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Atopic dermatitis (AD) is a common inflammatory skin disease of unknown etiology. Cutaneous infection with microbes such asMajor features of AD are pruritus, chronic relapsing course, and genetic predisposition (1-3). AD is divided into two types: (i) AD associated with IgE-mediated responses, affecting 70-80% of patients and termed ''extrinsic AD,'' and (ii) AD without IgEmediated responses, affecting 20-30% of patients and termed ''intrinsic AD.'' Patients with extrinsic AD show preferential deviation toward T helper type 2 (Th2) responses, together with accumulation of Th2 chemokines such as CCL17 (thymus-and activation-regulated chemokine) and CCL22 (monocyte-derived chemokine) in the cutaneous lesions (1, 2). However, recent clinical studies have revealed that the immunological aspects of the skin lesions are quite different among the clinical stages of AD (1-3). Nonetheless, the immunopathological bases for intrinsic AD are still unknown.Recently, we showed that transgenic mice that oversecrete IL-18 from their epidermal cells spontaneously develop AD-like dermatitis under specific pathogen-free (SPF) conditions, and that the deletion of il18, but not stat6, which encodes a signaling molecule necessary for Th2 and IgE responses, protects against the development of AD (4, 5). This finding suggests that excessive cutaneous IL-18 release is a causative factor for intrinsic-type AD. Recent clinical studies have revealed that IL-18 production levels closely parallel disease severity (6-8). Therefore, it is important to clarify whether, and how, endogenous IL-18 contributes to the development of AD when skin is exposed to natural infectious agents.Although it is well documented that cutaneous infection with Staphylococcus aureus exacerbates clinical AD (1, 3), the underlying mechanism is not fully understood. Recently, we demonstrated that protein A (SpA), a surface molecule and virulent factor of S. aureus (9), stimulates mouse epidermal cells to secrete IL-18 (10). However, cutaneous application of SpA alone did not induce major skin alterations in C57BL͞6 mice, despite the fact that it produced elevated serum levels of 10). This outcome led us to assume that additional factors are required for the development of AD. Because skin cleansing with detergent aggravates clinical AD (1, 11), skin barrier destruction seems to be a second important factor in AD development. Inasmuch as NC͞Nga mice, which have a genetically impaired skin barrier due to reduced ceramide production (12), frequently develop AD-like dermatitis after exposure to mites (13-15), we assumed that genetic skin barrier dysfunction was a third prerequisite for the development of AD. Here, we generated an intrinsic AD mouse model by daily application of SpA, after destruction of the skin barrier with a subclinical dose of SDS, a detergent (16). Neutralizing anti-IL-18 Abs could completely protect against SDS͞SpA-induced AD. Furthermore, il18 Ϫ/Ϫ BALB͞c mice evaded development of AD under SDS͞SpA challenge. Our present results clearly demonstrate th...

Increasing evidence suggests that α-synuclein (αS) aggregates in brains of individuals with Parkinson's disease and dementia with Lewy bodies can spread in a prion-like manner. Although the initial αS nuclei are pivotal in determining αS fibril polymorphs and resulting phenotypes, it is not clear how the initial fibril seeds are generated. Previous studies have shown that αS truncation might have an important role in αS aggregation. However, little is known about how this truncation influences αS's propagation properties. In the present study, we generated αS fibrils from a series of truncated human αS constructs, characterized their structures and conformational stabilities, and investigated their ability to convert the conformation of full-length αS , in cultured cells, and in WT mice. We show that both C- and N-terminal truncations of human αS induce fibril polymorphs and exhibit different cross-seeding activities. N-terminally 10- or 30-residue-truncated human αS fibrils induced more abundant αS pathologies than WT fibrils in mice, whereas other truncated fibrils induced less abundant pathologies. Biochemical analyses of these truncated fibrils revealed that N-terminal 10- or 30-residue truncations of human αS change the fibril conformation in a manner that increases their structural compatibility with WT mouse αS fibrils and reduces their stability. C-terminally 20-residue-truncated fibrils displayed enhanced seeding activity Our findings imply that truncation of αS can influence its prion-like pathogenicity, resulting in phenotypic diversity of α-synucleinopathies.