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Biomedical subjects

Eiji Matsuura

Publications and source records attributed to Eiji Matsuura.

At least 19 recordsLinked to original sources
PubMed2006

MRI studies of spinal visceral larva migrans syndrome.

We report serial MR findings in four patients with myelitis caused by visceral larva migrans syndrome due to Toxocara canis or Ascaris suum infection. MR imaging revealed spinal cord swelling with or without gadolinium enhancement in three patients. T2-weighted images showed high signal intensities preferentially located in both lateral and posterior columns. Antihelmintic and corticosteroid treatment yielded improvement in neurologic deficits and spinal lesions. However, one patient with T. canis infection relapsed associated with reappearance of MRI abnormalities.

Adrenal Cortex Hormones↗
PubMed2006

Oxidative modification of low-density lipoprotein and immune regulation of atherosclerosis.

Oxidized low-density lipoprotein (oxLDL) is thought to promote atherosclerosis through complex inflammatory and immunologic mechanisms that lead to lipid dysregulation and foam cell formation. Recent findings suggested that oxLDL forms complexes with beta2-glycoprotein I (beta2GPI) and/or C-reactive protein (CRP) in the intima of atherosclerotic lesions. Autoantibodies against oxLDL/beta2GPI complexes occur in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS) and significantly correlate with arterial thrombosis. IgG autoantibodies having similar specificity emerged spontaneously in non-immunized NZWxBXSB F1 mice, an animal model of APS, and a monoclonal autoantibody (WB-CAL-1; IgG2a) against complexed beta2GPI (oxLDL/beta2GPI complexes) was derived from the same mice. WB-CAL-1 significantly increased the in vitro uptake of oxLDL/beta(2)GPI complexes by macrophages. This observation strongly suggests that such IgG autoantibodies are pro-atherogenic. In contrast, IgM anti-oxLDL natural antibodies found in the atherosclerosis-prone mice (ApoE(-/-) and LDL-R(-/-) mice) have been proposed to be anti-atherogenic (protective). The presence of IgG anti-oxLDL antibodies in humans has been documented in many publications but their exact clinical significance remains unclear. In this article, we review recent progress in our understanding of the mechanisms involved in oxidation of LDL, formation of oxLDL complexes, and antibody mediated-immune regulation of atherogenesis.

Antibodies↗
PubMed2006

Accelerated atheroma in the antiphospholipid syndrome.

Increased cardiovascular morbidity and mortality due to the pre-mature or accelerated development of atherosclerosis has been reported in patients with systemic autoimmune diseases such as systemic lupus erythematosus. These findings motivated a great deal of research into the role of autoimmunity in atherogenesis. The relationship between atherosclerosis and cholesterol metabolism to atherosclerosis has been well established. However, the participation of newer inflammatory and immunologic mechanisms are emerging as relevant factors for the initiation and progression of atherosclerotic lesions.

Antibodies, Antiphospholipid↗
PubMed2005

Antigenic structures recognized by anti-beta2-glycoprotein I auto-antibodies.

Beta2-glycoprotein I (beta2-GPI) is a major antigen for anti-cardiolipin antibodies and their epitopes are cryptic. Conformation of each domain of beta2-GPI was optimized from its crystal structure by energy minimization and by molecular dynamics simulation. Three electrostatic interactions, i.e. D193-K246, D222-K317 and E228-K308, were observed between domains IV and V in the optimized structure that was constructed based on the consensus sequences obtained by the phage-displayed random peptide library. Antigenic structures determined by the epitope mapping mainly consisted of hydrophobic amino acids located on two discontinuous sequences in domain IV. These amino acid clusters, as an epitope, were covered by domain V and were of a hidden nature. A similar but incomplete counterpart to the epitopic clusters was found in domain I but was not in domains II or III. Binding of anti-beta2-GPI auto-antibodies to solid-phase beta2-GPI was significantly reduced either by L replacement for W235, a common amino acid component for the epitopes, or by V replacement for all of D193, D222 and E228. Structural analysis indicated a hypothesis that these electrostatic interactions between domains IV and V retained exposure to W235 and that epitope spreading occurred in the region surrounding W235. Thus, epitopic structures recognized by anti-beta2-GPI auto-antibodies are cryptic and inter-domain electrostatic interactions are involved in their in exposure.

Amino Acid Substitution↗
PubMed2005

Chemical xenobiotics and mitochondrial autoantigens in primary biliary cirrhosis: identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid.

