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Maternal non-transmitted HLA alleles influence the occurrence of IDDM
Abstracts
67
B-5.3 #121
B-5.3 #122
AMINO ACIDS AND PEPTIDES IN THE GROOVE INFLUENCE AN ANTIBODY-DEFINED, DISEASE ASSOCIATED HLA-DR EPITOPE. tS Drover. 2RW Karr, 3GT Nepom, 3S Kovats and ~WH Marshall. IMemorial University of Newfoundland, St. John's, Nfld, CANADA; 2 Monsanto Co., St. Louis, MO; 3Virginia Mason Research Center, Seattle, WA. A shared sequence on certain DR4 and DR1/3 chains is predicted to generate a shared epitope that promotes susceptibility to RA. Because the relative risk conferred by DR4 for susceptibility and severity is significantly higher than that for DRI, it is likely that the epitope(s) generated by these shared sequences are affected by different DR contexts. We utilized mAbs (NFLD.D2, NFLD.D3, NFLD.D8 and NFLD.D10) which map to the region in question and mAbs NFLD.D! 1 and NFLD.DI2 which are specific for DPq~I*0401. Bindin8 studies were performed on: 1) a panel of mouse L cell transfectants expressing either wild type or mutated DR~I*0401 molecules, and 2) two class II negative BCL transfectunts (T2-Dw4 and BLS-Dw4) expressing D1LS!"0401. The epitopes recognized by NFLD.D2, D3, DS, and DIO are overlapping; residue 70Q is critical, but substitutions on the alpha helix (67I and 74E) and on the floor (28E, 30L and 37F) signifiountly altered the conformation of all, but the NFLD.D l 0 binding epitope. NFLD.D 11 and NFLD.D12 binding was lost when DROI *0401 molecules were expressed on mouse cells; however, studies using human BCL suggest that the critical residue is 71K. Since residues that altered antibody binding epitopes arc also implicated in pelXide binding, we predicted that peptides may contribute to the formation of these epitopes. Binding studies with T2-Dw4, which is defective in peptide loading showed profoundly decreased binding of NFLD.D2, NFLD.D3 and NFLD.DS, but not of lqFLD.DI0, and showed total loss of NFLD.DI 1 and NFLDDI2 binding. Similar results were obtained for BLS-Dw4 while all mAbs strongly bound to DROI*0401 molecules on normal BCL. Taken altogether the data suggest that epitopes generated by shared sequences on the DR alpha helix are strongly influenced by the DR framework in which they reside and by peptide loadin~ of the antigen binding site. This being the case, these epitopes may also be recognized by T cells and may be important in determining T cell selection, end hence, could be the basis for altered susceptibility to diseases such as RA.
MATERNAL NON-TRANSMITTED HLA ALLELES INFLUENCE THE OCCURRENCE OF IDDM. J~WL~m_r~Lt~ and Glenys Thomson, Department of Integrative Biology, University of California, Berkeley CA and 14 collaborating centers. Recently ten Wolde et al. (Lancet 341:200, 1993) showed that the non-inherited maternal HLA gene products influence susceptibility to rheumatoid arthritis. Here, we document similar, and possibly stronger evidence, for the effect of a non-transmitted HLA class II allele affecting susceptibility to Type I diabetes (IDDM). In a collaborative study of over 900 HLA-typed Caucasian IDDM families, families were classified into a three-way statistical design of paternal allele transmitted to the proband X maternal allele transmitted X maternal allele not-transmitted. These tables tested significantly heterogeneous for three-way interaction, implying that the non-transmitted maternal allele effects Type I diabetes susceptibility as a function of the mother's genotype and the paternal antigen. No effect was present when the same test was performed using the paternal non-transmitted allele. The maternal effect is attributable to the non-transmitted DR3. Susceptibility is increased only when the maternal transmitted allele is not DR4 and the paternal transmitted is either DR3 or DR4. The immune system of the developing fetus is apparently conditioned by invading maternal cells, influencing IDDM susceptibility years later.
