Immunology Today, vol. 8, Nos 7 and8, 1987 i
toms related to CMV infections and no CMV is cultured from their saliva, blood or urine. Some of these changes in antibody titers may reflect continued production of antibodies by donor lymphocytes transferred with the transplant rather than by the response of recipient lymphocytes to active CMV infections. Proliferation of donor B lymphocytes also could contribute to some unexpected humoral responses following organ transplantation, such as the striking splenomegaly secondary to massive antibody production that occurs immediately after transplantation in ratszl. In humans elevated immunoglobulin levels, sometimes with spikes of monoclonal immunoglobulins, are frequently detected following renal transplantationzz and could reflect the expansion of limited numbers of donor B lymphocytes in the recipient. AIIotyping of antibodies produced subsequent to the transplantation of solid organs may help determine the extent of antibody production by donor versus recipient B lymphocytes.
1 Gleichmann,E., Pals,S.T.,Rolink,A.G. etaL (1984)Immunol. Today 5, 324 2 Simonsen,M, (1986)lmmunol. Rev. 88, 5 3 Bird, G,W,G. and Wingham, J. (1982) Transfusion (Phi/ade/ph/a)22, 400 4 Lundgren,G., Asaba, H,, Bergstrom,J. etal. (1981) Clin. Nephro/, 16, 211 S Mangal, A.K., Growe, G.H., Sinclair,M. etal. (1984) Transfusion (Phildelphia) 24, 201 li Nyberg,G,, Sandberg,L, Rydberg,L. etal. (1984)
Soluble
Transplantation 37, 529 7 Ramsey,G., Nusbacher,J., Starzl,T.E.etal. (1984)NewEngi. J. Med. 311, 1167 II Ramsey,G., Israel, L., Lindsay,G.D. etal. (1986) Transplantation 41,67 9 Swanson,J., Sastamonionen,R., Steeper,T. etal. (1984) Transfusion (Philadelphia) 24, 431 10 Swanson. J.. Sastamonionen,R., Sebring, E. etal. (1985) Transfusion (Philadelphia) 25, 467 11 Ahmed, K.Y., Nunn, G., Brazier, D.M. etal. (1987) Transplantation 43, 163 12 Mollison, P.L (1983) Blood Transfusion in Clinical Medicine, Blackwell ScientificPublications 13 Lefkovits, I. and Waldmann, H. (1979) Limiting Dilution Analysis of Cells in the Immune System, Cambridge University Press 14 Baldwin,W.M. III, Bollinger, R.R.and Sanfilippo, F. (1987) Transplant. Proc. (in press) 15 Maryniak, R.K., First, M.R. and Weiss, M.A. (1985) Kidney Int. 27, 799 16 Axelsen, R.A., Seymour,A.E., Mathew, T.H. etaL (1985) Clin. Nephrol. 23, 11 17 Berg, K.R.,Nghiem, D.D. and Corry, RJ. (1982) Transplantation 34, 344 18 Frisk,B., Rerglin, E. and Brynger, H. (1983) Transplantation 35, 352 19 Jeekel. J.. Marquet, R., Harder, F. et al. (1983) Transplant. Proc. 15, 973 20 Hamilton, J.D. (1982) Cytornegalovirus and Immunity, S. Karger 21 Baldwin,W.M. III, Hendry, W., Birinyi, L.K. and Tilney, N.L. (1979) Lab. Invest. 40, 695 22 Radl,J., Valentijn, R.M., Haaiman,J.J.and Paul, L.C. (1985) Clin. Imrnunol. Immunopathol. 37, 98
dass I antigens:a conundrum with no solution?
