The role of γδ T cells in priming macrophages to produce tumor necrosis factor-α

The secretion of tumor necrosis factor (TNF)-α from macrophages is regulated by both priming and triggering signals. We found that macrophages from mice lacking γδ T cells [T cell receptor (TCR) δ^?/- mice], which lack the gene encoding the δ chain, produced only small amounts of TNF-α in response to lipopolysaccharide (LPS) and showed a reduced level of expression of CD14. Pre-incubation of macrophages from TCR δ-/- mice with γδ T cells from their TCR δ^+/- littermates restored their capacity to produce TNF-α in response to LPS. The priming activity of γδ T cells was in part inhibited by neutralizing anti-interferon (IFN)-γ monoclonal antibodies. Collectively, these results suggest that γδ T cells play a role in priming macrophages to a steady state of activation via IFN-γ secretion, which allows them to produce TNF-α when exposed to LPS.     

Long-term follow-up of adalimumab monotherapy for rheumatoid arthritis in Japanese patients: a report of six cases

We present six cases of patients with Japanese rheumatoid arthritis (RA) treated with a tumor necrosis factor (TNF)-alpha blocking agent, adalimumab as monotherapy for 220?weeks. All six patients were women, and the median age was 54.0?±?7.07?years old. The median duration of the disease was 7.43?±?11.1?years, and the median disease activity score (DAS28-CRP) was 5.35?±?0.69. Three of six patients were able to continue to receive this treatment for 220?weeks successfully, and the DAS28-CRP decreased to 1.89?±?0.75. Two patients withdrew because of lack of efficacy, and one patient withdrew because of adverse events (non-Hodgkin lymphoma). Adalimumab resulted in a sustained clinical response in RA patients during 220-week follow-up.     

Sequential monitoring of serum IL-6, TNF-α, and IFN-γ levels in a CAEBV patient treated by plasma exchange and immunochemotherapy

We report the case of a female patient with chronic active Epstein?CBarr virus infection (CAEBV) accompanied by hemophagocytic syndrome (HPS). On admission, she presented with severe liver dysfunction and disseminated intravascular coagulation with elevation of serum IL-6, TNF-??, and IFN-?? levels. Plasma exchange (PE) followed by immunochemotherapy with prednisolone, cyclosporine A, and VP16 was performed. PE decreased serum cytokine levels dramatically and improved liver function. Following immunochemotherapy, CAEBV became inactive. Four months after discharge, however, CAEBV relapsed with HPS, and serum cytokine levels were extremely elevated again. There was no response to immunochemotherapy, and the patient died 1?day after admission. We examined the cytokines in five additional untreated-CAEBV patients and determined that they were elevated above the normal level in all patients. These results suggest that inflammatory cytokines may have roles in the development of CAEBV, and that their depletion can be an effective treatment for this disease.     

Protein tyrosine phosphatase receptor type Z is involved in hippocampus-dependent memory formation through dephosphorylation at Y1105 on p190 RhoGAP

Ptprz is a receptor-type protein tyrosine phosphatase predominantly expressed in the brain as a chondroitin sulfate proteoglycan. Ptprz-deficient mice exhibit an age (maturation)-dependent impairment of spatial learning in the Morris water maze test and enhancement of long-term potentiation (LTP) in the CA1 region in hippocampal slices. The enhanced LTP is canceled out by pharmacological inhibition of Rho-associated kinase (ROCK), suggesting that the lack of Ptprz causes learning impairment due to aberrant activation of ROCK. Here, we report that Ptprz-deficient mice exhibit impairments in hippocampus-dependent contextual fear memory because of abnormal tyrosine phosphorylation of p190 RhoGAP, a GTPase-activating protein (GAP) for Rho GTPase. We found that phosphorylation at Y1105, a major tyrosine phosphorylation site on p190 RhoGAP, is decreased 1h after the conditioning in the hippocampus of wild-type mice, but not of Ptprz-deficient mice. Pleiotrophin, a ligand for Ptprz, increased tyrosine phosphorylation of p190 RhoGAP in B103 neuroblastoma cells. Furthermore, Ptprz selectively dephosphorylated pY1105 of p190 RhoGAP in vitro, and the tyrosine phosphorylation at Y1105 controls p190 RhoGAP activity in vivo. These results suggest that Ptprz plays a critical role in memory formation by modulating Rho GTPase activity through dephosphorylation at Y1105 on p190 RhoGAP.     

