Elsevier

Immunology Letters

Volume 193, January 2018, Pages 67-76
Immunology Letters

Review
New mosaic tiles in childhood hereditary autoinflammatory disorders

https://doi.org/10.1016/j.imlet.2017.11.013Get rights and content

Highlights

  • Mutations in the genes implied in apoptosis, cytoskeletal signaling, and activation of the interleukin-1 (IL-1)-structured inflammasome contribute to the pathogenesis of hereditary autoinflammatory disorders (HAID), which are heralded by self-limited episodes of fever unrelated to infectious agents, autoantibody production or autoreactive cells.

  • The protean clinical phenotypes of HAID are caused by abnormal activation of innate immunity and consist of seemingly unprovoked inflammatory flares localized to multiple organs, such as skin, joints, serosal membranes, gut, or central nervous system.

  • Though IL-1 remains pivotal in many inflammasome-mediated diseases, other cytokinopathies involving IL-18, nuclear factor-kB, interferon, and tumor necrosis factor have provided new horizons in the definition of autoinflammatory-based diseases in children, and the list of HAID is has expanded as a consequence of the application of new genetic technologies.

Abstract

The protean clinical phenotypes of hereditary autoinflammatory disorders (HAID) are caused by abnormal activation of innate immunity and consist of seemingly unprovoked inflammatory flares localized to multiple organs, such as the skin, joints, serosal membranes, gut, and central nervous system. Different mutations in genes implied in activation of the interleukin-1 (IL-1)-structured inflammasome, cytoskeletal signaling and apoptosis contribute to the pathogenesis of different HAID, which mostly start in childhood with self-limited flares unrelated to infectious agents, autoantibody production or autoreactive cells. Though IL-1 remains pivotal in many inflammasome-mediated diseases, other cytokinopathies involving IL-18, nuclear factorκ-B, interferons, and tumor necrosis factor have provided new horizons in the definition of HAID of children: the list of HAID has expanded as a consequence of a better understanding of their pathogenetic molecular mechanisms and also application of new genetic technologies. However, diagnosis of most HAID is clinical and focused on several evidence-based criteria sets: their discrimination remains challenging for unexperienced pediatricians as there are no universally accepted algorithms, and a still relevant number of patients may linger without any clarifying genetic analysis, whose interpretation combined with processing of treatment options should be discussed on a multidisciplinary basis.

Section snippets

Introduction to abnormal innate immunity patterns of disease

The innate immunity relies on physiological barriers of the human body and on specific assets of immune responses operated by phagocytic cells, which have been preserved throughout millennia of evolution. Immune cells recognize invasive microbes or signs of danger in different organs and sound “alarms” that recruit other responder cells via specific receptors, initiating an immediate defensive reaction. An awesome alarm is triggered by cytosolic sensors of infections that assemble into

Familial mediterranean fever (FMF)

FMF is the most common monogenic autosomal recessive disease among HAID, mostly observed in Turkish, Armenian, Arabic, Sephardic Jewish communities and in people living around the Mediterranean sea, caused by mutations within the MEFV gene, which were first recognized in 1997 by two different research groups, encoding variants of the protein pyrin [8]. Pyrin works physiologically as an intracellular regulator of IL-1 production, though conflicting results have been reported in relationship with

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)

TRAPS is the most common autosomal dominant autoinflammatory disorder, caused by missense mutations in the TNFRSF1A gene, encoding the 55-kD receptor for TNF-α [23]. The discovery of TRAPS allowed the introduction of the “autoinflammation” concept, but our actual knowledge of this disease, its pathogenetic mechanisms and its genotype-phenotype correlations appears still fragmented due to both its rarity and continuous stream of newly discovered genetic variants [24]. Mutant TNF receptors

Cryopyrin-associated periodic syndrome (CAPS)

Mutations of the NOD-like receptor NLRP3 gene are responsible for NLRP3 inflammasome overactivity and generation of CAPS phenotype: this is a complex family of HAID with unexplained episodes of fever and severe localized inflammation, distinguished in three variants of increasing severity: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome and CINCA (chronic infantile neurologic cutaneous and articular) syndrome, otherwise termed “neonatal-onset multi-system inflammatory

Mevalonate kinase deficiency (MKD)

MKD is a rare recessive autoinflammatory condition caused by biallelic MVK mutations leading to partial or completely absent activity of the mevalonate kinase enzyme, which catalyzes a key-step in the synthetic pathway of cholesterol and non-sterol isoprenoids: the disease originates from decreased production of unsaturated lipid chains, known as non-sterol isoprenoids, in particular geranylgeranyl pyrophosphate, which are active in the post-translational modification of different inflammatory

Skin autoinflammatory disorders

A very rare dominantly-inherited condition named PAPA (pyogenic arthritis, pyoderma gangrenosum, acne) syndrome is characterized by the accumulation of neutrophil-rich exudates in the skin and joints with risk of disfiguring sterile abscesses [59]: the disease is caused by mutations in the PSTPIP1 gene, which encodes the proline-serine-threonine phosphatase-interacting protein 1, involved in the modulation of T cell and phagocyte activation and interacting with different intracytoplasmic

Autoinflammation with infantile enterocolitis

This early-onset enterocolitis is a rare autosomal dominant disorder involving the gastrointestinal tract, characterized by protean signs of macrophage activation, heralded by nonremitting fever, high serum levels of triglycerides and ferritin, severe liver disease, hypofibrinogenemia, clotting abnormalities, and rapidly evolving pancytopenia, that can even progress to deadly shock [79]. The disease is caused by gain-of-function heterozygous mutations in the NLRC4 gene, and its product NLRC4 is

Interferonopathies

Interferonopathies are a group of HAID characterized by upregulation of type I interferon (IFN), one of the most ancient first-line defenses against pathogens: any perturbation of proteins essential to IFN homeostasis can be included in this group, which includes proteasome-associated autoinflammatory syndrome (PRAAS), Aicardi-Goutières syndrome (AGS) and STING-associated vasculopathy with onset in infancy (SAVI), all starting within the first infancy and displaying multi-system features even

Defects in ubiquitination

The NF-κB signaling cascade is under tight regulation by a number of post-translational modifications, including ubiquitination of proteins that regulates diverse innate immune responses: ubiquitin is a small protein that recognizes abnormal proteins and “tags” them in a process called ubiquitination. Ubiquitin and proteasomes work together to destroy abnormal proteins within cells, and deubiquitination is a highly-regulated process cleaving ubiquitin or ubiquitin-like proteins from target

Conclusive remarks

The interest of many clinicians, not only pediatricians, in HAID, a heterogeneous group of both monogenic and, at a lesser extent, multifactorial diseases caused by primary dysfunction of the innate immune system, is increasing, as autoinflammation has provided new intriguing information about the subverted rules of inflammatory reactions and misplaced activation of innate immunity in the human body. Innate immunity cells, including monocytes, macrophages and neutrophils, work as the very first

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