Naturally occurring soluble class I major histocompatibility complex (MHC) antigens were first identified in human serum over 15 years ago 1-3. In man, HLA-A9 was found in the serum of individuals whose cells had been typed as HLA-A9-positive 1. Subsequently, serum MHC molecules, associated with the small subunit of class I antigens 132-microglobulin (and therefore presumed to be class I antigens) have been detected in other species4-7. In addition, in cell culture experiments histocompatibility antigens were 'shed' into the medium 8. Class I antigens are normally anchored to the membrane via a stretch of hydrophobic amino acids, and reports of soluble class I antigens have been interpreted as evidence of proteolytic removal of the membrane anchor. 'Shedding' of protein-lipid complexes would probably serve as a vehicle for the release of class I molecules with membrane anchors8. Molecular characterization of MHC class I genes has drastically altered this picture and clarified th~ origin of soluble or aberrant forms of known MHC molecules. In mouse and man, the number of class I genes per haploid genome is between 20 and 30, and among this multi220
i
Ne~erlands CancerIn~ute, Antoni van Leeuwenhoekhuis, 1066 CX Amsterdarn, The Netherlands
Detlef Giissowand Hidde Ploegh tude, the genes encoding the classical serologically defined molecules can be identified 9. The intron-exon organization of class I genes suggested the possibility that by alternate splicing membrane anchors could be removed at the pre-mRNA stage rather than by proteolysis of the protein product. Such splicing is reminiscent of the mechanism which controls synthesis of membranebound versus secreted IgM (Ref. 10). In addition, some of the newly discovered class I genes in mice apparently encode anchorless forms of ~l.-.ssI antigen heavy chains6. Several recent reports have described class I antigens that do not conform to the classical picture. They include class I heavy chains that have been altered by unusual splicing in the extracellular domains 11, that are secreted because the transmembrane-encoding segment was removed 12 or that have been shortened by several amino acids in the intracellular domain by alternate splicing involving the relevant exons 13-15. The products of genes in the Qa/Tla region of the mouse MHC that are or could be secreted because of a drastically shortened transmembrane segment - the result of a stop codon early in the transmembrane exon - also do not conform to the "CJ1987, ElsevierPublications,Cdmbridge 0167 -491 g;&71502.00
ImmunologyToday,vol.8, Nos 7 and 8, ~987
classical pattern6,16-19. The product of the mouse OlO gene stands out, because it is apparently secreted at a high rate but in a tissue-specific fashion: only liver cells produce the QIO molecule. Interestingly, not all /4-2 haplotypes express a QlO-like gene2o. Based on the survey of Lew et al. s it is likely that the evolutionary distribution of serum class I molecules similar to the Q 10 molecule is limited: only Rodentia5.7 and Perissodactyla (odd-toed ungulates)s have been shown to posses it so far. Nothing is known yet about the ungulate genes involved, nor about the genes for the rat serum class I molecule produced by liver and kidney that was reported recently7. By examining the kinetics of appearance of soluble class I molecules in the culture supernates of activated lymphocytes, Robinsonzl has now shown that Qa region antigens can in fact be released by at least two distinct mechanisms: the Qb-1 molecule, like the QIO molecule, is secreted much like a secretory glycoprotein but the Qa-2 antigen is released into the supernate by the processing of a bona fide membrane-anchored form. Soloski eta!. 22 also reported secretion of Qa-2 but 0,,~1 not clearly describe the mechanism of its release. Although different modes of membrane anchorage, as for example through a phosphatidylinositol linkage (cf. the Thy-1 molecule23) rather than a transmembrane segment, might require alternative modes of release, proteolysis would seem the more likely explanation for the processing to a soluble form of Qa-2 (Ref. 21). Soluble forms of class I antigens Qa-2, QIO and Qb-1 have now been documented in mice. In humans, the HLA-Aw24 (A9) gene apparently is more prone than any other class I gene to the production of mRNA in which the transmembrane exon has been removed by alternate spiicing, thus producing a soluble class I molecule. This finding was recently documented by Kr~nge112. Usually less than 5% of the total amount uf HLA-Aw24 antigen was recovered in its membraneanchorless form, from cell lines or mitogen-activated peripheral blood lymphocytes (PBL). The HLA specificities examined included 10 distinct HLA-A and 13 distinct HLA-B locus specificities, and although not all could be distinguished in these experiments, the only one secreted at a relatively high rate was HLA-Aw24 (Ref. 12). In summary, soluble class I molecules can be generated by three distinct mechanisms: alternate splicing may remove the membrane anchor; the gene itself may lack the information for a functional membrane anchor; or the membrane-anchored