IMMUNOREGULATORY DEFECTS IN INFLAMMATORY BOWEL DISEASE

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Over the past several years we have examined the hypothesis that the inflammatory bowel diseases, ulcerative colitis and Crohn's disease, is due most fundamentally to an abnormal immune response to one or more mucosal antigens that are always present in the mucosal environment. During this period we investigated this possibility by assessing TCR-V-beta family repertoire expression in T cells in the lamina propria (LPMC) and peripheral blood (PBMC) of IBD patients and control individuals. Our strategy for making such determinations was based on a quantitative RT-PCR technique that has been developed in this laboratory. This technique involves first the construction of internal mRNA standards having the same primer sites as the mRNA to be quantitated but having a different size from the latter and second the co-reverse transcription and amplification of the standard mRNA. The amount of "unknown" TCR-V-beta mRNA is determined in this method from an equivalence point at which standard and unknown are transcribed and amplified with equal efficiency. In our initial studies we found using a qualitative RT-PCR technique that LPMC mRNA of IBD patients contained a full repertoire of 20 TCR-V-beta families and that IBD is not associated with gross deletion or expansion of any family. In further studies with quantitative RT-PCR of four frequently expressed TCR-V-beta families, we found that relative TCR-V-beta expression in LPMC + PBMC was quite different, probably reflecting the somewhat different antigen-drive giving rise to these cell populations. More importantly, we found that mean mRNA values for TCR-V-beta2, but not TCR-V-beta6,7 and 14 were lower in IBD patients than in control individuals. These results indicate a selective abnormality of TCR-V-beta2 expression in both forms of IBD. They are therefore consistent with the concept that a particular antigen or superantigen is important in disease pathogenesis.