Biology subjects

Levesque, M. C.

Publications and source records attributed to Levesque, M. C..

4 recordsLinked to original sources

bioRxiv2025

IL-32 drives inflammatory responses in IFN-γ primed human macrophages via a Myddosome-dependent pathway and is elevated in COVID-19

IFN-{gamma} is secreted by multiple lymphoid subsets in response to antigen stimulation and can reprogram and prime macrophages epigenetically and transcriptionally to increase responses to inflammatory stimuli such as LPS, IL-1{beta} or TNF-. IFN-{gamma}-driven M1-like inflammatory macrophage states are shared across human immune-mediated inflammatory diseases (IMIDs) and while IFN-{gamma} is nonredundant for defense to intracellular pathogens it is unclear if this is also the case in IMIDs. To identify additional secreted ligands which could prime and induce M1-like macrophages we screened >600 human proteins in human primary macrophages. Using complementary functional genomics approaches, we discovered that IL-32{beta} induced an M1-like inflammatory state in non-primed and IFN-{gamma}-primed macrophages. IL-32{beta} induced signaling, transcriptional, tolerance, cross-tolerance, and inflammatory responses in macrophages which were MyD88, IRAK1 and Myddosome-dependent. These responses to host IL-32{beta} were similar to yet distinct from, those induced by microbial LPS. IL-32 protein was elevated in serum from patients with severe COVID-19 and IL-32{beta} together with IFN-{gamma} were expressed by T cells and induced a macrophage transcriptional response which was shared by monocytes and macrophages in mild and severe COVID-19.

immunology↗

bioRxiv2025

Clonal relationships between Tph and Tfh cells in patients with SLE and in murine lupus

Pathologic T cell-B cell interactions drive disease in systemic lupus erythematosus (SLE). The T cells that activate B cell responses include T peripheral helper (Tph) and T follicular helper (Tfh) cells, yet the developmental and clonal relationships between these B cell-helper T cell populations are unclear. Here we use T cell receptor (TCR) profiling to demonstrate substantial clonal overlap between Tph and Tfh cells in the circulation of patients with SLE. Expanded Tph and Tfh cell clones persist over the course of 1 year in patients with a new diagnosis of SLE, and clones are observed to shift both from Tfh to Tph cells and from Tph to Tfh cells over time. High resolution analysis of cells sorted as Tph cells (CXCR5- PD-1hi) from SLE patients revealed considerable heterogeneity among these cells and highlighted a subpopulation of cells with transcriptomic features of activated B cell-helper T cells. This cell population, marked by expression of TOX and CXCL13, was found in both sorted Tph and Tfh cells, and was clonally linked in these two populations. Analysis of B cell-helper T cells in murine pristane-induced lupus demonstrated similar populations of Tph and Tfh cells in both lung and spleen with strong clonal overlap. T cell-specific loss of Bcl6 prevented accumulation of Tfh cells and reduced accumulation of Tph cells in pristane-treated mice, indicating a role for Bcl6 in the survival and expansion of both populations. Together, these observations demonstrate a shared developmental path among pathologically expanded Tph and Tfh cells in SLE. The persistence of expanded Tph and Tfh cells clones over time may explain the lack of stable tolerance induction by immunosuppressive medications or by B cell depletion.

immunology↗

bioRxiv2022

The Clinical Response of Upadacitinib and Risankizumab is Associated with Reduced Inflammatory Bowel Disease Anti-TNFα Inadequate Response Mechanisms

Background and AimsJAK1 inhibitor upadacitinib and IL23 inhibitor risankizumab are efficacious in inflammatory bowel disease (IBD) patients who are anti-TNF inadequate responders (TNF-IR). We aimed to understand the mechanisms mediating the response of upadacitinib and risankizumab. MethodsEight tissue transcriptomic datasets from IBD patients treated with anti-TNF therapies along with single-cell RNAseq data from ulcerative colitis were integrated to identify TNF-IR mechanisms. RNAseq colon tissue data from clinical studies of TNF-IR Crohns disease patients treated with upadacitinib or risankizumab were used to identify TNF-IR mechanisms that were favorably modified by upadacitinib and risankizumab. ResultsWe found seven TNF-IR up-regulated modules (M1-M7) related to innate/adaptive immune responses, interferon signaling and tissue remodeling, and five TNF-IR down-regulated modules (M8-M12) primarily related to metabolism. TNF-IR up-regulated cell types were inflammatory fibroblasts, post-capillary venules, inflammatory monocytes, macrophages, dendritic cells, and cycling B cells while subtypes of immature enterocytes, WNT5B+ cells and myofibroblasts were TNF-IR down-regulated cell types. Upadacitinib was associated with a significant decrease in the expression of most TNF-IR up-regulated modules in JAK1 responders (JAK1-R); in contrast, there was no change in these modules among TNF-IR patients treated with a placebo or among JAK1 inadequate responders (JAK1-IR). In addition, four of the six TNF-IR up-regulated cell types were significantly decreased after upadacitinib treatment in JAK1-R but not among subjects treated with a placebo or among JAK1-IR patients. We observed similar findings from colon biopsy samples from TNF-IR patients treated with risankizumab. ConclusionsCollectively, these data suggest that upadacitinib and risankizumab affect TNF-IR up-regulated mechanisms, which may account for their clinical response among TNF-IR IBD patients.

immunology↗

bioRxiv2019

A Systems Immunology Approach Identifies Cytokine-Induced STAT Signaling Pathways Critical to Rheumatoid Arthritis Disease Activity and Treatment Response

Rheumatoid arthritis (RA), a chronic autoimmune disease characterized by circulating autoantibodies, involves many cytokine-mediated signaling pathways in multiple immune cell subsets. Most studies of immune cells in RA have limitations, such as analysis of a small number of cell subsets or pathways, and limited longitudinal data on patient phenotypes. In this study, we used an innovative systems immunology approach to simultaneously quantify up to 882 signaling nodes (Jak/STAT signaling readouts modulated by cytokines and other stimuli) in 21 immune cell subsets. We studied 194 RA patients and 41 controls, including 146 well-characterized RA patients prior to, and 6 months after, initiation of methotrexate or biologic agents from the Treatment Efficacy and Toxicity in RA Database and Repository (TETRAD). There was strikingly attenuated signaling capacity in RA patients in IFN stimulation followed by measurement of phosphorylated STAT1 [IFN[->]p-STAT1] in six immune cell subsets. Multiple nodes showed negative association with disease activity, including IFN[->]STAT5 signaling in naive and memory B cells. In contrast, IL-6-induced STAT1 and STAT3 activation in central memory CD4-negative T cells showed a positive association with disease activity. Multiple nodes were associated with treatment response, including IFN[->]STAT1 in monocytes and IL-6[->]STAT3 in CD4+ naive T cells. Decision tree analysis identified a model combining these two nodes as a high-performing classifier of treatment response to TNF inhibitors. Our study provides novel information on RA disease mechanisms and serves as a framework for the discovery and validation of biomarkers of treatment response in RA.

immunology↗