protein product may be released from the membrane, presumably through proteolysis. In addition, release of membraneous material containing membrane-anchored class I antigens may in part explain their presence in bodily fluids. What is the significance of soluble class I antigens? First, those resulting from aberrantly spliced mRNA molecules usually represent a minor fraction of the total amount of gene product synthesized. The bulk of the mRNA specifies the usual membrane-anchored class I heavy chains as characterized by extensive biochemical analysis. Except for products of viral genomes 24, IgM (Ref. 10) and fibronectin 2s are among the few examples in which alternate splicing makes an essential contribution to the regulation of expression or function. In many cases its extent may simply represent the intrinsic error rate of the pre-mRNA processing machinery. In our view,
this argument equally applies to 'alternately spliced" species involving the alphal/N1 or the cytoplasmic domains 11.15. Second, the Qa-region genes for which soluble products have been documented do not display the type and extent of variability observed for H-2K, D or L (Ref. 27). If we accept the tenet that class I antigens function as restriction elements for T cells, and that polymorphism is selected to cover the widest possible spectrum of antigens, the lack of polymorphism for Qa-region products - soluble or otherwise - is rather indigestible food for thought. The strongest statement on the function of soluble class I antigens was the hypothesis put forward by Kress et al.6,14, who postulated a role for soluble class I molecules in inducing self-tolerance (see also Ref. 3). Portions of the soluble class I molecule shared with the membrane-bound forms would be the moieties responsible for induction of self-tolerance 6. Yet the Q10 gene displays virtually no variability between haplotypes27. Could accessory self molecules, polymorphic in nature, act in concert with the serum QIO molecule to induce self-tolerance? However, not all I-I-2 haplotypes express the QIO molecule2o, and a s stated above, the evolutionary distribution of Q10-like molecules may be limited. It is therefore difficult to see how tolerance to self can be acquired, while alloreactivity of T cells is maintained, if all alloantigenically distinct members of the species use the identical molecule for the purpose. Other authors ~2.17.21simply state that there is, at present, no known function for soluble class I molecules. Soluble class I molecules do not necessarily have a function. There is about 80% sequence homology between the classical H-2K, D and Qa-region genes and a similar amount between alleles at the H-2K, D loci26. If homologous structure implies similar function it is very difficult to imagine that soluble class I molecules participate in or regulate T-cell recognition. There is nothing mysterious about aberrantly spliced and/or soluble class I antigens: because MHC-restriction requires the formation of a ternary complex between T-cell receptor, MHC antigen and antigen - processed or otherwise - at the interface of two membranes, soluble class I antigen is highly unliEeiy to perturb this process and th~s its presence wil~ not nacessarily be selected against. Attempts to define the capacity to function as restriction elements for class I antigens aberrantly spliced in the first extracellular domain have so far failed 28. Similarly, even though secretion of Qa-region products has been documented, it may be because the Qa region products have no function that the organism does not respond to their presence. The selective pressures that have moulded the MHC inevitably produce waste in the form of pseudogenes that cannot be expressed as a protein product. The possibility that certain gene products have no biological function should be considered, as pointed out by Klein26. In this sense it is significant that neither Qa nor Tla region genes (nor HLA-C) have been shown to encode functional restriction elements. Moreover, large deletions in the Qa region, possibly includlng Q10 (H-2 f haplotype29) are tolerated~ and even among closely related species great differences in number of Oa/Tla genes exist. The expansion or contraction of the Qa region is probably a recent event relative to the diversification of the H-2K and D alleles. If so, the sequence conservation of Oa genes is easily understood.
221
Immunology Today, voL8 Nos 7 and 8, 1987
............. ~~~ ~ ~
~
~~
.................................................................
Being usually present in a small amounts and with quite restricted tissue distribution, Qa molecules would not necessarily pose a large genetic burden. If it was selective pressure that generated polymorphism in the class I antigens that do function as restriction elements, their highly homologous counterparts which display far less or no polymorphism may well be irrelevant. A similar assessment could well be made of soluble class I histocompabbility molecules. we thank Anne Mahon for a critical readirg of the manuo script. D.G. is supported by KWF grant NKI-85-10 (Queen Wilhelmina Fund).