Emerging evidence has suggested environmental factors as causative agents in the pathogenesis of primary biliary cirrhosis (PBC). We have hypothesized that in PBC the lipoyl domain of the immunodominant E2 component of pyruvate dehydrogenase (PDC-E2) is replaced by a chemical xenobiotic mimic, which is sufficient to break self-tolerance. To address this hypothesis, based upon our quantitative structure-activity relationship data, a total of 107 potential xenobiotic mimics were coupled to the lysine residue of the immunodominant 15 amino acid peptide of the PDC-E2 inner lipoyl domain and spotted on microarray slides. Sera from patients with PBC (n = 47), primary sclerosing cholangitis (n = 15), and healthy volunteers (n = 20) were assayed for Ig reactivity. PBC sera were subsequently absorbed with native lipoylated PDC-E2 peptide or a xenobiotically modified PDC-E2 peptide, and the remaining reactivity analyzed. Of the 107 xenobiotics, 33 had a significantly higher IgG reactivity against PBC sera compared with control sera. In addition, 9 of those 33 compounds were more reactive than the native lipoylated peptide. Following absorption, 8 of the 9 compounds demonstrated cross-reactivity with lipoic acid. One compound, 2-octynoic acid, was unique in both its quantitative structure-activity relationship analysis and reactivity. PBC patient sera demonstrated high Ig reactivity against 2-octynoic acid-PDC-E2 peptide. Not only does 2-octynoic acid have the potential to modify PDC-E2 in vivo but importantly it was/is widely used in the environment including perfumes, lipstick, and many common food flavorings.

Amino Acid Sequence↗
PubMed2005

Significance of valine/leucine247 polymorphism of beta2-glycoprotein I in antiphospholipid syndrome: increased reactivity of anti-beta2-glycoprotein I autoantibodies to the valine247 beta2-glycoprotein I variant.

OBJECTIVE: To clarify the consequences of the valine/leucine polymorphism at position 247 of the beta(2)-glycoprotein I (beta(2)GPI) gene in patients with antiphospholipid syndrome (APS), by investigating the correlation between genotypes and the presence of anti-beta(2)GPI antibody. The reactivity of anti-beta(2)GPI antibodies was characterized using recombinant Val(247) and Leu(247) beta(2)GPI. METHODS: Sixty-five Japanese patients with APS and/or systemic lupus erythematosus who were positive for antiphospholipid antibodies and 61 controls were analyzed for the presence of the Val/Leu(247) polymorphism of beta(2)GPI. Polymorphism assignment was determined by polymerase chain reaction followed by restriction enzyme digestion. Recombinant Val(247) and Leu(247) beta(2)GPI were established to compare the reactivity of anti-beta(2)GPI antibodies to beta(2)GPI between these variants. The variants were prepared on polyoxygenated plates or cardiolipin-coated plates, and the reactivity of a series of anti-beta(2)GPI antibodies (immunized anti-human beta(2)GPI monoclonal antibodies [Cof-19-21] and autoimmune anti-beta(2)GPI monoclonal antibodies [EY1C8, EY2C9, and TM1G2]) and IgGs purified from patient sera was investigated. RESULTS: A positive correlation between the Val(247) allele and the presence of anti-beta(2)GPI antibodies was observed in the patient group. Human monoclonal/polyclonal anti-beta(2)GPI autoantibodies showed higher binding to recombinant Val(247) beta(2)GPI than to Leu(247) beta(2)GPI, although no difference in the reactivity of the immunized anti-beta(2)GPI between these variants was observed. Conformational optimization showed that the replacement of Leu(247) by Val(247) led to a significant alteration in the tertiary structure of domain V and/or the domain IV-V interaction. CONCLUSION: The Val(247) beta(2)GPI allele was associated with both a high frequency of anti-beta(2)GPI antibodies and stronger reactivity with anti-beta(2)GPI antibodies compared with the Leu(247) beta(2)GPI allele, suggesting that the Val(247) beta(2)GPI allele may be one of the genetic risk factors for development of APS.

Adult↗
PubMed2005

Increase of serum angiopoietin-2 during pregnancy is suppressed in women with preeclampsia.

