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Is selective IgA deficiency associated with central HLA genes or alleles of the DR-DQ region?
4 Goldstein, G., Fucello, A.J., Norman, D.J. et al. (1986) Transplantation 42, 507-570 5 Skerra, A. and Pluckthorn, A. (1988) Science 240, 1038-1041 6 Better, M., Chang, C.P., Robinson, R.R. and Horwitz, A.H. (1988) Science 240, 1041-1043 7 Chaudhary, V.K., Queen, C., Junghans, R.P. et al. (1989) Nature 339, 394-397 8 Sahagan, B.G., Dorai, H., Saltzgaber-Muller, J. et al. (1986) J. Immunol. 137, 1066-1074 9 LoBuglio, A.F., Wheeler, R.H., Trang, J. et al. (1989) Proc. Natl Acad. Sci. USA 86, 4220-4224 10 Begent, R.H.J., Ledermann, J.A., Bagshawe, K.D. et al. (1990) Antibody, Immunoconjugates and Radiopharmaceuticals (Vol. 3): Abstracts from the Fifth International Conference on Monoclonal Antibody Immunoconjugates for Cancer p. 86 11 Colcher, D., Horan-Hand, P., Nuti, M. and Schlom, J.
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(1~81) Proc. Natl Acad. Sci. USA 78, 3199-3203 12 Whittle, N., Adair, J., Lloyd, C. et al. (1987) Protein Eng. 1,499-505 13 Colcher, D., Milenic, D., Roselli, M. et al. (1989) Cancer Res. 49, 1738-1745 14 Queen, C., Schneider, W.P., Selick, H.E. et al. (1989) Proc. Natl Acad. Sci. USA 86, 10029-10033 15 Cockett, M.L, Bebbington, C.R. and Yarranton, G.T. (1990) Biotechnology 8,662-667 16 Committee for Proprietary Medical Products (1987) Trends Biotechnol. 5, G1-G4 17 Rhodes, M. and Birch, J. (1988) Biotechnology 6, 518-523 18 Duncan, M.E., Charlesworth, F.A. and Griffin, J.P. (1987) Trends Biotechnol. 5,325-328 19 Sherwood, R. (1988) Trends Biotechnol. 6, 135-136 20 Committee for Proprietary Medical Products (1989) Trends Biotechnol. 7, G13-G16
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Is selective IgA deficiency associated with central HLA genes or alleles of the DR-DQ region? M.
French
and
R. Dawkins
(Immunol. Today, 1990, 11, 271-
274) proposed that products of the central MHC genes might be involved in the susceptibility to selective IgA deficiency (IgA-D) and various autoimmune diseases associated with IgA-D. Our findings, summarized below, do not support this hypothesis. We have recently described positive associations with three D R - D Q haplotypes: DR1,DQw5; DR7,DQw2; and DRw17,DQw2, as well as a strong negative association with DRw15,DQw6 in IgA-D individuals 1. When looking for a shared feature between the observed D R - D Q associations, we observed that the DQf3 chains of the three 'susceptibility' haplotypes all had a neutral alanine or valine at position 57 of the DQJ3 chain. The 'protective' allele had the negatively charged aspartic acid at this position. Thus, selective IgA-D was shown to be one of the as yet rare HLA-associated diseases that are related to specific amino acids or epitopes of the major histocompatibility complex (MHC) class II molecules. In studies on patients with common variable immunodeficiency or combined IgA-IgG2 deficiency, we have found similar associations
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(Ref. 2 and L. Hammarstr6m et al., unpublished). In a study of patients with IgA-D or common variable immunodeficiency, Schaffer and co-workers 3 found that three genetic events/ markers of the HLA class III region were shared by the two immunodeficiency disorders: deletion of the C4A gene, deletion of the 21hydroxylase A pseudogene, and rare C2 restriction fragments. We have investigated the occurrence of C4A deletions in a large group of individuals with selective IgA-D (n = 95). IgA-D was found to be strongly positively associated with C4A deletion (P<10-s). However, C4A deletions were almost exclusively observed in DRw17,DQw2-positive patients and controls. Furthermore, all DRw17,DQw2 homozygous IgA-D individuals and controls also had homozygous C4A deletions. These data conclusively show that IgA-D is associated with the haplotype C4A-del, DRw17,DQw2, which is extended telomerically to the HLA class I region 4 but not towards the centromere 1. Is it possible to localize the 'susceptibility' locus within the HLA complex? As two of the D R - D Q haplotypes positively associated with IgA-D (DR7,DQw2 and DRw17,DQw2) have identical DQf3 chains (DQBI*0201), this shared feature can be used as one marker in two-locus linkage analysis 5. When such calculations were performed it was found that the DQBI*0201 association was primary (P<0.005).
Immunology Today
134
These data do not exclude the possibility that the etiology of IgA-D might be influenced by other genes within or outside the HLA region as well as by environmental factors. However, our previously published study 1 and the above linkage calculation demonstrate that the HLA class II region, or rather alleles of the HLA-DQB1 locus, is more closely associated with susceptibility to IgA-D than the central HLA genes. Olle Olerup C.I. Edvard Smith Lennart Hammarstr6m Center for Bio Technology, Karolinska Institute, N O VUM, Huddinge and Dept of Clinical Immunology, Karolinska Institute at Huddinge Hospital, Huddinge, Sweden.