.......
| Pellegrino, M.A., Ferrone, S., Pellegrino, A. etaL (1974) Eur. J. immunoi. 4, 250-255 :2 .Aster, R.H., Miskovich, B.H. and Rodey, G.E. (1973) Transplantation 16, 205-210 3 Van Rood, JJ., Van Leeuwen, A. and Van Santen, M.C.T. (1970) Nature (London)226, 366-367 4 Natori, T., Tanigaki, G.N. and Pressman, D. (1976) J !mmunogenet. 3, 123-134 SLew, A.M., Valas. R.B.,Maloy. W.L and Coligan, J.E.(1986) Immunogenetics23, 277-283 § Kress, M., Cosman, D., Khoury, G. and Jay, G. (1983) Ceil34, 189-196 7 Spencer, S.C. and Fabre, J.W. (1987) Immunogenetics25, 91-98 II Emerson, S.G. and Cone, R.E.(1981)J. Immunol. 127, 482-486 9 Steinmetz, M. and Hood, L (1983) Science222, 727-733 10 Early, P., Rogers, J., Davis, M. etal. (1980) Cell 20, 313-319 11 Transy, C., Lalanne, J-L and Kourilsky, P. (1984)EMBOJ. 3, 2382-2386
12 Krangel, M.S. (1986)J. Exp. Med. 163, 1173-1190 13 Lew, A.M., Margulies, D.H., Maloy, W.L etal. (1986) Proc. Nat/Acad. Sci. USA 83, 6084-6088 14 Barra, Y., Tanaka, K., Davidson, W. et al. (1985) in Cell Biology of the Majer Histocompatibility Complex (Pernis, B. and Vogel, HJ., eds), pp. 109-120, Academic Press 15 Transy, C., Lalanne, J-L., Cochet, M. etal. (1985) in Cell Biology of the Major Histocompatibility Complex(Pernis, B. and Vogel, HJ., eds), pp. 121-130, Academic Press 16 Cosman, D., Khoury, G. and Jay, G. (1982) Nature 295, 73-76 17 Devlin, JJ., Lew, A.M., Flavell, R.A. and Coligan, J.E. (1985) EMBOJ. 4, 369-374 18 Devlin, J.J., Weiss, E.H., Paulson, M. and Flavell, R.A. (1985) EMBOJ. 4, 3203-3207 19 Steinmetz, M, Moore, K.W., Frelinger, J. etal. (1981) Cell 25, 683-692 20 Lew, A.M., Maloy, W.L and Coligan, J.E.(1986) J. Immunol. 136, 254-258 21 Robinson, P.J.(1987)Proc NatlAcad. Sci. USA 84, 527-531 22 Soloski, MJ., Vernachio, J., Einborn, G. and Lattimore, A. (1986) Proc. Nati Acad. Sci. USA 83, 2949-2953 23 Low, M.G. and Kincade, P.W. (i 985) Nature 318, 62-64 24 Tooze, J. (ed.) (1982) DNA Turnout Viruses, Cold Spring Harbor LaboratoP.! 25 Konblihtt, A.R., Umezawa, K., Vibe-Pedersen, K. and Ba=ag~:,F.E.(1985) EMBOJ. 4, 1755-1759 26 Klein, J. (1986) Natural History of the Major Histocompatibility Complex, Wiley & Sons 27 Me,or, A.L., Weiss, E.H., Kress, M. etal. (1984) Cell 36, 139-144 28 Cochet, M., Kast, W.M., Kummer, A-M. etal. (1986) Immunogenetics24, 267-274 29 O'Neill, A.E., Reid, K., Garberi, J.C. etaL (1986) immunogenetics 24, 368-373
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toms related to CMV infections and no CMV is cultured from their saliva, blood or urine. Some of these changes in antibody titers may reflect continued production of antibodies by donor lymphocytes transferred with the transplant rather than by the response of recipient lymphocytes to active CMV infections. Proliferation of donor B lymphocytes also could contribute to some unexpected humoral responses following organ transplantation, such as the striking splenomegaly secondary to massive antibody production that occurs immediately after transplantation in ratszl. In humans elevated immunoglobulin levels, sometimes with spikes of monoclonal immunoglobulins, are frequently detected following renal transplantationzz and could reflect the expansion of limited numbers of donor B lymphocytes in the recipient. AIIotyping of antibodies produced subsequent to the transplantation of solid organs may help determine the extent of antibody production by donor versus recipient B lymphocytes.
