Team BOUAZIZ

Cutaneous Immunity and Inflammation

We decipher the immunological endotypes of severe dermatoses (nodular prurigo, interface dermatitis) through a systems immunology approach, in order to identify predictive biomarkers of severity and response to biotherapies, and to guide precision medicine.

In collaboration with Dr Reem Al-Daccak, we characterize, using the same systems immunology approach, the immune signatures associated with healthy aging in blood and skin, in order to understand the determinants of systemic and cutaneous resilience versus persistent inflammation. We also seek to identify translatable targets and levers capable of modulating and slowing age-associated persistent inflammation, and to guide the development of intervention strategies.

Approaches: We use systems immunology, which combines multiparametric cellular phenotyping (cytometry) and multi-omics profiling. In blood, we integrate transcriptomics (bulk and single-cell), proteomics, and metabolomics; in skin, we combine transcriptomics and tissue analyses with measurements of the cutaneous microbiome, as well as proteomic/metabolomic approaches where relevant.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare and severe disease caused by mutations in type VII collagen. It manifests as extreme fragility of the skin and mucous membranes, slow healing, and persistent ulcerations. Beyond these symptoms, abnormalities of the immune system and inflammatory response worsen the disease and promote chronic complications. In collaboration with Dr H. Le Buanec, our project aims to better understand the immune pathophysiology of RDEB in order to develop innovative therapeutic strategies. We analyze blood and skin samples from adult patients followed at the MAGEC National Reference Center – Saint-Louis Hospital, in comparison with healthy donors. Using state-of-the-art high-dimensional techniques — single-cell mass cytometry (CyTOF), mass imaging (Hyperion), energy metabolism profiling (SCENITH), and lipidomics — we map immune populations and their functional activity. The data are then integrated via artificial intelligence to define the global immunological signature of patients and identify mechanisms that could guide new targeted therapeutic approaches. Our ultimate goal is to reduce symptoms, improve healing and quality of life for patients, while paving the way for less invasive and more effective interventions.

Reprogramming the immune system to promote healing and tissue regeneration constitutes a promising strategy for RDEB patients. We are testing the hypothesis that extracellular vesicles (EVs/Exs) derived from primary trophoblasts and their HIPEC model cell line can — by reducing inflammation and restoring appropriate immune responses — represent an innovative, cell-free strategy to relieve RDEB symptoms and improve patients’ health and quality of life. We study their impact on adaptive and innate immune cells, their capacity to promote healing, and their role in modulating lipid metabolism, which is essential for immune cell activation and function. In parallel, we identify the active components of EVs/Exs — proteins and microRNAs — responsible for their regulatory activity, through omics approaches and targeted experiments. This work aims to lay the groundwork for an innovative acellular therapy capable of restoring immune homeostasis and supporting tissue repair in RDEB patients.

ImmuneSkinBank is a prospective translational cohort conducted at Saint-Louis Hospital, including 600 patients with moderate-to-severe inflammatory skin diseases. The 10-year longitudinal follow-up with repeated sampling enables a multi-omic approach integrating cutaneous transcriptomics, immunophenotyping of lymphocytic and neutrophilic populations (Th1/Th2/Th9/Th17/Th22/Treg), and cutaneous microbiome metagenomics, with the objective of identifying predictive biomarkers of therapeutic response and novel therapeutic targets in inflammatory dermatoses.

EARLY/HS is a prospective translational cohort aimed at addressing a major gap in the understanding of hidradenitis suppurativa: the average diagnostic delay of 10 years prevents any study of the early natural history of the disease. By enrolling 100 patients developing confirmed HS, the project deploys a multi-omic approach integrating single-cell RNA sequencing and shotgun metagenomics, in order to identify biological signatures predictive of progression toward severe scarring forms (Hurley II/III) and to define host-microbiome endotypes enabling early therapeutic stratification.

The WNT-HS project aims to elucidate the role of the Wnt/β-catenin pathway in hidradenitis suppurativa. This project is conducted in collaboration with the Karolinska Institutet in Stockholm, Sweden.

