Barker, J. N. | Search bioRxiv

bioRxiv2025

Transcriptomic profiling and machine learning uncover gene signatures of psoriasis endotypes and disease severity

BackgroundDespite increased understanding of psoriasis pathogenesis, molecular classification of clinical phenotypes and disease severity is poorly defined. Knowledge gaps include whether molecular endotypes of psoriasis underlie distinct clinical phenotypes and the positive and negative molecular regulators of disease severity across tissue compartments. MethodsWe performed comprehensive RNA-sequencing of skin and blood (n=718) from prospectively-recruited, deeply-phenotyped discovery and replication cohorts of 146 subjects with moderate-to-severe psoriasis initiating TNF-inhibitor (adalimumab) or IL-12/23-inhibitor (ustekinumab) therapy. ResultsUsing two complementary methods for dimensionality reduction, we defined distinct but interconnected co-expression modules and factors within skin and blood that were significantly associated with disease phenotypes and disease severity, as measured by Psoriasis Area Severity Index (PASI). We identified a 14-gene signature negatively associated with BMI in nonlesional skin and disease severity in lesional skin, respectively. Genotype integration revealed that HLA-DQA1*01 and HLA-DRB1*15 genotypes were positively associated with baseline disease severity. Using Gaussian process regression followed by SHAP (SHapley Additive exPlanations), we defined two core drug independent and disease severity-associated gene modules in lesional skin - one positive, one negative - and a lesional 9-gene signature predictive of disease severity. Disease severity signatures in blood were only seen following adalimumab exposure, suggesting greater systemic impact of adalimumab compared to ustekinumab, in line with its side effect profile. In contrast, a gene signature in blood linked to HLA-C*06:02 status was independent of disease severity or drug. ConclusionsThese findings delineate gene-environmental and genetic effects on the psoriasis transcriptome linked to disease severity. Plain Language SummaryPsoriasis is a common and debilitating skin disease, linked to multiple other inflammatory conditions. A lot is known about the mechanism of psoriasis and its inherited and external influences. Despite this, doctors cannot yet offer personalised treatments as it has been difficult to discover whether biological pathways are associated with disease severity, response to treatment or a persons likelihood of having other linked diseases. To help address this, we collected skin and blood samples and the personal characteristics of a group of people with severe psoriasis across the United Kingdom. Using computer-based methods, we discovered common biological processes underlying different psoriasis types, including genes that connect psoriasis severity with obesity, and another set of genes that help predict disease severity.

systems biology↗

bioRxiv2022

Imbalanced immune response and dysregulation of neural functions underline fatal opportunistic encephalitis caused by astrovirus

The incidence of infections of the central nervous system (CNS) in humans is increasing due to emergence and reemergence of pathogens and an increase in the number of immunocompromised patients. Many viruses are opportunists and can invade the CNS if the immune response of the host is impaired. Here we investigate neuropathogenesis of a rare CNS infection in immunocompromised patients caused by astrovirus and show that it shares many features with another opportunistic infection of the CNS caused by human immunodeficiency virus. We show that astrovirus infects CNS neurons with a major impact on the brainstem. In the setting of impaired peripheral adaptive immunity, host responses in the astrovirus infected brain are skewed to the innate immune response with exuberant activation of microglia and macrophages. Astrovirus infection of neurons and responses by phagocytic cells lead to disrupted synaptic integrity, loss of afferent innervation related to infected neurons, and global impairment of both excitatory and inhibitory neurotransmission. The response employed in the CNS against opportunistic viruses, such as astrovirus and HIV, may be a common compensatory defense mechanism which inadvertently leads to loss of neural functions due to the hosts exuberant innate immune response to pathogens when adaptive immunity is impaired.

microbiology↗

bioRxiv2018

Interleukin-36 promotes systemic Type-I IFN responses in severe psoriasis.

Psoriasis is an immune-mediated skin disorder associated with severe systemic co-morbidities. Both chronic and acute forms of the disease are characterised by abnormal interleukin (IL)-36 signalling. While the mechanisms whereby IL-36 promotes cutaneous inflammation are well established, its systemic effects have not been investigated. To address this issue, we initially measured leukocyte gene expression in generalised pustular psoriasis, an acute disease variant caused by mutations of the IL-36 receptor antagonist. By undertaking whole-blood and neutrophil RNA-sequencing in affected individuals, we identified a Type-I IFN signature, which correlated with IL-36 signalling up-regulation. We then validated these observations in patients with chronic plaque psoriasis. Finally, we demonstrated that IL-36 acts directly on plasmacytoid dendritic cells, where it potentiates Toll-like Receptor (TLR)-9 activation and IFN production. This effect was mediated by the induction of PLSCR1, an endosomal TLR-9 transporter. These results define an IL-36/TLR-9/Type-I IFN axis that could be targeted for the treatment of psoriasis co-morbidities.

immunology↗