Monogenic Autoinflammatory Syndromes

Abstract

• “Autoinflammatory syndromes” is the broad name given to a group of heritable conditions caused by defects in genes that regulate the innate immune system. • Initially, these conditions were termed hereditary periodic fever syndromes; however, autoinflammatory syndromes is the preferred name, because not all of the disorders that have been added to this class of inflammatory disorders present with periodic febrile episodes. • In contrast to autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, autoantibodies and antigen-specific T cells typically do not play a primary role in the pathogenesis of the autoinflammatory syndromes. Nonetheless, variable degrees of abnormality in the adaptive immunity have been described in several recently discovered diseases. • Although the term autoinflammatory syndromes is now commonly used to include polygenic diseases such as Behcet’s syndrome, adult-onset Still’s disease, and even type 2 diabetes, this chapter addresses the monogenic autoinflammatory syndromes. • Most autoinflammatory syndromes demonstrate a Mendelian inheritance pattern, and they can be inherited either as autosomal recessive or autosomal dominant traits. • The disorders commonly present in childhood. • Somatic mutations, typically in myeloid cells, have been reported in patients with late-onset diseases. • The syndromes include different conditions that often have overlapping clinical manifestations affecting joints, the bones, the skin, the abdomen, lymph nodes, and the nervous system. Currently, pathogenic mutations have been identified in close to 50 genes. • Most autoinflammatory syndromes are typified by intermittent febrile episodes of noninfectious origin that occur throughout life. The febrile episodes last for variable periods that are characteristic of each specific syndrome. The fevers are also accompanied by an intense acute-phase response. • Some patients present with an expanded immunological disease continuum that includes autoinflammation, autoimmunity, immunodeficiency, and atopy. • Autoinflammatory syndromes are caused by mutations that lead to a gain-of-function of the affected innate immune pathway. The most common examples are genetic mutations that lead to inappropriately elevated levels of inflammatory cytokines, such as interleukin-1. • Although some autoinflammatory syndromes can be differentiated based on their clinical manifestations such as duration of an inflammatory attack, skin manifestations, and gastrointestinal (GI) or central nervous system (CNS) inflammation, molecular testing has become instrumental in diagnostics of all inborn errors of immunity owing to an increasing number of patients who present with a continuum of features.