CD28‐dependent differentiation into the effector/memory phenotype is essential for induction of arthritis in interleukin‐1 receptor antagonist–deficient mice

Objective

Interleukin‐1 receptor antagonist (IL‐1Ra)–deficient mice on a BALB/c background spontaneously develop a chronic inflammatory polyarthropathy closely resembling that of rheumatoid arthritis in humans. To elucidate the role of CD28 costimulatory signals in the development of this disease, we studied IL‐1Ra/CD28–double‐deficient mice.

Methods

We crossed IL‐1Ra–deficient mice with CD28–deficient mice and observed the incidence and severity of arthritis. To investigate functions of IL‐1Ra/CD28–double‐deficient T cells, cells were stimulated with CD3 monoclonal antibody or allogeneic antigen‐presenting cells (APCs) and their proliferative responses and levels of cytokine production were measured.

Results

Disease severity was lower in IL‐1Ra/CD28–double‐deficient mice than in mice that were deficient only in IL‐1Ra, although incidence of arthritis was not affected by the presence or absence of CD28. When pathogenic IL‐1Ra–KO T cells were transferred into nude mice, severe arthritis developed. Even though T cells from double‐deficient mice showed the same diminished proliferative capacity as was seen in T cells from CD28–single‐deficient animals, nude mice into which double‐deficient T cells were transferred never developed arthritis.

Conclusion

These findings indicate that IL‐1Ra/CD28–double‐deficient T cells can be activated by IL‐1Ra–deficient activated APCs, resulting in induction of arthritis; however, these T cells did not induce the disease under normal conditions, because they did not differentiate into effector/memory phenotype.

     

Forthcoming Papers

Summary

A total of 1328 atomic bomb survivors in Hiroshima were studied to determine alterations in the number of blood lymphocytes belonging to T-cell subpopulations, the number of CD19 antigen-positive B cells and the number of Leu 7 and CD16 antigen-positive lymphocytes. Overall, with increasing age, significant decreasing trends in the numbers of some lymphocytes in T-cell subpopulations and of B cells were observed. Furthermore, the number of blood lymphocytes positive for CD5 antigen was significantly lower in the people exposed to radiation (> 1 Gy) in the older age group (more than 30 years old at the time of the bombing). A similar tendency for decreases in the numbers of CD4, CD8, and CD19 antigen-positive cells was observed in these older survivors, although the differences were not statistically significant. These results suggest that aging of the T-cell related immune system is accelerated in the irradiated people of advanced age. This may be explained by the age-related decrease in thymic function in those subjects who were older at the time of the bombing resulting in a decreased functional ability of the immune system after radiation injury. On the contrary, the number of Leu 7 or CD16 antigen-positive cells was found to be increased significantly in the older age group compared to the younger group, although there was little dependence on dose.     

Water and electrolyte balance after ileal J pouch-anal anastomosis in ulcerative colitis and familial adenomatous polyposis

The water and electrolyte balance was studied in 31 patients with ulcerative colitis (UC) and 22 with familial adenomatous polyposis (FAP) who underwent staged surgery involving colectomy and ileal J pouch-anal anastomosis (IAA), preoperatively, after terminal ileostomy, after high ileostomy, and after ileostomy closure. Serum electrolytes did not differ between each surgical stage. After terminal or high ileostomy, daily urine volume and urinary sodium loss was significantly lower, and daily fecal weight and fecal sodium loss was significantly higher than preoperatively. After ileostomy closure, urinary and fecal sodium loss became closer to preoperative value. Daily urinary potassium loss was significantly higher and fecal loss was lower after terminal and high ileostomy than preoperatively and did not show a significant change after ileostomy closure. The urinary sodium to potassium ratio after ileostomy closure was lower than preoperatively, but was higher than that after terminal and high ileostomy. Plasma aldosterone and renin levels were only significantly increased after high ileostomy. These findings indicate that high or terminal ileostomy caused chronic dehydration, which was compensated for by activation of the renin-aldosterone axis, while the water and electrolyte balance became closer to normal after ileostomy closure following ileoanal anastomosis.

