NKT cells and type-1 diabetes and the "hygiene hypothesis" to explain the rising incidence rates.

Immune-mediated (type-1) diabetes (IMD) is a multigenetic disease that is strongly influenced by the environment. Whereas the incidence rates are steadily rising worldwide, less than half of affected identical twins ever become concordant for IMD or even beta-cell autoimmunity. Worldwide, it is the tropical regions of the world that are replete in infectious and parasitic diseases that are the least affected. Repeated efforts to identify the putative inductive agents for beta-cell autoimmunity have proved unrewarding. Rather, we suggest that some environments are less protective than others and argue that it is the fall in incidences of infectious diseases and intestinal parasites that are likely responsible for the rise in autoimmune diseases like IMD in the West. Nonobese diabetic (NOD) mice reared in gnotobiotic environments have only worsened diabetes, while recent studies suggest that multiple defects in immune tolerance to self must be present before IMD can develop in the human or mouse. We speculate herein that the deficiency in natural killer T (NKT) cells in IMD in both species may be both genetic and environmentally influenced, predisposing to pancreatic beta-cell autoimmunity through a dysfunction of immunoregulatory T cells, with defective peripheral control of islet cell protein autoreactive cytotoxic CD8+ T cells. The encouraging results in NOD mice using alpha-galactosylceramide to stimulate NKT cells now warrant trials with this and other glycolipid NKT cell-stimulating agents in humans. Since it has become apparent that autoimmune diseases such as IMD are the result of an underlying immunodeficiency state, we strongly argue that its effective prevention will likely come through the use of immunostimulation and not through side effect-prone immunosuppression.