Genomics, Biology, and Human Illness

Abstract

SYNOPSIS The monogenic autoinflammatory diseases are a group of illnesses with prominent rheumatic manifestations that are characterized by genetically-determined recurrent sterile inflammation, and are thus inborn errors of innate immunity. Molecular targeted therapies against inflammatory cytokines such as IL-1 and TNF and intracellular cytokine signaling pathways have proven effective in many cases. Emerging next generation sequencing technologies have accelerated the identification of previously unreported genes causing autoinflammatory diseases. In this review we will cover several of the prominent recent advances in the field of autoinflammatory diseases, including gene discoveries, the elucidation of new pathogenic mechanisms, and the development of effective targeted therapies.

The Balance of TNF Mediated Pathways Regulates Inflammatory Cell Death Signaling in Healthy and Diseased Tissues

“…While TNF’s importance in driving inflammatory diseases is well-established, the recent identification of patients with defects in TNF signaling components have shown the importance of tightly regulating this pathway and the potential consequences of its dysregulation ( Manthiram et al, 2017 ; Oda and Kastner, 2017 ; Figure 3 ). In vitro and in vivo studies have suggested the critical role ubiquitin plays in TNF signaling, both in enabling signal complex formation and in protein degradation.…”

Rash, Fever, and Pulmonary Hypertension in a 6‐Year‐Old Female

“…Although targeted sequencing allows for the accurate analysis of specific genes or regions of interest a variety of next generation sequencing approaches exist including targeted sequencing panels and exome analysis. Next generation sequencing approaches are being employed widely in the diagnostic evaluation of patients with complex disorders including autoinflammatory disorders (25).…”

Current and future advances in genetic testing in systemic autoinflammatory diseases

“…More recently, protein truncating mutations were reported in IL1RN , IL36RN and TNFAIP3 genes associated with deficiency of IL-1 receptor antagonist, deficiency of IL-36 receptor antagonist (DITRA) and HA20. Rare large genomic deletions were identified in the IL1RN [74], ADA2 [75] and TNFAIP3 gene loci [76]. A comprehensive list of classified variants associated with autoinflammatory diseases can be found in the online database Infevers (https://infevers.umai-montpellier.fr/web/index.php) [77].…”