Autoinflammatory disease

Next-generation sequencing has led to the discovery of multiple rare autoinflammatory diseases, together with their corresponding disease-causing mutations, creating opportunities to develop personalized medicine and providing useful insight into more common forms of autoimmunity and autoinflammation.

In this Review, the authors discuss the role of IL-18 in human inflammatory disease. They describe the mechanisms of IL-18 biology, discuss how dysregulation of this biology leads to immunopathology, and note the biological and clinical circumstances in which therapeutic manipulation might alleviate suffering and save lives.

In this Review, the authors summarize the pathophysiological mechanisms of IL-1-mediated autoinflammation. They describe the epidemiological and clinical features of autoinflammatory diseases, challenges associated with diagnostics and disease management, and current and future therapies for targeting the IL-1 pathway.

Ubiquitylation is involved in the regulation of most cellular systems, including the innate immune system. Here, the authors describe the molecular pathogenesis of disorders of ubiquitylation that result in innate immune overactivation and systemic autoinflammatory disease.

Most rheumatic and musculoskeletal diseases (RMDs) fall along a spectrum of disorders from autoinflammatory diseases to autoimmune diseases, with ‘mixed-pattern’ RMDs having features of autoinflammation and autoimmunity. A better understanding of the pathogenic pathways of autoinflammation and autoimmunity in RMDs should enhance targeted treatment strategies.

Ankylosing spondylitis (AS) is a chronic inflammatory disease with hallmarks of both autoimmune and autoinflammatory pathology. In this Review, the authors examine the evidence for both disease processes and aim to reconcile the two.

Monogenic autoinflammatory diseases are linked to various germline and somatic pathogenic variants but numerous factors must be considered to explain their large phenotypic variability. This Review discusses genotype–phenotype relationships and the potential molecular mechanisms that might explain this variability.

In this Review, the authors discuss macrophage activation syndrome (MAS) in relation to other cytokine storm scenarios, and provide a framework for understanding MAS within the spectrum of innate and adaptive immunity in the context of gain or loss of immune function.

The concept of autoinflammation has evolved to include multifactorial conditions and disorders with autoimmune and immunodeficiency components. An appreciation of the contributions of various molecular mechanisms and systems could improve our understanding and treatment of the systemic autoinflammatory diseases.

Characterization of a new mouse model highlights allogeneic bone marrow transplantation and granulocyte colony-stimulating factor neutralization as potential avenues for the treatment of APLAID.

A new study provides an estimate of the prevalence of VEXAS syndrome based on the identification of pathogenic UBA1 variants in a clinical cohort.

New evidence from animal models and human studies suggests that mammalian target of rapamycin has a role in the pathophysiology of Still’s disease and macrophage activation syndrome.

New research reveals that ferritin has an essential role in neutrophil extracellular trap (NET)-mediated inflammation, and suggests that NETs or the ferritin receptor MSR1 could be targeted for the treatment of adult-onset Still disease.

Structural modification of RNA by adenosine-to-inosine editing renders self-RNA invisible to RNA sensors of the innate immune system. Lack of RNA editing unleashes inflammatory responses that can lead to autoinflammation. A deeper understanding of the associated signalling pathways might reveal potential targets for drug discovery for autoinflammatory diseases.

New research has identified an autoinflammatory syndrome caused by mutations in NEMO-encoding IKBKG, leading to NF-κB activation and type I interferon production.

Two new studies have identified mutations in UBA1 associated with the newly identified condition VEXAS syndrome in cohorts of patients with relapsing polychondritis, supporting the concept that relapsing polychondritis is more than one disease.