Cytokine signatures in hereditary fever syndromes (HFS)

Hereditary fever syndromes (HFS) include a group of disorders characterized by recurrent self-limited episodes of fever accompanied by inflammatory manifestations occurring in the absence of infection or autoimmune reaction. Advances in the genetics of HFS have led to the identification of new gene families and pathways involved in the regulation of inflammation and innate immunity. The key role of several cytokine networks in the pathogenesis of HFS has been underlined by several groups, and supported by the rapid response of patients to targeted cytokine blocking therapies. This can be due to the direct effect of cytokine overproduction or to an absence of receptor antagonist resulting in dysbalance of downstream pro- and anti-inflammatory cytokine networks.The aim of this study was to present an overview and to discuss the major concepts regarding the cellular and molecular immunology of HFS, with a particular focus on their specific cytokine signatures and physiopathological implications. Based on their molecular and cellular mechanisms, HFS have been classified into intrinsic and extrinsic IL-1β activation disorders or inflammasomopathies, and protein misfolding disorders. This review integrates all recent data in an updated classification of HFS.     

Location of the gene causing hyperimmunoglobulinemia D and periodic fever syndrome differs from that for familial mediterranean fever

The hyperimmunoglobulinemia D and periodic fever (hyper-IgD) syndrome is typified by recurrent febrile attacks with abdominal distress, joint involvement (arthralgias/arthritis), headache, skin lesions, and an elevated serum IgD level (>100U/ml). This familial disorder has been diagnosed in 56 subjects worldwide. As the hyper-IgD syndrome resembles familial Mediterranean fever, one could speculate that both result from mutations in the same gene. The gene causing familial Mediterranean fever (MEF) has been located on chromosome 16p. We have studied 10 families with 19 affected and 28 non-affected subjects. The clinical findings and IgD determinations from these families are compatible with autosomal recessive inheritance. Using highly polymorphic markers surrounding the MEF gene, only negative Lod scores were obtained, whereas haplotype analysis excluded this locus as the cause of the hyper-IgD syndrome. In addition, no indication for linkage was obtained with markers from other candidate gene regions on chromosomes 17q and 14q.Participants listed in the appendix     

Gene localization for an autosomal dominant familial periodic fever to 12p13.

We report gene localization in a family with a benign autosomal dominant familial periodic fever (FPF) syndrome characterized by recurrent fever associated with abdominal pain. The clinical features are similar to the disorder previously described as familial Hibernian fever, and they differ from familial Mediterranean fever (FMF) in that FPF episodes usually do not respond to colchicine and FPF is not associated with amyloidosis. Frequent recombination with the marker D16S2622, <1 Mb from FMF, at 16p13.3, excluded allelism between these clinically similar conditions. Subsequently, a semiautomated genome search detected linkage of FMF to a cluster of markers at 12p13, with a multipoint LOD score of 6.14 at D12S356. If penetrance of 90% is assumed, the FPF gene maps to a 19-cM interval between D12S314 and D12S364; however, if complete penetrance is assumed, then FPF maps to a 9-cM region between D12S314 and D12S1695. This interval includes the dentatorubropallidoluysian atrophy locus, which, with FPF, gave a maximum two-point LOD score of 3.7 at a recombination fraction of 0. This is the first of the periodic-fever genes, other than FMF, to be mapped. Positional candidate genes may now be selected for mutation analysis to determine the molecular basis for FPF. Together with the recent identification of the defective gene in FMF, identification of a gene for FPF might provide new insights into the regulation of inflammatory responses.     

Analysis of familial hypoalphalipoproteinemia syndromes

Familial hypoalphalipoproteinemias (HA) are a heterogenous group of disorders characterized by various degrees of HDL deficiency. Differential diagnosis involves clinical and biochemical evaluation after intervention designed to correct known secondary causes of low HDL. Two specific HAs are discussed in this report: 1. primary isolated HA (PIHA) is a poorly characterized entity with an apparent autosomal dominant transmission and distinct abnormalities in the structure and function of HDL. 2. Lecithin: cholesterol acyltransferase (LCAT) deficiency syndromes are caused by a number of different genetic defects that lead to at least two distinct clinical presentations i.e. familial LCAT deficiency and fish eye disease. PIHA is an example of a genetic disorder whose diagnosis would greatly be improved by the availability of molecular diagnostic tests. Conversely, the effect of the genetic heterogeneity of LCAT deficiency syndromes on diagnosis is best overcome by utilizing existing biochemical measurement of LCAT activity and the plasma cholesterol esterification rate.     

Effects of the histone deacetylase inhibitor ITF2357 in autoinflammatory syndromes

We explored the effects of the oral histone deacetylase (HDAC) inhibitor ITF2357 in patients with autoinflammatory syndrome. In this prospective open-label pilot study, eight patients were enrolled; one patient with tumor necrosis factor receptor-associated periodic syndrome (TRAPS), three patients with hyper-IgD and periodic fever syndrome (HIDS) and four patients with Schnitzler syndrome were closely followed during 90 d of ITF2357 treatment. Three patients with Schnitzler syndrome and one TRAPS patient experienced a partial remission. In four patients, there was no effect. In HIDS patients, there was a tendency toward a higher attack frequency and increasing attack severity. In two patients (one TRAPS and one HIDS), we observed a decrease of acute-phase response without signs of clinical improvement. One patient with Schnitzler syndrome showed a partial response despite an ongoing acute-phase response. In conclusion, ITF2357 monotherapy was able to induce partial response only in patients with Schnitzler syndrome and no response in patients with HIDS.     

