FUT2 non-secretor status is associated with Type 1 diabetes susceptibility in Japanese children.

AIM: To examine the contribution of the FUT2 gene and ABO blood type to the development of Type 1 diabetes in Japanese children. METHODS: We analysed FUT2 variants and ABO genotypes in a total of 531 Japanese children diagnosed with Type 1 diabetes and 448 control subjects. The possible association of FUT2 variants and ABO genotypes with the onset of Type 1 diabetes was statistically examined. RESULTS: The se2 genotype (c.385A>T) of the FUT2 gene was found to confer susceptibility to Type 1A diabetes in a recessive effects model [odds ratio for se2/se2, 1.68 (95% CI 1.20-2.35); corrected P value = 0.0075]. CONCLUSIONS: The FUT2 gene contributed to the development of Type 1 diabetes in the present cohort of Japanese children.

Variants associated with autoimmune Type 1 diabetes in Japanese children: implications for age-specific effects of cis-regulatory haplotypes at 17q12-q21.

AIMS: The aim of this study was to clarify the significance of previously reported susceptibility variants in the development of autoimmune Type 1 diabetes in non-white children. Tested variants included rs2290400, which has been linked to Type 1 diabetes only in one study on white people. Haplotypes at 17q12-q21 encompassing rs2290400 are known to determine the susceptibility of early-onset asthma by affecting the expression of flanking genes. METHODS: We genotyped 63 variants in 428 Japanese people with childhood-onset autoimmune Type 1 diabetes and 457 individuals without diabetes. Possible association between variants and age at diabetes onset was examined using age-specific quantitative trait locus analysis and ordered-subset regression analysis. RESULTS: Ten variants, including rs2290400 in GSDMB, were more frequent among the people with Type 1 diabetes than those without diabetes. Of these, rs689 in INS and rs231775 in CTLA4 yielded particularly high odds ratios of 5.58 (corrected P value 0.001; 95% CI 2.15-14.47) and 1.64 (corrected P value 5.3 × 10-5 ; 95% CI 1.34-2.01), respectively. Age-specific effects on diabetes susceptibility were suggested for rs2290400; heterozygosity of the risk alleles was associated with relatively early onset of diabetes, and the allele was linked to the phenotype exclusively in the subgroup of age at onset ≤ 5.0 years. CONCLUSIONS: The results indicate that rs2290400 in GSDMB and polymorphisms in INS and CTLA4 are associated with the risk of Type 1 diabetes in Japanese children. Importantly, cis-regulatory haplotypes at 17q12-q21 encompassing rs2290400 probably determine the risk of autoimmune Type 1 diabetes predominantly in early childhood.

Photoinduced metal-to-insulator transition in a manganite thin film.

A persistent photoinduced metal-to-insulator transition has been confirmed in a manganite thin film, Pr_(0.55)(Ca_(0.75)Sr_(0.25))_(0.45)MnO3, near a multicritical point by monitoring with transport measurements and x-ray photoemission spectroscopy. Together with the previously reported reverse effect, the photoinduced insulator-to-metal transition, it is found that the relative stability of the metallic and insulating phases interchanges around 80 K in the middle of a very wide hysteresis loop, which is a manifestation of the large potential barrier due to the long-range elastic energy. It is shown that photons are much more effective in overcoming the barrier via the electronically excited intermediate states than via the heat mode.

Intrinsic colossal magnetoresistance effect in thin-film Pr0.5Sr0.5MnO3 through dimensionality switching.

A homogeneous colossal magnetoresistance (CMR) effect at low temperatures has been found in a thin-film perovskite manganite Pr0.5Sr0.5MnO3. The transition is driven not by the spin alignment as in usual CMR in bulk samples but by the localization-delocalization transition switched by the change in the effective dimensionality. Two-dimensional (x2-y2)-orbital ordering enhanced by the substrate strain is essential for the stabilization of the insulating localized state, which is on the verge of the first-order transition to the three-dimensional metallic ferromangetic state.

Persistent and reversible all-optical phase control in a manganite thin film.

Persistent and reversible optical phase control has been achieved in a manganite thin film through a careful choice of the composition of Pr1-x(Ca1-ySr(y))xMnO3 near a multicritical point. Pulsed laser light brings the lower temperature metallic phase out of the higher temperature charge-ordered insulator, while a cw light reverses the effect by heating. We clearly demonstrate the two competing roles played by light, heating, and excitation across the charge gap, which are important in both the application and the understanding of the physics of electron correlation.

Accumulation of plasma cells expressing CXCR3 in the synovial sublining regions of early rheumatoid arthritis in association with production of Mig/CXCL9 by synovial fibroblasts.

