Phenotypic Characterization of Autoreactive B Cells—Checkpoints of B Cell Tolerance in Patients with Systemic Lupus Erythematosus

DNA-reactive B cells play a central role in systemic lupus erythematosus (SLE); DNA antibodies precede clinical disease and in established disease correlate with renal inflammation and contribute to dendritic cell activation and high levels of type 1 interferon. A number of central and peripheral B cell tolerance mechanisms designed to control the survival, differentiation and activation of autoreactive B cells are thought to be disturbed in patients with SLE. The characterization of DNA-reactive B cells has, however, been limited by their low frequency in peripheral blood. Using a tetrameric configuration of a peptide mimetope of DNA bound by pathogenic anti-DNA antibodies, we can identify B cells producing potentially pathogenic DNA-reactive antibodies. We, therefore, characterized the maturation and differentiation states of peptide, (ds) double stranded DNA cross-reactive B cells in the peripheral blood of lupus patients and correlated these with clinical disease activity. Flow cytometric analysis demonstrated a significantly higher frequency of tetramer-binding B cells in SLE patients compared to healthy controls. We demonstrated the existence of a novel tolerance checkpoint at the transition of antigen-naïve to antigen-experienced. We further demonstrate that patients with moderately active disease have more autoreactive B cells in both the antigen-naïve and antigen-experienced compartments consistent with greater impairment in B cell tolerance in both early and late checkpoints in these patients than in patients with quiescent disease. This methodology enables us to gain insight into the development and fate of DNA-reactive B cells in individual patients with SLE and paves the way ultimately to permit better and more customized therapies

International Migration in the Atlantic Economy, 1850-1940

This chapter focuses on the economic analysis of what has been called the age of mass migration, 1850 to 1913, and its aftermath up to 1940. This has captured the interest of generations of economic historians and is still a highly active area of research. Here we concentrate on migration from Europe to the New World as this is where the bulk of the literature lies. We provide an overview of this literature focusing on key topics: the determinants of migration, the development of immigration policy, immigrant selection and assimilation, and the economic effects of mass migration as well as its legacy through to the present day. We explain how what were once orthodoxies have been revisited and revised, and how changes in our understanding have been influenced by advances in methodology, which in turn have been made possible by the availability of new and more comprehensive data. Despite these advances some issues remain contested or unresolved and, true to cliometric tradition, we conclude by calling for more research

Silicon image sensor technology for in vivo detection of surfactant-induced corneocyte swelling and drying.

BACKGROUND: Several instrumental methods can indirectly assess some specific aspects of cutaneous irritation at the level of the stratum corneum (SC). OBJECTIVE: There is a need for developing more sensitive approaches in this field. METHODS: We assessed a recently introduced innovative tool (SkinChip) based on capacitive pixel-sensing technology in its potential to detect early discrete manifestations of skin irritation. The sensor generates a detailed non-optical picture corresponding to a capacitance map of the skin surface reaching 50 microm pixel resolution. Some topographical details can be easily disclosed and the SC hydration as well. Two surfactant solutions were tested on volunteers. These solutions were applied under test patches for 2 days on the volar forearms. Clinical and SkinChip assessments were performed 3 h after removing the patch. RESULTS: The generated images allowed a precise observation of skin irritation which appeared as a two-step process. Early changes consisted of darker pixels corresponding to overhydrated swollen corneocytes at the irritated sites. Two days later, the same area appeared as white pixels, indicating the loss of corneocyte hydration. CONCLUSION: The SkinChip device appears to be a very sensitive tool for detecting the early steps of surfactant-induced skin irritation affecting the SC