References 1 Olerup, O., Smith, C.I.E. and Hammarstr6m, L. (1990) Nature 347, 289-290 2 Hammarstr6m, L., Olerup, O., Bj6rkander, J. and Smith, C.I.E. in Progress in Immune Deficiency III (Chapel, H.M. and Webster, A.D.B., eds), The Royal Society of Medicine Services Ltd (in press) 3 Schaffer, F.M., Palermos, J., Zhu, Z.B. et al. (1989) Proc. Natl Acad. Sci. USA 86, 8015-8019 4 Ambrus, M., Hernfidi, E. and Bajtai, G. (1977) Clin. Immunol. Immunopathol. 7, 311-314 5 Tiwari, J.L. and Terasaki, P.I. (1985) HLA and Disease Associations, pp. 18-27, Springer-Verlag
Vo112 No. 4 1991
iiiii!i!i/!!i!i
(1~81) Proc. Natl Acad. Sci. USA 78, 3199-3203 12 Whittle, N., Adair, J., Lloyd, C. et al. (1987) Protein Eng. 1,499-505 13 Colcher, D., Milenic, D., Roselli, M. et al. (1989) Cancer Res. 49, 1738-1745 14 Queen, C., Schneider, W.P., Selick, H.E. et al. (1989) Proc. Natl Acad. Sci. USA 86, 10029-10033 15 Cockett, M.L, Bebbington, C.R. and Yarranton, G.T. (1990) Biotechnology 8,662-667 16 Committee for Proprietary Medical Products (1987) Trends Biotechnol. 5, G1-G4 17 Rhodes, M. and Birch, J. (1988) Biotechnology 6, 518-523 18 Duncan, M.E., Charlesworth, F.A. and Griffin, J.P. (1987) Trends Biotechnol. 5,325-328 19 Sherwood, R. (1988) Trends Biotechnol. 6, 135-136 20 Committee for Proprietary Medical Products (1989) Trends Biotechnol. 7, G13-G16
!!ii !3iliii!i!i!i!iiiiii!ii! U! !ii!0
Is selective IgA deficiency associated with central HLA genes or alleles of the DR-DQ region? M.
French
and
R. Dawkins
(Immunol. Today, 1990, 11, 271-
274) proposed that products of the central MHC genes might be involved in the susceptibility to selective IgA deficiency (IgA-D) and various autoimmune diseases associated with IgA-D. Our findings, summarized below, do not support this hypothesis. We have recently described positive associations with three D R - D Q haplotypes: DR1,DQw5; DR7,DQw2; and DRw17,DQw2, as well as a strong negative association with DRw15,DQw6 in IgA-D individuals 1. When looking for a shared feature between the observed D R - D Q associations, we observed that the DQf3 chains of the three 'susceptibility' haplotypes all had a neutral alanine or valine at position 57 of the DQJ3 chain. The 'protective' allele had the negatively charged aspartic acid at this position. Thus, selective IgA-D was shown to be one of the as yet rare HLA-associated diseases that are related to specific amino acids or epitopes of the major histocompatibility complex (MHC) class II molecules. In studies on patients with common variable immunodeficiency or combined IgA-IgG2 deficiency, we have found similar associations
!!iiiiii!iiiiiiii!i!iiii!ii!i!!i!ililiiii!i i!i !iiiii!!iilil!iiii!iiiiiiiili...
(Ref. 2 and L. Hammarstr6m et al., unpublished). In a study of patients with IgA-D or common variable immunodeficiency, Schaffer and co-workers 3 found that three genetic events/ markers of the HLA class III region were shared by the two immunodeficiency disorders: deletion of the C4A gene, deletion of the 21hydroxylase A pseudogene, and rare C2 restriction fragments. We have investigated the occurrence of C4A deletions in a large group of individuals with selective IgA-D (n = 95). IgA-D was found to be strongly positively associated with C4A deletion (P<10-s). However, C4A deletions were almost exclusively observed in DRw17,DQw2-positive patients and controls. Furthermore, all DRw17,DQw2 homozygous IgA-D individuals and controls also had homozygous C4A deletions. These data conclusively show that IgA-D is associated with the haplotype C4A-del, DRw17,DQw2, which is extended telomerically to the HLA class I region 4 but not towards the centromere 1. Is it possible to localize the 'susceptibility' locus within the HLA complex? As two of the D R - D Q haplotypes positively associated with IgA-D (DR7,DQw2 and DRw17,DQw2) have identical DQf3 chains (DQBI*0201), this shared feature can be used as one marker in two-locus linkage analysis 5. When such calculations were performed it was found that the DQBI*0201 association was primary (P<0.005).
Immunology Today
134
These data do not exclude the possibility that the etiology of IgA-D might be influenced by other genes within or outside the HLA region as well as by environmental factors. However, our previously published study 1 and the above linkage calculation demonstrate that the HLA class II region, or rather alleles of the HLA-DQB1 locus, is more closely associated with susceptibility to IgA-D than the central HLA genes. Olle Olerup C.I. Edvard Smith Lennart Hammarstr6m Center for Bio Technology, Karolinska Institute, N O VUM, Huddinge and Dept of Clinical Immunology, Karolinska Institute at Huddinge Hospital, Huddinge, Sweden.
References 1 Olerup, O., Smith, C.I.E. and Hammarstr6m, L. (1990) Nature 347, 289-290 2 Hammarstr6m, L., Olerup, O., Bj6rkander, J. and Smith, C.I.E. in Progress in Immune Deficiency III (Chapel, H.M. and Webster, A.D.B., eds), The Royal Society of Medicine Services Ltd (in press) 3 Schaffer, F.M., Palermos, J., Zhu, Z.B. et al. (1989) Proc. Natl Acad. Sci. USA 86, 8015-8019 4 Ambrus, M., Hernfidi, E. and Bajtai, G. (1977) Clin. Immunol. Immunopathol. 7, 311-314 5 Tiwari, J.L. and Terasaki, P.I. (1985) HLA and Disease Associations, pp. 18-27, Springer-Verlag
Vo112 No. 4 1991