
Darragh DuffyInstitut Pasteur · Department of Immunology
Darragh Duffy
PhD Immunology
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Publications (305)
Objective
The objective of this study was to evaluate the presence of different types of interferon in idiopathic inflammatory myopathies (IIM) and their subgroups using ultrasensitive cytokine detection techniques (SIMOA) and to assess their potential as activity biomarkers.
Methods
Disease activity was measured at the time of serum collection an...
Objective
Endogenous retroelements (EREs) stimulate type 1 interferon (IFN‐I) production but have not been explored as potential interferonogenic triggers in rheumatoid arthritis (RA). We investigated ERE expression in early RA (eRA), a period in which IFN‐I levels are increased.
Methods
ERE expression (long terminal repeat [LTR] 5, long intersper...
Introduction
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by an overactive immune response, particularly involving excessive production of type I interferons. This overproduction is driven by the phosphorylation of IRF7, a crucial factor in interferon gene activation. Current treatments for SLE are often not very effect...
Autoantibodies against cytokines (c‐aAb) have been implicated in the pathophysiology of autoimmune diseases, and a variety of infections. In addition, several independent studies have detected elevated titers of c‐aAb in the circulation of healthy individuals. To further understand their impact on immune responses, we measured c‐aAb against IFN‐α,...
Background: Gastrointestinal mucosal damage due to human immunodeficiency virus (HIV) infection leads to microbial translocation and immune activation, contributing to the development of non-infectious comorbidities (NICM) in people living with HIV (PLWH). Additionally, persistent proviral HIV-1 in the gut-associated lymphatic tissue (GALT) can tri...
Steroid hormone levels vary greatly among individuals, between the sexes, with age, and across health and disease states. Nevertheless, what drives variance in steroid hormones and, globally, how steroid hormones vary in an individual over time are not well-studied. To address this fundamental gap in knowledge, we measured the levels of 17 steroid...
Human immune responses are highly variable from one individual to another, with these differences determined by both genetic and environmental factors. We previously established the Milieu Interieur cohort to define the boundaries of healthy immune responses and identify and quantify its different determinants. From this cohort of 1,000 well-define...
Immune responses are highly variable from one individual to another, with this variability determined by factors such as age, sex, genetics and environment, which also affect physical and mental well-being. Systems immunology studies have been applied to human cohort studies to better understand these effects, but most are performed in Western popu...
Infectious, inflammatory and autoimmune conditions present differently in males and females. SARS-CoV-2 infection in naive males is associated with increased risk of death, whereas females are at increased risk of long COVID¹, similar to observations in other infections². Females respond more strongly to vaccines, and adverse reactions are more fre...
Hereditary C1q deficiency (C1QDef) is a rare monogenic disorder leading to defective complement pathway activation and systemic lupus erythematosus (SLE)-like manifestations. The link between impairment of the complement cascade and autoimmunity remains incompletely understood. Here, we assessed type 1 interferon pathway activation in patients with...
Inherited deficiency of the RNA lariat–debranching enzyme 1 (DBR1) is a rare etiology of brainstem viral encephalitis. The cellular basis of disease and the range of viral predisposition are unclear. We report inherited DBR1 deficiency in a 14-year-old boy who suffered from isolated SARS-CoV-2 brainstem encephalitis. The patient is homozygous for a...
Individuals with low socioeconomic status (SES) are at greater risk of contracting and developing severe disease compared with people with higher SES. Age, sex, host genetics, smoking and cytomegalovirus (CMV) serostatus are known to have a major impact on human immune responses and thus susceptibility to infection. However, the impact of SES on im...
Background
SITRAME (Systemic Inflammatory Truncular Recurrent Acute Macular Eruption) syndrome is a newly described disease [1]. Patients present in adulthood with recurrent flares of the disease associated with stereotypical truncal macular eruption, fever and fatigue. Flares are most commonly triggered by viral infection or injection of the mRNA...
Aicardi-Goutières syndrome (AGS) is an autoinflammatory disease characterized by aberrant interferon (IFN)-α production. The major cause of morbidity in AGS is brain disease, yet the primary source and target of neurotoxic IFN-α remain unclear. Here, we demonstrated that the brain was the primary source of neurotoxic IFN-α in AGS and confirmed the...