1 Gleichmann,E., Pals,S.T.,Rolink,A.G. etaL (1984)Immunol. Today 5, 324 2 Simonsen,M, (1986)lmmunol. Rev. 88, 5 3 Bird, G,W,G. and Wingham, J. (1982) Transfusion (Phi/ade/ph/a)22, 400 4 Lundgren,G., Asaba, H,, Bergstrom,J. etal. (1981) Clin. Nephro/, 16, 211 S Mangal, A.K., Growe, G.H., Sinclair,M. etal. (1984) Transfusion (Phildelphia) 24, 201 li Nyberg,G,, Sandberg,L, Rydberg,L. etal. (1984)
Soluble
Transplantation 37, 529 7 Ramsey,G., Nusbacher,J., Starzl,T.E.etal. (1984)NewEngi. J. Med. 311, 1167 II Ramsey,G., Israel, L., Lindsay,G.D. etal. (1986) Transplantation 41,67 9 Swanson,J., Sastamonionen,R., Steeper,T. etal. (1984) Transfusion (Philadelphia) 24, 431 10 Swanson. J.. Sastamonionen,R., Sebring, E. etal. (1985) Transfusion (Philadelphia) 25, 467 11 Ahmed, K.Y., Nunn, G., Brazier, D.M. etal. (1987) Transplantation 43, 163 12 Mollison, P.L (1983) Blood Transfusion in Clinical Medicine, Blackwell ScientificPublications 13 Lefkovits, I. and Waldmann, H. (1979) Limiting Dilution Analysis of Cells in the Immune System, Cambridge University Press 14 Baldwin,W.M. III, Bollinger, R.R.and Sanfilippo, F. (1987) Transplant. Proc. (in press) 15 Maryniak, R.K., First, M.R. and Weiss, M.A. (1985) Kidney Int. 27, 799 16 Axelsen, R.A., Seymour,A.E., Mathew, T.H. etaL (1985) Clin. Nephrol. 23, 11 17 Berg, K.R.,Nghiem, D.D. and Corry, RJ. (1982) Transplantation 34, 344 18 Frisk,B., Rerglin, E. and Brynger, H. (1983) Transplantation 35, 352 19 Jeekel. J.. Marquet, R., Harder, F. et al. (1983) Transplant. Proc. 15, 973 20 Hamilton, J.D. (1982) Cytornegalovirus and Immunity, S. Karger 21 Baldwin,W.M. III, Hendry, W., Birinyi, L.K. and Tilney, N.L. (1979) Lab. Invest. 40, 695 22 Radl,J., Valentijn, R.M., Haaiman,J.J.and Paul, L.C. (1985) Clin. Imrnunol. Immunopathol. 37, 98
dass I antigens:a conundrum with no solution?
Naturally occurring soluble class I major histocompatibility complex (MHC) antigens were first identified in human serum over 15 years ago 1-3. In man, HLA-A9 was found in the serum of individuals whose cells had been typed as HLA-A9-positive 1. Subsequently, serum MHC molecules, associated with the small subunit of class I antigens 132-microglobulin (and therefore presumed to be class I antigens) have been detected in other species4-7. In addition, in cell culture experiments histocompatibility antigens were 'shed' into the medium 8. Class I antigens are normally anchored to the membrane via a stretch of hydrophobic amino acids, and reports of soluble class I antigens have been interpreted as evidence of proteolytic removal of the membrane anchor. 'Shedding' of protein-lipid complexes would probably serve as a vehicle for the release of class I molecules with membrane anchors8. Molecular characterization of MHC class I genes has drastically altered this picture and clarified th~ origin of soluble or aberrant forms of known MHC molecules. In mouse and man, the number of class I genes per haploid genome is between 20 and 30, and among this multi220
i
Ne~erlands CancerIn~ute, Antoni van Leeuwenhoekhuis, 1066 CX Amsterdarn, The Netherlands
Detlef Giissowand Hidde Ploegh tude, the genes encoding the classical serologically defined molecules can be identified 9. The intron-exon organization of class I genes suggested the possibility that by alternate splicing membrane anchors could be removed at the pre-mRNA stage rather than by proteolysis of the protein product. Such splicing is reminiscent of the mechanism which controls synthesis of membranebound versus secreted IgM (Ref. 10). In addition, some of the newly discovered class I genes in mice apparently encode anchorless forms of ~l.-.ssI antigen heavy chains6. Several recent reports have described class I antigens that do not conform to the classical picture. They include class I heavy chains that have been altered by unusual splicing in the extracellular domains 11, that are secreted because the transmembrane-encoding segment was removed 12 or that have been shortened by several amino acids in the intracellular domain by alternate splicing involving the relevant exons 13-15. The products of genes in the Qa/Tla region of the mouse MHC that are or could be secreted because of a drastically shortened transmembrane segment - the result of a stop codon early in the transmembrane exon - also do not conform to the "CJ1987, ElsevierPublications,Cdmbridge 0167 -491 g;&71502.00