Oxidative stress status in familial Mediterranean fever with or without proteinuria

Although several studies have indicated oxidative system abnormalities in patients with familial Mediterranean fever, it is still obscure whether proteinuria seen in this disease has an effect on the oxidative system. In the present study, oxidative system changes were investigated in familial Mediterranean fever with or without proteinuria. Plasma malondialdehyde levels in proteinuric and nonproteinuric patients were higher than those of the controls and they were also significantly higher in the patients with proteinuria compared to patients without proteinuria. The patients had significantly lower plasma glutathione peroxidase activities than the controls. Glutathione peroxidase activities did not show statistically significant differences between the patients with and those without proteinuria. A significant difference was not established for erythrocyte superoxide dismutase activities. These data suggest that there is an increase in lipid peroxidation in familial Mediterranean fever. Decreased plasma glutathione peroxidase activities seem to be responsible for increased plasma malondialdehyde levels in both patient groups. However, the fact that higher plasma malondialdehyde levels in proteinuric patients were observed compared to nonproteinuric patients in the presence of the unchanged plasma glutathione peroxidase activities in these groups suggests that the nephrotic state may have a contribution to this situation.     

The familial syndromes of intestinal pseudoobstruction

Ten reported families with chronic intestinal pseudoobstruction were reviewed. Although clinical manifestations and gastrointestinal contrast roentgenograms are similar in these families, the pathology and inheritance are quite different. Five families have degeneration and fibrosis of the gastrointestinal tract and urinary bladder, three have normal intestinal morphology, and one has degeneration of the myenteric plexus throughout the gastrointestinal tract. Four families are consistent with dominant inheritance, three are consistent with X-linked dominant transmission, and three are compatible with recessive inheritance. Patients in these families have a wide spectrum and degree of chronic and/or intermittent gastrointestinal symptoms. As many as 20% of the family cases discovered are asymptomatic. Operative procedures to drain or resect short dilated intestinal segments may help to relieve symptoms.     

Amyloidosis and familial Mediterranean fever

Familial Mediterranean Fever (F. M. F.) is an autosomal recessive disorder occurring most commonly in Sepharadi Jews and Armenians. Two phenotypic features characterize the disease: brief episodic febrile attacks of peritonitis, pleuritis or synovitis recurring from childhood or adolescence and the development of systemic amyloidosis. Attacks are accompanied by striking elevations of acute phase proteins, including serum amyloid A protein. The amyloidosis of Familial Mediterranean Fever is of the AA type, and manifest clinically as a nephropathy that passes through proteinuria, nephrotic and uremic stages to renal death. Although there is ethnic variation in the incidence of amyloidosis of F. M. F. in our patient population--predominantly Sepharadi Jews of North African extraction--an amyloidotic death at an early age is their genetic destiny. Since the introduction in 1972 of colchicine to prevent the febrile attacks, the drug has been proven and become the main stay of therapy. Today, colchicine has been shown to be effective in preventing amyloidosis as well as the febrile attacks in Familial Mediterranean Fever. End stage renal disease is not the end of the road for patients with F.M.F. because of improving outlook for dialysis and renal transplantation in these patients.     

Next-generation screening of a panel of genes associated with periodic fever syndromes in patients with Familial Mediterranean Fever and their clinical characteristics

Familial Mediterranean Fever (FMF) is a hereditary fever syndrome that primarily affects Mediterranean populations. For the study, total number of 182 patients with FMF disease were enrolled and screening of a panel of genes , called “fever panel” which comprises 17 genes, was performed. The most common mutations in MEFV gene were homozygous M694V missense mutation (4.3%) and R202Q missense mutation (4.9%). The most common heterozygous mutations were R202Q (26.5%), M694V (25.9%) and E148Q (11.9%). Compound heterozygous and homozygous mutations were also detected. Also, different types of mutations were identified in NOD2, CARD14, NLRP12, NLRP3, NLRP7, IL1RN, LPIN2, TNFRSF1A, MVK and PSTPIP1 genes. Two novel missense variations in the MEFV gene, Gln34Pro and Ile247Val, which have not been previously reported in the databases, were identified. Also, Thr91Ile missense variation in the NOD2 gene, Gly461Cys missense variation in NLRP3 and Tyr732Stop nonsense variation in LPIN2 were firstly identified. The results of the current study suggest that in addition to the MEFV gene which has an important roles in FMF, molecular screening of other genes related to other autoinflammatory diseases might provide support in suspected cases and provide detailed information about the course of the disease.     

Immunological function of familial Mediterranean fever disease protein Pyrin

Pyrin,encoded by MEFV gene,is conserved in humans and mice.Mutations in the MEFV gene are associated with the human autoinflammatory disease familial Mediterranean fever(FMF).Pyrin can interact with the inflammasome adaptor ASC and induce inflammatory caspase-1 activation in monocytic cells,but the physiological function of Pyrin has been unknown for many years.Here we summarize previous studies of Pyrin function under the context of FMF and immunity,and discuss a recent study demonstrating that Pyrin forms an inflammasome complex for caspase-1 activation in innate immunity.Pyrin inflammasome detects inactivating modifications of host Rho GTPases by diverse bacterial toxins and infections,including Clostridium difficile glucosylating cytotoxin Tcd B,FIC-domain adenylyltransferase effectors from Vibrio parahaemolyticus and Histophilus somni,ADP-ribosylating Clostridium botulinum C3 toxin as well as Burkholderia cenocepacia infection.The mode of Pyrin action,i.e.,sensing pathogen virulence activity rather than directly recognizing a microbial molecule,represents a new paradigm in innate immunity.