Host Genome - Intestinal Flora Interactions in T1D Pathogenesis

Evidence in support of an environmental influence on the pathogenesis of T1D comes from the incomplete (35-80%) concordance observed in human monozygotic twin pairs. In humans, there is epidemiological evidence that good hygiene increases incidence of allergic conditions (asthma, hayfever, atopic eczema) whereas a farm environment is protective, especially when exposure occurs in early life. The increasing incidence of T1D mirrors that of allergy and epidemiological observations indicate that T1D is less frequent in children from low socioeconomic status and those exposed to early childhood infections. The main immunological explanations for the hygiene effects T-helper immune deviation, aberrant regulatory T cell populations or altered T lymphocyte repertoires, reviewed by us and others are extremely difficult to substantiate in humans.

In contrast to the human studies, the NOD and BB models are amenable to dissecting the mutual interactions between host genomics and environmental organisms because both elements can be systematically controlled and tested. However, a direct and systematic evaluation of T1D in these rodent models with rigorously controlled environmental conditions has not been done. NOD diabetes incidence is clearly higher in standard specific pathogen free (SPF) conditions than under conditions of infection. Gnotobiotic conditions have been reported to cause higher incidence and reduced latency of T1D in NOD mice, but the microbial status of the colonies was not characterized. Hygiene effects have also been suggested in the BB rat. We propose a genomic approach to analyzing the mechanistic basis of these environmental influences on the NOD and BB phenotypes that can be modified independent of the immunological alterations caused by the disease. This will be the first study of large scale and scope to assess host genome/environment interaction in autoimmunity.