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Biomedical subjects

Shinichi Sato

Publications and source records attributed to Shinichi Sato.

At least 91 records · Page 5Linked to original sources
PubMed2004

B Lymphocyte signaling established by the CD19/CD22 loop regulates autoimmunity in the tight-skin mouse.

Systemic sclerosis (SSc) is characterized by fibrosis and autoimmmunity. Peripheral blood B cells from SSc patients specifically overexpress CD19, a critical cell-surface signal transduction molecule in B cells. CD19 deficiency in B cells also attenuates skin fibrosis in the tight-skin (TSK/+) mouse, a genetic model for SSc. Herein we analyzed two transgenic mouse lines that overexpress CD19. Remarkably, 20% increase of CD19 expression in mice spontaneously induced SSc-specific anti-DNA topoisomerase I (topo I) antibody (Ab) production, which was further augmented by 200% overexpression. In TSK/+ mice overexpressing CD19, skin thickness did not increase, although anti-topo I Ab levels were significantly augmented, indicating that abnormal CD19 signaling influences autoimmunity in TSK/+ mice and also that anti-topo I Ab does not have a pathogenic role. The molecular mechanisms for abnormal CD19 signaling were further assessed. B-cell antigen receptor crosslinking induced exaggerated calcium responses and augmented activation of extracellular signal-regulated kinase in TSK/+ B cells. CD22 function was specifically impaired in TSK/+ B cells. Consistently, CD19, a major target of CD22-negative regulation, was hyperphosphorylated in TSK/+ B cells. These findings indicate that reduced inhibitory signal provided by CD22 results in abnormal activation of signaling pathways including CD19 in TSK/+ mice and also suggest that this disrupted B cell signaling contribute to specific autoantibody production.

Animals↗
PubMed2004

The diagnostic value of oesophageal transit scintigraphy for evaluating the severity of oesophageal complications in systemic sclerosis.

BACKGROUND: Oesophageal complications are common in systemic sclerosis (SSc). However, the ability to determine the severity of oesophageal complications according to SSc type and skin lesion has not been evaluated. METHODS: The study groups consisted of 35 patients with SSc who were classified into diffuse (n=20) and limited (n=15) cutaneous types, and 16 control subjects. An additional 26 consecutive patients were studied for an analysis of the reproducibility. The severity of a skin lesion was quantified by using a modification of Rodnan's total skin thickness scores. Oesophageal scans were performed after the subjects, in sitting and supine positions, had consumed potage soup. Condensed images of the dynamic study were classified into four patterns: normal, transient retention, slight retention and severe retention, in conjunction with parameters of retention fraction by analysing the time-activity curve. RESULTS: The highest reproducibility was obtained using retention at 90 s (R90, r=0.93). Analysis of the condensed images showed that the SSc patients had a higher incidence of severe retention than did the control subjects. Groups with diffuse-type SSc or a high skin thickness score showed a higher incidence of severe retention (P=0.041 and 0.0048, respectively) compared with the control and less severe groups. The R90 in the supine position differed significantly among the controls, the limited-type and diffuse-type SSc groups (mean+/-SEM, 10+/-1%, 24+/-5%, 38+/-6%, respectively; P=0.0004)). The group with high skin scores (i.e. > or =10) showed a higher R90 (41+/-6%) than did either the group with low skin scores (R90=23+/-5%) or the control group (P=0.0001). CONCLUSION: An oesophageal scan can detect both slight and severe types of oesophageal dysfunction, and can be used as a quantitative method that reflects functional abnormality in SSc.

Adult↗
PubMed2004

Novel autoantibody to Cu/Zn superoxide dismutase in patients with localized scleroderma.

Abnormal production of reactive oxygen species (ROS) induces tissue damage and superoxide dismutase (SOD) that converts superoxide radicals to hydrogen peroxide functions as defense against ROS. Cu/Zn SOD administration has been shown to be effective for various fibrotic conditions by inhibiting the fibrogenic effects of ROS. We hypothesized that autoimmune background in localized scleroderma induced anti-Cu/Zn SOD autoantibodies that inhibited SOD activity and thereby contributed to fibrosis by increasing ROS. ELISA using human purified Cu/Zn SOD revealed that IgG or IgM anti-Cu/Zn SOD Ab was detected in the serum of 89% of localized scleroderma patients, especially 100% of patients with generalized morphea, the severest form of localized scleroderma, but was positive only in the serum of less than 15% of patients with other autoimmune disorders, including systemic sclerosis, systemic lupus erythematosus, dermatomyositis, and autoimmune bullous disorders. The immunoblotting analysis confirmed the presence of IgG anti-Cu/Zn SOD Ab in sera from localized scleroderma patients. Remarkably, anti-Cu/Zn SOD autoantibody could inhibit Cu/Zn SOD enzymatic activity. Collectively, these results indicate that anti-Cu/Zn SOD Ab is a novel, major autoantibody in localized scleroderma, and also suggest that the autoantibody may play a role in the development of fibrosis by directly inhibiting SOD activity.

