History of oral tolerance and mucosal immunity.

Mucosal immunity depends on antigen stimulation in specialized lymphoepithelial structures such as the Peyer's patches. Although these inductive compartments were discovered more than 300 years ago, their functional role has become clear only over the last few decades. Research on homing of primed lymphoid cells to the intestinal mucosa began with animal experimentation in the 1960s and 1970s and has recently been brought to the molecular level. The major effector substance of mucosal immunity is secretory IgA (SIgA). The first evidence for its local antibody activity was obtained in humans in 1922, but its unique properties were not defined until the mid-1960s. Several models were subsequently proposed for selective external transport of IgA involving the secretory component (SC). In the early 1970s SC was suggested to act as a transmembrane polymeric Ig receptor common for dimeric IgA and pentameric IgM; this transport mechanism has now been confirmed by detailed studies at the level of cellular/molecular biology. Although SIgA antibodies performing immune exclusion are the main goal for exploitation of the mucosal immune system by oral vaccination, little is known about the precise mechanisms for induction of mucosal immunity against soluble proteins and chemicals. A peripheral immunosuppressive effect of oral immunization with such substances was apparently exploited by ancient people, and "oral tolerance" has since 1910 been subjected to numerous feeding experiments in rodents. The basis for the whole phenomenon appears to be intact epithelial barrier. Mucosal induction of suppression may in the future be exploited not only to modulate autoimmune diseases through the gut but also to prevent the development of IgE-mediated allergy and other untoward immune reactions by way of the respiratory tract.