Interleukin-10 secreted by B-1 cells modulates the phagocytic activity of murine macrophages in vitro

As demonstrated previously in our laboratory, B-1 cells migrate from the peritoneal cavity of mice and home to a distant site of inflammation to become macrophage-like cells. However, the influence that these cells might have on the kinetics and fate of the inflammatory process is not known. Considering that macrophages are pivotal in the inflammatory reaction, we decided to investigate the possible influence B-1 cells could have on macrophage activities in vitro. Our results show that peritoneal macrophages from Xid mice, a mouse strain deprived of B-1 cells, have higher phagocytic indexes for zymozan particles when compared with macrophages from wild-type mice. Moreover, macrophages from wild-type mice have a lower ability to release nitric oxide and hydrogen peroxide when compared with macrophages from Xid mice. Experiments using cocultures of B-1 cells and macrophages from Xid mice in transwell plates demonstrated that B-1 cells down-regulate macrophage activities. These observations also indicate that this phenomenon is not due to a physical interaction between these two cell populations. As B-1 cells are one of the main sources of interleukin (IL)-10, we demonstrate in this study that adherent peritoneal cells from Xid mice produce significantly less amounts of this cytokine in culture when compared with IL-10 production by cells from wild-type mice. When B-1 cells from IL-10 knock-out mice and macrophages from wild-type mice were cocultured in transwell plates, the phagocytic index of macrophages was not altered demonstrating that B-1 cells can influence the effector functions of macrophages in vitro via IL-10 secretion.     

Elevation of CD8+ CD11b+ Leu-8− T cells is associated with the humoral immunodeficiency in myeloma patients

Recurrent bacterial infections due to humoral immunodeficiency are an important cause of death in myeloma patients. Recent data indicate that CD8⁺ T lymphocytes and a reduction of T helper type 1 cells with disease progression may be involved in the regulation of polyclonal immunoglobulin secretion. In mixed lymphocyte cultures derived from peripheral blood mononuclear cells (PBMC) of 24 myeloma patients with reduced immunoglobulin serum levels we investigated the association of CD4⁺ and CD8⁺ T cell subsets and immunoglobulin-secreting B cells (ISC) upon mitogenic stimulation with pokeweed mitogen (PWM) and concanavalin A (Con A). In supernatants of cultured PBMC of myeloma patients the spontaneous secretion of the type 1 cytokine interferon-gamma was reduced. After PWM stimulation reduced numbers of polyclonal ISC were found in 79% of patients, and monoclonal ISC were observed in 12% of patients. After Con A stimulation, again formation of polyclonal ISC was reduced, but monoclonal ISC were found in 41% of patients. Elevation of monoclonal and reduction of polyclonal ISC after stimulation with Con A were associated with an increase of CD8⁺ CD11b⁺ Leu-8⁻ T cells (P < 0.05). We conclude that the elevated numbers of CD8⁺ CD11b⁺ Leu-8⁻ T cells play a role in the stimulation of monoclonal and suppression of polyclonal immunoglobulin secretion in myeloma patients.     

Patterns of differentiation in various sympathetic efferents induced by hypoxic and by central thermal stimulation in decerebrated rabbits

Summary The patterns of regional changes of sympathetic efferent activity evoked by thermal stimulation of the spinal cord and by arterial and primary tissue hypoxia were investigated in decerebrated, anesthetized and immobilized rabbits. Decerebration was performed either at the mid- or infracollicular level. The responses of the decerebrated rabbits evoked by spinal thermal stimulation were the same as those of intact rabbits, i.e., splanchnic and cardiac sympathetic activity increased and cutaneous sympathetic activity decreased during warming, while the reverse response was elicited by cooling. It is concluded that the typical thermoregulatory response pattern of the sympathetic nervous system can be produced also after the loss of hypothalamic integration, i.e., by integrative mechanisms in the lower brain stem and the spinal cord. In contrast, the responses of decerebrated rabbits to arterial and primary tissue hypoxia differed from those of intact rabbits in that they consisted in an overall activation in all investigated sympathetic branches. It is confirmed by this result that suprabulbar integration is essential for the generation of the inhibitory components in the differential sympathetic responses to hypoxia, which typically consist in cutaneous and cardiac sympathetic inhibition with splanchnic activation during arterial hypoxia and in cutaneous sympathetic inhibition with cardiac and splanchnic sympathetic activation during primary tissue hypoxia.     

Inhibitory Fc Gamma Receptors: From Gene to Disease

Multiple lines of evidence have revealed a key role for inhibitory Fc gamma receptors class IIb (FcgammaRIIb) as negative modulators of innate and adaptive immune responses. Acquired and genetic factors regulate the expression of FcgammaRIIb receptors and modify their inhibitory potential. Recent advances have highlighted the importance of FcgammaRIIb receptors in influencing the development of cancer and autoimmunity. The association of increased FcgammaRIIb expression with tumor development is believed to operate at effector cell level resulting in inhibition of antitumor cytotoxicity. In autoimmune diseases, FcgammaRIIb receptors play a major role in controlling the amplitude of antibody- and immune complex-mediated reactions. Generally, FcgammaRIIb deficiency is associated with increased susceptibility and severity to organ-specific and systemic autoimmunity. This article discusses the proposed mechanisms for FcgammaRIIb deregulation associated with malignant and autoimmune pathology in animal models and human diseases.     

Circulating immune complexes may play a regulatory and pathogenic role in experimental autoimmune uveoretinitis.