Adult↗
PubMed2004

[Pharmacoeconomic analysis of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor therapy for the secondary prevention of coronary heart disease].

OBJECTIVE: The pharmacoeconomics of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (pravastatin) therapy were evaluated using data from an open-labeled, randomized, controlled trial (PCS: Prevention of Coronary Sclerosis study) with a two-year follow-up period. METHODS: Patients with a serum total cholesterol concentration of between 180 and 219 mg/dL at baseline were randomly assigned to two groups: the pravastatin group (n=54) and the group that did not receive cholesterol-lowering drugs (no-pravastatin group, n=66). A cost-minimization analysis and a cost-effectiveness analysis were then performed from the perspective of a health insurance company, using insurance information obtained from the subjects. In the cost-minimization analysis, the expected costs associated with percutaneous transluminal coronary angioplasty (PTCA) and the pravastatin prescription were compared; the total medication costs between the two groups were also compared. In the cost-effectiveness analysis, the estimated savings per event-free year were calculated. RESULTS: The median cost of a PTCA procedure was 1,323,492 yen. The expected insurance cost for two years was 182,532 yen per patient in the pravastatin group and 224,444 yen per patient in the no-pravastatin group. The cost-minimization analysis showed that the cost of healthcare for the no-pravastatin group was higher than that for the pravastatin group. The mean total cost of medication was 729,849 yen per patient in the pravastatin group and 989,606 yen per patient in the no-pravastatin group. The cost-effectiveness ratio for coronary heart disease was 2,766,994 yen. CONCLUSION: Pravastatin therapy in normocholesterolemic patients with coronary sclerosis seems to have an excellent pharmacoeconomic profile.

Adult↗
PubMed2004

Relationship between sleep-disordered breathing and blood pressure levels in community-based samples of Japanese men.

To examine the relationship between sleep-disordered breathing (SDB) and blood pressure levels among Japanese men, we conducted a population-based cross-sectional study of 1,424 men aged 40-69 years in rural and urban communities. The 3% oxygen desaturation index (ODI) was selected as the indicator of SDB, representing the number of desaturation events per hour of recording time in which blood oxygen fell by > or = 3% according to overnight pulse oximetry. To estimate the associations of 3% ODI levels with blood pressure levels and hypertension, multiple linear regression and logistic regression analyses were performed. The 3% ODI level was positively associated with systolic and diastolic blood pressure levels (SBP/DBP); a 5 event per hour increment of the 3% ODI level was associated with 0.8 mmHg (95% confidence interval [CI], 0.0-1.6) greater SBP and 0.7 mmHg (95% CI, 0.3-1.1) greater DBP after adjustment for age, body mass index, ethanol intake, smoking category and community. The multivariate odds ratio of hypertension for the low vs. high category of 3% ODI level was 1.63 (95% CI, 1.1-2.5). These associations were more evident among overweight than non-overweight individuals. The significant association of nocturnal oxygen desaturation with high blood pressure levels suggests that SDB plays a role in the development of hypertension among Japanese men.

Adult↗
PubMed2004

[A case of amyopathic dermatomyositis with acute interstitial pneumonia (DAD pattern)].