Multivariate analysis is becoming central in studies investigating high-throughput molecular data, yet, some important features of these data are seldom explored. Here, we present MANOCCA (Multivariate Analysis of Conditional CovAriance), a powerful method to test for the effect of a predictor on the covariance matrix of a multivariate outcome. The...
Background
Ageing leads to altered immune responses, resulting in higher susceptibility to certain infections in the elderly. Immune ageing is a heterogeneous process also associated with inflammaging, a low-grade chronic inflammation. Altered cytotoxic T cell responses and cytokine storm have previously been described in severe COVID-19 cases, how...
The gut microbiome is a complex ecosystem whose members develop local interactions to form coherent functional communities. Variability in these communities, typically investigated through taxa co-abundance, might provide critical insights on the biological links between the gut microbiome and human phenotypes. However, existing methods to investig...
Vaccine-preventable diseases (VPDs) and common viral infections (CVIs) pose substantial public health challenges. Despite data collected through routine vaccination programs and through hospital-based case reporting systems, the understanding of population-level immunity to VPDs and CVIs remains limited. To address this challenge, this study focuse...
Individuals differ widely in their immune responses, with age, sex and genetic factors having major roles in this inherent variability 1–6 . However, the variables that drive such differences in cytokine secretion—a crucial component of the host response to immune challenges—remain poorly defined. Here we investigated 136 variables and identified s...
Acquired mutations in the UBA1 gene were recently identified in patients with severe adult-onset auto-inflammatory syndrome called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). However, the precise physiological and clinical impact of these mutations remains poorly defined. Here we study a unique prospective cohort of VEXAS pati...
Objectives: Endogenous retroelements (EREs) stimulate type 1 interferon (IFN-I) production but have not been explored as potential interferonogenic triggers in Rheumatoid Arthritis (RA). We investigated ERE expression in early RA (eRA), a period where IFN-I is increased.
Methods: ERE expression in DMARD naive eRA whole blood (LINE1, RT-PCR) and bul...
Inherited deficiency of the RNA lariat-debranching enzyme 1 (DBR1) is a rare etiology of brainstem viral encephalitis. The cellular basis of disease and the range of viral predisposition are unclear. We report inherited DBR1 deficiency in a 14-year-old boy who suffered from isolated SARS-CoV-2 brainstem encephalitis. The patient is homozygous for a...
Candida albicans is a commensal yeast present in the gut of most healthy individuals but with highly variable concentrations. However, little is known about the host factors that influence colonization densities. We investigated how microbiota, host lifestyle factors, and genetics could shape C. albicans intestinal carriage in 695 healthy individua...
This study was conducted to identify the contribution of myositis-specific antibodies (MSAs) on the correlation between type I interferon (IFN-I) plasma levels and disease activity in juvenile dermatomyositis (JDM) patients. We prospectively obtained 198 samples from 49 JDM patients. Autoantibody levels were determined for all patients. Muscle acti...
Immunoglobulins are among the most important anti-viral effectors of the human immune system. The biological mechanisms underlying antibody production and maintenance are relatively well understood. However, a broader model of how host intrinsic factors and external processes influence humoral responses to viral infections is lacking. Here, we inve...
While anti‐SARS‐CoV‐2 antibody kinetics have been described in large populations of vaccinated individuals, we still poorly understand how they evolve during a natural infection and how this impacts viral clearance. For that purpose, we analyzed the kinetics of both viral load and neutralizing antibody levels in a prospective cohort of individuals...
Flow cytometry is the method of choice for immunophenotyping in the context of clinical, translational, and systems immunology studies. Among the latter, the Milieu Intérieur (MI) project aims at defining the boundaries of a healthy immune response to identify determinants of immune response variation. MI used immunophenotyping of a 1000 healthy do...
Introduction
Among immune cells, activated monocytes play a detrimental role in chronic and viral-induced inflammatory pathologies, particularly in Juvenile Idiopathic Arthritis (JIA), a childhood rheumatoid arthritis (RA) disease. The uncontrolled activation of monocytes and excessive production of inflammatory factors contribute to the damage of...
Multivariate analysis is becoming central in studies investigating high-throughput molecular data, yet, some important features of these data are seldom explored. Here, we present MANOCCA (Multivariate Analysis of Conditional CovAriance), a powerful method to test for the effect of a predictor on the covariance matrix of a multivariate outcome. The...
