Pemphigus vulgaris: the role of IL-1 and IL-1 receptor antagonist in pathogenesis and effects of intravenous immunoglobulin on their production

Intravenous immunoglobulin (IVIG) is increasingly being used for the treatment of autoimmune diseases. In the present report, the role of IVIG on in vivo and in vitro production of IL-1 and IL-1 receptor antagonist (Ra) was studied in patients with pemphigus vulgaris (PV). Serum samples from 20 untreated patients with active PV prior to initiation of systemic therapy, 20 patients receiving IVIG treatment, 20 patients in clinical remission after conventional therapy, and 20 normal human controls were studied to determine the serum levels of IL-1alpha, IL-1beta, and IL-1Ra. The in vitro production of these cytokines was measured in the culture supernatant of peripheral blood mononuclear cells (PBMC) from 10 PV patients immediately before and after IVIG therapy and from age and sex-matched 10 healthy donors simultaneously. Elevated levels of IL-1alpha and IL-1beta were detected (i) in the serum of untreated PV patients with active disease prior to systemic therapy and (ii) before IVIG infusions in patients receiving IVIG therapy. These increased levels are statistically significant when compared to the levels in healthy controls (P < 0.01). A marked reduction of IL-1alpha and IL-1beta was detected (i) in the serum of patients in prolonged clinical remission and (ii) immediately after IVIG infusion in those patients on IVIG therapy. Increased level of IL-1Ra was detected in PV patients in prolonged clinical remission and after IVIG infusion in those receiving IVIG therapy. These differences were statistically significant when compared to the levels in normal controls and to the levels in the sera of patients with active disease (P < 0.01) or just before the beginning of IVIG infusion (P < 0.01). Similar differences in the levels of IL-1alpha, IL-1beta, and IL-1Ra were found in the culture supernatant of PBMC isolated from the PV patients pre and post IVIG therapy. These observations suggests that, compared to normal controls, patients with active PV have reversed levels of IL-1alpha, IL-1beta, and IL-1Ra. IVIG therapy may down-regulate production of IL-1alpha and IL-1beta and enhance production of IL-1Ra, in vivo and in vitro. This might be one of the important mechanisms by which IVIG produces its early therapeutic effects in pemphigus vulgaris.     

Postnatal development of somatostatin-containing neurons in the visual cortex of normal and dark-reared rats

Summary The distribution of somatostatin (SRIF)-immunoreactive neurons in the visual cortical areas 17, 18 and 18a of Wistar rats from birth to adulthood was followed in both normal and dark-reared animals. The SRIF neurons show difference in distribution amongst the three cortical areas studied as early as the first postnatal week. Area 17 was distinguished by fewer SRIF cells in the upper layers (I–III), which results in a lower overall density. The SRIF neurons in all areas appeared to increase in numbers up to about 3 weeks and then decline dramatically to adult levels, which were 14–19% of the peak levels. Although this decline was still obvious, it moderated to 25–31% in dark-reared animals. The greatest effect was seen in area 18 where, at 60 days of age, there were twice as many SRIF cells in darkreared as in normal controls. It is suggested that, under conditions of dark rearing, the overall pattern of development of SRIF neurons, being uninfluenced by extrinsic factors, reveals the cells' genetic potential.     

胰岛素对白细胞介素1产生及作用的影响

本文研究胰岛素对白细胞介素1(IL—1)的产生及其作用的影响.实验证实:腴岛素能促进LPS刺激的巨噬细胞IL—1的产生,并可增强胸腺细胞对Con A的反应.但用尼龙毛处理胸腺细胞除去粘附细胞后,胸腺细胞在无外源性IL—1存在时,对Con A的反应很弱.胰岛素不能增强经尼龙毛处理后的胸腺细胞对Con A的反应.加入外源性IL—1后,胰岛素可显著增强胸腺细胞对IL—1的应答,促进细胞增殖.这些结果表明。胰岛素是通过促进IL—1的产生及增强其作用来调节激活T细胞的.     

T cell clones from a Sjögren's syndrome salivary gland biopsy produce high levels of IL-10

Sjögren''s syndrome (SS) is characterized by a focal periductal salivary gland infiltrate consisting mainly of T and B lymphocytes. Most of the T cells bear the memory of CD4⁺ Th-1-like phenotype and express high levels of class II, though CD8⁺ cells are also present. We have studied 17 labial salivary gland and 15 peripheral blood T cell clones from a patient with primary SS. The tissue clones were 71% CD8⁺ and 29% CD4⁺, and the peripheral blood-derived clones were 60% CD8⁺ and 40% CD4⁺. The CD4⁺ T cell clones from both the salivary gland and autologous peripheral blood were of the Th1 phenotype, in that they produced interferon-gamma (IFN-γ) and IL-2 but very little IL-4 after 24 h stimulation with phorbol myristate acetate and anti-CD3 antibody. The salivary gland-derived CD4⁺ clones produced 15 times more IL-10 (7·92 ng/ml) than peripheral blood-derived CD4⁺ clones (0·52 ng/ml, P≤0·02). The tissue CD8⁺ clones produced 1·2 times (P<0·04) more IFN-γ and CD4⁺ clones produced 3·5 times less IL-2 (P<0·02) than the respective PBM-derived clones. The accumulation of Th1-type cells producing high levels of IL-10 in the salivary gland suggests a specific immunoregulatory function at the site of inflammation in SS.     