ImmunologyToday,vol.8, Nos 7 and 8, ~987
classical pattern6,16-19. The product of the mouse OlO gene stands out, because it is apparently secreted at a high rate but in a tissue-specific fashion: only liver cells produce the QIO molecule. Interestingly, not all /4-2 haplotypes express a QlO-like gene2o. Based on the survey of Lew et al. s it is likely that the evolutionary distribution of serum class I molecules similar to the Q 10 molecule is limited: only Rodentia5.7 and Perissodactyla (odd-toed ungulates)s have been shown to posses it so far. Nothing is known yet about the ungulate genes involved, nor about the genes for the rat serum class I molecule produced by liver and kidney that was reported recently7. By examining the kinetics of appearance of soluble class I molecules in the culture supernates of activated lymphocytes, Robinsonzl has now shown that Qa region antigens can in fact be released by at least two distinct mechanisms: the Qb-1 molecule, like the QIO molecule, is secreted much like a secretory glycoprotein but the Qa-2 antigen is released into the supernate by the processing of a bona fide membrane-anchored form. Soloski eta!. 22 also reported secretion of Qa-2 but 0,,~1 not clearly describe the mechanism of its release. Although different modes of membrane anchorage, as for example through a phosphatidylinositol linkage (cf. the Thy-1 molecule23) rather than a transmembrane segment, might require alternative modes of release, proteolysis would seem the more likely explanation for the processing to a soluble form of Qa-2 (Ref. 21). Soluble forms of class I antigens Qa-2, QIO and Qb-1 have now been documented in mice. In humans, the HLA-Aw24 (A9) gene apparently is more prone than any other class I gene to the production of mRNA in which the transmembrane exon has been removed by alternate spiicing, thus producing a soluble class I molecule. This finding was recently documented by Kr~nge112. Usually less than 5% of the total amount uf HLA-Aw24 antigen was recovered in its membraneanchorless form, from cell lines or mitogen-activated peripheral blood lymphocytes (PBL). The HLA specificities examined included 10 distinct HLA-A and 13 distinct HLA-B locus specificities, and although not all could be distinguished in these experiments, the only one secreted at a relatively high rate was HLA-Aw24 (Ref. 12). In summary, soluble class I molecules can be generated by three distinct mechanisms: alternate splicing may remove the membrane anchor; the gene itself may lack the information for a functional membrane anchor; or the membrane-anchored protein product may be released from the membrane, presumably through proteolysis. In addition, release of membraneous material containing membrane-anchored class I antigens may in part explain their presence in bodily fluids. What is the significance of soluble class I antigens? First, those resulting from aberrantly spliced mRNA molecules usually represent a minor fraction of the total amount of gene product synthesized. The bulk of the mRNA specifies the usual membrane-anchored class I heavy chains as characterized by extensive biochemical analysis. Except for products of viral genomes 24, IgM (Ref. 10) and fibronectin 2s are among the few examples in which alternate splicing makes an essential contribution to the regulation of expression or function. In many cases its extent may simply represent the intrinsic error rate of the pre-mRNA processing machinery. In our view,
this argument equally applies to 'alternately spliced" species involving the alphal/N1 or the cytoplasmic domains 11.15. Second, the Qa-region genes for which soluble products have been documented do not display the type and extent of variability observed for H-2K, D or L (Ref. 27). If we accept the tenet that class I antigens function as restriction elements for T cells, and that polymorphism is selected to cover the widest possible spectrum of antigens, the lack of polymorphism for Qa-region products - soluble or otherwise - is rather indigestible food for thought. The strongest statement on the function of soluble class I antigens was the hypothesis put forward by Kress et al.6,14, who postulated a role for soluble class I molecules in inducing self-tolerance (see also Ref. 3). Portions of