Expression of Selected Integrins and Selectins in Bullous Pemphigoid

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Abstract

Blister development in bullous pemphigoid (BP) results from destruction of hemidesmosomes and basement membrane components within the dermoepidermal junction by autoantibodies. Adhesion molecules can take part in pathogenesis of this disease. The aim of the study was to determine the localization and expression of L- and E-selectins and β1, β3, and β4 integrins by immunohistochemistry in skin lesions of 21 patients with BP, compared with 10 healthy subjects. Expression of L and E selectins and β1, β3 integrins was detected mainly in basal keratinocytes and in inflammatory infiltrates in the dermis, expression of β4 integrin was irregular and was detected mainly in dermal part of the blister, while in the control group only weak and single expression of the examined molecules was detected in basal keratinocytes and endothelium cells. The obtained results reveal the important role of selected selectins and integrins in development of skin lesions in BP.

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Natalizumab for active Crohn's disease.

Paul Rutgeerts, Eran Goldin, Subrata Ghosh … (2003)

In chronic inflammatory conditions such as Crohn's disease, the migration of leukocytes from the circulation into the parenchyma and their activation within inflammatory sites are mediated in part by alpha4 integrins. We conducted a double-blind, placebo-controlled trial of the alpha4 integrin-specific humanized monoclonal antibody natalizumab in 248 patients with moderate-to-severe Crohn's disease. Patients were randomly assigned to receive one of four treatments: two infusions of placebo; one infusion of 3 mg of natalizumab per kilogram of body weight, followed by placebo; two infusions of 3 mg of natalizumab per kilogram; or two infusions of 6 mg of natalizumab per kilogram. Infusions were given four weeks apart. Outcomes included changes in scores for the Crohn's Disease Activity Index (higher scores indicate more severe disease), the health-related quality of life, and C-reactive protein levels. The group given two infusions of 6 mg of natalizumab per kilogram did not have a significantly higher rate of clinical remission (defined by a score of less than 150 on the Crohn's Disease Activity Index) than the placebo group at week 6 (the prospectively defined primary end point in the efficacy analysis). However, both groups that received two infusions of natalizumab had higher remission rates than the placebo group at multiple time points. Natalizumab also produced a significant improvement in response rates (defined by a reduction of at least 70 points in the score on the Crohn's Disease Activity Index). The highest remission rate was 44 percent and the highest response rate was 71 percent (at week 6 in the group given two infusions of 3 mg per kilogram). Overall, the two infusions of 6 mg of natalizumab per kilogram and of 3 mg per kilogram had similar effects. The quality of life improved in all natalizumab groups; C-reactive protein levels improved in groups receiving two infusions of natalizumab. The rates of adverse events were similar in all four groups. Treatment with the selective adhesion-molecule inhibitor natalizumab increased the rates of clinical remission and response, improved the quality of life and C-reactive protein levels, and was well tolerated in patients with active Crohn's disease. Copyright 2003 Massachusetts Medical Society

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Integrin cytoplasmic domains mediate inside-out signal transduction

R Tamura, H Ginsberg, K Peter … (1994)

We analyzed the binding of fibronectin to integrin alpha 5 beta 1 in various cells; in some cells fibronectin bound with low affinity (e.g., K562 cells) whereas in others (e.g., CHO), it bound with high affinity (Kd approximately 100 nM) in an energy-dependent manner. We constructed chimeras of the extracellular and transmembrane domains of alpha IIb beta 3 joined to the cytoplasmic domains of alpha 5 beta 1. The affinity state of these chimeras was assessed by binding of fibrinogen or the monoclonal antibody, PAC1. The cytoplasmic domains of alpha 5 beta 1 conferred an energy-dependent high affinity state on alpha IIb beta 3 in CHO but not K562 cells. Three additional alpha cytoplasmic domains (alpha 2, alpha 6A, alpha 6B) conferred PAC1 binding in CHO cells, while three others (alpha M, alpha L, alpha v) did not. In the high affinity alpha chimeras, cotransfection with a truncated (beta 3 delta 724) or mutated (beta 3(S752-->P)) beta 3 subunit abolished high affinity binding. Thus, both cytoplasmic domains are required for energy-dependent, cell type-specific affinity modulation. In addition, mutations that disrupted a highly conserved alpha subunit GFFKR motif, resulted in high affinity binding of ligands to alpha IIb beta 3. In contrast to the chimeras, the high affinity state of these mutants was independent of cellular metabolism, cell type, and the bulk of the beta subunit cytoplasmic domain. Thus, integrin cytoplasmic domains mediate inside-out signaling. Furthermore, the highly conserved GFFKR motif of the alpha subunit cytoplasmic domain maintains the default low affinity state.