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Résumé Un bilan hydro-électrolytique a été établi chez 31 patients porteurs d'une recto-colite ulcéro-hémorragique et 22 porteurs d'une polypose familiale; tous avaient subi plusieurs temps chirurgicaux comprenant une colectomie et la confection d'une anastomose iléoanale avec une pochen en J. Les dosages ont été réalisés à 4 péeriodes au cours du suivi chirurgical, en particulier en préopératoire, après la colectomie avec confection d'une iléostomie terminale, après l'anastomose iléo-anale sous couvert d'une iléostomie de protection et après fermeture de l'iléostomie de protection. Les taux sériques d'électrolytes ne diffèrent pas entre les 4 périodes chirurgicales. Après iléostomie terminale ou après iléostomie de protection, le volume urinaire quotidien et les pertes de sodium urinaire étaient significativement plus basses alors que le poids fécal quotidien et les pertes de sodium fécales étaient significativement plus élevées qu'en préopératoire. Après fermeture de l'iléostomie, les valeurs d'excrétion du sodium urinaire et fécal étaient voisines à celles de la valeur pré-opératoire. L'élimination journalière de potassium par les urinaires était plus élevée et les pertes fécales plus basses après iléostomie terminale et iléostomie de protection que celles observées en préopératoire; ces valeurs ne changeaient pas de manière significative après fermeture de l'iléostomie. Le rapport sodium/potassium urinaire après fermeture de l'iléostomie est abaissé par rapport à la valeur pré-opératoire mais demeure plus élevé qu'après iléostomie terminale et iléostomie de protection. Le taux d'aldostérone et le taux de rénine plasmatique étaient significativement augmentés après une iléostomie de protection. Ces données tendent à démontrer qu'une iléostomie terminale ou une iléostomie de protection favorisent une déshydratation chronique avec une perte sodique compensée par l'activation du mécanisme rénine-aldostérone.

     

NO-1886 decreases ectopic lipid deposition and protects pancreatic beta cells in diet-induced diabetic swine

The synthetic compound NO-1886 (ibrolipim) is a lipoprotein lipase activator that has been proven to be highly effective in lowering plasma triglycerides. Recently, we found that NO-1886 also reduced plasma free fatty acids and glucose in high-fat/high-sucrose diet-induced diabetic rabbits. In the current study, we investigated the effects of NO-1886 treatment on ectopic lipid deposition and the islet pathology in miniature swine fed a high-fat/high-sucrose diet. Our results showed that feeding this diet to miniature swine caused insulin resistance, increased lipid deposition in non-adipose tissue, such as in the heart, skeletal muscle, liver and pancreas, and also caused pancreatic beta cell damage. However, supplementing 1% NO-1886 (200 mg/kg per day) into the high-fat/high-sucrose diet decreased ectopic lipid deposition, improved insulin resistance, and alleviated the beta cell damage. These results suggest that improvement of lipid disorder, non-adipose tissue steatosis and insulin resistance may be very important for the protection of beta cell damage. Therefore, NO-1886 is potentially beneficial for the treatment of insulin-resistance syndrome.     

Circulating level of hepatocyte growth factor as a useful tumor marker in patients with early-stage gastric carcinoma

