Interferon‐γ and urine neopterin in attacks of the hyperimmunoglobulinaemia D and periodic fever syndrome

Abstract

Abstract. The hyperimmunoglobulinaemia D and periodic fever (hyper-IgD) syndrome is typified by recurrent unpredictable febrile attacks with abdominal pain, joint involvement (arthralgias/arthritis), headache, skin lesions and a polyclonal elevation of serum IgD ( > 100 U mL-'). Interferon-gamma (IFN-y) is a major proinflammatory cytokine which could play a role in the pathogenesis of the attacks. There is a need for parameters (if possible non-invasive) to monitor disease activity. A potential candidate is neopterin which is released by monocytes/macrophages when stimulated with IFN-y, excreted unchanged in urine, and appears to be an early and sensitive marker for activation of the immune system. We measured rectal body temperature, serum IFN-y, and urine neopterin in 10 hyper-IgD patients both during and between attacks. The body temperature rose to a mean of 38.9"C on the first day of the attack and normalized within 5 days. Serum IFN-y during the first day of the attack was 2.98 IU mL-' and was significantly lower during remissions. The urine neopterin excretion was 268 f 170 pmolmol-' creatinine between attacks and was significantly increased to 638 f 275 pmolmol-' creatinine on the first day of symptoms. Maximal urine neopterin values were reached on the fourth day of the attack (1051 f 387 pmol mol-' creatinine) and excretion gradually declined and attained values below 400 pmol mol-' creatinine after 9 days. There was a good correlation between serum IFN-y and urine neopterin. The increases in serum IFN-y and urine neopterin suggest activation of the cellular immunity during the febrile attacks of the hyper-IgD syndrome. Furthermore, the activation of the cellular immune system appears to persist several days after normalization of the body temperature. The significant correlation between IFN-y and urine neopterin in the hyper-IgD syndrome accords with experimental data suggesting that IFN-y is the dominant factor in the release of neopterin. Our study shows that urinary neopterin is a good quantitative and qualitative parameter to monitor disease activity in patients with the hyper-IgD syndrome

Immunoglobulin D enhances the release of tumour necrosis factor‐α, and interleukin‐1β as well as interleukin‐1 receptor antagonist from human mononuclear cells

“…Indeed, elevated circulating concentrations of the inflammatory mediators TNF-a, IL-1 receptor antagonist (IL-1ra), IL-6, interferon-g, and soluble receptors for TNF-a (sTNFr) have been detected during the febrile episodes. 6,9 Upon stimulation with bacterial lipopolysaccharide (LPS, endotoxin), monocytes/macrophages are able to produce a wide array of cytokines such as IL-1b, IL-6 and TNF-a. 10 During attacks of HIDS, incubation of whole blood with LPS for 24 hr, resulted in an augmented ex vivo secretion of TNF-a, IL-1b and IL-1ra in the supernatants compared with convalescence.…”

Increased urinary leukotriene E4during febrile attacks in the hyperimmunoglobulinaemia D and periodic fever syndrome

“…The affected children often have striking cervical lymphadenopathy and may have splenomegaly, hepatomegaly, arthritis, and a variety of skin rashes 2. In the patient's blood, markers of inflammation such as white cell counts, erythrocyte sedimentation rate, and serum concentrations of several proinflammatory cytokines, are raised during febrile episodes,3 and the urine concentration of neopterin is acutely raised 4. Mutations in the MVK gene, which encodes mevalonate kinase, have been identified as the underlying genetic defect 5…”

Lack of isoprenoid products raises ex vivo interleukin‐1β secretion in hyperimmunoglobulinemia D and periodic fever syndrome

“…Serum levels of proinflammatory cytokines, such as interleukin-6 (IL-6) and interferon-␥ (IFN␥), rise during fever attacks (3,4). Also, between attacks, isolated peripheral blood mononuclear cells (PBMCs) from HIDS patients secrete large amounts of proinflammatory cytokines, such as IL-1␤ (5).…”