We have constructed a continuous index map of 25 microsatellite markers on human chromosome 11. The markers have been typed in 40 CEPH families, have heterozygosities of 69% or higher and can be typed by PCR. The odds against inversion of adjacent marker loci order are at least 10(5):1. The sex average map covers a total of 162 cM with no gap exceeding 15 cM. Total lengths for female and male maps are 205 and 123 cM, respectively. By use of a hybrid cell panel or by in situ hybridization, 16 of the markers have also been mapped cytogenetically, providing a good correlation of the index map with the cytogenetic map. The map will facilitate high resolution mapping of additional polymorphic loci and of disease genes on chromosome 11.
Psoriasis is a T cell and IL-17 dependent inflammatory skin disease. Helper T cells have been assumed to be the major source of IL-17 in psoriasis but other cell types can also produce this cytokine. We immunostained human psoriatic lesions (n¼15) and healthy skin (n¼10) for IL-17A, T cells (CD4, CD8) and neutrophils (myeloperoxidase, MPO). We found that 32% of MPO+ neutrophils in psoriasis samples produced IL-17A, compared with less than 1% of total CD4 + and CD8 + cells. There were on average 10.6 IL-17A producing neutrophils per 10 high power fields in psoriasis, compared to 2.7 IL-17A producing T cells (p¼0.008). IL-17A producing neutrophils outnumbered IL-17A producing T cells four-fold demonstrating that neutrophils are an important source of IL-17A in psoriasis. To explore potential interactions between keratinocytes and neutrophils in psoriasis, we co-cultured these cells in vitro and studied neutrophil cytokine production by quantitative RT-PCR and intracellular immunostaining and flow cytometry analysis. Neutrophils co-cultured with keratinocytes upregulated production of IL-17A, IL-17F and IL-22 at both the protein and RNA levels. Neutrophils cultured with keratinocytes lost CD62L and upregulated CD11b, consistent with activation. In summary, this study suggests that neutrophils, known for long to be a part of the histologic landscape of psoriasis, are a major source of IL-17A production and have the potential to contribute to inflammation by producing IL-17F and IL-22. This is, to our knowledge, the first report that human neutrophils can produce IL-17F and IL-22.
Autoimmune disease is the leading cause of morbidity among women. For largely unknown reasons, many autoimmune diseases show a striking female bias. Fibrosis is a common feature of female-biased autoimmune diseases. This is exemplified by systemic sclerosis (SSc), a debilitating disease marked by progressive skin hardening and organ damage that affects women at ninefold the rate of men. We previously identified the transcriptional cofactor VGLL3 as an immune regulator enriched in female skin whose targets overlap significantly with genes dysregulated in SSc. We further showed that excess epidermal VGLL3 causes cutaneous and systemic autoimmune disease in mice. However, how VGLL3 promotes autoimmunity in the skin remains entirely unexplored. By combining IP-mass spectrometry, RNA-seq, and ChIP-seq approaches in cell culture and transgenic mice with epidermal VGLL3 overexpression, we have found that VGLL3 binds key factors in the Hippo signaling pathway to modulate both immune genes and established Hippo pathway targets. These targets include the pro-fibrotic factor CTGF and members of the TGF-b pathway, both of which have been implicated in SSc pathogenesis. Consistent with this, transgenic mice with epidermal VGLL3 overexpression show gross and microscopic features of skin fibrosis. These findings elucidate the molecular mechanisms by which VGLL3 promotes autoimmunity and leads to the hallmark fibrosis of many autoimmune diseases such as SSc. Furthermore, this reveals a previously unexplored connection between autoimmune disease and the Hippo signaling pathway, which has recently been linked to organ fibrosis.
Poster abstracts 65 cations to oncology research we have developed the AmpliOnc TM I array, which contains 3 spots for each of over 50 target loci (mostly oncogenes) that have been shown to be potentially amplified in tumour tissues. In hybridizations of normal female (green) against normal male (red) total human DNA, the spots containing the androgen receptor (X chromosome) revealed a green/red ratio significantly higher than the ratios of all other loci (>99% confidence level). This suggests sufficient sensitivity for single copy-change detection. In tests with defined tumour cell lines, the expected ratios were obtained for multiple amplifications with more than 95% confidence on each chip. Multiple tumour cell lines and primary tumours have been analysed with the AmpliOnc TM chip. In all cases known oncogene amplifications were confirmed, and in some instances additional and so far unknown amplifications were discovered.
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