Pauci-immune focal necrotizing glomerulonephritis (FNGN) is a severe inflammatory disease associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA). Here we characterize autoantibodies to lysosomal membrane protein-2 (LAMP-2) and show that they are a new ANCA subtype present in almost all individuals with FNGN. Consequently, its prevalence is nearly twice that of the classical ANCAs that recognize myeloperoxidase or proteinase-3. Furthermore, antibodies to LAMP-2 cause pauci-immune FNGN when injected into rats, and a monoclonal antibody to human LAMP-2 (H4B4) induces apoptosis of human microvascular endothelium in vitro. The autoantibodies in individuals with pauci-immune FNGN commonly recognize a human LAMP-2 epitope (designated P [41][42][43][44][45][46][47][48][49] ) with 100% homology to the bacterial adhesin FimH, with which they Correspondence should be addressed to R.K. (renate.kain@meduniwien.ac.at). 7 Present addresses: Interne, Hämato-Onkologie, Krankenhaus der Elisabethinen, Fadingerstrasse 1, 4010 Linz, Austria (R.Z.) and Vela Laboratories. Entwicklung und Laboranalytik Gesellschaft mit beschränkter Haftung, Brunnerstrasse 69/3, 1230 Wien, Austria (R.J.). 8 These authors contributed equally to this work. Here we establish that autoantibodies to human LAMP-2 are highly prevalent in pauci-immune FNGN and provide evidence of their pathogenicity by showing that they activate neutrophils and kill human blood microvascular endothelium in vitro and cause pauci-immune FNGN when administered to rodents. Unexpectedly, auto-antibodies to LAMP-2 in individuals with FNGN commonly recognize an epitope with considerable homology to the bacterial adhesin FimH and cross-react with it. We therefore determined whether exposure to FimH could induce antibodies to human LAMP-2 and initiate pauci-immune FNGN through molecular mimicry. The results lead us to propose a previously undescribed molecular mechanism both for the induction and development of injury in this human disease. RESULTS Autoantibodies to human LAMP-2 are common in FNGNWe established the prevalence of autoantibodies to hLAMP-2 in sera from 84 individuals with biopsy-proven active pauci-immune FNGN, either at presentation (n = 62) or during relapse (n = 22). ANCA were detectable by standard immunofluorescence assays in 80 of them (95%), and ELISA for the canonical ANCA were positive in 70 of them (83%); myeloperoxidasespecific ANCA were found in 38 people, and proteinase-3-specific ANCA were found in 39 people, including seven with antibodies to both antigens. Using a specific ELISA, we detected antibodies to human LAMP-2 in 78 of the 84 (93%) sera (Fig. 1a), and we validated the results by western blotting and indirect immunofluorescence on the O-glycosylation deficient CHO cell line ldlD cells stably expressing human LAMP-2 on their surface ( Supplementary Fig. 1a online). Notably, the human LAMP-2 ELISA was negative in all but six of the individuals when they were in remission after immunosuppressive therapy. Assays for human LA...

The results suggest a considerable degree of underprovision and inadequate provision of outpatient psychotherapeutic care. With regard to special population groups, further research is necessary to identify utilisation barriers towards psychotherapy.

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Information about the scope of mental disorders (MDs), resource use patterns in health and social care sectors and economic cost is crucial for adequate mental healthcare planning. This study provides the first representative estimates about the overall utilisation of resources by people with MDs and the excess healthcare and productivity loss costs associated with MDs in Austria. Data were collected in a cross-sectional survey conducted on a representative sample ( n = 1008) between June 2015 and June 2016. Information on mental health diagnoses, 12-month health and social care use, medication use, comorbidities, informal care, early retirement, sick leave and unemployment was collected via face-to-face interviews. Generalised linear model was used to assess the excess cost of MDs. The healthcare cost was 37% higher ( p = 0.06) and the total cost was twice as high ( p < 0.001) for the respondents with MDs compared to those without MDs. Lost productivity cost was over 2.5-times higher ( p < 0.001) for those with MDs. Participants with severe MDs had over 2.5-times higher health and social care cost ( p < 0.001) and 9-times higher mental health services cost ( p < 0.001), compared to those with non-severe MDs. The presence of two or more physical comorbidities was a statistically significant determinant of the total cost. Findings suggest that the overall excess economic burden on health and social care depends on the severity of MDs and the number of comorbidities. Both non-severe and severe MDs contribute to substantially higher loss productivity costs compared to no MDs. Future resource allocation and service planning should take this into consideration.