Understanding Systemic Autoinflammatory Diseases: History, Characteristics, and Associated Genes

Systemic autoinflammatory diseases (SAIDs) are a group of disorders caused by a dysregulation of the innate immune system. These diseases are characterized by systemic pathobiology, which means that symptoms can affect the entire body, and they can be viewed as the counterpart to autoimmune diseases. The first known systemic autoinflammatory disease, familial Mediterranean fever (FMF), was described in 1945, and the term "autoinflammatory" was coined in 1999. Since then, more than 40 disorders have been discovered, unraveling essential mechanisms in human immunity.

SAIDs are a complex group of conditions that may overlap with autoimmunity, immunodeficiency, and allergy. In many cases, SAIDs have a strong genetic background with mutations in single genes. For example, MEFV was the first gene identified as disease causing for Familial Mediterranean Fever, the most common hereditary SAID. Since 1997, more than 30 new genes associated with autoinflammatory diseases have been identified, affecting different parts of the innate immune system. However, for at least 40–60% of patients with phenotypes typical for SAIDs, a distinct diagnosis cannot be met, leading to undefined SAIDs (uSAIDs). SAIDs can also be of polygenic or multifactorial origin, with environmental influence modulating the phenotype.

The name "autoinflammatory disease" was proposed in 1999 by McDermott et al. The main cell types of the innate immune system are monocytes, macrophages, and neutrophils, whereas the adaptive immune response is mediated by B and T cells. The initial defining criteria for SAIDs are the lack of high-titer autoantibodies or antigen-specific T cells and a fluctuating degree of fever, as well as abdominal, articular, and cutaneous signs that may lack specificity, making a clinical diagnosis difficult.

The pathogenesis of SAIDs is linked to the identification of the underlying genetic and molecular basis for inflammation. More than 30 genetically defined autoinflammatory diseases, many with direct and indirect links to the IL-1 pathway, have been described. Monogenic autoinflammatory disorders are caused by mutations in single genes related to control of inflammation. Mechanistically, monogenic autoinflammatory disorders lead to persistent activation of the NLPR3 or pyrin inflammasomes and subsequent activation of caspase 1, resulting in IL-1 release and autoinflammation. Other monogenic disorders lead to IL-1 activation through pathways other than direct inflammasome activation.

Diagnosis is often based on clinical presentation and genetic testing. The timeline from onset to diagnosis takes up to 7.3 years, highlighting the indisputable need to identify new treatment and diagnostic targets. Recently, other factors are under investigation as additional contributors to the pathogenesis of SAIDs. This review gives an overview of pathogenesis and etiology of SAIDs, and summarizes recent diagnosis and treatment options.

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