Immunogenetics of Autoimmune Disease

utoimmunity is the downstream outcome of a rather extensive and coordinated series of events that include loss of self-tolerance, peripheral lymphocyte Aactivation, disruption of the blood-systems barriers, cellular infiltration into the target organs and local inflammation. Cytokines, adhesion molecules, growth factors, antibodies, and other molecules induce and regulate critical cell functions that perpetuate inflammation, leading to tissue injury and clinical phenotype. The nature and intensity of this response as well as the physiological ability to restore homeostasis are to a large extent conditioned by the unique amino acid sequences that define allelic variants on each of the numerous participating mol­ ecules. Therefore, the coding genes in their germline configuration play a primary role in determining who is at risk for developing such disorders, how the disease progresses, and how someone responds to therapy. Although genetic components in these diseases are clearly present, the lack of obvious and homogeneous modes of transmission has slowed progress by prevent­ ing the full exploitation of classical genetic epidemiologic techniques. Furthermore, autoimmune diseases are characterized by modest disease risk heritability and m- tifaceted interactions with environmental influences. Yet, several recent discoveries have dramatically changed our ability to examine genetic variation as it relates to human disease. In addition to the development of large-scale laboratory methods and tools to efficiently recognize and catalog DNA diversity, over the past few years there has been real progress in the application of new analytical and data-manage­ ment approaches.