Présentation de l'équipe
Summary
Our research focuses on the pathophysiology of inflammatory and allergic skin diseases, particularly eczema (contact eczema and atopic eczema), drug allergy, and more recently a neutrophilic dermatosis, hidradenitis suppurativa, also known as Verneuil disease. These conditions result from a failure of immune tolerance toward allergens present in our everyday environment.
Eczema (contact eczema / atopic eczema) (Figure 1).
Contact eczema is induced by chemical compounds, known as haptens, which possess reactive functions capable of binding to self proteins. Atopic eczema, more commonly referred to as atopic dermatitis, is triggered by contact with environmental proteins (house dust mites, flour, pollens, cat dander, etc.). Both diseases are very common inflammatory dermatoses in industrialized countries. They are defined as delayed-type hypersensitivity reactions. Indeed, whereas the vast majority of individuals do not develop adaptive immunity—and therefore do not generate effector T lymphocytes (T cells)—following repeated exposure to allergens (tolerance), these inflammatory dermatoses are induced, in sensitized patients, by the recruitment and activation of cytotoxic T lymphocytes (CTLs) in the skin. These CTLs are capable of inducing apoptosis of keratinocytes presenting the allergen, which represents a major immunohistological hallmark of eczema.
Drug allergy (Figure 2).
There are many forms of drug allergy. Our research focuses more specifically on severe cutaneous adverse drug reactions, including (i) maculopapular exanthema (MPE), which is frequent but usually benign, and (ii) DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) and (iii) toxic epidermal necrolysis (TEN), which are rare and severe conditions that are life-threatening in up to 30% of cases. The pathophysiological mechanisms leading to the development of these diseases after oral or parenteral drug administration remain poorly understood, in particular due to the lack of appropriate experimental models. The current paradigm suggests that symptoms develop through mechanisms similar to those described in eczema, with a central role played by drug-specific T cells in the development of skin lesions.
Hidradenitis suppurativa (Figure 3).
Hidradenitis suppurativa (HS) is a chronic, debilitating skin disease associated with the development of painful, purulent inflammatory lesions in skin folds (axillae, groin, inframammary folds). HS lesions are characterized by inflammation of the pilosebaceous unit of variable severity, with the progressive development of folliculitis, nodules, abscesses, and fistulas in the most advanced stages.
With a profound impact on quality of life and a prevalence of approximately 1%, HS represents a major public health issue, with limited therapeutic options currently available. The pathogenesis of HS remains poorly understood to date: the pilosebaceous tropism of the disease and the fact that patients respond to combinations of antibiotics and/or immunosuppressive treatments suggest the involvement of three closely interrelated factors: (i) the presence of microbial dysbiosis, (ii) dysfunction of the pilosebaceous unit, and (iii) an inappropriate immune response.
Aims and applications of our research.
Our research focuses on tissue-infiltrating lymphocytes (TILs), including tissue-resident memory T cells (TRMs), which are key players in the development of the diseases we study. TILs and TRMs produce multiple inflammatory mediators (type 1, 2, or 17 cytokines, and cytotoxic proteins) that initiate and shape the clinical manifestations of these conditions. Our projects aim to decipher the mechanisms by which environmental antigens particularly chemical allergens (haptens, drugs) or protein allergens—as well as irritants, pollutants, and the skin microbiome, stimulate or, conversely, bypass immune tolerance to induce inflammatory and/or allergic responses. To address these questions, we rely on a broad toolbox combining 2D and 3D in vitro skin models, murine models, and patient-derived samples. Ultimately, our work aims to support the development of new diagnostic and/or therapeutic strategies for these diseases.
RESEARCH THEMES
Cutaneous inflammation, eczema, drug allergy, hidradenitis suppurativa, T lymphocytes, immune tolerance
Research strategy.
Our laboratory has long-standing expertise in the use and development of preclinical models of inflammatory and allergic skin diseases, as well as in conducting clinical and translational studies in patients. In this context, we work in close collaboration with four clinical teams based at Lyon-Sud and Édouard Herriot hospitals, together forming the Department of Allergology, Clinical Immunology and Dermatology:
a) Department of Allergology and Clinical Immunology, Lyon-Sud Hospital, headed by Frédéric Bérard and Audrey Nosbaum. This is an expert center dedicated to the management of inflammatory and allergic skin diseases, as well as to training in allergology. Approximately 2,000 hospitalized patients per year and 5,000 outpatient consultations per year. Several cohorts of patients with eczema or drug allergy.
b) Department of Dermatology, Édouard Herriot Hospital, headed by Denis Jullien. This is an expert center dedicated to the management of dermatological diseases. Approximately 1,000 hospitalized patients per year and 14,000 outpatient consultations per year. Several patient cohorts with hidradenitis suppurativa or other neutrophilic dermatoses.
