Gina A. Montealegre Sanchez, MD, MS, Adriana Almeida de Jesus, MD, PhD and Raphaela Goldbach-Mansky, MD, MHS∗goldbacr@mail.nih.gov,     Translational Autoinflammatory Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Building 10, Room 6D47-B, 10 Center Drive, Bethesda, MD 20892, USA

∗Corresponding author.

The pathogenesis of monogenic autoinflammatory diseases converges on the presence of exaggerated immune responses that are triggered through activation of altered pattern recognition receptor (PRR) pathways and result in cytokine/chemokine amplification loops and the inflammatory clinical phenotype seen in autoinflammatory patients. The PRR response can be triggered by accumulation of metabolites, by mutations in sensors leading to their constitutive overactivation, or by mutations in mediator cytokine pathways that lead to amplification and/or inability to downregulate an inflammatory response in hematopoietic and/or nonhematopoietic cells. The study of the pathogenesis of sterile inflammation in patients with autoinflammatory syndromes continues to uncover novel inflammatory pathways.

Keywords

Cryopyrin-associated periodic syndrome (CAPS) • Neonatal-onset multisystem inflammatory disease (NOMID) • Proteasome-associated autoinflammatory syndrome (PRAAS) • Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) • Deficiency of the IL-1 receptor antagonist (DIRA) • Inflammasome • Autoinflammatory diseases • Intracellular pattern recognition receptors (PRR)

Key points

Old and emerging new concepts

Monogenic autoinflammatory diseases can be defined as a group of immune dysregulatory conditions marked by excessive inflammation that is predominantly mediated by increased responses to known and unknown triggers by cells and molecules of the innate immune system (Table 1).1 These illnesses typically present in childhood and can mimic infections or hematologic malignancies, but the inflammatory lesions are aseptic and nonmalignant. The discovery of single-gene defects in the interleukin (IL)-1 pathway that cause the spectrum of the cryopyrinopathies or cryopyrin-associated periodic syndromes (CAPS) and the rare condition, deficiency of the IL-1 receptor antagonist (DIRA), pointed to the pivotal role of IL-1 and provided deeper insights into the molecular bases that drive the inflammatory phenotypes. These findings translated into therapeutic approaches using IL-1 blocking agents, which have become standard of care for the cryopyrinopathies and DIRA, and their use has been expanded to other monogenic disorders, the periodic fever syndromes, and to disorders with unidentified genetic causes, including aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome, systemic-onset juvenile idiopathic arthritis (SJIA), adult-onset Still disease (AOSD), and Behçet disease, that share clinical similarities with monogenic autoinflammatory diseases.

The journey of deciphering inflammatory phenotypes started in 1997 with the discovery of the genetic cause of familial Mediterranean fever (FMF), the most prevalent autoinflammatory disease worldwide,2,3 followed by the discovery of the genetic cause of 2 other periodic fever syndromes, tumor necrosis factor (TNF) receptor–associated periodic syndrome (TRAPS)4 and hyperimmunoglobulinemia D with periodic fever syndrome (HIDS).5–7 These 3 syndromes share the episodic nature of fever and periods of remission and can be grouped as classic hereditary periodic fever syndromes. The cryopyrinopathies, comprising familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic cutaneous and articular (CINCA) syndrome; and DIRA are caused by single-gene mutations in loci regulating IL-1 processing, secretion, and signaling. Therapeutic interventions blocking IL-1 in an autoinflammatory bone disease with clinical similarities to DIRA, namely Majeed syndrome, confirmed a prominent role for IL-1 in this condition as well.

A group of recently described autoinflammatory syndromes that are unresponsive to IL-1 blocking therapy include the proteasome-associated autoinflammatory syndromes (PRAAS) or chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), an autoinflammatory condition presenting with lipodystrophy and myositis; deficiency of IL-36 receptor antagonist (DITRA) and CARD14-mediated psoriasis (CAMPS), 2 conditions presenting with pustular skin disease; and early-onset inflammatory bowel disease (IBD). Other newly discovered conditions that present with inflammatory dysregulation only partially involving IL-1 include disorders caused by mutations in PLCγ28,9 and pyogenic arthritis pioderma gangrenosum and acne (PAPA) syndrome.10 Studies of the disease pathogenesis of other disorders point to a role of cytokine dysregulation in pathways involving interferon (IFN), NF-κB/IL-17 and IL-10 signaling pathways. The complex clinical and laboratory features, which, in some novel conditions, can overlap with those seen in patients with autoimmune diseases, illustrate that innate and adaptive immune responses can be dysregulated in some conditions and need to be viewed as coexisting consequences of mutations in adaptive and innate immunity cells. Mutant protein in CAMPS and DITRA is mainly expressed in keratinocytes, which points to a role of primary keratinocyte dysregulation in pustular, neutrophilic dermatitis, and provides us with clues to tissue-specific factors that lead to organ-specific disease manifestations.