Autoimmunity in primary immunodeficiency disorders

There are more than 300 distinct primary immunodeficiencies, the majority being defined by single-gene defects. With an increased identification of primary immunodeficiencies through genomic sequencing, it is clear that many primary immunodeficiencies are characterized not only by susceptibility to infection but also by dysregulation of the immune response manifesting as autoimmunity. With improved prevention of infectious complications, even well-characterized “classic” primary immunodeficiencies such as T and B-cell deficiencies are recognized to have immune dysregulation. The clinical findings together with delineation of the genetic basis for many of these “experiments of nature” have led to an expanded understanding of various pathways involved in immune homeostasis and the maintenance of self-tolerance. In this chapter the major primary immunodeficiency disorders associated with immune dysregulation and autoimmunity are presented, paying particular attention to the mechanisms by which defects in different arms of the immune system cause autoimmunity.