Humans display substantial interindividual clinical variability after SARS-CoV-2 infection1–3, the genetic and immunological basis of which has begun to be deciphered⁴. However, the extent and drivers of population differences in immune responses to SARS-CoV-2 remain unclear. Here we report single-cell RNA-sequencing data for peripheral blood monon...
Familial adenomatous polyposis (FAP) is an inherited disease characterized by the development of large number of colorectal adenomas with high risk of evolving into colorectal tumors. Mutations of the Adenomatous polyposis coli (APC) gene is often at the origin of this disease, as well as of a high percentage of spontaneous colorectal tumors. APC i...
The need to understand the mechanisms and pathways of immune responses in pathogenic conditions such as cancer and autoimmunity requires awareness of natural immune variability in healthy subjects. To this end, various systems immunology studies have been established. Among them, the Milieu Interieur (MI) study was established to define the boundar...
Oxylipins are major immunomodulating mediators, yet studies of inflammation focus mainly on cytokines. Here, using a standardized whole-blood stimulation system, we characterized the oxylipin-driven inflammatory responses to various stimuli and their relationships with cytokine responses. We performed a pilot study in 25 healthy individuals using 6...
Type I IFNs are critical for host responses to viral infection and are also implicated in the pathogenesis of multiple autoimmune diseases. Multiple subtypes exist within the type I IFN family, in particular 13 distinct IFN‐α genes, which signal through the same heterodimer receptor that is ubiquitously expressed by mammalian cells. Both evolutiona...
Background:
Gain of function (GOF) variants of JAK1 drive a rare immune dysregulation syndrome associated with atopic dermatitis, allergy and eosinophilia.
Objectives:
To describe the clinical and immunological characteristics associated with a new GOF variant of JAK1 and report the therapeutic efficacy of JAK inhibition.
Methods:
We identifie...
The paradigm type I interferonopathy Aicardi-Goutières syndrome (AGS) is most typically characterized by severe neurological involvement. AGS is considered an immune-mediated disease, poorly responsive to conventional immunosuppression. Premised on a chronic enhancement of type I interferon signaling, JAK1/2 inhibition has been trialed in AGS, with...
Background
While anti-SARS-CoV-2 antibody kinetics have been well described in large populations of vaccinated individuals, we still poorly understand how they evolve during a natural infection and how this impacts viral clearance.
Methods
For that purpose, we analyzed the kinetics of both viral load and neutralizing antibody levels in a prospecti...
Systemic lupus erythematosus (SLE) is characterized by increased expression of type I interferon (IFN)-regulated genes in 50%–75% of patients. We report that out of 501 patients with SLE analyzed, 73 (14%) present autoantibodies against IFNα (anti-IFN-Abs). The presence of neutralizing-anti-IFN-Abs in 4.2% of patients inversely correlates with low...
Dear Editor, Data on osteonecrosis (ON) in JDM are limited [1]. It is usually considered as the result of corticosteroid therapy. Herein, we report a case series of five patients among a cohort of 71 patients with JDM who developed severe ON. All of them had anti-MDA5 positive JDM, which suggests that MDA5-positive JDM patients may have predisposin...
Objective:
Myasthenia gravis (MG) is a neuromuscular disease mediated by antibodies against the acetylcholine receptor (AChR). The thymus plays a primary role in AChR-MG and is characterized by a type I interferon (IFN) signature linked to IFN-β. We investigated if AChR-MG was characterized by an IFN-I signature in the blood, and further investiga...
Tuberculosis (TB) remains a major public health problem and we lack a comprehensive understanding of how Mycobacterium tuberculosis (M. tb) infection impacts host immune responses. We compared the induced immune response to TB antigen, BCG and IL-1β stimulation between latently M. tb infected individuals (LTBI) and active TB patients. This revealed...
Introduction
Juvenile systemic lupus erythematosus (j-SLE) is a rare chronic autoimmune disease affecting multiple organs. Ranging from minor features, such as headache or mild cognitive impairment, to serious and life-threatening presentations, j-neuropsychiatric SLE (j-NPSLE) is a therapeutic challenge. Thus, the diagnosis of NPSLE remains diffic...