A 61-year-old man was admitted to our hospital because of edematous erythema on his upper eyelids and dry cough. No subjective nor objective findings suggestive of skeletal muscle involvement, such as muscle weakness and elevated levels of aldolase and creatine phosphokinase were noted. Chest high-resolution computed tomography revealed a ground glass opacity and consolidation of his lower lung. Skin biopsy findings were compatible with dermatomyositis. Therefore, he was diagnosed as amyopathic dermatomyositis (ADM) with acute interstitial pneumonia and treatment with steroid pulse therapy was started. Since histological evaluation showed diffuse alveolar damage during the initial treatment, the treatment was changed into the combination therapy of prednisolone and cyclosporine. However, his acute interstitial pneumonia did not respond to this treatment and passed away by aggravation of a breathing state and concurrence of disseminated intravascular coagulation. Japanese patients with ADM have been shown to be more frequently associated with intractable acute interstitial pneumonia than Caucasian patients, suggesting that the racial difference influences the occurrence of acute interstitial pneumonia in ADM. Since autoantibodies specific for ADM have not been detected, we performed immunoprecipitation analysis using 35S methionine-labeled K562 cells to identify them. His sera immunoprecipitated a polypeptide of 140 kDa. The 140 kDa polypeptide might be one of autoantibodies specific for ADM with acute interstitial pneumonia, although future analysis using a larger number of patients with ADM will be required to confirm this result.

Dermatomyositis↗
PubMed2004

Elevated circulating CD40L concentrations in patients with systemic sclerosis.

OBJECTIVE: B cell activation, fibrosis, and expression of adhesion molecules on endothelial cells are regulated by soluble CD40L (sCD40L)/CD40 interactions. Since these effects are characteristic in patients with systemic sclerosis (SSc), serum concentrations of sCD40L were determined in patients with SSc. METHODS: Fifty-two Japanese patients with SSc were examined. They were grouped into 24 patients with limited cutaneous SSc (lSSc) and 28 with diffuse cutaneous SSc (dSSc). Serum sCD40L levels were examined by ELISA. As a disease control, serum samples from 20 patients with systemic lupus erythematosus (SLE) were also examined. In addition, a retrospective longitudinal study was performed in 71 serum samples from 18 patients with SSc. RESULTS: Serum sCD40L levels were elevated in SSc patients compared with healthy controls (p < 0.001). Levels of sCD40L in patients with SSc were higher than in patients with SLE (p < 0.001) that had elevated sCD40L levels compared with healthy controls. Among SSc subsets, there were no differences in sCD40L levels between lSSc and dSSc. sCD40L levels correlated positively with C-reactive protein levels in SSc patients (p < 0.0001, r = 0.449). In a cross-sectional study and a longitudinal study, serum sCD40L levels in dSSc patients were persistently elevated, although those in lSSc patients were temporarily elevated at the early phase of the disease process. CONCLUSION: Patients with SSc exhibited elevated sCD40L levels that may correlate with disease activity. These results suggest that CD40/CD40L interactions may be potential therapeutic targets in SSc.

Adolescent↗
PubMed2004

[Trends for stroke incidence, severity, and prognosis in a rural community with a long-term stroke prevention program].

OBJECTIVE: To examine the benefit of a long-term community-based stroke prevention program, we explored 35 years of surveillance data of stroke incidence for residents in a rural area in Japan. METHOD: The surveyed community was Ikawa town (population in 2000 was 6,116) in Akita prefecture, where a community-based stroke prevention program has been conducted since 1963. Incidence rates and numbers of stroke episodes, proportions for loss of consciousness and motor paralysis at onset, proportions for each seriousness category (A: death within one day after onset, B: death during 2-7 days after onset, C: survival more than 8 days after onset with complete hemiparesis, D: survival more than 8 days after onset with incomplete or no hemiparesis), and one-year survival rates and activity of daily living were investigated for 1964-69, 1970-79, 1980-89 and 1990-98. RESULTS: Stroke incidence declined 66% and 64% among the 30-69 years age group and 70 years over age group, respectively between 1964-69 and 1990-98. Incident numbers of stroke episodes declined 41% among those aged 30-69 years and, while it increased 100% in the 70 years over age group, this was much less than the increase rate of 271% rated for the corresponding aged population growth over time. In the 30-69 years age group, the proportion of patients with no loss of consciousness at onset increased from 53-64% during the former three periods to 79% in 1990-98. The proportion of patients with no motor paralysis also increased progressively over the study periods and the proportions for A or B categories in the seriousness classification decreased between 1964-69 and 1990-98 while the proportion in the D category increased between 1980-89 and 1990-98. One-year survival rates increased from 71% and 36% in 1964 to 86% and 61% in 1990-98 among the 30-69 years age group and 70 years over age group, respectively. With both, the numbers of totally dependent patients at one-year after onset, did not change significantly over time, despite the marked increase in the population of risk. CONCLUSION: The present study showed that a long-term community-based stroke prevention program can not only decrease stroke incidence and number of episodes, but also reduce the likelihood of severe stroke attack and improve prognosis, thereby suppressing the increase of totally dependent patients expected from growth of the old population in the community.