Accumulation of plasma cells in the synovium is one of the diagnostic hallmarks in the histopathological manifestations of rheumatoid arthritis (RA). This seems to be prominent even prior to significant B cell infiltration and/or formation of lymphoid follicles in the synovium. To clarify the mechanism of early plasma cell accumulation, we examined in situ expression of chemokines and their receptors using synovial targeting biopsy specimens, which were obtained under arthroscopy from early RA patients. By immunohistochemical staining, plasma cells were found to express a chemokine receptor CXCR3, while synovial fibroblasts in the synovial sublining regions expressed its ligand, Mig/CXCL9. By reverse transcription-polymerase chain reaction (RT-PCR), using targeted lesions of synovial tissues obtained by laser capture microdissection, expression levels of Mig/CXCL9 in the synovial sublining regions were remarkably high and were likely to be associated with interferon (IFN)-gamma expression. Furthermore, cultured synovial fibroblasts were confirmed to produce Mig/CXCL9 upon stimulation with IFN-gamma. Our results indicate that in the early stage of RA, plasma cells expressing CXCR3 may be recruited directly from the circulation into the synovial sublining regions by its ligand, Mig/CXCL9, produced by synovial fibroblasts.

Changes in Helicobacter pylori status in patients with rheumatoid arthritis under non-steroidal anti-inflammatory drugs.

BACKGROUND: The role of Helicobacter pylori infection in rheumatoid arthritis (RA) patients during treatment with non-steroidal anti-inflammatory drugs (NSAID) is still unclear. METHODS: By means of endoscopy and biopsy, gastroduodenal lesions and H. pylori status were repeatedly examined in 88 RA patients at intervals ranging from 26 to 49 months. Histology and culture were applied to determine H. pylori status. Serial changes in gastroduodenal lesions and histologic score for mucosal atrophy were compared among groups classified by initial and second H. pylori status. RESULTS: There were 28 patients with continuously positive H. pylori infection (CP group), 33 patients with continuously negative H. pylori infection (CN group), 7 patients in whom H. pylori status became negative (PN group), and 20 patients in whom H. pylori status could not be determined (UD group). Age, duration and species of NSAID, disease activity of RA, gastroprotective drugs applied and the prevalence of gastroduodenal mucosal lesions were not different among the groups at either the initial or the second examination. In the PN group, the score for mucosal atrophy at the second examination was significantly lower than at the initial examination, whereas no difference was found for the CP, CN and UD groups. Overall, histologic score for mucosal atrophy was higher in H. pylori-positive patients than in H. pylori-negative patients at both initial and second examination. CONCLUSIONS: In RA patients using NSAIDs, H. pylori infection may not affect the course of gastroduodenal lesions and activity of RA, but the infection contributes to mucosal atrophy.

IgG and IgA antibody titers against human heat-shock protein (hsp60) in sera of rheumatoid arthritis and osteoarthritis patients.

Abstract To learn whether heat-shock proteins (HSP) are involved in the pathogenesis of rheumatoid arthritis (RA), antirecombinant human heat-shock protein 60 (hsp60) IgG and IgA in sera of RA and osteoarthritis (OA) patients were investigated. Only the anti-hsp60 IgG titer of seropositive (RF-positive) patients was found to be elevated. Although RF titers of the sera of seropositive RA patients were increased, there was no correlation between the individual anti-hsp60 IgG titer and the corresponding RF titer. In contrast, all the anti-hsp60 IgA titers of the sera of OA, seronegative RA, and seropositive RA patients were found to be elevated. Among them, only the serum IgA concentration of seropositive RA patients was increased. Thus, it was suggested that the increased anti-hsp60 IgG reflects the pathogenesis of RA and its activity. It was also suggested that the increased anti-hsp60 IgA response reflects an involvement of hsp60 in the pathogenesis of arthritides rather than the pathogenesis of RA.

Mode of inheritance of HLA-DRB1 shared epitope in Japanese familial rheumatoid arthritis.

OBJECTIVE: To clarify the mode of genetic contribution of the HLA-DR shared epitope (SE) to the pathogenesis of familial cases of Japanese rheumatoid arthritis (RA). METHODS: Fifty-three unrelated Japanese RA families that had more than 2 affected sibs were selected. The HLA-DR shared epitope typing was carried out by the PCR method and PCR-SSCP (single stranded DNA conformation polymorphism) method. Affected sib pair analysis was carried out using the MAPMAKER/SIB 2.0 program. The mode of inheritance was also calculated based on the sharing of genes identical by descent (IBD) between siblings in each of the 53 affected sib-pairs (propositus and the 2nd affected sib). RESULTS: The maximum LOD score of HLA-DR was 0.437, and the sharing of 2 IBDs, 1 IBD, and no IBDs between affected sibs were 0.330, 0.500, and 0.170, respectively. The sharing distribution of IBD was confirmed to be compatible with the dominant or additive mode since the observed gene frequency of SE was 0.255. CONCLUSION: The HLA-DR shared epitope participated in the pathogenesis of familial cases of Japanese RA. The SE contributes to this pathogenesis in either the dominant or additive mode of inheritance.

Helicobacter pylori infection in rheumatoid arthritis: effect of drugs on prevalence and correlation with gastroduodenal lesions.

