Circulating adhesion molecules in humans: role of hyperglycemia and hyperinsulinemia.

BACKGROUND: We assessed the role of glucose and insulin in the regulation of circulating levels of soluble intercellular adhesion molecule-1 (sICAM-1) and vascular adhesion molecule-1 (sVCAM-1) in normal subjects and in patients with type 2 diabetes. METHODS AND RESULTS: Plasma glucose concentrations were acutely raised in 10 normal subjects and 10 newly diagnosed, complication-free type 2 diabetic patients and maintained at 15 mmol/L for 2 hours. In normal subjects, plasma sICAM-1, but not sVCAM-1, levels rose significantly (P<0.01) at 1 hour and returned to basal values at 2 hours. In another study, octreotide was infused during the hyperglycemic clamp to block the release of endogenous insulin; this prevented the late fall of plasma sICAM-l levels observed in under control clamp conditions. The diabetic patients had plasma sICAM-1 levels significantly higher (P<0.01) than those of the control subjects; plasma sVCAM-1 levels were similar. Both sICAM-l and sVCAM-1 concentrations did not change significantly during the control hyperglycemic clamp; however, octreotide infusion increased plasma sICAM-1 levels, which remained significantly (P<0.05) above baseline during the whole clamp. In an additional 10 type 2 diabetic patients, overnight euglycemia (plasma glucose 5.5 mmol/L) obtained with the aid of an artificial pancreas or supplementation with l-arginine (10 g PO for 30 days), the natural precursor of NO, normalized the increased plasma sICAM-1 levels. CONCLUSIONS: Acute hyperglycemia increases circulating sICAM-1 levels in normal subjects, whereas the correction of hyperglycemia with insulin or l-arginine supplementation restored to normal levels the increased plasma sICAM-1 levels of type 2 diabetic patients.

Hashimoto's thyroiditis is associated with peripheral lymphocyte activation in patients with systemic sclerosis.

OBJECTIVE: To investigate whether autoimmune thyroiditis [HT] (i.e., a TH1 disease) influences the pattern of peripheral lymphocyte activation in systemic sclerosis [SSc] (commonly regarded as a TH2 disease). Twenty SSc patients, 6 with (SSc+HT+) and 14 without HT (SSc+HT-) and 20 controls were investigated for the intracellular content of IFN-gamma and IL-4 in unstimulated and stimulated (25 ng/ml PMA and 1 microg/ml ionomycin) CD4+ and CD8+ T lymphocytes. Results Under basal conditions the percentages of CD4+IFN-gamma, CD4+IL-4+ and CD8+IFN-gammawere significantly higher in the patients than the control subjects, no significant differences being detectable between the two patient subgroups. Upon PMA stimulation, the 20 SSc patients showed a higher percentage of CD4+IFN-gamma+ and CD8+IFN-gamma+ than the control subjects. In particular, the 14 SSc+HT- patients showed a higher number of CD4+IFN-y+ and CD4+IL-4+ cells, while the SSc+HT+ patients showed higher percentage of CD8+IFN-gamma+ cells. The latter patients showed a reduced percentage of CD4+IL-4+ cells and an increased percentage of CD8+IFN-y+ in comparison with the SSc+HT- patients. Type-1 activation in the peripheral blood of SSc patients has been already pointed out by other authors and ourselves. This study shows that such activation mainly affects SSc patients with coexistent HT.

Pathogenicity of the intercellular antibodies of pemphigus and their periodic removal from the circulation by plasmapheresis.

The authors are convinced that the intercellular antibodies of pemphigus are pathogenic. Consequently periodic plasmapheresis in two patients with pemphigus has been performed to remove the antibodies from the circulation. After larger plasma-exchanges there was a decrease of the antibody titre and a parallel improvement of the clinical condition.

Cell membrane predictors of response to lithium prophylaxis of affective disorders.

HLA antigens and RBC/plasma lithium ratio were studied in a sample of 49 patients, diagnosed as bipolar affective psychotics (n = 22), unipolar depressive psychotics (n = 18) and cycloid psychotics (n = 9), receiving prophylactic lithium for 1-4 years and maintained at lithium plasma levels of 0.6-1.2 mEq/1. Mean values of the ratio were found to be significantly higher in patients who responded to treatment when compared with non-responders, whereas the frequency of the HLA-A3 antigen was significantly higher in non-responders. The only 6 patients with a lithium ratio above the median and the absence of the HLA-A3 antigen coexistent with bipolarity and a family history of the illness were all good responders to treatment. Further research in this field will probably bring about the isolation of a subgroup of lithium-responsive patient with well-defined clinical and biological features. When patients were divided into two subgroups according to their lithium ratios (above and below the median), the HLA-A3 and Aw26 antigens were found to be significantly more frequent in those with ratios below the median. It can be hypothesized tha these antigens disturb transport in some way, leading to low lithium ratio values.

Antinuclear antibodies in first-degree relatives of patients with polymyositis-dermatomyositis: analysis of the relationship with HLA haplotypes.

Antinuclear antibodies (ANA), as detected by indirect immunofluorescence on HEp-2 cells, have been investigated in five spouses and 41 first-degree relatives of nine probands with polymyositis-dermatomyositis (PM-DM) and in 41 sex- and age-matched controls. ANA were detected in 12 out of the 41 first-degree relatives and in two controls (chi 2 = 6.97; P less than 0.01). HLA typing was done in four out of the nine families; in two of them only, ANA segregated with a haplotype. ANA positivity was not correlated either to sex or to age or to household contact. Our results show that ANA occur in a significant percentage of first-degree relatives of patients with PM-DM. The finding seems to be genetically conditioned.

