Randall Division of Cell and Molecular Biophysics

About: Randall Division of Cell and Molecular Biophysics is a based out in . It is known for research contribution in the topics: Actin cytoskeleton & Skeletal muscle. The organization has 576 authors who have published 1229 publications receiving 78279 citations.

Biased use of VH5 IgE-positive B cells in the nasal mucosa in allergic rhinitis

Abstract: Background IgE antibody-producing B cells are enriched in the nasal mucosa in patients with allergic rhinitis because of local class switching to IgE. The expressed IgE V H genes also undergo somatic hypermutation in situ to generate clonal families. The antigenic driving force behind these events is unknown. Objective To examine the possible involvement of a superantigen in allergic rhinitis, we compared the variable (V H ) gene use and patterns of somatic mutation in the expressed IgE heavy-chain genes in nasal biopsy specimens and blood from allergic patients and the IgA V H use in the same biopsy specimens and also those from nonallergic controls. Methods We extracted mRNA from the nasal biopsy specimens of 13 patients and 4 nonallergic control subjects and PBMCs from 7 allergic patients. IgE and IgA V H regions were RT-PCR amplified, and the DNA sequences were compared with those of control subjects. We constructed a molecular model of V H 5 to locate amino acids of interest. Results We observed a significantly increased frequency of IgE and IgA V H 5 transcripts in the nasal mucosa of the allergic patients compared with the normal PBMC repertoire. Within IgE and IgA V H 5 sequences in the nasal mucosa, the distribution of replacement amino acids was skewed toward the immunoglobulin framework regions. Three of 4 nonintrinsic hotspots of mutation identified in the V H 5 sequences were in framework region 1. The hotspots and a conserved V H 5-specific framework residue form a tight cluster on the surface of V H 5. Conclusion Our results provide evidence for the activity of a superantigen in the nasal mucosa in patients with allergic rhinitis.

Structure of an ‘open’ clamp type II topoisomerase-DNA complex provides a mechanism for DNA capture and transport

Abstract: Type II topoisomerases regulate DNA supercoiling and chromosome segregation. They act as ATP-operated clamps that capture a DNA duplex and pass it through a transient DNA break in a second DNA segment via the sequential opening and closure of ATPase-, G-DNA- and C-gates. Here, we present the first ‘open clamp’ structures of a 3-gate topoisomerase II-DNA complex, the seminal complex engaged in DNA recognition and capture. A high-resolution structure was solved for a (full-length ParE-ParC55)2 dimer of Streptococcus pneumoniae topoisomerase IV bound to two DNA molecules: a closed DNA gate in a B-A-B form double-helical conformation and a second B-form duplex associated with closed C-gate helices at a novel site neighbouring the catalytically important β-pinwheel DNA-binding domain. The protein N gate is present in an ‘arms-wide-open’ state with the undimerized N-terminal ParE ATPase domains connected to TOPRIM domains via a flexible joint and folded back allowing ready access both for gate and transported DNA segments and cleavage-stabilizing antibacterial drugs. The structure shows the molecular conformations of all three gates at 3.7 A, the highest resolution achieved for the full complex to date, and illuminates the mechanism of DNA capture and transport by a type II topoisomerase.

The allergic march from Staphylococcus aureus superantigens to immunoglobulin E.

Abstract: Staphylococcus aureus is a commensal bacterium in the respiratory tract mucosa of most people and infects the skin of atopic dermatitis patients. This might imply a symbiotic relationship between host and bacterium or a standoff between bacterial infection and the host immune system. But superantigens produced by S. aureus in these locations are of particular interest because they are strongly implicated in the pathogenesis of allergic disorders and airway disease. They appear to act locally in these conditions by stimulating polyclonal T cell and B cell proliferation and driving somatic hypermutation, class switching to immunoglobulin (Ig) E and the production of allergen-specific IgE in mucosal B cells. IgE antibodies directed against the superantigens ('superallergens') themselves engender chronic inflammation and the persistent sensitization to conventional allergens of mast cells and antigen-presenting cells in mucosal tissues in atopic dermatitis, rhinitis and asthma. Moreover, S. aureus superantigens inhibit the activity of T regulatory cells that normally control inflammation, and generate a state of steroid resistance that confounds treatment of allergic disorders and airway disease.

Inhibition of allergen-dependent IgE activity by antibodies of the same specificity but different class

Abstract: IgG4 purified from patients undergoing specific allergen immunotherapy inhibits the activities of the serum IgE in in vitro assays and is thought to reduce the symptoms of the disease. However, it is not known whether this is related to an intrinsic property of this subclass or only the allergen specificity. We tested the hypothesis that allergen specificity is the critical determinant for this activity using a panel of antibodies with identical specificity but different subclasses. The different antibodies were all able to inhibit the activity of IgE to the same extent. We demonstrate that specificity is the dominant factor determining the ability of an antibody to block allergen-dependent IgE activity.