We cloned the cDNAs encoding the feline homologues of B-lymphocyte activation antigens B7-1 (CD80) and B7-2 (CD86). We expressed recombinant feline CD80 and CD86 molecules by the baculovirus expression system, and demonstrated their binding ability to human CTLA4-murine immunoglobulin fusion protein.
Exhaustive gene identification followed by assignment of the genes identified to corresponding loci is a key step in elucidating the physical structure of a multigene family. However, problems occur in this process because genes in a multigene family usually share a high degree of sequence identity and are highly polymorphic. To address these problems, an efficient population-based approach was developed. Using this approach, sequences in the human immunoglobulin VH4 family were amplified by PCR with family-specific primers. Denaturing gradient gel electrophoresis (DGGE) was used to separate the resulting sequences with either very similar or identical sizes and differing by as little as 1 base pair (bp). Eighteen distinct bands and 21 banding patterns were observed in the samples collected from 41 unrelated individuals. Of the 18 bands, 12 were polymorphic. No sample had all 18 bands. The estimated frequencies for the alleles represented by the 18 bands ranged from 1.2 to 100%. The 18 sequences differed from each other by 1-19 bases (0.7 to 13%) within the 145-146-bp amplified region. Sequences in eight bands (44%) were not reported previously. These results were used to assign the majority (14 out of 18) of the VH4 sequences to 10 loci. This PCR-DGGE method, in conjunction with a population-based assay, may also be used to study other multigene families including those involved in the development of the immune system.
HLA-associated relative risks of type 1 (insulin-dependent) diabetes mellitus were analysed in population-based Swedish patients and controls aged 0-34 years. The age dependence of HLA-associated relative risks was assessed by likelihood ratio tests of regression parameters in separate logistic regression models for each HLA category. The analyses demonstrated an attenuation with increasing age at onset in the relative risk for the positively associated DQB1*0201-A1*0502/B1*0302-A1*0301 (DQ2/8) genotype (P = 0.02) and the negatively associated DQB1*0602-A1*0102 (DQ6.2) haplotype (P = 0.004). At birth, DQ6.2-positive individuals had an estimated relative risk of 0.03, but this increased to 1.1 at age 35 years. Relative risks for individuals with DQ genotype 8/8 or 8/X or DQ genotype 2/2 or 2/X, where X is any DQ haplotype other than 2, 8 or 6.2, were not significantly age-dependent. An exploratory analysis of DQ haplotypes other than 2, 8 and 6.2 suggested that the risk of type 1 diabetes increases with age for DQB1*0604-A1*0102 (DQ6.4) and that the peak risk for the negatively associated DQB1*0301-A1*0501 haplotype is at age 18 years. There was also weak evidence that the risk for DQB1*0303-A1*0301 (DQ9), which has a positive association in the Japanese population, may decrease with age. We speculate that HLA-DQ alleles have a significant effect on the rate of beta cell destruction, which is accelerated in DQ2/8-positive individuals and inhibited, but not completely blocked, in DQ6.2-positive individuals.
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