Introduction
Des mutations acquises du gène UBA1, survenant dans les cellules myéloïdes et entraînant l’expression d’une isoforme catalytiquement altérée de l’enzyme E1, ont été récemment identifiées chez des patients atteints d’un syndrome auto-inflammatoire sévère survenant à l’âge adulte et appelé VEXAS (vacuoles, enzyme E1, X-linked, autoinflam...
Objective
Primary Sjögren's syndrome (SS) is the second most frequent systemic autoimmune disease, affecting 0.1% of the general population. To characterize the molecular and clinical variabilities among patients with primary SS, we integrated transcriptomic, proteomic, cellular, and genetic data with clinical phenotypes in a cohort of 351 patients...
Natural resistance to infection is an overlooked outcome after hepatitis C virus (HCV) exposure. Between 1977 and 1979, 1,200 Rhesus D-negative Irish women were exposed to HCV-contaminated anti-D immunoglobulin. Here, we investigate why some individuals appear to resist infection despite exposure (exposed seronegative [ESN]). We screen HCV-resistan...
Acquired mutations in the UBA1 gene, occurring in myeloid cells and resulting in expression of a catalytically impaired isoform of the enzyme E1, were recently identified in patients with severe adult-onset auto-inflammatory syndrome called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). The precise physiological and clinical impa...
Environmental enteric dysfunction (EED) is an inflammatory syndrome postulated to contribute to stunted child growth and to be associated with intestinal dysbiosis and nutrient malabsorption. However, the small intestinal contributions to EED remain poorly understood. This study aimed to assess changes in the proximal and distal intestinal microbio...
Purpose
Type I IFNs and their autoantibodies are implicated in the pathogenesis of Systemic lupus erythematosus (SLE), but their incidence and importance is still unclear. Neutralizing autoantibodies against IFNα have been previously reported in patients with autoimmune polyendocrinopathy syndrome type I (APS-1), rheumatoid arthritis, thymoma and m...
S10.3 The mycobiome characterization: future perspectives or just a trend?, September 24, 2022, 10:30 AM - 12:00 PM
Objectives
Candida albicans is both a harmless commensal intestinal yeast in healthy individuals and a harmful opportunistic pathogen in immunocompromised patients, causing life-threatening invasive candidiasis. C. albicans intestina...
Objectives:
An interferon (IFN) gene signature (IGS) is present in approximately 50% of early, treatment naive rheumatoid arthritis (eRA) patients where it has been shown to negatively impact initial response to treatment. We wished to validate this effect and explore potential mechanisms of action.
Methods:
In a multicentre inception cohort of...
Stunting and environmental enteric dysfunction (EED) may be responsible for altered gut and systemic immune responses. However, their impact on circulating immune cell populations remains poorly characterized during early life. A detailed flow cytometry analysis of major systemic immune cell populations in 53 stunted and 52 non-stunted (2 to 5 year...
Background
An interferon gene signature (IGS) is present in approximately 50% of early, treatment naive rheumatoid arthritis (eRA) patients. We previously demonstrated it negatively impacts on initial disease outcomes.
Objectives
To 1) reproduce previous findings demonstrating the harmful effects of the IGS on early RA clinical outcomes, 2) identi...
Host immunity to infection with SARS-CoV-2 is highly variable, dictating diverse clinical outcomes ranging from asymptomatic to severe disease and death. We previously reported that reduced blood type I interferon (IFN-I) in severe COVID-19 patients preceded clinical worsening. These results were supported by studies which identified genetic mutati...
SignificanceThere is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the ris...
The Rhesus D antigen (RhD) has been associated with susceptibility to several viral infections. Reports suggest that RhD-negative individuals are better protected against infectious diseases and have overall better health. However, potential mechanisms contributing to these associations have not yet been defined. Here, we used transcriptomic and ge...
NLRP3 inflammasome is suggested to contribute to the complex pathogenesis of systemic lupus erythematosus, but its role in cutaneous lupus erythematosus has not been addressed. This study investigated the expression of NLRP3 inflammasome components and levels of type I interferons in the skin of 20 patients with cutaneous lupus erythematosus. Expre...
Background
Blood plasma proteins play an important role in immune defense against pathogens, including cytokine signaling, the complement system, and the acute-phase response. Recent large-scale studies have reported genetic (i.e., protein quantitative trait loci, pQTLs) and non-genetic factors, such as age and sex, as major determinants to inter-i...