Search

Background: The hyperimmunoglobulinaemia D and periodic fever syndrome is a hereditary periodic fever, caused by deficiency of the enzyme mevalonate kinase. It is unclear how this defect leads to recurrent fever episodes., Aim: To assess the involvement of cysteinyl leukotrienes in the pathogenesis of fever attacks as reflected by urinary leukotriene E(4) (LTE(4)) excretion., Methods: Urinary LTE(4) was measured in seven patients while febrile and afebrile., Results: LTE(4) was raised during fever in all subjects (46-199 nmol/mol creatinine, mean 92; normal <40). Urinary LTE(4) was normal between attacks, as well as in normal children with fever as a result of miscellaneous causes., Conclusion: Our results suggest that cysteinyl leukotrienes play a role in the pathophysiology of this disorder. As no effective treatment is yet available, leukotriene receptor antagonists might offer a new therapeutic approach for patients with the hyperimmunoglobulinaemia D and periodic fever syndrome.

The hyperimmunoglobulinemia D syndrome (HIDS) is an autosomal recessive disorder characterized by recurrent febrile attacks with abdominal, articular, and skin manifestations. Apart from elevated immunoglobulin D (IgD) levels (>100 IU/ml), there are high IgA levels in the majority of cases. Mutations in the gene encoding mevalonate kinase constitute the molecular defect in HIDS. The cause of elevated IgA concentrations in HIDS patients remains to be elucidated. We studied the hyper-IgA response in serum of a group of HIDS patients. Elevated IgA concentrations result from increased IgA1 concentrations. IgA and IgA1 concentrations correlated significantly with IgD concentrations, and levels of IgA polymers were significantly higher than the levels in healthy donors. These results indicate a continuous, presumably systemic, stimulation of IgA in HIDS patients.

Serum immunoglobulinD (IgD) concentration is usually low in healthy individuals as compared to other immunoglobulin classes. Most studies on serum IgD are concerned with serum levels in healthy adults but reference values for young children and infants are not easily available. In order to establish age specific reference values we measured IgD levels in serum of 184 healthy Icelandic children, age 0-14 years and 60 healthy blood donors age 18-63, using the ELISA technique. Special attention was paid to the youngest age groups. Results showed low IgD values in infants and young children, gradually increasing until the age of 10 but then decreasing with age. We conclude that IgD gradually increases with age in childhood as other immunoglobulin classes but later declines. These findings can be of importance in revealing the function of IgD in the immune system as well as in the diagnosis of the hyper-IgD syndrome.

Five patients with hyper-immunoglobulin D syndrome (hyper-IgD syndrome) were followed up for 3 to 8 years. In all patients studied, serum IgG3 was high. IgM decreased during the follow-up in all patients. In four of the patients serum IgA was elevated. In four patients the serum IgD kappa/lambda ratio was measured and was found to be raised in all. However, the serum total light-chain ratio and IgG, IgA, and IgM kappa/lambda ratios separately were virtually normal. In two of the patients, clinical symptoms preceded the increase in serum IgD. All patients had a history of severe reactions on immunizations in early childhood. We conclude that in hyper-IgD syndrome, other immunoglobulins may also be affected, in particular, IgA, IgM, and IgG3. The IgD light-chain ratio is also disturbed. We emphasize that clinical symptoms may herald immunological changes. This may be the result of an underlying factor causing both the clinical symptoms and, later, the increasing serum IgD levels.

Increased levels of serum IgD can be found in single patients with a variety of clinical syndromes and in the disease entity designated hyper-IgD syndrome which is associated with periodic fever and lymphadenopathy. We investigated 17 patients, both children and adults, with high serum IgD levels ranging from 220 to 5300 IU/ml. Eight patients had periodic fever and lymphadenopathy, four showed a humoral immunodeficiency, and the remainder had a variety of clinical abnormalities. Serum IgA levels were consistently high in all patients except in those with an immunodeficiency. Serum IgD complexes were detectable in each serum, which indicates that the occurrence is not pathognomic for the syndrome of periodic fever. Antibody formation against the primary antigen Helix pomatia hemocyanine and the secondary antigen tetanus toxoid showed no abnormalities in the patients without an immunodeficiency. Bone marrow origin of serum IgD was strongly suggested by enumeration of IgD-containing plasma cells. We conclude that no apparent relationship exists between the several clinical syndromes and increased serum IgD.