Biology subjects

van Doorn, R.

Publications and source records attributed to van Doorn, R..

4 recordsLinked to original sources

bioRxiv2023

Autoantibody subclass predominance is not driven by aberrant class switching or impaired B cell development

A subset of autoimmune diseases is characterized by predominant pathogenic IgG4 autoantibodies (IgG4-AIDs). Why IgG4 predominates in these disorders is unknown. We hypothesized that dysregulated B cell maturation or aberrant class switching causes overrepresentation of IgG4+ B cells and plasma cells. Therefore, we compared the B cell compartment of patients with muscle-specific kinase (MuSK) myasthenia gravis (MG), pemphigus, leucine-rich glioma inactivated (LGI1) encephalitis and contactin-associated protein-like 2 (CASPR2) encephalitis (four IgG4-AIDs) to patients with acetylcholine receptor (AChR) MG, Lambert-Eaton myasthenic syndrome (LEMS) (two IgG1-3-AIDs) and age-matched healthy donors, using flow cytometry. B cell subset relative abundance at all maturation stages was normal, except for a, possibly treatment-related, reduction in immature and naive CD5+ cells in IgG4-AIDs. IgG4+ B cell and plasma cell fractions were normal in IgG4-AID patients, however they had an (sub)class-independent 8-fold increase in circulating mature CD20-CD138+ plasma cells. No autoreactivity was found in this subset after sorting. In conclusion, patients with IgG4-AID do not show increased numbers of IgG4-expressing cells. These results argue against aberrant B cell development in these patients and rather suggest the autoantibody subclass predominance to be antigen-driven. The similarities between B cell subset numbers among these patients suggest that these IgG4-AIDs, despite displaying variable clinical phenotypes, share a similar underlying immune profile. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/546522v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1444429org.highwire.dtl.DTLVardef@d70867org.highwire.dtl.DTLVardef@168a7c0org.highwire.dtl.DTLVardef@1dd4483_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Melanin enhances metastatic melanoma colonization by inhibiting ferroptosis

Melanoma associated death is mainly caused by metastatic disease. Increased melanin levels are associated with decreased melanoma patient survival, yet the contribution of melanin to this process is unknown. Here we show that melanin protects circulating melanoma cells from ferroptosis, enhancing their metastatic potential. We observed that melanin levels in patient-derived uveal melanoma cells as well as cutaneous and conjunctival melanoma cell lines correlate with their metastatic potential in zebrafish xenografts. We find strong associations of the melanin biosynthesis gene TYRP1, ferroptosis related enzyme GPX4 and mitochondrial anion channel (VDAC1) with reduced melanoma-specific survival in TCGA data of cutaneous melanoma. Modulation of melanin levels significantly impacts melanoma metastatic potential, increasing or decreasing in concordance with melanin levels. Furthermore, melanin depletion significantly sensitized melanoma cells to ferroptosis leading to a decreased metastatic capacity and enhanced efficacy of ferroptosis induction based anti-cancer therapeutic strategies. Collectively, our results reveal that combined inhibition of melanin biosynthetic enzymes and induction of ferroptosis has potential as a treatment strategy of metastatic melanoma. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=148 SRC="FIGDIR/small/535376v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1fc21a5org.highwire.dtl.DTLVardef@502b6org.highwire.dtl.DTLVardef@f522beorg.highwire.dtl.DTLVardef@1bbfdfa_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Impact of pathogen genetics on clinical phenotypes in a population of Talaromyces marneffei from Vietnam

Talaromycosis, a severe and invasive fungal infection caused by Talaromyces marneffei, is difficult to treat and impacts those living in endemic regions of southeast Asia, India, and China. While 30% of infections result in mortality, our understanding of the genetic basis of pathogenesis for this fungus is limited. To address this, we apply population genomics and genome wide association study approaches to a cohort of 336 T. marneffei isolates collected from patients who enrolled in the Itraconazole versus Amphotericin B for Talaromycosis (IVAP) trial in Vietnam. We find that isolates from northern and southern Vietnam form two distinct geographical clades, with isolates from southern Vietnam associated with increased disease severity. Leveraging longitudinal isolates, we identify multiple instances of disease relapse linked to unrelated strains, highlighting the potential for multi-strain infections. In more frequent cases of persistent talaromycosis caused by the same strain, we identify variants arising over the course of patient infections that impact genes predicted to function in the regulation of gene expression and secondary metabolite production. By combining genetic variant data with patient metadata for all 336 isolates, we identify pathogen variants significantly associated with multiple clinical phenotypes. In addition, we identify genes and genomic regions under selection across both clades, highlighting loci undergoing rapid evolution, potentially in response to external pressures. With this combination of approaches, we identify links between pathogen genetics and patient outcomes and identify genomic regions that are altered during T. marneffei infection, providing an initial view of how pathogen genetics affects disease outcomes.

genomics↗

bioRxiv2019

Interplay between TERT promoter mutations and methylation culminates in chromatin accessibility and TERT expression

The telomerase reverse transcriptase (TERT) gene is responsible for telomere maintenance in germline and stem cells, and is re-expressed in 90% of human cancers. Contrary to common concepts, CpG methylation in the TERT promoter (TERTp), was correlated with TERT mRNA expression. Furthermore, two hotspot mutations in TERTp, dubbed C228T and C250T, have been revealed to assist binding of transcription factor ETS/TCF and subsequent TERT expression. This study aimed to elucidate the combined contribution of epigenetic (promoter methylation and higher-order chromatin structure) and genetic (promoter mutations) mechanisms in regulating TERT gene expression in healthy skin and in melanoma cell lines (n=61). We unexpectedly observed that the methylation of TERTp was as high in a subset of healthy skin cells, mainly keratinocytes, as in cutaneous melanoma cell lines. In spite of the high promoter methylation fraction in wild-type (WT) samples, TERT mRNA was only expressed in the melanoma cell lines with high methylation or intermediate methylation in combination with TERT mutations. TERTp methylation was positively correlated with chromatin accessibility and expression in 8 melanoma cell lines. Cooperation between epigenetic and genetic mechanisms were best observed in heterozygous mutant cell lines as chromosome accessibility preferentially concerned the mutant allele. Combined, these results suggest a complex model in which TERT expression requires either a widely open chromatin state throughout the promoter in TERTp-WT samples due to high methylation or a combination of moderate methylation fraction/chromatin accessibility in the presence of the C228T/C250T mutations. Author summaryPvdV and RvD formulated research goals and aims and supervised the overall progress. Wet-lab experiments, preparation of the manuscript and statistical analysis were performed by CS and CR. CS designed the novel assays. RN was involved in the experimental setup. RvD, NG and PvdV were responsible for funding acquisition. CR, RN, NG, RvD and PvdV critically reviewed the manuscript.

cancer biology↗