BACKGROUND: Numerous recent reports demonstrated that changes in serum levels of angiogenesis-related factors were associated with preeclampsia. Here, we determined the serum concentration of angiopoietin-2 (Ang-2), a natural antagonist of angiopoietin-1 (Ang-1) involved in promoting angiogenesis in the presence of angiogenic stimuli such as vascular endothelial growth factor (VEGF), in women with preeclampsia. METHODS: The levels of serum Ang-2 and Tie-2, a receptor for Ang-1 expressed on endothelial cells, were determined by enzyme-linked immunosorbent assay. RESULTS: The concentrations of serum Ang-2 were significantly elevated in healthy pregnant women (18.9 ng/mL) as compared to nonpregnant women or women in postpartum period. Increase in the levels of serum Ang-2 was significantly suppressed in preeclamptic women (4.5 ng/mL). The serum Ang-2 concentrations inversely correlated with gestational age in healthy pregnant women, but not in preeclamptic women. The serum Ang-2 concentrations positively correlated with placental weight or mean blood pressure (BP) in healthy pregnant women, but not in preeclamptic women. The serum Ang-2 concentrations inversely correlated with proteinuria in preeclamptic women. The serum concentrations of Tie-2 were not significantly different between preeclamptic and nonpreeclamptic women. CONCLUSIONS: These results suggest the potential requirement of circulating Ang-2 in proper formation of placental vasculatures during pregnancy. Although we cannot exclude the possibility that suppression in the increase of serum Ang-2 levels during pregnancy in preeclampsia as a consequence rather than a cause, measurement of serum Ang-2 concentration in pregnant women may serve as a useful marker in the diagnosis and potentially in predicting subsequent development of preeclampsia.

Adult↗
PubMed2005

Research around beta 2-glycoprotein I: a major target for antiphospholipid antibodies.

Beta2-glycoprotein I (beta2GPI), a phospholipid-binding protein, is one of the major target antigens for antiphospholipid antibodies (aPL) found in patients with antiphospholipid syndrome (APS). Thrombophilic disorders in APS patients are strongly associated with aPL, and their pathogenic properties depend on the presence of beta2GPI. Procoagulant cell stimulation by aPL, via beta2GPI, is one of the most plausible mechanisms of thrombosis in APS, and p38 mitogen activated protein kinase (MAPK) pathway plays a crucial role in such activation. beta2GPI is proteolytically cleaved in domain V by activated factor X or plasmin, leading to the generation of the nicked form of beta2GPI. Recently, increasing attention is focused on the role of nicked-beta2GPI as a regulator of extrinsic fibrinolysis pathway.

Amino Acid Sequence↗
PubMed2005

Characterization of a murine anti-laminin-1 monoclonal antibody (AK8) produced by immunization with mouse-derived laminin-1.

Laminin-1 is a structural glycoprotein that forms an integral part of the scaffolding of basement membranes, and plays an important role during embryonic development. We have recently demonstrated a significant association between anti-laminin1 antibodies (Abs) and reproductive failure, such as recurrent spontaneous abortions and infertility-associated endometriosis in both human and mouse studies. In the present study, we established an IgM (micro, kappa) monoclonal anti-laminin-1 Ab (AK8) by immunizing mice with mouse Engelbreth-Holm-Swarm sarcoma (EHS)-derived laminin-1. The AK8 monoclonal antibody (mAb) reacted with particular peptide sequences from the globular G domain of mouse laminin-alpha1 chain of using ELISA and Western blot techniques. The peptide tertiary structure of the epitope recognized by AK8 mAb was predicted using eight synthesized domain peptide sequences and three consensus sequences obtained by phage displayed random peptide library. Basement membranes of endometrium of pregnant mice and humans were immunostained with AK8 mAb. Thus, AK8 mAb recognized a common structure present in the G domain of the laminin-alpha1 chain in both mice and humans. The passive immunization of mice with AK8 mAb may represent a suitable animal model for anti-laminin-1 Ab-mediated reproductive failure.

Amino Acid Sequence↗
PubMed2005

Oxidized low-density lipoprotein/beta2-glycoprotein I complexes and autoantibodies in patients with type 2 diabetes mellitus.

Diabetes mellitus (DM) is associated with a high incidence of atherosclerotic cardiovascular complications that result from chronic metabolic abnormalities such as hyperglycemia-induced oxidative stress. The oxidative-modification of low-density lipoproteins (oxLDL) and oxLDL/beta(2)-GPI complex formation have been reported in patients with autoimmune disorders. OxLDL/beta(2)-GPI complexes and autoantibodies to these complexes were measured by ELISA in serum samples from 50 type 2 DM patients and 50 age/sex-matched healthy controls. Mean OD for oxLDL/beta(2)-GPI complexes in DM was 0.099 +/- 0.065 with 50% of patients reacting above the assay cutoff (P < 0.001 vs. controls). Mean OD for controls was 0.037 +/- 0.015 with 2% positives. Thirty-six (72%) DM patients were taking cholesterol-lowering statins and had a significantly lower mean OD complex level (0.092 +/- 0.071, P = 0.05) compared to patients not taking statins (0.112 +/- 0.05). Mean OD for IgG anti-oxLDL/beta(2)-GPI antibodies in DM was 0.157 +/- 0.112, similar to the controls (0.146 +/- 0.098, P = 0.328). Increased serum levels of oxLDL/beta(2)-GPI complexes may be a consequence of oxidative stress and LDL modification in DM. Lower levels of oxLDL/beta(2)GPI complexes in DM patients taking statins are in agreement with the antioxidant and antithrombotic properties of these drugs. No significant IgG autoantibody production was observed in this group of DM patients. The interaction of oxLDL with beta(2)-GPI in circulation suggests the intriguing possibility that oxLDL/beta(2)-GPI complexes may also play a role in the development of atherosclerosis and/or cardiovascular complications in DM.

