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Human prion diseases are prominently heterogeneous. In sporadic Creutzfeldt-Jakob disease (sCJD), the most prevalent prion disease, heterogeneity is largely predicated on the common methionine (M)/valine (V) polymorphism at codon 129 of the prion protein (PrP) gene and the disease-associated PrP (PrPDis) that are distinguished in types 1 and 2 based on the electrophoretic mobility of their protease-resistant regions.1 However, despite this remarkable heterogeneity, all well-established sporadic prion diseases (here operationally defined as nonacquired prion diseases free of mutations in the PrP gene coding region) have been shown to share the same basic pathogenetic mechanism; PrPDis interacts with the normal or cellular PrP and converts it into PrPDis, triggering an autocatalytic process that leads to the accumulation of PrPDis and ultimately to the clinical disease.2 In 2008, we described 11 cases affected by a new disease involving PrP; we named this disease protease-sensitive prionopathy (PSPr).3 Subsequently, 2 additional cases of PSPr have been independently reported.4,5 PSPr differed from known sporadic prion diseases in the clinical presentation, in the histopathologic and immunohistochemical features, and in the basic characteristics of the PrPDis. Furthermore, all 11 cases had the 129VV genotype and no mutation in the PrP gene open reading frame (ORF). We now report 15 additional cases, all of which bear features of the PSPr as originally reported. However, the new cases also include, in addition to new 129VV subjects, individuals who are 129MV heterozygous and 129MM homozygous. Although the affected subjects belonging to the 3 genotypes share several important characteristics, they also display basic variations that allow the 3 corresponding phenotypes to be distinguished. Therefore, the new cases show that the disease originally described as PSPr, like sCJD, affects all 3 129 genotypes and to some extent mimics the 129-related phenotypic heterogeneity of sCJD, although the PSPr characteristics underline basic differences from sCJD and similarities with Gerstmann-Straussler-Scheinker disease (GSS), a rare phenotype, which to date has been reported as exclusively associated with PrP gene mutations. In view of the increased protease-resistance of the PrPDis associated with the new 129 genotypes compared to that of the 129VV cases, we propose to revise the original PSPr label to VPSPr or “variably protease-sensitive prionopathy.” Parts of these findings have been presented previously.6–9

Klinische, epidemiologische und experimentelle Daten deuten darauf hin, dass Autoimmunkrankheiten wie z.B. rheumatoide Arthritis, multiple Sklerose oder Typ I Diabetes durch Infektionen ausgelöst oder verschlimmert werden können. Bis heute ist jedoch nicht bekannt, welche molekularen und zellulären Mechanismen den Zusammenhang zwischen Infektion und Autoimmunität vermitteln. Eine Hypothese, die diesen Zusammenhang zu erklären versucht, ist die Hypothese der molekularen Mimikry. Dieser Hypothese zufolge sind kreuzreaktive Lymphozyten, die sowohl Selbst- als auch Fremdantigene erkennen, für die Induktion von Autoimmunität verantwortlich. Die Hypothese der molekularen Mimikry erklärt die Kreuzreaktivität von Lymphozyten durch Sequenzhomologie oder Identität von Selbst- und Fremdantigenen. Wir haben diese Hypothese an zwei Modellen, der chronischen Lyme Arthritis und einem Maus Modell der multiplen Sklerose, getestet und dabei festgestellt, dass Kreuzreaktivität von Lymphozyten weitaus häufiger ist als bis vor kurzem noch vermutet wurde. Wir konnten weiterhin zeigen, dass nicht die Primärstruktur sondern definierbare strukturelle Motive die Ursache für die Kreuzerkennung von Selbst- und Fremdpeptiden sind, und das Kreuzreaktivität in den seltensten Fällen von pathogenetischer Relevanz ist. Die Vorstellung, immunologische Kreuzreaktivität zwischen einem definierten mikrobiellen Antigen und einem definierten Selbstantigen sei für die Pathogenese von Autoimmunkrankheiten verantwortlich, ist also zu einfach. Der zweite Schwerpunkt dieser Arbeit ist die immunologische Analyse eines von uns charakterisierten Th2-spezifisch exprimierten Moleküls, T1/ST2. Wir konnten zeigen, dass T1/ST2 auf Th2, nicht jedoch Th1-Zellen exprimiert wird; dass die Expression von T1/ST2 ex vivo die Lokalisation aktueller Th2-Antworten widerspiegelt; und dass T1/ST2 von funktioneller Bedeutung für die Th2 Zellen ist: Kreuzvernetzung des T1/ST2 Moleküls durch einen T1/ST2-spezifischen monoklonalen Antikörper induziert Proliferation und die Produktion von Typ 2 Zytokinen. In vivo läßt sich durch Applikation des löslichen Antikörpers gegen T1/ST2 die pathogene Th2-Immunantwort im Mausmodell von Asthma modulieren. T1/ST2 ist also ein Kandidat für die gezielte immunmodulatorische Therapie Th2-dominierter Erkrankungen wie Asthma und Allergie. Clinical, epidemiological, and experimental data suggest that infections can sometimes trigger or exacerbate autoimmune diseases such as multiple sclerosis, type I diabetes, or rheumatoid arthritis. To date, the molecular and cellular mechanisms leading from infection to autoimmunity have not been defined. The molecular mimicry hypothesis proposes that crossreactive lymphocytes that recognize both self- and microbial antigens are key factors in the pathogenesis of autoimmunity. According to the molecular mimicry hypothesis, sequence identity or marked sequence similarity between self- and microbial antigens is the cause of such crossreactivity. We have examined the molecular mimicry hypothesis systematically in two different models: treatment-resistant Lyme arthritis and experimental autoimmune encephalitis (EAE). The major findings were: i) crossreactivity at the level of peptide recognition by T cells is far more frequent than previously expected; ii) structural criteria rather than sequence similarity determine cross-recognition; iii) immunoregulatory mechanisms normally prevent pathogenic effects mediated by crossreactive lymphocytes. Thus, the idea that crossrecognition of a defined microbial peptide and a particular self-peptide would explain autoimmunity is most likely too simple. The other major topic of this work was the immunological analysis of T1/ST2, a Th2-specific molecule that we characterized. Here, we could show that T1/ST2 is expressed on Th2 but not Th1 cells. Furthermore, T1/ST2 expression can be used to identify sites of ongoing Th2 reactions directly ex vivo. Most importantly, T1/ST2 is important for Th2 effector functions: crosslinking of T1/ST2 via a T1/ST2-specific monoclonal antibody induces proliferation and type 2-cytokine production. In vivo, administration of the soluble antibody against T1/ST2 ameliorates the immunological parameters of bronchial hyperreactivity in a murine model of asthma. Thus, T1/ST2 is a candidate target for therapeutic immunomodulation of diseases such as allergy and asthma.