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  • 1
    ISSN: 1573-4951
    Keywords: anti-(H2A-H2B) autoantibodies ; antigen binding mechanism ; comparative molecular modeling ; electrostatic interactions ; nucleosome ; systemic lupus erythematosus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The value of comparative molecular modeling for elucidating structure-function relationships was demonstrated by analyzing six anti-nucleosome autoantibody variable fragments. Structural models were built using the automated procedure developed in the COMPOSER software, subsequently minimized with the AMBER force field, and validated according to several standard geometric and chemical criteria. Canonical class assignment from Chothia and Lesk's [Chottin and Lesk, J. Mol. Biol., 196 (1987) 901; Chothia et al., Nature, 342 (1989) 877] work was used as a supplementary validation tool for five of the six hypervariable loops. The analysis, based on the hypothesis that antigen binding could occur through electrostatic interactions, reveals a diversity of possible binding mechanisms of anti-nucleosome or anti-histone antibodies to their cognate antigen. These results lead us to postulate that anti-nucleosome autoantibodies could have different origins. Since both anti-DNA and anti-nculeosome autoantibodies are produced during the course of systemic lupus erythematosus, a non-organ specific autoimmune disease, a comparative structural and electrostatic analysis of the two populations of autoantibodies may constitute a way to elucidate their origin and the role of the antigen in tolerance breakdown. The present study illustrates some interests, advantages and limits of a methodology based on the use of comparative modeling and analysis of molecular surface properties.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1520-6882
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-069X
    Keywords: Key words Pemphigus ; Immunoelectron microscopy ; Desmosomes ; Adherens junctions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are autoimmune blistering diseases characterized by a loss of cell–cell adhesion and by autoantibodies directed against epidermal cadherins. PF antigen has been established as desmoglein I which is located strictly on the desmosome, whereas the precise ultrastructural localization of PV antigen remains unclear and controversial to date. To further investigate this question, we compared the location of immune deposits in 14 patients with PV and 10 patients with PF by both direct and indirect immunoelectron microscopy (IEM). Inclusion criteria were based upon clinical features, histological level of cleavage and characterization of circulating antibodies by Western blot on epithelial bovine tongue extracts. IEM was performed on unfixed 0.7-mm slices of skin for the direct technique or on normal skin for the indirect technique using peroxidase labelling. In PF, by both direct and indirect IEM, immune deposits were located on the extracellular part of desmosomes (desmoglea) in all the samples studied. In PV, by both direct and indirect IEM, deposits were situated on the desmoglea and along large portions of the keratinocyte membrane without desmosomal structures in 15 of the 18 samples studied and only on the desmoglea in 3 samples. These results suggest that, in contrast to PF, the target antigen in PV is not always restricted to desmosomes. As various types of adherens junctions have been reported to mediate cell adhesion in the epidermis, the PV antigen could be a component of desmosomes and of other focal adhesions.
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  • 5
    ISSN: 1471-0528
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Objectives To determine if inherited thrombophilia and immunological disorders represent risk factors for small for gestational age infants, and to assess their relationship with neonatal status.Design Case–control study.Population Ninety-seven consecutive women who had pregnancies complicated by unexplained small for gestational age infants, defined as a birthweight below the third centile and 97 women as controls who delivered infants with a birthweight ≥10th centile.Methods Patients were included in the immediate postpartum period and tested for antithrombin III, protein C, protein S, anticardiolipin and antinuclear antibodies, lupus anticoagulant, Factor V Leiden mutation, prothrombin 20210A mutation, and methylenetetrahydrofolate reductase (MTHFR) polymorphism. Women with small for gestational age infants were then divided into subgroups depending on haemostatic and immunologic status in order to compare neonatal events.Results Frequencies for anticardiolipin and antinuclear antibodies were higher in women with small for gestational age infants compared with controls (P= 0.02 and P= 0.004, respectively), and overall prevalence of inherited thrombophilia were comparable in cases and controls (19.6% and 18.6%, respectively). The subgroups of patients with small for gestational age infants were women with only one inherited thrombophilia (n= 10), only one imunological disorder (n= 14), combined disorders (n= 9), and no detected abnormality (n= 64). Admission to paediatric ward significantly increased in the group with combined disorders (P= 0.002) compared with the other groups. Also one-third of the babies from this group had a poor neonatal outcome. However, most of the neonatal deaths (6/7 = 85.7%) occurred in the group with no detected abnormality.Conclusion The prevalence of inherited thrombophilia was considered to be similar between the case and the control groups even when immunological disorders were significantly elevated in pregnancies complicated by the baby being small for gestational age. Combined disorders may represent a potential risk factor for severe small for gestational age infants. However, the aetiology of small for gestational age infants with poor neonatal outcomes remains unknown in most cases.
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