Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes

Abstract

Familial periodic fever syndromes, otherwise known as hereditary autoinflammatory syndromes, are inherited disorders characterized by recurrent episodes of fever and inflammation. The general hypothesis is that the innate immune response in these patients is wrongly tuned, being either too sensitive to very minor stimuli or turned off too late. The genetic background of the major familial periodic fever syndromes has been unraveled, and through research into the pathophysiology, a clearer picture of the innate immune system is emerging. After an introduction on fever, interleukin-1beta and inflammasomes, which are involved in the majority of these diseases, this manuscript offers a detailed review of the pathophysiology of the cryopyrin-associated periodic syndromes, familial Mediterranean fever, the syndrome of pyogenic arthritis, pyoderma gangrenosum and acne, Blau syndrome, TNF-receptor-associated periodic syndrome and hyper-IgD and periodic fever syndrome. Despite recent major advances, there are still many questions to be answered regarding the pathogenesis of these disorders.

Coexistence of Familial Mediterranean Fever and Hyperimmunoglobulinemia D Syndrome in a Child

“…HIDS and FMF are both autosomal recessively inherited disorders and they have different clinical, epidemiologic and genetic characters. Molecular genetic defects on different chromosomes have helped us to differentiate periodic fever syndromes and will provide new insight to the pathogenesis [1,3]. MEFV gene is cloned on chromosome 16, which is responsible for FMF, is different from the gene MVK mapped on chromosome 12, which is responsible for HIDS [1,2].…”

“…The diagnosis of FMF is based on characteristic clinical course, family history and physician's experience [2]. In periodic fever syndromes patients' inflammatory response is set wrongly and is not terminated at the appropriate time [3]. Isoprenoid pathway and also pyrin's effect on caspase-1 mediated activation of IL-1B is responsible for inflammation in the pathogenesis of HIDS and FMF respectively [4].…”

Síndromes autoinflamatórias hereditárias na faixa etária pediátrica

“…The pathophysiology of TRAPS is believed to involve multiple factors. 42 Some affected individuals have decreased shedding of the mutant receptor from the cell surface. Receptor shedding is believed to be necessary for blocking TNF-alpha activity and preventing exacerbated inflammatory response.…”

“…Receptor shedding is believed to be necessary for blocking TNF-alpha activity and preventing exacerbated inflammatory response. 42,43 Additional studies have suggested that the mutated receptor has defective intracellular trafficking; it is retained in the endoplasmic reticulum. This intracellular buildup of the receptor could lead to spontaneous activation, triggering an inflammatory response.…”

“…66 In healthy individuals, activation of the inflammasome is inhibited by an interaction between distinct portions of the cryopyrin molecule itself. 42 CIAS1 mutations lead to a disruption of this inactive conformation of cryopyrin, leading to activation of the inflammasome, increasing IL1-beta secretion and triggering systemic inflammatory symptoms. [66][67][68] Clinical manifestations vary among the three cryopyrinopathies, but several common features are often found, such as fever, pseudourticarial rash, joint involvement, and profoundly elevated inflammatory markers.…”