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Serum levels of autoantibodies to BP180 correlate with disease activity in patients with bullous pemphigoid.

Enno Schmidt, E B Bröcker, D Zillikens … (2000)

To investigate the possible correlation of levels of circulating anti-BP180 autoantibodies with disease activity in bullous pemphigoid (BP). Diagnostic study. Regional referral center at a university dermatology department. Fifteen patients with typical clinical, histologic, and immunofluorescence findings of BP who had not received prior systemic treatment. Initially, 6 consecutive patients with BP were treated with oral doxycycline and niacinamide. Subsequently, 9 consecutive patients with BP received a combination of oral dapsone and prednisolone. Disease activity, serum levels of autoantibodies to BP180, and titers of antibasement membrane zone autoantibodies were assayed before initiation of treatment and 4 and 8 weeks later. Reactivity to BP180 was analyzed by enzyme-linked immunosorbent assay using a recombinant form of BP180 NC16A. Titers of anti-basement membrane zone autoantibodies were assayed by indirect immunofluorescence on 1-mol/L sodium chloride-split human skin. In both treatment groups, disease activity correlated with serum levels of autoantibodies to BP180 NC16A (P = .004 [dapsone-prednisolone] and .007 [doxycycline-niacinamide]). No correlation was seen between disease activity and indirect immunofluorescence reactivity (P = .18 and .16, respectively). In patients receiving dapsone plus prednisolone, the dose of corticosteroids necessary to suppress new blister formation correlated with anti-BP180 reactivity (P = .002). In contrast to indirect immunofluorescence reactivity that reflects reactivity to both BP 180 and BP230, serum levels of autoantibodies to BP180 correlate with disease activity in BP. Assaying reactivity to BP180 should be a helpful guide for the therapeutic management of patients with this disease. Our results underline the pathogenic relevance of autoantibodies to human BP180.

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Author and article information

Journal

Journal ID (nlm-ta): Mediators Inflamm

Journal ID (publisher-id): MI

Title: Mediators of Inflammation

Publisher: Hindawi Publishing Corporation

ISSN (Print): 0962-9351

Publication date (Print): 2007

Publication date (Electronic): 2 April 2007

Volume: 2007

Electronic Location Identifier: 31051

Affiliations

¹Department of Dermatology and Venereology, Medical University of Lodz, 94-017 Lodz, Poland

²Laboratory of Nephropathology, Medical University of Lodz, 94-017 Lodz, Poland

³Laboratory of Immunodermatology, Department of Dermatology and Venereology, Medical University of Lodz, 94-017 Lodz, Poland

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*Ewa Joss-Wichman: ewajw@ 123456wp.pl

Article

DOI: 10.1155/2007/31051

PMC ID: 1868076

PubMed ID: 17515951

SO-VID: 68ee5989-9a35-4926-8f2d-e805ac8fc0ea

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This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 30 November 2006

Date revision received : 23 January 2007

Date accepted : 6 February 2007

Expression of Selected Integrins and Selectins in Bullous Pemphigoid

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Most cited references 40

Natalizumab for active Crohn's disease.

Integrin cytoplasmic domains mediate inside-out signal transduction

Serum levels of autoantibodies to BP180 correlate with disease activity in patients with bullous pemphigoid.

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