The lecture began with a review of the mechanisms by which T and B lymphocytes generate antigenic recognition diversity, followed by an introduction to a number of autoimmune diseases. The examples of systemic lupus erythematosus (a so-called systemic autoimmunity, essentially involving autoantibodies) and multiple sclerosis (an autoimmunity targeting the nervous system, essentially involving T lymphocytes). It has long been known that heredity is associated with the risk of autoimmune diseases (increased frequency in identical twins, for example), but this risk is relatively low. Nevertheless, analysis of this heredity, while not predictive of individual risk, can identify susceptibility genes and thus contribute to understanding the pathophysiology of these diseases. Modern methods of genomic analysis using genetic linkage studies have identified hundreds of loci in the genome where sequence variations confer a risk of (or protect against) autoimmune diseases. These loci often correspond to coding genes or regulatory regions of the genome involved in the immune responses of T lymphocytes, B lymphocytes and monocytes, thus pointing to relevant biological pathways. Biological validation of the effect of certain variants has been obtained, but it must be borne in mind that each of these variants contributes only modestly to the individual risk of autoimmune disease. A fraction of these variants represent risk factors shared by several autoimmune diseases, while others may be restricted to a given disease or even a given population, adding to the complexity of the analysis. Interestingly, some of these genetic variants appear to have been evolutionarily selected as variants conferring protection against particular microorganisms.
In contrast to these frequent but low-impact variations, it's worth looking at the rare examples offered by Mendelian genetics of susceptibility to autoimmune diseases. These exceptional situations have the advantage of simplifying analysis and identifying key elements in the control of autoimmunity and autoinflammation. Five such mechanisms have been identified and will be discussed in the first seminar and forthcoming lectures.
