ORCID Profile
0000-0002-5705-8727
Current Organisation
University of Nottingham
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Publisher: The American Association of Immunologists
Date: 06-2013
Abstract: Graves’ disease results from thyroid-stimulating Abs (TSAbs) activating the thyrotropin receptor (TSHR). How TSAbs arise from early precursor B cells has not been established. Genetic and environmental factors may contribute to pathogenesis, including the bacterium Yersinia enterocolitica. We developed two pathogenic monoclonal TSAbs from a single experimental mouse undergoing Graves’ disease, which shared the same H and L chain germline gene rearrangements and then ersified by numerous somatic hypermutations. To address the Ag specificity of the shared germline precursor of the monoclonal TSAbs, we prepared rFab germline, which showed negligible binding to TSHR, indicating importance of somatic hypermutation in acquiring TSAb activity. Using rFab chimeras, we demonstrate the dominant role of the H chain V region in TSHR recognition. The role of microbial Ags was tested with Y. enterocolitica proteins. The monoclonal TSAbs recognize 37-kDa envelope proteins, also recognized by rFab germline. MALDI-TOF identified the proteins as outer membrane porin (Omp) A and OmpC. Using recombinant OmpA, OmpC, and related OmpF, we demonstrate cross-reactivity of monoclonal TSAbs with the heterogeneous porins. Importantly, rFab germline binds recombinant OmpA, OmpC, and OmpF confirming reactivity with Y. enterocolitica. A human monoclonal TSAb, M22 with similar properties to murine TSAbs, also binds recombinant porins, showing cross-reactivity of a spontaneously arising pathogenic Ab with Y. enterocolitica. The data provide a mechanistic framework for molecular mimicry in Graves’ disease, where early precursor B cells are expanded by Y. enterocolitica porins to undergo somatic hypermutation to acquire a cross-reactive pathogenic response to TSHR.
Publisher: Wiley
Date: 17-01-2022
DOI: 10.1111/GEB.13453
Abstract: The distribution of Yersinia pestis , the pathogen that causes plague in humans, is reliant upon transmission between host species however, the degree to which host species distributions dictate the distribution of Y. pestis , compared with limitations imposed by the environmental niche of Y. pestis per se, is debated. We test whether the present‐day environmental niche of Y. pestis differs between its native range and an invaded range and whether biotic factors (host distributions) can explain observed discrepancies. North America and Central Asia. Yersinia pestis . We use environmental niche models to determine whether the current climatic niche of Y. pestis differs between its native range in Asia and its invaded range in North America. We then test whether the inclusion of information on the distribution of host species improves the ability of models to capture the North American niche. We use geographical null models to guard against spurious correlations arising from spatially autocorrelated occurrence points. The current climatic niche of Y. pestis differs between its native and invaded regions. The Asian niche overpredicted the distribution of Y. pestis across North America. Including biotic factors along with the native climatic niche increased niche overlap between the native and invaded models, and models containing only biotic factors performed better than the native climatic niche alone. Geographical null models confirmed that the increased niche overlap through inclusion of biotic factors did not, with a couple of exceptions, arise solely from spatially autocorrelated occurrences. The current climatic niche in Central Asia differs from the current climatic niche in North America. Inclusion of biotic factors improved the fit of models to the Y. pestis distribution data in its invaded region better than climate variables alone. This highlights the importance of host species when investigating zoonotic disease introductions and suggests that climatic variables alone are insufficient to predict disease distribution in novel environments.
Publisher: Springer Science and Business Media LLC
Date: 06-2014
DOI: 10.1038/NBT0614-592C
Publisher: Wiley
Date: 18-02-2013
Publisher: Springer Science and Business Media LLC
Date: 12-08-2012
DOI: 10.1038/NBT.2316
Publisher: MyJove Corporation
Date: 25-01-2012
DOI: 10.3791/3636
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Steve Atkinson.