Adult↗
PubMed2004

Comparative study of serum surfactant protein-D and KL-6 concentrations in patients with systemic sclerosis as markers for monitoring the activity of pulmonary fibrosis.

OBJECTIVE: To clarify the clinical significance of surfactant protein-D (SP-D) and KL-6 in the diagnosis and monitoring of pulmonary fibrosis (PF) in patients with systemic sclerosis (SSc), and to evaluate the differences between SP-D and KL-6. METHODS: Serum SP-D and KL-6 concentrations were determined by ELISA in 42 SSc patients. In a retrospective longitudinal study, 83 serum samples from 6 SSc patients were analyzed during a followup period of 0.6-6.3 years. RESULTS: SP-D and KL-6 concentrations at the first visit were higher in patients with SSc, especially those with PF, compared with healthy controls. Increased concentrations of SP-D were associated with decreased DLCO and decreased vital capacity in SSc patients more strongly than those of KL-6. The sensitivity and specificity for PF were 91% and 88% for SP-D and 39% and 100% for KL-6, respectively. In the longitudinal study, both SP-D and KL-6 concentrations were associated with activity of PF in patients with SSc. SP-D concentrations changed more rapidly than KL-6 concentrations, in parallel with the PF activity. CONCLUSION: SP-D was a more sensitive marker for PF than KL-6. By contrast, KL-6 showed higher specificity than SP-D. Combined use of these 2 serum markers would be more helpful to diagnose and monitor the PF activity in patients with SSc than single use of each marker.

Adult↗
PubMed2004

[Comparative studies on activities of antimicrobial agents against causative organisms isolated from patients with urinary tract infections (2002). I. Susceptibility distribution].

The bacterial strains isolated from 491 patients diagnosed as having urinary tract infections (UTIs) in 13 institutions in Japan were supplied between August 2002 and July 2003. The susceptibilities of them to many kinds of antimicrobial agents were investigated. Of them, 578 strains were estimated as causative bacteria and used for the investigation. The number of them was 578 strains consisting of 177 gram-positive bacterial strains (30.6%) and 401 gram-negative bacterial strains (69.4%). Against Staphylococcus aureus, vancomycin (VCM) showed a strong activity and prevented the growth of all strains with 1 microg/mL. The susceptibility of Staphylococcus epidermidis to cephems including cefotiam (CTM) was relatively good. Against Enterococcus faecalis, ampicillin (ABPC), imipenem (IPM), and VCM showed the strongest antibacterial activity (MIC90: 2-4 microg/mL). In addition, the low sensitive strains (MIC: > or = 256 microg/mL) to clarithromycin (CAM) were detected at 48.3% but none to cefozopran (CZOP). The antibacterial activity of cephems to Escherichia coli was generally good, and especially CZOP and cefpirome (CPR) showed the highest activity (MIC90: < or = 0.125 microg/mL). Quinolone resistant E. coli was detected at frequency of 13.5%, which was higher than that in the last year. The antibacterial activity of cephems to Citrobacter freundii was generally low but CZOP and CPR had a strong acitivity (MIC90: 0.25 and 0.5 microg/mL, respectively). The antibacterial activity of cephems to Klebsiella pneumoniae was good and especially cefmenoxime (CMX), cefixime (CFIX), flomoxef (FMOX), CPR, and CZOP showed stronger activity (MIC90: < or = 0.125 microg/mL). Against Serratia marcescens, meropenem (MEPM) had the highest antibacterial activity followed by CPR and CZOP. Against Proteus mirabilis, CMX, ceftazidime (CAZ), CPR, MEPM, carumonam (CRMN), and levofloxacin (LVFX) showed the strongest activity (MC90: < or = 0.125 microg/mL). Among other cephems, CZOP and CFIX were also strong (MIC90: 0.25 microg/mL). The antibacterial activity of the drugs to Pseudomonas aeruginosa was generally low, and MIC90 of all the drugs were ranged from 64 to > or = 256 microg/mL except IPM and amikacin (AMK) having 16 microg/mL. The antibacterial activity of CZOP was relatively good (MIC50: 8 microg/mL).

Anti-Bacterial Agents↗
PubMed2004

[Comparative studies on activities of antimicrobial agents against causative organisms isolated from patients with urinary tract infections (2002). II. Background of patients].