Association of single nucleotide polymorphisms of the interleukin-10 promoter gene and susceptibility to primary biliary cirrhosis: immunogenetic differences in Italian and Japanese patients

Several lines of data suggest that genetic factors play an important role in the onset and/or progression of primary biliary cirrhosis (PBC). Since PBC is an autoimmune disease, it is reasoned to assume that genes encoding cytokines may confer susceptibility to disease. Amongst these factors, interleukin-10 (IL-10) has received significant attention. The promoter region of IL-10 gene has three single nucleotide polymorphisms (SNPs) at positions -1082, -819 and -592. To elucidate the association of the three SNPs of IL-10 promoter region with susceptibility of PBC in two different genetic populations, 159 unrelated patients with PBC (94 Italian and 65 Japanese) and 143 local controls (72 Italian and 71 Japanese) were enrolled. SNPs were determined using allele-specific PCR/RFLP. In Italian PBC patients, the frequency of homozygosity for G/G at position -1082 was significantly higher than that of local controls (p < 0.041, OR = 2.44, 95% C.I.; 1.02-5.86). The frequencies of haplotype GCC in PBC patients, possibly linked to higher IL-10 production, were also significant higher than local controls (p < 0.033). However, in Japanese population, there were no significant differences in the three SNPs and haplotypes between PBC patients and controls. Excessive production of IL-10 may play an important role in some populations in modulating the onset of PBC. Further, immunogenetic studies of PBC should take into account ethnic and geographic variations; this makes such studies in heterogeneous population, like the USA, more difficult.     

Evolution of myelodysplastic syndrome and acute myelogenous leukaemia in children with hepatitis-associated aplastic anaemia

In hepatitis-associated aplastic anaemia (HAA), an immune-mediated mechanism is solely responsible for the development of pancytopenia. We retrospectively analysed the clinical outcome of 61 children with HAA, diagnosed between 1988 and 1996. Of 61 patients, 41 did not receive bone marrow transplantation (BMT) and their survival rate at 7 years was 61.4 +/- 9.3%(+/- SE). Five of these 41 patients developed myelodysplastic syndrome (MDS) or acute myelogenous leukaemia (AML) 7-57 months after the diagnosis of HAA. The incidence of MDS/AML in severe HAA patients who did not receive BMT (n = 30, 27.0 +/- 10.8%) appeared to be similar to that of severe idiopathic AA patients (n = 155, 14.7 +/- 3.7%) treated in the same period.     

Changing site distribution of colorectal cancer in Japan

PURPOSE: In North America and other high-risk areas, there has been a proximal shift in the subsite distribution of colorectal cancer. We wanted to determine whether any similar change has occurred in Japan, and where the incidence of this disease has increased sharply. METHODS: Data from the Reports of the Japanese Society for Cancer of the Colon and Rectum were used to analyze the time trend of colorectal cancer in Japan between 1974 and 1994 according to the patients age at diagnosis and sex, and the site of the tumor within the colon or rectum. RESULTS: The percentage of patients over the age of 70, especially females, increased. The increase in the percentage of right-sided colon cancer in colorectal cancer cases was accompanied by a continuous decline in the percentage of rectal cancer in both sexes at all ages. In general, the percentage of right-sided colon cancer in colon cancer cases was stable in men, but increased in women. The rate among patients older than 70 years increased in men, but predominated and remained stable in women. No proximal shift in colon cancer was found in either sex under the age of 69. CONCLUSION: These findings indicated that a proximal shift in the subsite distribution of colorectal cancer has occurred in Japan. This rightward shift of colorectal cancer is due to the decreasing proportion of rectal cancer. Furthermore, the increasing proportion of older patients, especially females, may be another major determinant of the changing colon cancer subsite distribution.