-9. KOURILSKY, P. & CLAVERIE, J. M. (1989). Cell 56, 327-329. MARGULIES, D. H. (1989). Nature, Lond. 342, 124-125. MARRACK, P. & KAPPLER, J. (1986). Sci. Am. 254 (2), 36-45. MARSTON, F. A. O. (1986). Biochem. Z 240, 1-12. PORCELLI, S., BRENNER, M. B., GREENSTEIN, J. L., BALK, S. P., TERHORST, C. & BLEICHER, P. A. (1989). Nature, Lond. 341, 447-450. RAFF, M. (1989). In: Molecular Biology of the Cell 2nd edn New York: Garland. p. 1040. SCHWARTZ, R. H. (1989). Cell 57, 1073-1081. VIDOVIC, D., ROGLIC, M., MCKUNE, K., GUERDER, S., MACKAY, C. & DEMBIC, Z. (1989). Nature, Lond. 340, 646-649. ZINKERNAGEL, R. M. & DOHERTY, P. C. (1974). Nature, Lond. 248, 701-702.
Early Evolution of M H C Polymorphism D. R. FORSDYKE
Departrr,'nt of Biochemistry, Queen's University, Kingston, Ontario, Canada K 7 L 3 N 6 (Received on 1 May 1990, Accepted on 3 January 1991) There is unwarranted satisfaction with the view that MHC polymorphism evolved because there was a selective advantage in having a variety of MHC proteins to bind a variety of peptide subsets for presentation to T cells. While this may, in part, explain its maintainance, polymorphism may have evolved initially to reject foreign virus "grafts". The possession of similar membranes promotes aggregation between "like" cells, but it also promotes aggregation between the ceils and viruses which retain membrane components of their previous host. The selection pressure afforded by hostile virus "grafts" would favour cells which developed polymorphic membrane components (since "like" will not aggregate with "not-like'). This polymorphism would have evolved before the appearance of multicellular organisms. Thus, the evolution of modem immune systems would have been imposed upon pre-existing polymorphic systems. A path this evolution may have taken involves the development of mechanisms for intracellular distinction between self and not-self.
1. Introduction The hypotheses that the education of potential immunologically competent cells requires both negative selection (Burnet, 1959) and positive selection (Forsdyke, 1975) have found considerable experimental support (reviewed in Schwartz, 1989). However, the relationship of these processes to the p h e n o m e n o n of MHC polymorphism is poorly understood. It is argued that, although histocompatibility antigens were first recognized through tissue grafting experiments, such grafting does not normally occur in nature. Thus, M H C polymorphism could not have evolved in response to a selection pressure generated by the need to reject foreign grafts. So we must look elsewhere for an explanation for the origin of MHC polymorphism. This view is widely disseminated in textbooks and popular science journals (Marrack & Kappler, 1986; Hopkins, 1987; Grey et al., 1989; Raft, 1989). The discovery of MHC-restricted immune responsiveness (Zinkernagel & Doherty, 1974) and the role o f M H C molecules in antigen presentation (Grey et al., 1989) provided a convenient explanation for M H C polymorphism. Extensive M H C polymorphism means that most individuals are heterozygotes. Since all potentially immunogenic peptides cannot bind to one M H C gene product (Grey et al., 1989), having two M H C gene products doubles the chance that an individual will be able to assemble a functional M H C - p e p t i d e complex ("heterozygote advantage", "overdominant selection"; Hughes & Nei, 1989). However, this factor-of-two advantage does not seem particularly compelling. A doubling of the number o f M H C loci would achieve the same result. Those of the " g r o u p selectionist" school would argue 451
0022-5193/91/120451+06 $03.00/0
© 1991 Academic Press Limited
452
D.R.
FORSDYKE
for a much greater advantage at the population level. Thus, a group which had M H C polymorphism would be likely to have at least some members who would have a M H C protein able to form a functional complex with a peptide from a virulent pathogen. However, the general validity of group selectionist arguments has been questioned (Dawkins, 1976).