Effects of C5a and FMLP on Interleukin-8 Production and Proliferation of Human Umbilical Vein Endothelial Cells

Interleukin-8 (IL-8), C5a and N-formyl-methionyl-leucyl-phenylalanine (fMLP) are chemotactic peptides with predominant effects on leukocytes during inflammation. With emphasis on C5a we studied the regulation of the production of IL-8 by human umbilical vein endothelial cells (HUVEC) in vitro. Primary HUVEC cultures were incubated with IL-1, TNF, C5a and fMLP for 24 h and 48 h prior to measurement of IL-8 in supernatants of the cells by an enzyme immunoassay. Whereas IL-1 and TNF significantly increased the levels of IL-8, C5a decreased the IL-8 production after 48 h. In addition, the ability of IL-1, TNF, C5a, fMLP and IL-8 to induce cell proliferation was compared by means of a ³H-thymidine incorporation assay. In contrast with IL-1 and TNF, both C5a and fMLP increased cell proliferation of HUVEC. This increase occurred with increasing concentrations of C5a contrary to IL-8, which showed increased cell proliferation at low, but not high IL-8 concentrations.     

氧化苦参碱对LAK细胞活性的影响

ＬＡＫ细胞具有很强的广谱杀瘤作用，而氧化苦参碱具有较强的免疫抑制作用。本文研究了氧化苦参碱对ＬＡＫ细胞活力的影响，结果表明：氧化苦参碱可抑制ＩＬ－２对小鼠脾细胞的促增殖作用，并且对ＩＬ－２活化ＬＡＫ细胞杀伤Ｐ８１５的能力也有抑制作用。当ＩＬ－２（５００ｕ／ｍｌ）与２００μｇ／ｍｌ的氧化苦参碱共同孵育４ｄ后，可使ＬＡＫ细胞杀瘤能力（在效靶比为１００：１时）的８２．５％被抑制。同时氧化苦参碱本身对Ｐ８     

Specific immunotherapy prevents increased levels of allergen-specific IL-4- and IL-13-producing cells during pollen season

BACKGROUND: Specific allergen immunotherapy (SIT) is effective for treatment of IgE-mediated diseases: however, the mechanisms of action still remain unclear. Earlier, we showed that IL-4 and IL-13 are produced in response to specific allergens. The aim of this study was to investigate whether these cytokine responses were affected by allergen SIT, and, furthermore, to evaluate the effect of SIT on allergen-specific IgE and IgG4 levels. METHODS: Blood samples from pollen-sensitized individuals were collected before the pollen season (before treatment) and during the pollen season (after SIT or placebo treatment). Peripheral blood mononuclear cells were activated in vitro with allergens and the numbers of IL-4-, IL-13-, IL-10-, and IFN-gamma-producing cells were determined by ELISPOT. Serum levels of allergen-specific IgE and IgG4 were measured by RAST and ELISA, respectively. RESULTS: The numbers of IL-4- and IL-13-producing cells were shown to be increased in the placebo group during the pollen season, an increment which was absent in patients receiving allergen SIT. We found an increase in allergen-specific IgG4 in the SIT-treated individuals, but not in the placebo group. Both groups displayed elevated specific IgE levels during the pollen season. CONCLUSIONS: Taken together, our data show a downregulation of IL-4- and IL-13-producing cells in peripheral blood after SIT, suggesting induction of nonresponsiveness/tolerance or a redistribution of these cells. Furthermore, we demonstrate that SIT acts on antibody production by increasing the specific IgG4 levels.     

Soluble IL-2 receptor and CD25 cells in psoriasis: effects of cyclosporin A and PUVA therapy.

A study was conducted to quantify soluble IL-2 receptor (sIL-2R) levels in sera of 57 chronic plaque psoriasis patients and correlate these measurements with disease activity and the number of IL-2R-positive (CD25+) lymphocytes in lesional biopsies of 11 cyclosporin A (CsA) and 13 psoralen plus ultraviolet radiation (PUVA) treated patients. Levels of sIL-2R showed a strong correlation with the psoriasis area and severity index (PASI). CsA and PUVA significantly reduced the PASI and sIL-2R levels to a similar degree after 4 weeks of treatment. Although the majority of CsA-treated patients who were biopsied showed reductions in lesional CD25+ cells, these did not reach statistical significance; in five patients biopsied who had PUVA treatment, no consistent effect on the numbers of CD25+ cells was observed. A significant correlation was found between CD25+ cells in lesional biopsies and the PASI score.     

Production of IL-6 by T cells from the femoral head of patients with rapidly destructive coxopathy (RDC)

RDC is a syndrome with unknown etiology that causes rapid destruction of a hip joint. We have investigated the production of osteoclast-activating cytokines (IL-6, IL-1α and tumour necrosis factor-alpha (TNF-α)), interferon-gamma (IFN-γ) and IL-8 by T cells in the affected joint. The level of IL-6 produced by the T cell lines (TCL) established from the femoral head was significantly higher than that from patients' or healthy donors' peripheral blood mononuclear cells (PBMC). IL-6 production by the TCL from synovial membrane or from patients' PBMC was also significantly higher than that from healthy donors' PBMC. IL-1α production by the TCL from the femoral head was significantly higher than any of the other groups when all the TCL were used for the analysis. TNF-α production was highest in the TCL from patients' PBMC. The levels of IFN-γ or IL-8 were not significantly different among these four groups. The plasma levels of all these cytokines except for IFN-γ, that was rather lower, in RDC patients were not significantly different from those in osteoarthrosis or trauma patients, or healthy donors. These results suggest that T cells at the affected femoral head, and also synovial membrane to some extent, are involved in bone resorption through the production of IL-6 and probably IL-1α in patients with RDC.