A total of 615 bacterial strains isolated from 491 patients diagnosed as having urinary tract infections (UTIs) in 13 institutions in Japan were supplied between August 2002 and July 2003. Then, the clinical background of patients were investigated such as sex, age, and type of infections and kind of bacteria, frequency of bacteria isolation by age and infections, bacteria and infections by timing of antibiotics administration, and bacteria and infections by surgical procedures. The bacterial strains were divided by the age and sex of the patients and the types of infections. In males, the number of patients aged less than 50 years was few and the complicated UTIs without indwelling catheter was observed most frequently. In the present time, the bacteria most frequently isolated were Escherichia coli. Pseudomonas aeruginosa and Enterococcus faecalis were also relatively frequently isolated. E. coli decreased and P. aeruginosa increased with the complication of the infections. E. faecalis tended to be isolated more frequently in the complicated UTIs than in the uncomplicated UTIs. With respect to the relation of these results to the age of the patients, in the uncomplicated UTIs, the isolation frequency of E. coli was the highest in all age groups, accounting for 70.8% in 20-49 years old. In the complicated UTIs without indwelling catheter, the isolation frequency of E. coli decreased with aging of the patients and was lower than that of E. faecalis in the patients aged 70 or more (18.3 vs 20.6%). In the complicated UTIs with indwelling catheter, the isolation frequency of E. coli was lower than in the uncomplicated UTIs in all age groups and P. aeruginosa and E. faecalis were more frequently isolated. In comparison of causative bacteria in UTIs between before and after the administration of antibiotics, E. coli decreased and P. aeruginosa increased after the administration in any UTIs. In comparison of causative bacteria in UTIs with or without surgery, E. coli was more frequently isolated in the patients without surgery, while P. aeruginosa was more in the patients with surgery in any UTIs. E. faecalis was more frequently isolated in the patients with surgery in uncomplicated and complicated UTIs without indwelling catheter and in the patients without surgery in complicated UTIs with indwelling catheter.

Age Factors↗
PubMed2004

[Comparative studies on activities of antimicrobial agents against causative organisms isolated from patients with urinary tract infections (2002). III. Secular changes in susceptibility].

The bacteria (Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Klebsiella spp. and Pseudomonas aeruginosa) isolated from patients diagnosed as urinary tract infections (UTIs) in 13 institutions in Japan were supplied between August 2002 and July 2003. The susceptibilities of these bacteria to various antimicrobial agents were examined. The bacteria were divided into 2 groups consisting of uncomplicated UTIs and complicated UTIs (with and without indwelling catheter) based on their isolation origins. The results were compared with those obtained between 1993 and 2001. The drug sensitivity of S. aureus in this year was similar to those in up to the previous year and S. aureus showed the best susceptibility to vancomycin. The drug sensitivity of E. faecalis in this year also was similar to those in up to the previous year. The drug sensitivity of E. coli in this year was generally good except penicillins and was similar to those in up to the previous year. Among cephems, cefozopran (CZOP) and cefpirome (CPR) showed the highest potency (MIC90: < or = 0.125 microg/mL). An antibacterial activity of cefotiam (CTM) was similar to it in 10 years ago and was fine (MIC90: < or = 1 microg/mL). The sensitivity of E. coli to carbapenems and carumonam (CRMN) also was good like to CZOP. However, the sensitivity of the complicated UTIs group to quinolones decreased after 2000 and was suggested to develop the resistance to the drug. The drug sensitivity of Klebsiella spp. in this year also was similar to those in up to the previous year. The bacteria showed good susceptibility (MIC: < or = 0.125 microg/mL) to cefmenoxime (CMX), CPR, cefixime (CFIX), flomoxef (FMOX), and CZOP among cephems. The drug sensitivity of P. aeruginosa was generally low. Most of the bacteria were little sensitive to cephems except CZOP and ceftazidime (CAZ). The sensitive bacteria to CZOP and ceftazidime (CAZ) were observed to be 26.8% (15/56 strains) and 39.3% (22/56 strains) in complicated UTIs group, respectively. The sensitivity profile of P. aeruginosa to the other tested drugs was not much different from that in up to the previous year. However, the sensitivity of the bacteria to carbapenems tended to decrease after 2000, and the low sensitive strains (MIC: > or = 256 microg/mL) were detected at 22.2% (2/9 strains) in the uncomplicated UTIs group and 3.6% (2/56 strains) in the complicated UTIs group.