2. Viruses are Grafts
There would be no need to look to explanations such as the above if graft transplantation were an "experiment of nature". Actually, such experiments have probably been going on since life first evolved. When a virus passes from one host cell to another it may transfer some of the cell membrane components of its former host. These may include MHC proteins (Hecht & Summers, 1976; Bubbers & Lilly, 1977; Gelderblom et al., 1987). Such a virus is, in essence, a graft. Individuals highly polymorphic for a membrane component transferred by the virus are likely to reject the virus "graft" as foreign, just as they would a cellular allograft. This rejection response could have evolved before the evolution of the immune response as we know it today. The membranes of the "survival machines" within which the early "replicators" (RNA, DNA) encased themselves (Dawkins, 1976), are initially likely to have been quite similar to each other. We and others have shown that, in an appropriate environment, it can be thermodynamically favourable for cells with similar surface membranes to aggregate preferentially, "like with like" (Forsdyke & Ford, 1983a, b; Armstrong, 1989). Similarly, a nucleic acid fragment (selfish gene/virus) could readily transfer by budding from its cell of origin and, enveloped in the cell membrane of its former host, aggregating with a "like" target cell (Fig. 1). In this circumstance, a cell which had evolved prototypic M H C proteins with some degree of polymorphism, would be better prepared to maintain the integrity of its own nucleic acid by preventing invasion by a foreign nucleic acid (since "like" does not aggregate with "not-like"). MHC proteins could have evolved as a defence against viruses before the evolution of multicellular organisms. The evolutionary pressure to generate extensive polymorphism would have been high, since the greater the polymorphism, the less likely would be a virus to encounter a "like" cell.
3. Multicellularity Provokes Acceleration of the Arms Race
However, multicellular organisms, each cell of which would bear "like" polymorphic antigens, would provide a fertile soil for viruses to spread between cells. Thus, the evolution of the multicellular state should be accompanied by a strong pressure for the evolution of immune systems. This evolution would be imposed upon, and might incorporate and adapt, a pre-existing polymorphic M H C system. As long as they d e p e n d e d upon the like-with-like mechanism to associate with their target cell membrane, virus envelopes would have been indistinguishable from self. However, at an early stage of their evolution, balked by the development of
MHC
POLYMORPHISM
453
(a)
(b)
(c)
(d)
FIG. 1. Early evolution of virus-cell interactions. (a) A virus enveloped in the membrane of its former host is able to bind to a "like" target cell possessing similar membrane characteristics. Host and virus genomes are represented by wavy lines. The rectangle in the host genome represents a gene encoding a minor host surface component. The latter is represented by open boxes embedded in the membrane with "caps" pointing to the exterior. (b) Polymorphism of membrane components (represented on the left by closed boxes and on the right by closed boxes with caps) prevents viral attachment by the tow affinity like-with-like mechanism. (c) A virus incorporates the host gene encoding the minor membrane component and directs increased synthesis of this component. This permits low efficiency encounters with its target cell by the like-with-like mechanism, (d) Mutation of the viral copy of the host gene (shaded rectangle) to generate a surface ligand with high affinity for the target cell receptor. M H C - p o l y m o r p h i s m , viruses w o u l d have d e v e l o p e d specific coat p r o t e i n s c a p a b l e o f r e c o g n i z i n g n o n - p o l y m o r p h i c host cell surface p r o t e i n s as receptors for virus a t t a c h m e n t . Steps in d e v e l o p i n g this capacity m i g h t have i n c l u d e d , (i) i n c o r p o r a t i o n o f a copy o f the host gene e n c o d i n g the n o n - p o l y m o r p h i c p r o t e i n into the virus g e n o m e , a n d (ii) m u t a t i o n o f the latter to increase the affinity o f b i n d i n g of the g e n e p r o d u c t with the e x t r a c e l l u l a r d o m a i n o f the host-ceU surface d e t e r m i n a n t (Fig. 1). T h u s , the p r e - e x i s t i n g like-with-like affinity o f host m o l e c u l e s p r e s e n t i n g n o n - p o l y m o r p h i c surface d e t e r m i n a n t s w o u l d have b e e n e n h a n c e d by m u t a t i o n s o f the viral copy of the s a m e gene. The virus coat p r o t e i n i i g a n d a n d its host cell r e c e p t o r w o u l d have e v o l v e d from a c o m m o n source, a p r o t o t y p i c n o n - p o l y m o r p h i c host cell receptor. I n e n t e r i n g a n " a r m s r a c e " with its host ( D a w k i n s , 1976), the
454
D. R, F O R S D Y K E
virus would have "shown its colours" (i.e. acquired a virus-specific surface protein), thus paving the way for specific recognition by a prototypic host immune system. Initially this might have taken the form of the release of soluble decoy receptors from target cells (Ehrlich, 1900). With tissue differentiation, certain cells would specialize in generating decoy receptors. A local tendency to hypermutate would generate a decoy receptor (prototypic antibody) repertoire which might protect organisms against a range of viruses. This would require the coevolution of extracellular mechanisms for distinguishing self from not-self, as discussed previously (Forsdyke, 1968, 1969, 1975). In such a frame-work the immune system as we know it today could have evolved. 4. Simplicity Precedes Complexity. Positive Selection
