Untangling the web of systemic autoinflammatory diseases

Abstract

The innate immune system is involved in the pathophysiology of systemic autoinflammatory diseases (SAIDs), an enlarging group of disorders caused by dysregulated production of proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α, in which autoreactive T-lymphocytes and autoantibodies are indeed absent. A widely deranged innate immunity leads to overactivity of proinflammatory cytokines and subsequent multisite inflammatory symptoms depicting various conditions, such as hereditary periodic fevers, granulomatous disorders, and pyogenic diseases, collectively described in this review. Further research should enhance our understanding of the genetics behind SAIDs, unearth triggers of inflammatory attacks, and result in improvement for their diagnosis and treatment.

Figure 1

Anteroposterior radiograph performed in a 12-year-old boy with chronic infantile neurological cutaneous and articular (CINCA) syndrome, showing a calcified mass-like region in the physis of the distal femur (see white arrows). Osteoarthropathy of CINCA patients is a unique feature of this condition, caused by abnormal endochondral bone growth, mainly affecting large joints and long bones, beginning in the first infancy and causing striking changes until skeletal maturity.

Figure 2

Schematic representation of the main pathophysiologic mechanisms involved in the less frequently diagnosed systemic autoinflammatory diseases. Blau syndrome (BLAU) and NLRP12-associated autoinflammatory disorder (NLRP12-AD) are caused by altered nuclear factor-κB (NF-κB) regulation, caused, respectively, by NOD2 and NLRP12 gene mutations. Deficiency of the interleukin-1 (IL-1) receptor antagonist (DIRA) and deficiency of interleukin-36 (IL-36) receptor antagonist (DITRA) are linked to mutations of genes coding, respectively, for IL-1 receptor antagonist (IL-1Ra) and IL-36 receptor antagonist (IL-36Ra). These mutations lead to the loss of IL-1β and IL-36 natural inhibition, resulting in uncontrolled proinflammatory responses. PAPA syndrome (PAPAs) is associated with increased IL-1β processing and secretion, as a consequence of proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene mutations. Proteasome-associated diseases (PAD) are caused by mutations in the proteasome subunit beta type 8 (PSMB8), which lead to the accumulation of ubiquitinated proteins (Ub-proteins) and in turn to p38 phosphorylation, resulting in enhanced proinflammatory responses.

Figure 3

Cold-induced skin rash in a young patient with NLRP12-associated autoinflammatory disorder.