Peripheral blood T lymphocytes from systemic sclerosis patients show both Th1 and Th2 activation.

Our objective was to investigate the phenotype of helper T cells in the peripheral blood of patients with systemic sclerosis (SSc). PBMC from 15 patients with SSc and 15 sex- and age-matched controls were investigated for lymphocyte subpopulations (CD3, CD4, CD8, CD19, CD16/CD56, CD3-DR); IL-2, IL-4, and IFN-gamma mRNAs; and the relative cytokines in their cytoplasm. The last assay was carried out both in unstimulated and in PMA-activated PBMC. SSc patients presented a higher percentage of activated T cells, CD3+ DR+ (19.7 +/- 9.9 vs 5.1 +/- 2.5%; P < 0.0001); 12 of them presented IFN-gamma mRNA-positive cells; and none IL-2 or IL-4 mRNAs. Under basal conditions, PBMC from six SSc patients contained IL-2, IL-4, and IFN-gamma (i.e., they showed both Th1 and Th2 activation), and 1 IFN-gamma only. PMA-stimulated PBMC of patients differed from those of controls only in the increased percentage of IFN-gamma positive cells (52 +/- 12 vs 37 +/- 11%; P < 0.01). Our study demonstrates that Thl activation occurs in the peripheral blood of SSc patients. This evidence must be faced with from both a pathogenetic and a therapeutical point of view.

Rat seminal vesicle protein SV-IV and its transglutaminase-synthesized polyaminated derivative SPD2-SV-IV induce cytokine release from human resting lymphocytes and monocytes in vitro.

Micromolar amounts of SV-IV, one of the major proteins secreted from the rat seminal vesicle epithelium, induce in vitro a marked release of a variety of cytokines (interferon-gamma, tumor necrosis factor-alpha, interleukin 6, and granulocyte-monocyte colony-stimulating factor) from human resting peripheral blood mononuclear cells as well as from isolated resting lymphocytes and monocytes. This effect was found to be significantly higher when the spermidine adduct of SV-IV (Spd2-SV-IV), synthesized in vitro by the enzyme transglutaminase, was used instead of the native protein. Furthermore, the pretreatment of monocytes with transglutaminase caused an increase of the inducing effect of both native and modified SV-IV on the release of interleukin 6 from these cells. The inducing effect of these proteins on the cytokine release was markedly inhibited by actinomycin D and cycloheximide.

Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins.

CONTEXT: Increased levels of homocysteine are associated with risk of cardiovascular disease. Homocysteine may cause this risk by impairing endothelial cell function. OBJECTIVE: To evaluate the effect of acute hyperhomocysteinemia with and without antioxidant vitamin pretreatment on cardiovascular risk factors and endothelial functions. DESIGN AND SETTING: Observer-blinded, randomized crossover study conducted at a university hospital in Italy. SUBJECTS: Twenty healthy hospital staff volunteers (10 men, 10 women) aged 25 to 45 years. INTERVENTIONS: Subjects were given each of 3 loads in random order at 1-week intervals: oral methionine, 100 mg/kg in fruit juice; the same methionine load immediately following ingestion of antioxidant vitamin E, 800 IU, and ascorbic acid, 1000 mg; and methionine-free fruit juice (placebo). Ten of the 20 subjects also ingested a placebo load with vitamins. MAIN OUTCOME MEASURES: Lipid, coagulation, glucose, and circulating adhesion molecule parameters, blood pressure, and endothelial functions as assessed by hemodynamic and rheologic responses to L-arginine, evaluated at baseline and 4 hours following ingestion of the loads. RESULTS: The oral methionine load increased mean (SD) plasma homocysteine level from 10.5 (3.8) micromol/L at baseline to 27.1 (6.7) micromol/L at 4 hours (P<.001). A similar increase was observed with the same load plus vitamins (10.0 [4.0] to 22.7 [7.8] micromol/L; P<.001) but no significant increase was observed with placebo (10.1 [3.7] to 10.4 [3.2] micromol/L; P=.75). Coagulation and circulating adhesion molecule levels significantly increased after methionine ingestion alone (P<.05) but not after placebo or methionine ingestion with vitamins. While the mean (SD) blood pressure (-7.0% [2.7%]; P<.001), platelet aggregation response to adenosine diphosphate (-11.4% [4.5%]; P=.009) and blood viscosity (-3.0% [1.2%]; P=.04) declined in these parameters 10 minutes after an L-arginine load (3 g) following placebo, the increase after methionine alone (-2.3% [1.5%], 4.0% [3.0%], and 1.5% [1.0%], respectively; P<.05), did not occur following methionine load with vitamin pretreatment (-6.3% [2.5%], -7.9% [3.5%], and -1.5% [1.0%], respectively; P=.24). CONCLUSION: Our data suggest that mild to moderate elevations of plasma homocysteine levels in healthy subjects activate coagulation, modify the adhesive properties of endothelium, and impair the vascular responses to L-arginine. Pretreatment with antioxidant vitamin E and ascorbic acid blocks the effects of hyperhomocysteinemia, suggesting an oxidative mechanism.