It is possible that one prototypic antibody locus (with multiple V region genes) would have had the opportunity to develop evolutionarily before duplication to generate other loci. A simple model has been considered elsewhere, perhaps corresponding to an organism which once existed (or may even still exist). The model organism had a single hypervariable locus and could have mounted both cellmediated and humoral immune responses (Forsdyke, 1968, 1969, 1975). The model proposed that enhanced immunological reactivity against "near-self" MHC antigens ("alloaggression") is not encoded in the germ line as suggested by Jerne (1971), but requires a phase of positive selection of the immunological repertoire (Forsdyke, 1975). MHC proteins and other membrane components (Bluestone et al., 1988; Porcelli et al., 1989; Vidovik et al., 1989) would play a major role in the shaping of this repertoire. It was also pointed out that expanded clones of anti-near-self immunologically competent cells would present a barrier opposing the progressive mutation of molecules of a pathogen towards forms indistinguishable from host molecules ("molecular mimicry"). 5. lntracellular Distinction between Self and Not-self
It is argued that "there are no obvious cues to distinguish self from foreign proteins inside the cell" (Bevan, 1989). Recently it was stated that the "finding... that the transfected gene encoding influenza nucleoprotein yields MHC class-I-associated peptides on the cell surface has suggested that the transfected cell, not being an immune system, cannot know that the influenza gene is foreign" (Kourilsky & Claverie, 1989). Thus, it is envisaged that "foreign proteins have to compete with more than 10 000 species of self proteins for presentation at the cell surface" (Bevan, 1989). However, absence of evidence is not evidence of absence. Absence of a known mechanism for intracellular self/non-self distinction does not mean that such a mechanism does not exist. Indeed, the principle of intracellular self/non-self distinction was firmly established with the discovery of bacterial DNA restrictionmodification systems (Arber & Linn, 1969). A mechanism for distinction at the protein level, based on concentration-dependent (lyotropic) phase transitions, has been proposed (Forsdyke, 1985). Proteins which exceed their solubility limits in the
MHC
POLYMORPHISM
455
crowded intracellular environment will aggregate and mark themselves as different from other proteins (Marston, 1986). The synthesis and breakdown of viral proteins would not be so tightly regulated as in the case of host cell proteins. After all, the raison d'etre of a virus is to increase in number. Changes in environmental conditions (e.g. heat shock), which might favour the aggregation of self proteins, would be dealt with by special mechanisms, such as the activation of chaperonin-like proteins which would reverse aggregation (Fischer & Schmid, 1990). Having been marked as different, foreign aggregates would be degraded, first to peptides and then to amino acids. This level of coping with foreign material could be achieved by unicellular organisms. Association of foreign peptide fragments with prototypic polymorphic MHC proteins en route to the cell surface would not seem advantageous at the unicellular stage of evolution. However, in multicellular organisms, the modified, "near-self", MHC antigenic determinants so created would be recognized by host immunologically competent cells which would already have been educated, by mechanisms such as outlined previously (Forsdyke, 1975), to respond against near-self. By associating peptide fragments with MHC determinants, the organism would merely be taking advantage of the pre-existence of a large population of immunologically competent cells reactive with near-self. A cell displaying modified MHC proteins would have become labelled for destruction by immunologically competent cells or their products, a feature of considerable selective advantage for the organism. The pre-existing polymorphism of MHC proteins would increase the chance that a successful MHC-peptide complex would be formed and, in the continuing evolutionary arms race with pathogens, modifications of MHC proteins might have occurred to enhance their recognition of sets of structural features shared by many peptides. Since the critical self-vs.-non-self decision had already been made intracellularly, it would be sufficient for the peptide-MHC protein complex to be recognizable as near-self. This might involve recognition by T cell receptors both of conformational changes in MHC molecules and of features of the associated peptide. There would be no necessity for a stage in the education of immunologically competent cells in which cells reactive with complexes of MHC proteins and self-peptides derived from the organism's intracellular proteins would be eliminated (Berg et al., 1989). This would then leave open to the organism the option of destroying cells inwhich the regulation of the intracellular concentration of one of its own proteins had become disordered. 6. Positive Selection in Different Environments. Cell Lineages
Duplication of hypervariable loci and segregation of their expression to different tissue compartments would provide opportunity for exposure of different populations of potential immunologically competent cells to different spectra of antigens during the phase of positive selection. Thus, cell lineages (e.g. prototypic T and B lineages) might have arisen. This would provide the opportunity for the evolution of a division of labour. One lineage would be concerned primarily with cell-mediated responses and another lineage with humoral responses.
456
D.R.
FORSDYKE
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