No abstract

Several lines of evidence indicate that the monocytes of subjects with localized juvenile periodontitis (LJP) are functionally distinct from cells of age-and race-matched nonperiodontitis (NP) subjects. Among the abnormalities are the propensity to secrete large amounts of prostaglandin E 2 and the induction of immunoglobulin G2 (IgG2) antibodies. The experiments described here were performed to further characterize the LJP monocytes and to determine if these cells mature differently than NP monocytes. When adherent monocytes from LJP subjects were cultured in the presence of human serum, both macrophages and cells with the morphology of immature monocyte-derived dendritic cells (MDDC) were observed. Within 4 days the prevalence of the immature MDDC was approximately twofold higher in LJP cultures than in NP cultures. In addition to their dendritic morphology, these cells were CD11c ؉ and CD14 ؊ or CD14 low and stimulated potent autologous mixed leukocyte reactions, consistent with differentiation to the MDDC phenotype. Like LJP monocytes, cultures of MDDC generated with interleukin-4 and granulocyte-macrophage colony-stimulating factor selectively induced IgG2 in cultures of pokeweed mitogen-stimulated NP leukocytes. Together, these data suggest that the monocytes of LJP subjects have a propensity to differentiate into MDDC and that this differentiation may be related to the high levels of IgG2 that are observed in the sera of LJP subjects. As high levels of circulating IgG2 are correlated with less severe disease, the propensity of LJP monocytes to differentiate into MDDC may have important implications for both the host response against oral pathogens and the progression of LJP.Localized juvenile periodontitis (LJP) is a form of earlyonset periodontitis that tends to run in families. Several oral pathogens have been linked to the etiology of the disease, including Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis (4,22,36,37). However, mounting evidence suggests that alterations in the host response may contribute to the pathogenesis of LJP. Several studies have highlighted abnormalities in the myeloid compartment of LJP subjects. For example, LJP neutrophils exhibit reduced chemotactic and calcium responses (7, 10) and have altered diacylglycerol metabolism (32) compared to cells from nonperiodontitis (NP) individuals. The peripheral blood of LJP subjects contains abnormally large numbers of immature granulocytes, which express low levels of CD16 (25). It also appears that the monocytes of LJP subjects are somewhat abnormal, as these cells produce abnormally large amounts of prostaglandin E 2 (PGE 2 ) in response to stimulation with lipopolysaccharide (26, 30). Our group has been particularly intrigued by the unique relationship that appears to exist between LJP monocytes and antibody production.LJP patients exhibit elevated levels of circulating immunoglobulin G2 (IgG2) compared to age-and race-matched NP subjects (23). In contrast, the levels of other isotypes of IgG are similar in NP and L...

SUMMARYPreviously, a solublemouse CD23 chimera,composedofanN-terminaltrimeric isoleucinezippermotif (lz) followed by the entire extracellular region (amino acids 48-331) of CD23 (lz-CD23 48À331

We sought to discover the mechanisms explaining increased IgE production seen at low cell densities when IL-21 is added to human B cell cultures activated with anti-CD40 and IL-4. When cells were cultured in the absence of BCR ligation, qPCR demonstrated dramatic increases in mRNA for the plasma cell transcription factors BLIMP1 and XBP1. Furthermore, a majority of viable cells expressed high levels of CD38 while losing expression of surface IgD. In contrast, in the presence of BCR stimulation, both the XBP1 mRNA levels and CD38 cell surface expression were markedly reduced, and a large population of cells retained IgD expression, indicating reduced plasma cell differentiation. IgE levels were reduced in the BCR stimulated cultures by 90%, while IgG4 levels remained unchanged. In summary, IL-21 enhances IgE production at low densities through stimulating cell division and plasma cell differentiation and this activity is reduced upon BCR cross-linking.

A chimeric soluble CD23, consisting of the extracellular domain of mouse CD23 and a modified leucine zipper (lz-CD23), has been shown to inhibit IgE binding to the FcεRI. A similar human CD23 construct was also shown to inhibit binding of human IgE to human FcεRI. In both systems, the inhibition was found to be temperature dependent; a 10-fold molar excess of lz-CD23 gave 90–98% inhibition at 4°C, dropping to 20–30% inhibition at 37°C. Surface plasmon resonance analysis of lz-CD23 binding to an IgE-coated sensor chip suggested that the effective concentration of lz-CD23 was lower at the higher temperatures. Analysis of 125I-IgE binding to CD23+-Chinese hamster ovary cells also indicated that increased temperature resulted in a lower percentage of IgE capable of interacting with CD23. In contrast, IgE interacts more effectively with FcεRI+-rat basophilic leukemia cells at 37°C compared with 4°C. The results support the concept that the open and closed IgE structures found by crystallography interact differently with the two IgE receptors and suggest that temperature influences the relative percentage of IgE in the respective structural forms. Changes in CD23 oligomerization also plays a role in the decreased binding seen at physiological temperatures.