Biology subjects

Tsokos, G. C.

Publications and source records attributed to Tsokos, G. C..

4 recordsLinked to original sources

bioRxiv2022

Melanocyte-secreted Fibromodulin constrains skin inflammation in mice injected with lupus serum

Skin pigmentation has been linked to the development, prevalence, and severity of several immune-mediated diseases such as SLE. Here, we asked whether fibromodulin (FMOD), which is highly expressed in skin with light complexion, can explain the known differences in the magnitude of inflammation. C57 mice with different levels of pigmentation and FMOD were injected with human lupus serum to induce skin inflammation. Histopathologic studies revealed that black C57 FMOD+/+ that produce low levels of FMOD and white C57 FMOD -/- mice develop more severe inflammation compared with white FMOD +/+ mice. This study also revealed that dark pigmentation and FMOD deletion correlates with the increased numbers of Langerhans cells. Altogether, we identify low pigmentation and FMOD are linked to low severity of inflammation and approaches to promote FMOD expression should offer clinical benefit.

immunology↗

bioRxiv2020

A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury during the COVID-19 pandemic

Drug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease arising from SARS-CoV-2 infection. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury (ALI) and respiratory distress syndrome (ARDS), and correlate with poor clinical outcomes. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce MUC1 protein abundance. Our screen identified Fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo, Fostamatinib reduced MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by Fostamatinib promoted MUC1 removal from the cell surface. Our work reveals Fostamatinib as a repurposing drug candidate for ALI and provides the rationale for rapidly standing up clinical trials to test Fostamatinib efficacy in patients with COVID-19 lung injury.

cell biology↗

bioRxiv2018

Plasmacytoid dendritic cells are functionally exhausted while non-haematopoietic sources of type I interferon dominate human autoimmunity

Autoimmune connective tissue diseases arise in a stepwise fashion from asymptomatic preclinical autoimmunity. Type I interferons (IFNs) have a crucial role in the progression to established autoimmune diseases such as systemic lupus erythematosus (SLE). However, their cellular source and regulation in disease initiation are unclear. The current paradigm suggests that plasmacytoid dendritic cells (pDCs) are activated in SLE contributing to excessive IFN production. Here, we show that in preclinical autoimmunity, established SLE, and primary Sjogrens Syndrome, pDCs are not effector cells, but rather have lost their capacity for TLR-mediated IFN- and TNF production and fail to induce T cell activation, independently of disease activity and blood IFN signature. In addition, pDCs present a transcriptional signature of cellular stress and senescence accompanied by increased telomere erosion. Instead, we demonstrate a marked enrichment of IFN signature in non-lesional skin in preclinical autoimmunity. In these individuals and SLE patients, type I IFNs were abundantly produced by keratinocytes in the absence of infiltrating leucocytes. These findings revise our understanding of the role of IFN in the initiation of human autoimmunity, with non-haematopoietic tissues perpetuating IFN responses, which in turn predict clinical disease. These data indicate potential therapeutic targets outside the conventional immune system for treatment and prevention.

immunology↗

bioRxiv2017

Genome-Wide Association Study Reveals Genetic Link Between Diarrhea-Associated Entamoeba histolytica Infection And Inflammatory Bowel Disease

Diarrhea is the second leading cause of death for children globally, causing 760,000 deaths each year in children under the age of 5. Amoebic dysentery contributes significantly to this burden, especially in developing countries. We hypothesize that genetic variation contributes to susceptibility to diarrhea-associated Entamoeba histolytica infection in Bangladeshi infants; thus, we conducted a genome-wide association study (GWAS) in two independent birth cohorts of diarrhea-associated E. histolytica infection. Cases were defined as children with at least one diarrheal episode positive for E. histolytica through either PCR or ELISA within the first year of life. Controls were children without any episodes positive for E. histolytica in the same time frame. Meta-analyses under a fixed-effects inverse variance weighting model identified variants in two neighboring genes on chromosome 10: CUL2 (cullin 2) and CREM (cAMP responsive element modulator) associated with E. histolytica infection, with SNP rs58000832 achieving genome-wide significance (Pmeta=4.2x10-10). Each additional risk allele (an intergenic insertion between CREM and CCNY) of rs58000832 conferred 2.5 increased odds of a diarrhea-associated E. histolytica infection. The most associated SNP within a gene was in an intron of CREM (rs58468685, Pmeta=2.3x10-9), which with CUL2, has been implicated as a susceptibility locus for Inflammatory Bowel Disease (IBD) and Crohns Disease. Gene expression resources suggest these loci are related to the higher expression of CREM, but not CUL2. Increased CREM expression is also observed in early E. histolytica infection. Further, CREM-/- mice were more susceptible to E. histolytica amebic colitis. These genetic associations reinforce the pathological similarities observed in gut inflammation between E. histolytica infection and IBD.

genetics↗