CANDLE Syndrome As a Paradigm of Proteasome-Related Autoinflammation

Abstract

CANDLE syndrome (Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature) is a rare, genetic autoinflammatory disease due to abnormal functioning of the multicatalytic system proteasome–immunoproteasome. Several recessive mutations in different protein subunits of this system, located in one single subunit (monogenic, homozygous, or compound heterozygous) or in two different ones (digenic and compound heterozygous), cause variable defects in catalytic activity of the proteasome–immunoproteasome. The final result is a sustained production of type 1 interferons (IFNs) that can be very much increased by banal triggers such as cold, stress, or viral infections. Patients start very early in infancy with recurrent or even daily fevers, characteristic skin lesions, wasting, and a typical fat loss, all conferring the patients a unique and unmistakable phenotype. So far, no treatment has been effective for the treatment of CANDLE syndrome; the JAK inhibitor baricitinib seems to be partially helpful. In this article, a review in depth all the pathophysiological, clinical, and laboratory features of CANDLE syndrome is provided.

Primary immunodeficiencies in cytosolic pattern‐recognition receptor pathways: Toward host‐directed treatment strategies

“…Normally, formation of the immunoproteasome is mainly induced by interferons to keep up with the increased demand of catalytic activity within the cell 148 . The assembly and maturation of these multiprotein structures are governed by facilitating proteins such as the proteasome maturation protein (POMP).…”

“…The combination of autoinflammation, autoimmunity, and immunodeficiency poses difficulties for treatment. Oral corticosteroids and methotrexate have provided some improvement, but etanercept (anti‐TNF‐α), anakinra (anti‐IL‐1), tocilizumab (anti‐IL‐6), and calcineurin inhibitors were shown to be ineffective 148,150 . Recently, multiple studies have reported that treatment with the JAK inhibitor baricitinib in CANDLE patients leads to remarkable amelioration of clinical severity scores and systemic inflammation 159‐162 …”

Genetic aspects of the pathogenesis of systemic lupus erythematosus in children

“…Мутации в вышеописанных генах, а также редкие мутации в генах SAMHD1, ADAR1, IFIH1, результатом которых является гиперпродукция ИФН I типа, описаны не только при различных вариантах синдрома Айкарди-Гутьереса, но и у больных с ненаследственными формами СКВ, а также в связи с интерферонопатиями -широким спектром заболеваний со множественными аутоиммунными проявлениями [20]. Мутация в гене NEIL3 -фермента, участвующего в репарации ДНК, -обнаружена в семье с историей близкородственных браков, у сибсов с рецидивирующими респираторными инфекциями, иммунной цитопенией и нарушением аутотолерантности В-клеток [21].…”

The ubiquitin proteasome system as a potential therapeutic target for systemic sclerosis

“…Indeed, rare mutations in the immunoproteasome PSMB8 gene have been identified in severe autoinflammatory disorders [89][90][91][92][93] . Moreover, recent studies have identified recessive mutations of immunoproteasome and proteasome genes resulting in altered proteolytic activity of the proteasome and sustained production of type 1 interferons in patients with the rare, genetic autoinflammatory CANDLE syndrome (Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature) 94 . Taken together these data suggest that the absence or mutation of immunoproteasome subunits contributes to the onset of autoinflammatory and autoimmune diseases.…”