Anti-Bacterial Agents↗
PubMed2003

Prospective study of major and minor ST-T abnormalities and risk of stroke among Japanese.

BACKGROUND AND PURPOSE: The association between minor ST-T abnormalities and stroke incidence has not been well elucidated. We sought to examine the relationship between nonspecific minor or major ST-T abnormalities and the incidence of stroke among Japanese men and women. METHODS: A 15.4-year prospective study was conducted with 10 741 men and women aged 40 to 69 years in 4 Japanese communities. Electrocardiograms were taken at baseline and were read according to the Minnesota Code. The incidence of stroke was ascertained using systematic surveillance. RESULTS: During the 15.4-year follow-up, 602 strokes (339 ischemic strokes, 129 intracerebral hemorrhages, 80 subarachnoid hemorrhages, and 54 unclassified strokes) occurred. Both men and women with major ST-T abnormalities had approximately 3-fold higher age-adjusted relative risk and 2-fold higher multivariate-adjusted relative risk of total stroke than did those without such abnormalities. Men with minor ST-T abnormalities had a 2.3-fold higher age-adjusted relative risk of total stroke, both ischemic and hemorrhagic, than did those without such abnormalities. After we adjusted further for hypertension category, the relative risk for minor ST-T abnormalities was reduced substantially but remained statistically significant: 1.8 (95% CI, 1.3 to 2.4) for total stroke, 1.9 (95%CI, 1.3 to 2.8) for ischemic stroke, and 1.7 (95% CI, 1.0 to 3.0) for hemorrhagic stroke. For women, however, there was no relation between minor ST-T abnormalities and stroke incidence. CONCLUSIONS: Minor ST-T abnormalities have predictive value for the risk of total stroke, both ischemic and hemorrhagic, among middle-aged Japanese men, as do major ST-T abnormalities for both sexes.

Adult↗
PubMed2003

Cerebroside sulfotransferase deficiency ameliorates L-selectin-dependent monocyte infiltration in the kidney after ureteral obstruction.

Mononuclear cells infiltrating the interstitium are involved in renal tubulointerstitial injury. The unilateral ureteral obstruction (UUO) is an established experimental model of renal interstitial inflammation. In our previous study, we postulated that L-selectin on monocytes is involved in their infiltration into the interstitium by UUO and that a sulfated glycolipid, sulfatide, is the physiological L-selectin ligand in the kidney. Here we tested the above hypothesis using sulfatide- and L-selectin-deficient mice. Sulfatide-deficient mice were generated by gene targeting of the cerebroside sulfotransferase (Cst) gene. Although the L-selectin-IgG chimera protein specifically bound to sulfatide fraction in acidic lipids from wild-type kidney, it did not show such binding in fractions of Cst(-/-) mice kidney, indicating that sulfatide is the major L-selectin-binding glycolipid in the kidney. The distribution of L-selectin ligand in wild-type mice changed after UUO; sulfatide was relocated from the distal tubules to the peritubular capillaries where monocytes infiltrate, suggesting that sulfatide relocated to the endothelium after UUO interacted with L-selectin on monocytes. In contrast, L-selectin ligand was not detected in Cst(-/-) mice irrespective of UUO treatment. Compared with wild-type mice, Cst(-/-) mice showed a considerable reduction in the number of monocytes/macrophages that infiltrated the interstitium after UUO. The number of monocytes/macrophages was also reduced to a similar extent in L-selectin(-/-) mice. Our results suggest that sulfatide is a major L-selectin-binding molecule in the kidney and that the interaction between L-selectin and sulfatide plays a critical role in monocyte infiltration into the kidney interstitium.

Animals↗
PubMed2003

Ultraviolet light exposure suppresses contact hypersensitivity by abrogating endothelial intercellular adhesion molecule-1 up-regulation at the elicitation site.

