Defective apoptosis of peripheral-blood lymphocytes in hyper-IgD and periodic fever syndrome

Bodar, E.J.; Hilst, Jeroen Van der; Heerde, Waander L. van; Meer, J.W.M. van der; Drenth, Joost P.H.; Simon, Anna

doi:10.1182/blood-2005-10-039578

Cited by 35 publications

(17 citation statements)

References 11 publications

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“…We and others have observed recurrent disease flares and elevated acute-phase markers after initiation of TNF blockade in some patients (15,37). TNF blockade inhibits only the component of inflammation dependent on TNF feedback through the WT TNFR1 but would not affect the TNFindependent components of the TRAPS phenotype that we have identified here.…”

Section: Discussionsupporting

confidence: 43%

Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome

Simon¹,

Park

Maddipati

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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176

153

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TNF, acting through p55 tumor necrosis factor receptor 1 (TNFR1), contributes to the pathogenesis of many inflammatory diseases. TNFR-associated periodic syndrome (TRAPS, OMIM 142680) is an autosomal dominant autoinflammatory disorder characterized by prolonged attacks of fevers, peritonitis, and soft tissue inflammation. TRAPS is caused by missense mutations in the extracellular domain of TNFR1 that affect receptor folding and trafficking. These mutations lead to loss of normal function rather than gain of function, and thus the pathogenesis of TRAPS is an enigma. Here we show that mutant TNFR1 accumulates intracellularly in peripheral blood mononuclear cells of TRAPS patients and in multiple cell types from two independent lines of knockin mice harboring TRAPSassociated TNFR1 mutations. Mutant TNFR1 did not function as a surface receptor for TNF but rather enhanced activation of MAPKs and secretion of proinflammatory cytokines upon stimulation with LPS. Enhanced inflammation depended on autocrine TNF secretion and WT TNFR1 in mouse and human myeloid cells but not in fibroblasts. Heterozygous TNFR1-mutant mice were hypersensitive to LPS-induced septic shock, whereas homozygous TNFR1-mutant mice resembled TNFR1-deficient mice and were resistant to septic shock. Thus WT and mutant TNFR1 act in concert from distinct cellular locations to potentiate inflammation in TRAPS. These findings establish a mechanism of pathogenesis in autosomal dominant diseases where full expression of the disease phenotype depends on functional cooperation between WT and mutant proteins and also may explain partial responses of TRAPS patients to TNF blockade. autoinflammatory disease | genetic disease

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Section: Discussionsupporting

confidence: 43%

Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome

Simon¹,

Park

Maddipati

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

176

153

View full text Add to dashboard Cite

show abstract

“…250 There is also a defect in apoptosis in the peripheral blood leukocytes of HIDS patients. 251 A mouse model of HIDS was generated by deleting a single MVK allele, and this resulted in increased blood mevalonate and IgD levels. 252 It is unlikely, however, that elevations in IgD itself are the cause of fever and inflammation; there are a number of other conditions, including diabetes mellitus, pregnancy, and cigarette smoking, in which IgD levels are modestly increased 240 but there are no symptoms compatible with HIDS.…”

Section: Geneticsmentioning

confidence: 99%

“…Elevated urinary mevalonic acid levels during the crises have been used in the past to corroborate a HIDS diagnosis. 251 IgD serum levels are persistently elevated ($100 U/ml) in more than 90% of HIDS patients, and 80% of them present with concomitant increased IgA ($260 mg/dl). 240 However, IgD concentrations may be normal, especially in children under 3 years of age.…”

Section: Clinical Presentationmentioning

confidence: 99%

Classic Autoinflammatory Diseases

Jesús

Ferguson

Goldbach‐Mansky

2014

Stiehm's Immune Deficiencies

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“…Apoptosis plays an important role in the downregulation of the inflammatory response. Therefore, a defect in apoptosis of lymphocytes could lead to an exaggerated inflammatory response [12].…”

Section: Reduced Activity Of Mvk Leads To Isoprenoid Deficiencymentioning

confidence: 99%

Hyperimmunoglobulin D Syndrome in Childhood

Hilst

Frenkel

2010

Curr Rheumatol Rep

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Hyperimmunoglobulinemia D and periodic fever syndrome, an autoinflammatory syndrome, is caused by mutations in the gene coding for mevalonate kinase. The disease is clinically characterized by recurrent attacks of fever accompanied by an array of inflammatory symptoms including lymphadenopathy, rash, arthritis, and gastrointestinal complaints. Most patients have their first attack in the first year of life, typically after a childhood vaccination. The frequency of attacks is highest during childhood, with a gradual decrease after adolescence. Frequent fever attacks impair quality of life and the achievement of educational milestones. Recent reports show promising results with anakinra and etanercept to treat the attacks.

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Defective apoptosis of peripheral-blood lymphocytes in hyper-IgD and periodic fever syndrome

Cited by 35 publications

References 11 publications

Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome

Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome

Classic Autoinflammatory Diseases

Hyperimmunoglobulin D Syndrome in Childhood

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