67
B-5.3 #121
B-5.3 #122
AMINO ACIDS AND PEPTIDES IN THE GROOVE INFLUENCE AN ANTIBODY-DEFINED, DISEASE ASSOCIATED HLA-DR EPITOPE. tS Drover. 2RW Karr, 3GT Nepom, 3S Kovats and ~WH Marshall. IMemorial University of Newfoundland, St. John's, Nfld, CANADA; 2 Monsanto Co., St. Louis, MO; 3Virginia Mason Research Center, Seattle, WA. A shared sequence on certain DR4 and DR1/3 chains is predicted to generate a shared epitope that promotes susceptibility to RA. Because the relative risk conferred by DR4 for susceptibility and severity is significantly higher than that for DRI, it is likely that the epitope(s) generated by these shared sequences are affected by different DR contexts. We utilized mAbs (NFLD.D2, NFLD.D3, NFLD.D8 and NFLD.D10) which map to the region in question and mAbs NFLD.D! 1 and NFLD.DI2 which are specific for DPq~I*0401. Bindin8 studies were performed on: 1) a panel of mouse L cell transfectants expressing either wild type or mutated DR~I*0401 molecules, and 2) two class II negative BCL transfectunts (T2-Dw4 and BLS-Dw4) expressing D1LS!"0401. The epitopes recognized by NFLD.D2, D3, DS, and DIO are overlapping; residue 70Q is critical, but substitutions on the alpha helix (67I and 74E) and on the floor (28E, 30L and 37F) signifiountly altered the conformation of all, but the NFLD.D l 0 binding epitope. NFLD.D 11 and NFLD.D12 binding was lost when DROI *0401 molecules were expressed on mouse cells; however, studies using human BCL suggest that the critical residue is 71K. Since residues that altered antibody binding epitopes arc also implicated in pelXide binding, we predicted that peptides may contribute to the formation of these epitopes. Binding studies with T2-Dw4, which is defective in peptide loading showed profoundly decreased binding of NFLD.D2, NFLD.D3 and NFLD.DS, but not of lqFLD.DI0, and showed total loss of NFLD.DI 1 and NFLDDI2 binding. Similar results were obtained for BLS-Dw4 while all mAbs strongly bound to DROI*0401 molecules on normal BCL. Taken altogether the data suggest that epitopes generated by shared sequences on the DR alpha helix are strongly influenced by the DR framework in which they reside and by peptide loadin~ of the antigen binding site. This being the case, these epitopes may also be recognized by T cells and may be important in determining T cell selection, end hence, could be the basis for altered susceptibility to diseases such as RA.
MATERNAL NON-TRANSMITTED HLA ALLELES INFLUENCE THE OCCURRENCE OF IDDM. J~WL~m_r~Lt~ and Glenys Thomson, Department of Integrative Biology, University of California, Berkeley CA and 14 collaborating centers. Recently ten Wolde et al. (Lancet 341:200, 1993) showed that the non-inherited maternal HLA gene products influence susceptibility to rheumatoid arthritis. Here, we document similar, and possibly stronger evidence, for the effect of a non-transmitted HLA class II allele affecting susceptibility to Type I diabetes (IDDM). In a collaborative study of over 900 HLA-typed Caucasian IDDM families, families were classified into a three-way statistical design of paternal allele transmitted to the proband X maternal allele transmitted X maternal allele not-transmitted. These tables tested significantly heterogeneous for three-way interaction, implying that the non-transmitted maternal allele effects Type I diabetes susceptibility as a function of the mother's genotype and the paternal antigen. No effect was present when the same test was performed using the paternal non-transmitted allele. The maternal effect is attributable to the non-transmitted DR3. Susceptibility is increased only when the maternal transmitted allele is not DR4 and the paternal transmitted is either DR3 or DR4. The immune system of the developing fetus is apparently conditioned by invading maternal cells, influencing IDDM susceptibility years later.