Biology subjects

Ochoa, S.

Publications and source records attributed to Ochoa, S..

4 recordsLinked to original sources

bioRxiv2026

Distinct EBV-Associated Phenotypes Due to a Novel Homozygous Missense Variant in CD27.

Biallelic deficiencies of CD27 and its ligand CD70 underlie selective susceptibility to Epstein-Barr virus (EBV) infection and its acute and chronic complications, underscoring their non-redundant roles in anti-EBV immunity. To date, 16 pathogenic CD27 variants have been reported. Here, we describe three patients from two unrelated families, homozygous for a novel loss-of-function (LOF) CD27 variant, resulting in substitution of serine 70 with proline (S70P). All three patients presented with EBV viremia and lymphoproliferative disease, with variable immune dysregulation or recurrent otosinopulmonary infections. One patient developed EBV-associated Hodgkin lymphoma. Functional studies demonstrated that the S70P variant impaired surface expression of CD27 and abolished CD70 binding, rendering complete LOF. Together, S70P represents a novel pathogenic CD27 variant causing autosomal recessive (AR) CD27 deficiency, characterized by a unified susceptibility to EBV yet variable clinical manifestations, ranging from chronic viremia to malignancy.

immunology↗

bioRxiv2025

Pro-endometriosis macrophage release of IL-33 is key for endometriosis pain and lesion formation

Endometriosis is a painful gynecological inflammatory disease affecting up to 10% of females. When released by sensory neurons, calcitonin gene-related peptide (CGRP) shapes immunity, a process known as neuroimmune communication. We previously showed that nociceptor-derived CGRP polarizes macrophages into pro-endometriosis macrophages (PEMs) that mediates endometrial epithelial (endo-epi) cell proliferation and pain. However, the key mediators involved in this PEM-induced cell proliferation were unknown. Using unbiased approaches, we discovered that nociceptor-derived CGRP induces PEMs to produce IL-33. IL-33 binding to its receptor ST2 is key for endometriotic lesion growth and pain during endometriosis in mice as anti-IL-33 antibody treatment reduced evoked and spontaneous pain as well as lesion size. Chemical or genetic ablation of nociceptors or macrophages also resulted in lower levels of lesion IL-33, demonstrating a neuroimmune-driven mechanism for IL-33 production during endometriosis. In humans, we found that IL-33 is correlated with increased number of glands and fibrosis in lesions and that IL-33 expression in macrophages is also associated with genetic risk of endometriosis. We also provided evidence that suggests a dual role for IL-33 in endometriosis, in which, it is initially required for lesion formation and later for lesion maintenance only, and associated pain. Therefore, targeting IL-33/ST2 signaling may effectively treat endometriosis pain.

neuroscience↗

bioRxiv2024

M2 Macrophages are Major Mediators of Germline Risk of Endometriosis and Explain Pleiotropy with Comorbid Traits

Endometriosis is a common gynecologic condition that causes chronic life-altering symptoms including pain, infertility, and elevated cancer risk. There is an urgent need for new non-hormonal targeted therapeutics to treat endometriosis, but until very recently, the cellular and molecular signatures of endometriotic lesions were undefined, severely hindering the development of clinical advances. Integrating inherited risk data from analyses of >450,000 individuals with [~]350,000 single cell transcriptomes from 21 patients, we uncover M2-macrophages as candidate drivers of disease susceptibility, and nominate IL1 signaling as a central hub impacted by germline genetic variation associated with endometriosis. Extensive functional follow-up confirmed these associations and revealed a pleiotropic role for this pathway in endometriosis. Population-scale expression quantitative trail locus analysis demonstrated that genetic variation controlling IL1A expression is also associated with endometriosis risk variants. Manipulation of IL1 signaling in state-of-the-art in vitro decidualized assembloids impacted epithelial differentiation, and in an in vivo endometriosis model, treatment with anakinra (an interleukin-1 receptor antagonist) resulted in a significant, dose-dependent reduction in both spontaneous pain and evoked pain. Together these studies highlight non-diagnostic cell types as central to endometriosis susceptibility and support IL1 signaling as an important actionable pathway for this disease.

immunology↗

bioRxiv2017

Co-mutation and exclusion analysis in human tumors, a means for cancer biology studies and treatment design

BackgroundMalignant tumors originate from genomic and epigenomic alterations, which lead to loss of control of the cellular circuitry. These alterations relate with each other in patterns of mutual exclusion and co-occurrence that affect prognosis and treatment response and highlight the need for multitargeted therapy. However, to the best of our knowledge, there are no systematic reports in the literature of co-dependent and mutually exclusive mutations across all types of cancer. In addition, the studies reported so far generally deal with whole genes instead of specific mutations, ignoring the fact that different alterations in the same gene can have widely different effects.\n\nResultsHere we present a systematic analysis of co-dependencies of somatic mutations across all cancer types. Combining multi testing with conditional and expected mutational probabilities, we have found pairs and networks of co-mutations and exclusions, some of them in particular types of cancer and others widespread. We have also determined that driver loci are present in more types of cancer than non driver loci, that they tend to pair within a single gene and that those pairs are more often exclusions than co-mutations.\n\nConclusionsBased on this properties, we propose new drivers that warrant experimental validation. Our analysis is potentially relevant for cancer biology and classification, as well as for the rational selection of multitargeted therapeutic approaches.

cancer biology↗