BACKGROUND: Although conventional tumor markers including carcinoembryonic antigen (CEA) and carbohydrate antigen (CA19-9) have been used in gastric cancer patients, clinically useful markers of early gastric cancer have not been identified. The present study was designed to clarify the clinical significance of the circulating level of hepatocyte growth factor (HGF) as a tumor marker, especially in early-stage gastric cancer patients. METHODS: Preoperative serum HGF levels were measured with an enzyme-linked immunosorbent assay in 30 early-stage and 42 advanced-stage gastric cancer patients. RESULTS: The mean value of serum HGF in 72 patients was significantly higher than that in the normal subjects. There was a significant increase in serum HGF levels in both advanced-stage and early-stage patients compared with normal subjects. The positivity rates of HGF in early disease cases were higher than those of CEA and CA19-9. The serum HGF level was significantly higher in patients with vessel invasion than in those without invasion. In smaller early gastric cancers, serum HGF elevation was associated with lymphatic invasion. CONCLUSIONS: The serum HGF level may be a clinically significant tumor marker in patients with early-stage, as well as advanced-stage, gastric cancer. HGF elevation in early-stage patients may help us to predict the risk of lymph node metastasis of early gastric tumors, even of smaller tumor size. HGF may be a useful indicator for appropriate lymphadenectomy in early gastric cancer.     

X-linked ectodermal dysplasia and immunodeficiency caused by reversion mosaicism of NEMO reveals a critical role for NEMO in human T-cell development and/or survival

X-linked ectodermal dysplasia and immunodeficiency (XL-EDA-ID) is an X-linked recessive disease caused by a mutation in the nuclear factor-kappaB (NF-kappaB) essential modulator (NEMO). Here we report an XL-EDA-ID patient with atypical features of very few naive-phenotype T cells and defective mitogen-induced proliferation of peripheral blood mononuclear cells (PBMCs). The patient's NEMO defect was diagnosed by flow cytometric analysis of intracellular NEMO staining. Specific cell lineages (monocytes and neutrophils) expressed reduced levels of NEMO, but 2 populations of T, B, and NK cells were detected with normal and reduced expression of NEMO. Genomic analysis revealed that duplication of a 4.4-kb sequence ranging from intron 3 to exon 6 caused the reduced expression of NEMO. Polymorphism analysis showed that the patient's B- and T-cell lines with reduced and normal expression of NEMO had the same X chromosome, indicating that the somatic mosaicism was not due to fetomaternal transfusion but was most likely due to postzygotic reversion. This XLEDA-ID case adds to our understanding of NEMO biology, indicating that NEMO is critical for T-cell development and/or survival in humans as well as in mice.     

Hypereosinophilia associated with increased serum levels of carcinoembryonic antigen

We report a case of hypereosinophilia associated with increased serum levels of carcinoembryonic antigen (CEA). The patient developed fever, diarrhea, erythroderma and eosinophilia. Disorders known to be associated with eosinophilia were not detected. The typical malignant diseases related to a rise in CEA levels were not identified. The CEA value reached a maximum of 81.4 ng/ml a few weeks late for the peak of the eosinophilic count. Corticosteroid therapy was effective in improving clinical symptoms and the CEA values decreased in association with the improvement of those manifestations, suggesting a pathophysiological link between the disease activity of hypereosinophilia and the changes in CEA level.     

Impaired Contractile Motility of the Gallbladder after Gastrectomy

Contractile motility of the gallbladder was compared using a real-time ultrasonography in 13 patients with gastric ulcer and 31 patients with gastric cancer who had undergone either subtotal or total gastrectomy within 1 month previously. Contractile motility of the gallbladder after oral administration of dried egg yolk (Daiyan, Maruishi, Osaka), which was slightly but not significantly reduced in patients with gastric ulcer, was remarkedly impaired in patients with gastric cancer who had either subtotal or total gastrectomy including radical lymph node dissection. Especially, maximum contractile rate after Daiyan in Billroth II patients was significantly reduced than that of Billroth I patients. Intramuscular injection of naloxone (0.4 mg), which had no effects on contractions after Daiyan in healthy subjects, significantly improved the hypomotility in response to Daiyan in these gastric cancer patients. It was suggested, therefore, that the possible roles of various anatomical and mechanical changes resulting from gastrectomy including vagotomy and sympathectomy, and in particular exclusion of duodenum from digestive circuits and relative or absolute excess of endogenous opioids, were involved in the control of the gallbladder motility within 1 month after gastrectomy including lymphadenectomy.