OBJECTIVE: The aim of this study was to investigate the impact of Helicobacter pylori infection on clinical features in patients with rheumatoid arthritis (RA) under medication with non-steroidal anti-inflammatory drugs. METHODS: One hundred and eighty-four patients with RA were tested for the presence of H. pylori infection. Clinical features and gastroduodenal lesions were compared between H. pylori-positive and -negative patients. RESULTS: One hundred and thirteen patients were positive and 71 patients were negative for H. pylori. The age, severity of RA, prevalence of gastrointestinal symptoms and gastroduodenal lesions and the class of gastroprotective drugs were not different between the two groups. Reflux oesophagitis was less frequent and sulphasalazine was less frequently administered in the H. pylori-positive group. CONCLUSIONS: The severity of RA, prevalence of gastroduodenal lesions other than reflux oesophagitis and the application of gastroprotective drugs do not seem to depend upon H. pylori infection in RA patients. Sulphasalazine may be protective against H. pylori infection.

Histopathological characteristics of early rheumatoid arthritis: a case one month after clinical onset.

Abstract A 68-year-old woman with early rheumatoid arthritis (RA) was admitted to the hospital because of tender and swollen knee joints. We performed a targeted synovial biopsy under arthroscopy to examine the histopathological characteristics 1 month after clinical onset. The synovia showed the typical histopathology of RA. Although the inflammatory changes were predominantly limited to the surface area of the synovia, associated with neovascularization and cell infiltrates composed mainly of T cells, plasma cells, and macrophages, lesions with fibrin deposition, mesenchymoid transformation and/or immature lymphoid follicles were also observed in part, indicating that this case was in the progression phase of RA. What we regularly call "early" might be "too late" even if it is within 1 month of clinical onset.

In vitro IgG rheumatoid factor production by CD5-negative murine B cells in response to immune complexes of lipopolysaccharide.

We studied the in vitro production of rheumatoid factor (RF) by spleen cells of normal adult mice. IgG RF cross-reactive with rabbit IgG was produced in response to immune complexes of TNP-lipopolysaccharide (LPS) with murine IgG anti-TNP antibody in an Fc-specific manner, but not to a mixture of IgG and LPS. Antibody-uncomplexed LPS induced little IgG RF production, but suppressed the subsequent IgG RF response to antibody-complexed LPS, whereas IgM RF was induced by either LPS or antibody-complexed LPS. The IgG RF production followed as rapid a time course as IgM RF production; the rate of IgG RF production reached its maximum soon after a lag period of 1 day and declined after 5 days. Treatment of splenic B cells from BALB/c mice with anti-Ly-1.2 antibody and rabbit complement resulted in a selective reduction of IgM RF production by 90%, with little effect of IgG RF production. These results suggest that IgG RF is derived primarily from CD5- memory B cells which have been developed in normal mice by an unknown mechanism. Unlike the CD5+ precursor cells for IgM RF, these memory cells are unresponsive to polyclonal stimulation by LPS but are activated by simultaneous stimulation by aggregated Fc epitopes and the mitogenic stimulus from LPS.

IgG isotype and isotype specificity of murine monoclonal IgG rheumatoid factors.

Immune complexes of lipopolysaccharide (LPS) with homologous IgG antibody induces rheumatoid factor (RF) predominantly of the IgG class in normal mice, while LPS alone induces mostly IgM RF directed to homologous IgG1. In this study, IgG monoclonal RFs (mRF) were prepared from hybridomas derived from spleen cells of BALB/c mice which were immunized with complexes of TNP-LPS with anti-TNP mouse IgG and their specificity to mouse IgG subclasses was assessed by analysing dissociation kinetics of the ligands due to RF-specific and non-specific interactions. Of the 19 IgG mRFs (11 IgG1, five IgG2a, one IgG2b and two IgG3 types) tested, 14 were directed to either IgG3 or IgG2b or both, while only one exhibited a significant binding capacity to IgG1. Other mRFs, although reactive to rabbit IgG, exhibited little homophilic activity. None of these mRFs reacted strongly with their own isotypes. The results suggest that the IgG RF producing cells are not direct progenies of the IgG1-directed IgM RF-producing cells but may have developed via a rigorous selection process to eliminate clones that produce self-reactive RF.

Comparison between arthroscopic and open synovectomy for the knee in rheumatoid arthritis.

Ten surgical anterior capsulosynovectomies following Mori's four-block capsular incision technique in nine rheumatoid patients and 14 arthroscopic synovectomies utilizing a Wolf arthroscope with a large pituitary rongeur or a motorized intra-articular shaver in 11 patients were performed in our department. In three patients with bilateral involvement at nearly the same stage (III), we operated on the knees simultaneously, using open capsulosynovectomy on one side and arthroscopic synovectomy on the other side; we comparatively assessed the postoperative course, the subjective evaluation of the patients, and the follow-up results. Surgical intervention is milder in the arthroscopic operation, and postoperative knee pain during motion exercise is markedly less in the arthroscopically synovectomized knee. Although the postoperative management was more complex for open capsulosynovectomized knees, the results obtained at 1-2 months after synovectomy showed no significant difference between the two procedures.