In order to investigate the genetic control of human immune responses, the inheritance of several genes known to play important roles in a variety of immune processes has been analyzed in human families. HLA and T cell receptor (TCR) genes have been examined by Southern blot analyses using specific DNA probes to identify restriction fragent length polymorphism (RFLP). These studies have shown that their is limited polymorphism of TCR genes detected by RFLP in that few restriction enzymes reveal polymorphism with a given prob and when polymorphism is observed there are few allelic forms of each marker. However, there is considerable polymorphism in the combination of markers inherited together in both TCR alpha and TCR beta haplotypes. These observations have an important impact upon studies to determine whether TCR genes are associated with disease susceptibility. TCR and disease associated studies will most informatively be performed in families showing a predisposition to a particular disease. There is compelling evidence that susceptibility to Multiple Sclerosis is inherited and that T lymphocytes play a role in the pathogenesis of the disease. HLA and TCR haplotypes were determined in sibships with two or more members concordant for MS. Of the 16 families studies to date, 4 affected sib-pairs shared both TCR beta haplotypes, 11 pairs shared 1 haplotype and 1 pair shared 0 haplotypes. In addition to the preponderance of shared haplotypes by patients there was also a TCR beta RFLP which was present as an increased frequency in unrelated MS patients. Correlation between RFLP and sequence difference in TCR beta V region coding sequences was examined by amplification of genomic DNA using the polymerase chain reaction (PCR), cloning into m13, and DNA sequence analysis.