Adult↗
PubMed2005

Pregnancy loss and endometriosis: pathogenic role of anti-laminin-1 autoantibodies.

Laminin-1 is a major multifunctional glycoprotein that forms an integral part of the scaffolding network of basement membranes, and is the earliest synthesized component during embryogenesis. This protein (alpha1beta1gamma1) plays an important role in basement membrane assembly and epiblast differentiation during embryonic development. Anti-laminin-1 autoantibodies are known to cause infertility and recurrent spontaneous abortion in animals. Recently, we reported that the presence of IgG anti-laminin-1 antibodies (Abs) in the blood is significantly associated with recurrent first-trimester miscarriages and subsequent negative pregnancy outcomes. Interestingly, these antibodies are also strongly associated with infertility, especially infertility caused by endometriosis. Laminin-alpha1, laminin-beta1, and laminin-gamma1 mRNAs were also detected in 90% of endometriotic lesions, and all laminin-alpha1, laminin-beta1, and laminin-gamma1 chains were localized to the basement membranes of glandular epithelium in endometriotic peritoneal lesions. ELISA showed specific reactivity of the autoantibodies to a particular region of the laminin-1 molecule, that is, the alpha1 chain G domain. IgM monoclonal anti-laminin-1 Abs, which we recently established, also recognized the G domain and cross-reacted with human alpha1 chain located in the basement membrane of the glandular epithelium of human endometrium. We also established an animal model that produced high titers of anti-laminin-1 Abs after immunization with mouse laminin-1. Anti-laminin-1 Abs from the immunized mice caused a higher fetal resorption rate with lower embryonic and placental weights. Thus, anti-laminin-1 Abs may be important in the development of autoimmune-mediated reproductive failures, and the assessment of the such antibodies may provide a novel means for noninvasive diagnosis of endometriosis.

Abortion, Habitual↗
PubMed2005

OxLDL/beta2GPI complexes and autoantibodies in patients with systemic lupus erythematosus, systemic sclerosis, and antiphospholipid syndrome: pathogenic implications for vascular involvement.

Oxidized low-density lipoprotein (oxLDL) interacts with beta2GPI, forming oxLDL/beta2GPI complexes. Autoimmune vascular inflammation (and oxidative stress) may promote the formation of these complexes. The coexistence of oxLDL/beta2GPI complexes with autoantibodies to these complexes suggests an active pro-atherogenic role in vascular thrombosis and atherosclerosis. Immunoglobulin G (IgG) anti-oxLDL/beta2GPI antibodies have been regarded as pro-atherogenic, whereas IgM antibodies are thought to be anti-atherogenic. For this study, oxLDL/beta2GPI complexes, IgG, and IgM anti-oxLDL/beta2GPI antibodies were measured using enzyme-linked immunosorbent assay (ELISA). Measurements were taken in two patient groups: (1) those with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and rheumatoid arthritis (RA); and (2) those with primary and secondary antiphospholipid syndrome (APS). For oxLDL/beta2GPI complexes, SLE and SSc patients had the highest mean optical densities (ODs) (P <.001), followed by RA (P = .139) and healthy controls. IgG anti-oxLDL/beta2GPI antibody distribution followed the same pattern observed with oxLDL/beta2GPI complexes, SLE and SSc (P <.001), RA (P = .08), and controls. IgM antibodies showed a reverse pattern, with the highest mean OD in RA (P <.001), followed by SSc (P = .007) and SLE (P = 143). Both IgG and IgM anti-oxLDL/beta2GPI antibodies were significantly higher in secondary APS patients compared with SLE controls without APS. In addition, the highest mean OD and prevalence of IgG anti-oxLDL/beta2GPI antibodies were observed in APS patients with a history of arterial thrombosis. These results may reflect the widespread vascular involvement seen in SLE and SSc, in contrast to the relatively low vascular involvement in RA. In SLE and SSc, high serum levels and prevalence of circulating oxLDL/beta2GPI complexes and IgG anti-oxLDL/beta2GPI antibodies indicate significant vascular oxidative stress as well as a possible pathogenic role in autoimmune-mediated atherosclerosis.

