Classification of Genetically Defined Autoinflammatory Diseases

Abstract

Autoinflammatory diseases are hyperinflammatory, immune-dysregulatory conditions that typically present in early childhood with fever, rashes and disease-specific patterns of sterile organ inflammation of predominantly innate immune cells. The identification of disease-causing genetic mutations in key innate immune pathways that regulate pro-inflammatory cytokines, paired with the impressive clinical responses to cytokine blocking therapies has led to the concept that cytokine activation drives “cytokine amplification loops” that lead to the development of systemic and organ-specific disease manifestations of autoinflammatory diseases. While the initial discoveries of the genetic causes of autoinflammatory diseases and the clinical treatment successes centered around conditions that were presumed to be caused by interleukin (IL)-1 overproduction and signaling, more recent studies are providing insights into proinflammatory cytokine dysregulation, that includes Type-I interferon (IFN), IL-17, IL-18 or IL-36 and more generally ubiquitination disorders that affect nuclear factor kappa B (NF-kB) dysregulation. Characteristic clinical findings such as fever patterns, type of skin lesions and pattern of organ inflammation track with specific innate immune pathways. In this chapter we use two different classification systems of the known genetically-defined autoinflammatory diseases, a clinical classification system based on skin lesions, other characteristic clinical features and the pattern of the inflammatory episodes (i.e. fever pattern), and a pathophysiological classification based on innate immune sensor and cytokine pathways that are dysregulated. The clinical and pathophysiological classification systems can be integrated.