c) Clinical Research Unit “Lyrec,” Lyon-Sud Hospital, Head: Sophie Gilibert. Approximately 400 patients or healthy volunteers enrolled per year. More than 30 clinical studies conducted in recent years.
d) “Allergobiotec” Biobank (Hospices Civils de Lyon – Inserm), with 6,400 stored samples, which has been replaced since 2023 by the “ImmunoPeau” Biobank, a Biological Resource Center at Lyon-Sud Hospital.
e) Reference Center for Severe Drug Allergies (Toxibul), headed by Denis Jullien, Benoît Ben-Saïd, and Marie Tauber, Édouard Herriot Hospital. Approximately 500 patients per year with severe, life-threatening conditions (e.g., toxic epidermal necrolysis and DRESS syndrome).
The scientific objectives of the Department of Allergology, Clinical Immunology and Dermatology are: (i) to improve patient care; (ii) to develop basic and clinical research; (iii) to promote education and training in allergology and immunology, particularly in the fields of drug allergy, immunodermatology, and immunotherapy; and (iv) to foster communication and interactions with patient associations and the general public. Further information on all our clinical, scientific, and societal activities is available at: https://allergolyon.fr/.
RECENT RESULTS
Pathophysiology of Cutaneous Allergy.
All of our work to date has contributed to a better understanding of the pathophysiology of cutaneous allergic diseases (Figure 4).
Our early findings showed in particular that allergen-specific cytotoxic CD8⁺ T cells (CTLs) are the main effectors of cutaneous allergy and play a key role in the initiation of eczema (Scheinman et al., Nat Rev Dis Primers, 2021).
Over the past five years, we have (i) confirmed the central role of CTLs in cutaneous allergy, (ii) characterized the contribution of skin tissue-resident memory T cells (TRMs) to the chronicity of eczema, and (iii) analyzed the role of the epithelium (UV-derived cis-urocanic acid), as well as specific subsets of skin dendritic cells, in the initiation and regulation of cutaneous allergic responses.
CD8⁺ CTLs are major effector cells in drug-induced cutaneous allergy. Our recent results have confirmed these observations and extended them to severe cutaneous adverse drug reactions (Cadot et al., Allergy, 2024; Vocanson et al., J Allergy Clin Immunol, 2020). We demonstrated that both the quantity (highly expanded T-cell clones) and the quality (high cytotoxic potential) of drug-specific CD8⁺ T cells activated in patients with toxic epidermal necrolysis (TEN) (clinical study, 32 patients) determine disease severity (Villani et al., Sci Adv, 2021). Importantly, this study allowed us to identify biomarkers expressed by pathogenic T cells that may serve as future therapeutic targets for TEN (Inserm Transfert patent PCT/EP2021/083093). We are currently setting up a phase I/II clinical trial using a marketed therapeutic antibody targeting one of these biomarkers on cytotoxic CD8⁺ T cells from TEN patients (PHRCi, Hospices Civils de Lyon). With this new therapeutic approach, we aim to block or limit disease progression and long-term sequelae in patients with TEN.
Skin TRMs, which persist for months within the skin, are responsible for disease severity and chronicity in cutaneous allergic diseases. Using both preclinical models and samples from patients with eczema (contact eczema and atopic dermatitis), we showed that allergen-specific CTLs, as well as other tissue-infiltrating lymphocytes producing type-17 or type-2 cytokines, accumulate as tissue-resident memory T cells at sites of previously affected skin. These TRMs are responsible for disease flares and exacerbations upon renewed allergen exposure (Gamradt et al., J Allergy Clin Immunol, 2019; Lefevre et al., Curr Opin Allergy Clin Immunol, 2021; Nosbaum et al., Eur J Dermatol, 2021; Patra et al., Front Med, 2022). Interestingly, microbiota-specific TRMs (directed against Staphylococcus aureus) that accumulate in atopic dermatitis skin are not only pathogenic but also protective, as they limit bacterial colonization (Braun et al., J Allergy Clin Immunol, 2024). Finally, we recently demonstrated that standard therapies such as topical corticosteroids, which have been successfully used for years to treat allergic inflammation, are ineffective at preventing the generation, maintenance, and expansion of allergen-specific TRMs (Ono et al., Allergy, 2021). These fundamental studies, which fostered major collaborations for the team, form the basis of our current research program aimed at better understanding the mechanisms underlying TRM generation and long-term survival, and at developing new strategies to specifically target TRMs.
CD8⁺ regulatory T cells: an additional UV-induced layer of regulation controlling CTL-driven cutaneous allergy.