Antiphospholipid Syndrome↗
PubMed2005

The role of innate and adaptive immunity to oxidized low-density lipoprotein in the development of atherosclerosis.

Atherosclerosis is a chronic inflammatory process of the arterial wall associated with systemic and local immune responses to various antigens, oxidized low-density lipoprotein (oxLDL) being the most significant. Both IgM and IgG antibodies to oxLDL are produced during atherosclerosis. Some studies have shown that elevated levels of antibody to oxLDL correlate with the degree of atherosclerosis. Other studies reported that immunization of experimental animals with oxLDL induces high levels of antibodies to oxLDL, with decreased atherosclerosis, suggesting that the immune response to oxLDL may be antiatherogenic. The accelerated development of atherosclerosis has been observed in patients with systemic autoimmune diseases. In patients with antiphospholipid syndrome (APS), beta2-glycoprotein I (beta2GPI) is a major antigenic target for anticardiolipin antibodies (aCLs). We recently reported that oxLDL interacts with beta2GPI via oxLDL-derived specific ligands, such as 7-ketocholesteryl-9-carboxynonanoate (oxLig-1) to form complexes. In vitro, anti-beta2GPI autoantibodies bind to oxLDL/beta2GPI complexes that are actively taken up by macrophages via Fcgamma receptors. Circulating oxLDL/beta2GPI complexes were detected in patients with systemic lupus erythematosus (SLE) and APS, at higher levels than in healthy individuals. Autoantibodies against these complexes were also present; however, IgG anti-oxLig-1/beta2GPI antibody levels in SLE patients with APS were significantly higher than those in SLE patients without APS and those in healthy individuals.

Animals↗
PubMed2005

Intravenous immunoglobulin and atherosclerosis.

Several inflammatory and immunological factors have been established as important contributors to atherogenesis. Among these, oxidized low-density lipoprotein (oxLDL) play a central role in the initiation and progression of atherosclerotic lesions. In atherosclerotic lesions, oxLDL was also found to co-localize with beta2-glycoprotein I (beta2-GPI). Immunoglobulin (Ig)G autoantibodies against beta2-GPI complexed with oxLDL are pro-atherogenic because they increase uptake of the complexes by macrophages. In contrast, IgM natural anti-oxLDL antibodies derived from atherosclerosis-prone apolipoprotein E (ApoE) deficient mice reduced incidence of atherosclerosis. Such anti-oxLDL antibodies have been found in humans, and the accumulating evidences seem to support the idea that anti-oxLDL antibodies have a protective role for atherogenesis. Intravenous immunoglobulins (IVIgs) contain natural anti-oxLDL antibodies and infusion of IVIg into ApoE-deficient mice has been reported to decrease atherosclerosis. The anti-atherogenic property of IVIg may be derived from non-antigen-specific antibody binding to FCgamma receptors, which blocks foam cell formation of macrophages. Several other possible mechanisms are also discussed.

Animals↗
PubMed2004

From animal models to human genetics: research on the induction and pathogenicity of autoantibodies.

The revolutionary techniques of modern molecular and cellular biology enhance almost daily our knowledge of immunity and autoimmunity in men and experimental animals. Our fragmentary puzzle of the immune system is going to form a fascinating picture of a masterpiece of evolution. Although many of these aspects were achieved by analysis of human body fluids and tissues, the etiopathogenesis of autoimmune diseases cannot readily be analyzed without appropriate animal models. Therefore, the 7th Dresden Symposium on Autoantibodies has focused on experimental autoimmune models. The 295 attendants of the symposium listened to and discussed about the pathogenesis and therapy of autoimmunity in experimental mouse models, natural and pathogenic autoantibodies, molecular mechanisms of xenobiotic-induced autoimmunity, the genetic background of autoimmune diseases, novel autoantibodies and their pathogenic and/or clinical relevance, autoantibodies in systemic and neurological diseases, the occurrence and measurement of therapy-induced antibodies and methodical aspects as well as novel diagnostic strategies including multiplex assays for autoantibody profiling. Those who are interested to read the full length articles are referred to the book published in parallel to this meeting ([Conrad K, Bachmann MP, Chan EKL, Fritzler MJ, Humbel RL, Sack U, Shoenfeld Y, editors. From animal models to human genetics: research on the induction and pathogenicity of autoantibodies, Report on the 7th Dresden Symposium on Autoantibodies held in Dresden on September 1-4, 2004. Germany: Pabst Science Publishers; 2004.]; www.pabst-publishers.de).

Animals↗