Immunological research carried out during the second half of the twentieth century was essentially dedicated to understanding the cellular and molecular mechanisms that are responsible for the selective recognition of bacterial or viral antigens through T and B lymphocytes. These cells are the effectors of adaptive immunity that appeared in the course of evolution in vertebrates some 400 million years ago. Nevertheless, essential issues remained unsolved, namely the mechanisms that ensure the initial recognition of microbes that have breached physical barriers (e.g. the epidermis and epithelial surfaces) and the activation and modulation of the adaptive immune response in higher animals. Thanks to studies carried out by Hoffmann and Beutler, the solution to these problems has been found.
Invertebrates possess a defence system against infectious agents. It is less sophisticated than that of vertebrates, and based on the rapid production of anti-microbial and anti-fungal peptides whose actions cover a broad spectrum. This type of immunity, called innate, appeared before adaptive immunity in the course of evolution and has been conserved in mammals, including humans.
The discovery of the genetic mechanism that launches and controls innate immunity in insects was made by Jules Hoffmann and his group at the University of Strasbourg, and is part of a series of brilliant studies that appeared from the end of the 1980s onwards. One of the crucial phases was the publication in Cell in 1996, which showed that the gene encoding a membrane receptor called Toll (already known for its role in the development of Drosophila) was critical for the release of the fly’s defences against a fungal infection. The genes involved in the cascade that leads from the receptor Toll to the production of antifungal and antibacterial peptides (for Gram positive bacteria) as well as the mechanisms fighting Gram negative bacteria were subsequently identified by the Strasbourg team. These findings were followed by the discovery of TLR (Toll Like Receptors) in mammals, which are counterparts to the Toll receptor in insects.
In 1998, Professor Bruce Beutler was the first to clone the gene of one of these TLRs where the ligand is a bacterial lipopolysaccharide, LPS, also called endotoxin, and is responsible for septic shock. A total of 13 TLRs have subsequently been identified in mammals. They are expressed by dendritic cells, B lymphocytes as well as by many other types of cells. Each has specificity for one antigenic substance or a group of them: TLR4 is the one that recognizes LPS, others bind to nucleic acids (TLR3, TLR7, TLR8, and TLR9), to lipoproteins and glycolipids (TLR2), to flagellin (a component of bacterial flagella) (TLR5), etc. TLRs are thus key sensors in interactions between the organism and its environment. These discoveries have led to clinical applications. A great deal of work has been done on TLRs, with the aim of increasing, modulating or inhibiting inflammatory reactions in different circumstances: for example, with the goals of devising superior vaccines, mitigating allergic states and auto-immune reactions, and correcting immuno-deficiencies. In addition, Bruce Beutler isolated tumor necrosis factor (TNF), and discovered its major role in inflammatory processes. Agents that block TNF activity are now widely used in medical practice to inhibit the progression of several auto-immune diseases.
These two researchers have collaborated closely in the elaboration of the new vision that we now have of the defence mechanisms that animals across the evolutionary spectrum use against infectious agents. The development of our knowledge of genetic and molecular mechanisms of innate immunity – the only form of immunity present in invertebrates – has led to a revolution in our understanding of immunity in vertebrates. In the past, little attention had been given to its role in immune defence. Research during the past two decades has shown the importance of innate immunity in mammals, including man, the conservation of the molecular and genetic mechanisms that control it in the course of evolution, and the close links that it has with adaptive immunity.