Mechanisms of Autoantibody-Induced Pathology

Autoantibodies are frequently observed in healthy individuals. In a minority of these individuals, they lead to manifestation of autoimmune diseases, such as rheumatoid arthritis or Graves' disease. Overall, more than 2.5% of the population is affected by autoantibody-driven autoimmune disease. Pathways leading to autoantibody-induced pathology greatly differ among different diseases, and autoantibodies directed against the same antigen, depending on the targeted epitope, can have diverse effects. To foster knowledge in autoantibody-induced pathology and to encourage development of urgently needed novel therapeutic strategies, we here categorized autoantibodies according to their effects. According to our algorithm, autoantibodies can be classified into the following categories: (1) mimic receptor stimulation, (2) blocking of neural transmission, (3) induction of altered signaling, triggering uncontrolled (4) microthrombosis, (5) cell lysis, (6) neutrophil activation, and (7) induction of inflammation. These mechanisms in relation to disease, as well as principles of autoantibody generation and detection, are reviewed herein

Identitaet zu verkaufen Probleme und Entwicklungsoptionen des Internet Domain Service (DNS)

Available from UuStB Koeln(38)-971102576 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Identitaet zu verkaufen Probleme und Entwicklungsoptionen des Internet Domain Service (DNS)

Wie funktioniert die dezentralisierte self-governance des Internet und wo versagt sie? Der Autor beschreibt am Bespiel des Domain Name Service (DNS), mit welchen Mechanismen das Netz der Netze prekaere Allokationsentscheidungen in die Haende lokaler Akteure legt. Mit diesem ansonsten erfolgreichen Prinzip ist es nicht gelungen, den Namensraum anders als flach zu strukturieren. Am dadurch entstandenen Druck auf eine Liberalisierung sind die netzeigenen Modelle der Konsensfindung gescheitert, mit denen die offenen technischen Standards entwickelt werden. Fuer die Entwicklung weithin akzeptierter policies stehen zur Zeit keine funktionierenden Strukturen bereit. Das Internet International Ad Hoc Committee war ein Versuch, bezogen auf ein konkretes Problem diese Luecke zu fuellen. An der Krise des DNS stellen sich Verfassungsfragen des Internet in neuer Schaerfe. Diese konstitutionelle Debatte wird andauern, auch wenn die Fortentwicklung des DNS gelingen sollte. Der Autor gibt eine Einfuehrung in die Technik des DNS und analysirt die konkurrierenden Vorstellungen ueber die kuenftige Ordnung des Namensraums. (HH)'How does the Internet's decentralized self-governance work and when does it fail? Using the Domain Name Service (DNS) as an example, this paper describes the mechanisms the network of networks uses to place precarious decisions in the hands of local actors. With this principle, obviously, it was not possible to structure the namespace in another manner than flat. Under the pressure generated by this failure the network's own models of manufacturing consent, widely used for the development of open technical standards, did not succeed. At the moment, there are no working structures for the development of broadly accepted policies. The Internet International Ad Hoc Committee tried to fill this gap, aimed at the actual problem. The DNS crisis poses pointed constitutional questions for the Internet. The constitutional debate will continue, even in case further development of DNS is achieved. The paper gives an introduction to the technique of DNS and analyses competing conceptions of the namespace's future order.' (author's abstract)SIGLEAvailable from UuStB Koeln(38)-971102576 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Methylprednisolone Blocks Autoantibody-Induced Tissue Damage in Experimental Models of Bullous Pemphigoid and Epidermolysis Bullosa Acquisita through Inhibition of Neutrophil Activation

Corticosteroids are regularly used to treat autoimmune diseases, such as bullous pemphigoid (BP). In BP, autoantibodies bind to type XVII collagen (COL17), located at the dermal-epidermal junction. A crucial role of neutrophils in experimental BP has been established. Specifically, reactive oxygen species and proteolytic granule enzymes mediate tissue injury. Therefore, we investigated the effects of methylprednisolone (MP) on neutrophils, which are likely to be affected by topical treatment. First, MP inhibited dermal-epidermal separation ex vivo in cryosections of the human skin induced by co-incubation of BP autoantibodies with neutrophils from healthy volunteers. Next, MP inhibited neutrophil activation in vitro induced by immune complexes (ICs) of COL17 and autoantibodies. This neutrophil activation was associated with phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38 mitogen-activated protein kinase (MAPK), and Akt. In turn, inhibition of ERK1/2, p38 MAPK, or Akt phosphorylation inhibited neutrophil activation by IC in vitro and dermal-epidermal separation ex vivo. In addition, we observed an increase of p38 MAPK phosphorylation in dermal infiltrates of BP patients. Treatment of mice with either MP or inhibitors of p38-MAPK or ERK1/2 phosphorylation impaired induction of autoantibody- or irritant-induced neutrophil-dependent inflammation. We here identify the inhibition of Akt, ERK1/2, and p38 MAPK phosphorylation as molecular mechanisms to promote MP's therapeutic effects.Journal of Investigative Dermatology advance online publication, 4 April 2013; doi:10.1038/jid.2013.91