Hapten sensitization through UV-exposed skin induces systemic immune suppression, which is experimentally demonstrated by inhibition of contact hypersensitivity (CHS). Although this UV-induced effect has been shown to be mediated by inhibition of the afferent phase of the CHS, the UV effects on the efferent (elicitation) phase remain unknown. In this study, UV effects on endothelial ICAM-1 expression at elicitation sites were first examined. Mice were sensitized by hapten application onto UV-exposed back skin, and ears were challenged 5 days later. ICAM-1 up-regulation at nonirradiated elicitation sites following hapten challenge was eliminated by UV exposure on sensitization sites distant from elicitation sites. To assess whether loss of the ICAM-1 up-regulation at elicitation sites contributed to UV-induced immunosuppression, we examined CHS responses in UV-exposed ICAM-1-deficient (ICAM-1(-/-)) mice that genetically lacked the ICAM-1 up-regulation. ICAM-1(-/-) mice exhibited reduced CHS responses without UV exposure, but UV exposure did not further reduce CHS responses in ICAM-1(-/-) mice. Furthermore, ICAM-1 deficiency did not affect the afferent limb, because ICAM-1(-/-) mice had normal generation of hapten-specific suppressor and effector T cells. This UV-induced immunosuppression was associated with a lack of TNF-alpha production after Ag challenge at elicitation sites. Local TNF-alpha injection before elicitation abrogated the UV-induced CHS inhibition with increased endothelial ICAM-1 expression. TNF-alpha production at elicitation sites was down-regulated by IL-10, a possible mediator produced by hapten-specific suppressor T cells that are generated by UV exposure. These results indicate that UV exposure inhibits CHS by abrogating up-regulation of endothelial ICAM-1 expression after Ag challenge at elicitation sites.

Animals↗
PubMed2003

CD19 regulates innate immunity by the toll-like receptor RP105 signaling in B lymphocytes.

Lipopolysaccharide (LPS) is a major gram-negative bacterial component that stimulates innate immune response and also induces B-lymphocyte activation. Recent studies have revealed that common molecular patterns of microorganisms such as LPS are recognized by toll-like receptors (TLRs). B cells have 2 known TLRs that mediate LPS signaling, TLR4 and RP105 (CD180). While TLR4 is expressed on immune cells of various types, RP105 is preferentially expressed on mature B cells. Here we demonstrate that CD19 plays a major role in regulating signal transduction through RP105. Anti-RP105 ligation induced normal proliferation of B cells from mice deficient for MyD88, an adaptor protein that mediates most TLR pathways. By contrast, the loss of CD19 resulted in modest B-cell proliferation against anti-RP105 stimulation as well as LPS stimulation. LPS induced tyrosine phosphorylation of CD19, which was RP105-dependent but TLR4-independent. CD19 formed a complex with Lyn and Vav following RP105 ligation, and CD19 expression was required for optimal Lyn activation and Vav phosphorylation. Consistently, B cells deficient for CD19 exhibited specific defect in the activation of c-Jun N-terminal kinases following RP105 ligation and LPS stimulation. In contrast, CD19 and phosphatidylinositol 3-kinase independently regulated intracellular calcium mobilization induced by anti-RP105 stimulation. Thus, signaling through the B-cell-specific LPS receptor RP105 is uniquely regulated by the B-cell-specific signaling component, Lyn/CD19/Vav complex.

Animals↗
PubMed2003

L-selectin or ICAM-1 deficiency reduces an immediate-type hypersensitivity response by preventing mast cell recruitment in repeated elicitation of contact hypersensitivity.

Repeated Ag exposure results in a shift in the time course of contact hypersensitivity (CH) from a typical delayed-type to an immediate-type response followed by a late phase reaction. Chronic CH responses are clinically relevant to human skin allergic diseases, such as atopic dermatitis, that are usually caused by repeated stimulation with environmental Ags. Chronic inflammatory responses result in part from infiltrating leukocytes. To determine the role of leukocyte adhesion molecules in chronic inflammation, chronic CH responses were assessed in mice lacking L-selectin, ICAM-1, or both adhesion molecules. Following repeated hapten sensitization for 24 days at 2-day intervals, wild-type littermates developed an immediate-type response at 30 min after elicitation, followed by a late phase reaction. By contrast, loss of ICAM-1, L-selectin, or both, eliminated the immediate-type response and inhibited the late phase reaction. Similar results were obtained when wild-type littermates repeatedly exposed to hapten for 22 days were treated with mAbs to L-selectin and/or ICAM-1 before the elicitation on day 24. The lack of an immediate-type response on day 24 paralleled a lack of mast cell accumulation after 30 min of elicitation and decreased serum IgE production. Repeated Ag exposure in wild-type littermates resulted in increased levels of serum L-selectin, a finding also observed in atopic dermatitis patients. The current study demonstrates that L-selectin and ICAM-1 cooperatively regulate the induction of the immediate-type response by mediating mast cell accumulation into inflammatory sites and suggests that L-selectin and ICAM-1 are potential therapeutic targets for regulating human allergic reactions.

Administration, Cutaneous↗