the soluble class I molecule shared with the membrane-bound forms would be the moieties responsible for induction of self-tolerance 6. Yet the Q10 gene displays virtually no variability between haplotypes27. Could accessory self molecules, polymorphic in nature, act in concert with the serum QIO molecule to induce self-tolerance? However, not all I-I-2 haplotypes express the QIO molecule2o, and a s stated above, the evolutionary distribution of Q10-like molecules may be limited. It is therefore difficult to see how tolerance to self can be acquired, while alloreactivity of T cells is maintained, if all alloantigenically distinct members of the species use the identical molecule for the purpose. Other authors ~2.17.21simply state that there is, at present, no known function for soluble class I molecules. Soluble class I molecules do not necessarily have a function. There is about 80% sequence homology between the classical H-2K, D and Qa-region genes and a similar amount between alleles at the H-2K, D loci26. If homologous structure implies similar function it is very difficult to imagine that soluble class I molecules participate in or regulate T-cell recognition. There is nothing mysterious about aberrantly spliced and/or soluble class I antigens: because MHC-restriction requires the formation of a ternary complex between T-cell receptor, MHC antigen and antigen - processed or otherwise - at the interface of two membranes, soluble class I antigen is highly unliEeiy to perturb this process and th~s its presence wil~ not nacessarily be selected against. Attempts to define the capacity to function as restriction elements for class I antigens aberrantly spliced in the first extracellular domain have so far failed 28. Similarly, even though secretion of Qa-region products has been documented, it may be because the Qa region products have no function that the organism does not respond to their presence. The selective pressures that have moulded the MHC inevitably produce waste in the form of pseudogenes that cannot be expressed as a protein product. The possibility that certain gene products have no biological function should be considered, as pointed out by Klein26. In this sense it is significant that neither Qa nor Tla region genes (nor HLA-C) have been shown to encode functional restriction elements. Moreover, large deletions in the Qa region, possibly includlng Q10 (H-2 f haplotype29) are tolerated~ and even among closely related species great differences in number of Oa/Tla genes exist. The expansion or contraction of the Qa region is probably a recent event relative to the diversification of the H-2K and D alleles. If so, the sequence conservation of Oa genes is easily understood.
221
Immunology Today, voL8 Nos 7 and 8, 1987
............. ~~~ ~ ~
~
~~
.................................................................
Being usually present in a small amounts and with quite restricted tissue distribution, Qa molecules would not necessarily pose a large genetic burden. If it was selective pressure that generated polymorphism in the class I antigens that do function as restriction elements, their highly homologous counterparts which display far less or no polymorphism may well be irrelevant. A similar assessment could well be made of soluble class I histocompabbility molecules. we thank Anne Mahon for a critical readirg of the manuo script. D.G. is supported by KWF grant NKI-85-10 (Queen Wilhelmina Fund).
.......
| Pellegrino, M.A., Ferrone, S., Pellegrino, A. etaL (1974) Eur. J. immunoi. 4, 250-255 :2 .Aster, R.H., Miskovich, B.H. and Rodey, G.E. (1973) Transplantation 16, 205-210 3 Van Rood, JJ., Van Leeuwen, A. and Van Santen, M.C.T. (1970) Nature (London)226, 366-367 4 Natori, T., Tanigaki, G.N. and Pressman, D. (1976) J !mmunogenet. 3, 123-134 SLew, A.M., Valas. R.B.,Maloy. W.L and Coligan, J.E.(1986) Immunogenetics23, 277-283 § Kress, M., Cosman, D., Khoury, G. and Jay, G. (1983) Ceil34, 189-196 7 Spencer, S.C. and Fabre, J.W. (1987) Immunogenetics25, 91-98 II Emerson, S.G. and Cone, R.E.(1981)J. Immunol. 127, 482-486 9 Steinmetz, M. and Hood, L (1983) Science222, 727-733 10 Early, P., Rogers, J., Davis, M. etal. (1980) Cell 20, 313-319 11 Transy, C., Lalanne, J-L and Kourilsky, P. (1984)EMBOJ. 3, 2382-2386
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