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

Abstract

SUMMARYImmunoglobulin D (IgD) is normally present in only low concentrations in serum. In the hyper-IgD and periodic fever syndrome (HIDS), however, serum levels exceed 140 mg/l. This syndrome is further characterized by recurrent inflammatory febrile attacks together with an acute phase response and appearance of cytokines in the circulation. The role of IgD in the pathogenesis of HIDS and its relation to the increased cytokine concentrations is unclear. Therefore, we tested whether IgD, IgG and a 1 -acid glycoprotein (AGP) isolated from human serum influence the synthesis of interleukin-1b (IL-1b), tumour necrosis factor-a (TNF-a), and IL-1ra, as measured by specific radioimmunoassays, in human peripheral blood mononuclear cells (PBMC). Incubation of PBMC with IgD and AGP for 24 hr led to increased release of IL-1b, TNF-a, and IL-1ra. The magnitude of stimulation of IgD exceeded that of AGP; the effect by IgD was dose-dependent and showed a 30-fold (TNF-a) to almost 150-fold (IL-1b) increase at the highest concentration (50 mg/l), while AGP (750 m g/ml) only increased the cytokine secretion fourfold (TNF-a) to almost 30-fold (IL-1b). The effect of IgD on IL-1ra was less dramatic but a fivefold increase was observed at 50 mg/l compared with a 2 . 5-fold increase with AGP. IgD potentiated the effect of lipopolysaccharide (LPS) on secretion of both IL-1b and TNF-a, although the effect was most apparent for TNF-a. Apart from inducing IL-1ra synthesis, IgG did not influence cytokine release in human PBMC. These data indicate that IgD is a potent inducer of TNF-a, IL-1b and IL-1ra and thus may contribute to the pathogenesis of HIDS.

Hyper-Immunoglobulin A in the Hyperimmunoglobulinemia D Syndrome

“…The procedure for the enzyme-linked immunosorbent assay (ELISA) for measurement of IgD has been published earlier (11). Briefly, microtiter plates (Nunc, Roskilde, Denmark) were coated with rabbit anti-human IgD (Dako, Copenhagen, Denmark).…”

“…The level of serum IgD in HIDS does not correlate with disease severity or frequency of attacks, and attacks of HIDS antedate the rise of serum IgD levels above age-dependent reference values and/or 100 IU/ml (14,15). On the other hand, IgD stimulates peripheral blood mononuclear cells to produce inflammatory cytokines (11), which does suggest a possible role in the pathogenesis of attacks.…”

The Histone Deacetylase Inhibitor ITF2357 Reduces Production of Pro-Inflammatory Cytokines In Vitro and Systemic Inflammation In Vivo

“…Indeed, severe systemic inflammatory diseases are due to greater release of active IL-1β from cultured PBMCs in vitro compared with PBMCs from healthy subjects. These diseases include systemic onset juvenile idiopathic arthritis (39), Muckle-Wells syndrome (26,40), familial cold-induced auto-inflammatory syndrome (41), neonatalonset multisystem inflammatory disease (24,25,27), hyper IgD syndrome (42), and Schnitzler syndrome (43). The increased secretion of IL-1β in some of these diseases is due to a single point mutation in the NALP3 gene, which controls the activation of procaspase-1 (40,44).…”

Immunoglobulin D: Properties, Measurement, and Clinical Relevance

“…IgD can also participate in the generation and maintenance of B-cell memory and might have an important role in the transition from a stage of susceptibility to induction of B-cell tolerance to one of responsiveness (22,142). Finally, IgD is a potent inducer of tumor necrosis factor alpha (TNF-␣), IL-1␤, and IL-1 receptor antagonist (38). IgD also induces release of IL-6, IL-10, and leukemia inhibitory factor from peripheral blood mononuclear cells.…”

“…IgD also induces release of IL-6, IL-10, and leukemia inhibitory factor from peripheral blood mononuclear cells. Monocytes seem to be the main producers of cytokines in vitro in the presence of IgD (38).…”