The experiments described in this research proposal utilize a hypervariable DNA probe hybridizing with a region of multi- allelic tandem repeats approximately 10 centimorgans away from the T-cell receptor beta-chain gene complex on the seventh human chromosome. Using this probe, as well as DNA probes for the V beta and C beta genes from the human beta-chain receptor gene complex, restriction fragment length polymorphism (RFLP) analysis for association between one maternal or paternal seventh chromosome haplotype and susceptibility to Type I insulin- dependent diabetes, and sero-positive rheumatoid arthritis, will be carried out by studying a series of 10 or more families with each disease, in which two or more individuals in a sibships are affected. Given the multi-allelic nature of the probe, the high degree of heterozygosity detected in the population, and its close linkage to the T-cell receptor beta-chain gene complex, these experiments should permit definitive establishment of linkage or non-linkage of the T-cell receptor beta-chain gene complex with susceptibility to these two diseases. Experiments are also described utilizing a 33-base pair tandem repeat sequence from the myoglobin intron, and a 16-base pair """"""""core"""""""" sequence contained within this 33-base pair repeat sequence, as probes to identify other hypervariable """"""""mini-satellite"""""""" regions of DNA on the human complex. If these experiments are successful, similar attempts to establish linkage or non-linkage of susceptibility to these two diseases with the T-cell receptor alpha-chain gene complex will then be carried out. Arguments are presented which suggest that, second only to the class II MHC genes which predispose to these two diseases, T-cell receptor alpha- and/or beta-chain variable region genes are the most likely candidates for additional genes influencing susceptibility to these two autoimmune diseases, in which susceptibility is clearly inherited by a polygenic form of inheritance.
| Bell, J I; Steinman, L; Toyka, K et al. (1987) HLA-DQ restriction fragment length polymorphisms in myasthenia gravis. Ann N Y Acad Sci 505:382-7 |
| Lee, B S; Bell, J I; Rust, N A et al. (1987) Structural and functional variability among DQ beta alleles of DR2 subtypes. Immunogenetics 26:85-91 |
| Bell, J I; Denney Jr, D; Foster, L et al. (1987) Allelic variation in the DR subregion of the human major histocompatibility complex. Proc Natl Acad Sci U S A 84:6234-8 |
| Lee, B S; Rust, N A; McMichael, A J et al. (1987) HLA-DR2 subtypes form an additional supertypic family of DR beta alleles. Proc Natl Acad Sci U S A 84:4591-5 |
| Bell, J; Rassenti, L; Smoot, S et al. (1986) HLA-DQ beta-chain polymorphism linked to myasthenia gravis. Lancet 1:1058-60 |
| Hardy, D A; Bell, J I; Long, E O et al. (1986) Mapping of the class II region of the human major histocompatibility complex by pulsed-field gel electrophoresis. Nature 323:453-5 |
| McDevitt, H O (1986) The molecular basis of autoimmunity. Clin Res 34:163-75 |