In the past, we actively investigated regulatory and tolerance mechanisms controlling CTL activation or promoting the resolution of cutaneous inflammation (Vocanson et al., J Allergy Clin Immunol, 2011). More recently, we identified an additional regulatory layer beyond conventional CD4⁺FOXP3⁺ regulatory T cells, mediated by CD8⁺ regulatory T cells activated by dendritic cells during extracorporeal photochemotherapy (psoralen plus UVA irradiation). This therapy is commonly used by our clinicians to treat patients with cutaneous T-cell lymphoma or to manage allograft rejection (Hequet et al., Eur J Immunol, 2020).
Epithelial immunity plays a key role in the initiation and regulation of allergic responses.
The production of cytokines or early inflammatory mediators by epidermal cells is considered a triggering event in allergic responses. We recently focused on detoxification mechanisms in the skin and demonstrated that a deficiency in the Nrf2 protein in Langerhans cells is sufficient to initiate an allergic response to weak chemical sensitizers (collaboration with S. Kerdine-Romer, Paris Saclay). We also investigated interactions between cis-urocanic acid (cis-UCA), a major UVB photoproduct with potent immunomodulatory properties, and skin bacteria. By modulating cis-UCA concentrations at the skin surface, bacteria expressing an enzyme called urocanase reduce the anti-inflammatory and tolerogenic properties of cis-UCA. Notably, topical application of a urocanase inhibitor prevents cis-UCA metabolism by urocanase-positive bacteria and restores its immunomodulatory activity. Such inhibitors could be incorporated into dermo-cosmetic or cosmetic creams to enhance the beneficial effects of sunlight, or used during UV phototherapy protocols for the treatment of inflammatory skin diseases (Patra et al., J Invest Dermatol, in press; Patra et al., Sci Rep, 2023; Inserm Transfert patent EP24306213.0).
Translational research on inflammatory and allergic skin diseases.
Building on our knowledge of the pathophysiology of cutaneous inflammation, we have been developing for several years a range of tools aimed at improving the prognosis, diagnosis, treatment, and prevention of our diseases of interest.
Development of new diagnostic tests for cutaneous allergy.
We recently characterized the molecular signatures of chemical-induced cutaneous inflammation and conducted three translational clinical studies involving more than 100 patients with contact eczema, either during the active phase of the disease or in the context of allergological work-ups. Our results showed that distinct pathways characterize allergic versus irritant contact dermatitis (Galbiati et al., Arch Toxicol, 2023; Lefevre et al., Allergy, 2021), and that molecular profiling of skin lesions helps strengthen clinical diagnosis (Lefevre et al., J Am Acad Dermatol, 2024; Lefevre et al., Contact Dermatitis, 2022). We are currently working on the development of a new rapid diagnostic test that could be used in routine clinical practice.
Development of new allergen-specific immunotherapy approaches to restore cutaneous tolerance in allergic patients.
The development of new therapeutic strategies is one of our major objectives. We therefore investigated the mechanisms underlying the efficacy of allergen-specific immunotherapy. Using a preclinical model of epicutaneous immunotherapy (EPIT), we demonstrated that the acquisition of functional specialization by skin dendritic cells during EPIT is a cornerstone of the desensitization process (Laoubi et al., J Allergy Clin Immunol, 2022).
Evaluation of new therapeutic approaches for inflammatory skin diseases.
In parallel, over the past few months, we have explored the pathophysiology of inflammatory skin diseases with unclear etiology, such as eosinophilic cellulitis (EC, also known as Wells syndrome, a rare eosinophilic dermatosis) and chronic hand eczema (CHE), a common and highly heterogeneous condition affecting the hands, with multifactorial origins and triggered by endogenous/genetic factors or exogenous/environmental exposures. We also evaluated the efficacy of novel therapies in these conditions. We showed that EC lesions are characterized by marked type 2 inflammation and preferential activation of the JAK1/JAK2–STAT5 pathways, supporting the therapeutic potential of JAK1/JAK2-targeted approaches in patients with EC (Morot et al., JAMA Dermatol, 2023). In addition, we discovered that skin lesions from patients with CHE share complex transcriptomic signatures with those observed in atopic dermatitis and psoriasis, and we demonstrated robust efficacy of dupilumab (a therapeutic antibody targeting the IL-4Rα receptor), regardless of a history of atopic dermatitis or environmental triggers (Géry et al., under submission; phase 2b randomized, multicenter, double-blind, placebo-controlled clinical trial including 94 patients with CHE).
Covid-19
Although COVID-19 was not our primary field of interest, during the pandemic we investigated the impact of therapeutic plasma exchange (TPE) on immune cell recovery and the development of appropriate antiviral responses in patients with severe COVID-19 (Guironnet-Paquet et al., Frontiers in Immunology, 2025).