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Genetics of monogenic autoinflammatory diseases: past successes, future challenges

Abstract

The term autoinflammation was initially coined to distinguish disorders characterized by recurrent episodes of inflammation in the absence of high-titer autoantibodies and antigen-specific T cells from the more common autoimmune diseases. Although this concept originally applied to monogenic hereditary recurrent fevers, it has expanded over time to include polygenic (complex) autoinflammatory diseases. Understanding of the pathogenesis of autoinflammatory diseases has grown rapidly in the past decade owing to advances in genome research and technology. Genome-wide linkage analysis, positional cloning, homozygosity mapping and candidate gene screening have led to the identification of mutations in 12 genes that are associated with monogenic diseases. Genome-wide association studies have begun to elucidate the molecular basis of complex autoinflammatory diseases. The discovery of disease-causing genetic variants has defined autoinflammation as disorder within the innate immune system, implicating IL-1 as a master cytokine, and has led to a breakthrough in therapy, with IL-1 inhibitors producing rapid and sustained amelioration of symptoms. Despite major advances, however, a substantial number of patients have no mutations in the known autoinflammatory genes. The challenge now is to find the undiscovered genes, considering that most cases are sporadic or occur within small families. New approaches and tools such as next-generation sequencing are discussed.

Key Points

  • A new nosology, autoinflammation, has been proposed to distinguish inherited diseases of the innate immune system from chronic inflammatory diseases that are mediated by the adaptive immune system

  • Most causal variants associated with systemic autoinflammatory diseases are missense nucleotide changes, a possible explanation for the intermittent nature of the inflammatory symptoms characteristic of these diseases

  • Mutations in the same protein have been associated with different phenotypes in human disease, and phenotypes associated with disease-causing mutations vary in animal models and human disease

  • Animal studies suggest that most causal variants of autoinflammatory diseases seem to be gain-of-function mutations, regardless of the mode of disease inheritance in humans

  • Many of the affected genes are directly or indirectly involved in the regulation of the IL-1 cytokine signaling pathway

  • Molecular insights have provided the basis for new therapeutic interventions that have had an immediate and dramatic impact on the treatment of autoinflammatory disorders

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Figure 1: Schematic representation of recessively inherited FMF-associated mutations in the MEFV gene.
Figure 2: Schematic representation of mutations in MVK that have been identified in patients presenting with MA or HIDS.
Figure 3: Mechanisms of autoinflammatory diseases mediated by IL-1β and IL-10.
Figure 4: Schematic representation of mutations in the TNFR1 protein that are associated with TRAPS.
Figure 5: Schematic representation of dominantly inherited NLRP3 mutations in patients with CAPS.

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I. Aksentijevich researched data for the article, and I. Aksentijevich and D. L. Kastner contributed equally to discussing content, writing the article, and reviewing/editing of the manuscript before submission.

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Correspondence to Ivona Aksentijevich.

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Aksentijevich, I., Kastner, D. Genetics of monogenic autoinflammatory diseases: past successes, future challenges. Nat Rev Rheumatol 7, 469–478 (2011). https://doi.org/10.1038/nrrheum.2011.94

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