We compared the time course of changes in serum levels of circulating immune complexes (CICs) and of IgG antibody after sensitization of albino Lewis and pigmented Lister strain rats with uveitogenic (retinal S-antigen) and non-uveitogenic (ovalbumin) protein antigens of comparable molecular weight. Normal levels of CICs were far lower in Lewis rats in which experimental autoimmune uveoretinitis (EAU) takes the form of a severe panuveitis, than in Lister rats, in which the disease is mild, focal, confined to the posterior segment, and of lower incidence. After sensitization with either S-antigen or ovalbumin, polyethylene-glycol-precipitable CIC (PEG-CIC) peaked and fell as IgG antibody levels rose in both rat strains. However, peak levels of PEG-CIC were lower and subsequent IgG antibody levels were higher in the Lewis strain than in the less susceptible Lister strain. In both strains of rat these linked PEG-CIC/IgG antibody responses occurred earlier after sensitization with uveitogenic (S-) antigen than with ovalbumin, whether or not individual S-antigen-sensitized Lister rats developed EAU. In contrast, complement-binding CIC rose substantially only in those rats of both strains displaying EAU in response to S-antigen and not in response to ovalbumin. We suggest that immune complex (idiotypic) regulation of IgG antibody responses may be more readily perturbed by a pathogenic autoantigen (S-antigen) than by a bland antigen (ovalbumin). We also suggest that differences between the balance of regulatory and pathogenic CIC responses to uveitogenic retinal antigen may underlie or reflect strain differences in susceptibility to and severity of EAU.     

Phosphatidylglycerolphosphate synthase encoded by the PEL1/PGS1 gene in Saccharomyces cerevisiae is localized in mitochondria and its expression is regulated by phospholipid precursors

The PEL1/PGS1 gene of the yeast Saccharomyces cerevisiae is essential for the viability of rho ^–/rho° mutants and the normal cardiolipin content of cells. The PEL1-GFP fusion gene has been found to complement the pel1/pgs1 mutation and its fluorescent protein was localized to mitochondria similarly to the β-galactosidase activity of a protein encoded by the PEL1-lacZ fusion gene. The expression of the PEL1-lacZ reporter gene was repressed in cells grown in the presence of inositol and choline, reduced in the ino2 and ino4 strains, but constitutive in the opi1 null-mutant strain. The results demonstrate that Pel1p, playing a vital role in cells impaired in the mitochondrial DNA, is localized in the mitochondria and expressed in response to inositol and choline. Received: 15 June / 15 July 1998     

Salivary cooling,escape reaction and heat pain in capsaicin-desensitized rats

Salivary thermolytic mechanism (weight of salivary glands, effect of desalivation on water intake and body temperature, grooming activity) as well as escape behaviour and reaction to heat pain were studied in capsaicin-desensitized and control rats exposed to various warm ambient temperatures. Body temperature of the desensitized rats increased more than the controls at all the ambient temperatures studied (32, 34 and 36°C); however, significant differences in the mechanism of salivary cooling were obtained only at 34 and 36°C. Central impairment of saliva spreading in desensitized rats seems evident. Complete surgical desalivation did not increase hyperthermia of control and desensitized animals in warm environments. Therefore other mechanisms, primarily vasodilatatory, must also be involved in the rat's thermolytic normal response. Although desensitized rats did not show a tendency to escape from the warm environment their response to heat pain was normal. In conclusion, it is suggested that heat perception in desensitized animals is impaired; however, the existence of some capsaicin-insensitive thermolytic mechanisms (prone extension of the body) cannot be excluded.Supported by the Scientific Research Council, Ministry of Health, Hungary /4-05-0303-04-2/0/ and MTA-OM-MÉM-EÜM 70.211/79     

人参三醇皂甙对人淋巴结细胞IL—5基因表达的促进效应

应用mRNA麦胚无细胞体外转译体系,动态地观察了人参三醇皂甙(PTGS)对人淋巴结细胞IL-5基因表达的促进效应。结果表明,PTGS可以明显促进PHA活化人淋巴结细胞分泌IL-5,最大促进效应可达66.67％。PTGS+PHA共刺激后人淋巴结细胞浆IL-5 mRNA转译IL-5的量明显高于单纯PHA组,最大促进效应40％。上述结果首次证明PTGS对IL-5的促诱生效应是通过调节IL-5基因表达而实现的。     

Increased allergen concentration enhances IFN-gamma production by allergic donor T cells expressing a peripheral tissue trafficking phenotype

BACKGROUND: Clinically effective allergen-specific immunotherapy correlates with decreased circulating allergen-specific IL-4+ T cells but increased IFN-gamma+ cells at sites of allergen challenge. Whether immunotherapy promotes trafficking of IFN-gamma+ T cells to peripheral tissues is unknown. As aeroallergen is administered at higher concentrations during immunotherapy than those encountered naturally, the effect of allergen concentration on adhesion molecule (CD62L and CD49d) and chemokine receptor (CCR3 and CCR5) expression by peripheral-blood T cells was analysed in parallel with cytokine production. METHODS: House dust mite-allergic donor peripheral blood mononuclear cells were cultured for 14 days with different allergen concentrations. Cytokine profiles of were analysed by flow cytometry. RESULTS: Cultures stimulated with 100 microg/ml house dust mite extract compared with 1 microg/ml had increased proportions and numbers of CD62Llo, CD49dhi or CCR5+ T cells expressing IFN-gamma. CCR3-positive CD4+ and CD8+ T cell numbers were very low and did not differ between cultures. In contrast the proportions of 'peripheral tissue trafficking' CD4+ T cells expressing IL-4 were decreased in cultures stimulated with high in comparison with low allergen concentration. CONCLUSION: These results indicate the importance of achieving high allergen doses during immunotherapy to promote IFN-gamma production and expression of a 'peripheral tissue trafficking' phenotype by allergen-specific CD4+ and CD8+ T cells. The net change in cytokine milieu at sites of allergen encounter would then down-regulate clinical manifestations of allergic disease.