(i) Improving knowledge of the pathophysiology of healing in keloids, cicatricial fibroses, frontal fibrosing alopecia, burns, and aged skin.

(1) Dystrophic healing: Keloid scars are benign collagen-rich scar tumors resulting from an abnormal healing process. We are deepening our work on fibroblast heterogeneity (the main players in keloid formation) by distinguishing superficial/extensive and nodular entities, and within the same keloid, superficial and deep dermis or center and periphery. We study the genetic (single-cell RNAseq) and functional alterations (proliferation, migration, traction forces, etc.) of keloid fibroblasts, and complement our approach using algorithms recently designed by artificial intelligence in order to discover new therapeutic avenues for these benign but difficult-to-treat dystrophic scars.

(2) Healing in burn patients: In order to improve healing and epithelialization mechanisms in burn patients — often impaired in aged skin — we have set up an in vitro/in vivo study with the Reconstructive Surgery Department–Burns Center at Saint-Louis Hospital. This study focuses on the effects of platelet-rich plasma (PRP) components on the functions of cutaneous cells in vitro and in vivo.

(3) Age and healing: Transcriptomic analysis (RNAseq) and the study of secretomic and proteomic signatures (HPLC/mass spectrometry) of young (<35 years) and aged (>55 years) skin fibroblasts, either quiescent or stimulated by TGFβ, have demonstrated differential expression of the majority of cytoskeleton-associated proteins between the two age groups, correlating with altered traction forces and migratory and contractile functions of fibroblasts. These data open up major molecular targets for reversing the signs of skin aging, which we are addressing pharmacologically using innovative phytomolecules encapsulated in emulsions.

(4) Age and hair loss: Our work on cutaneous immunosenescence associated with hair loss in men (androgenetic alopecia) and female fibrosing alopecia is leading us to continue identifying biomarkers, this time in cicatricial alopecia in women (CIFRE PhD 2024–2027 in partnership with L’Oréal). We are conducting an in vivo study in a cohort of 80 pre- or post-menopausal women to quantify biophysical parameters of hair in situ and to identify, from scalp biopsies, molecular and genetic biomarkers associated with age-related hair loss in peri-menopausal women.

(ii) Demonstrating the key role of the innate immune response (neutrophils, NK cells, macrophages, etc.) in the healing process, with the aim of improving the clinical management of wounds and developing new medical devices. Fundamental in vitro studies on innate immune system cells — NK lymphocytes, M2 versus M12 macrophages, and neutrophils — in-depth analysis of their interactions with mesenchymal tissue cells, and study of the effects of calcium alginate dressings commonly used in clinical practice.

Objective: Development of new topical formulations for inflammatory dermatoses and other cutaneous pathologies involving an interaction between immune cells infiltrating the skin and resident cells of the cutaneous microenvironment.

Description: Within the framework of 3 successive ANR projects (ELUSUB 2016–2020, NOEMID 2021–2024, and CRYSTALEM 2025–2028), in collaboration with Prof. Nicolas Huang, physical chemist (Institut Galien), we are developing Pickering emulsions that allow the co-encapsulation of multiple active ingredients: an immunosuppressive agent (e.g., tacrolimus or JAK/STAT inhibitor) inserted into nanoparticles (NPs); an anti-inflammatory agent (e.g., calcitriol, curcumin, etc.) in the oily phase stabilized by the NPs; and a third agent (e.g., hyaluronic acid) in the external aqueous phase, to enhance the smoothness of the preparation and limit — through its moisturizing and anti-aging properties — skin dryness and accelerated aging often seen in inflammatory dermatoses. Targeting more or less rare cutaneous pathologies, whether inflammatory (psoriasis, atopic dermatitis) or fibrosing (e.g., alopecia areata, keloids, morphea, GVHD, scleroderma), all pruritic, by targeting the neuroinflammatory component linked to the cutaneous HPA axis.

IgA vasculitis (IgAV) is one of the most common vasculitides. It affects the skin in almost all cases, and sometimes the digestive system and kidneys, which determines the prognosis of the disease. Treatments are poorly codified and conventional immunosuppressants are frequently used in the absence of targeted alternatives. The pathophysiology of IgAV is poorly understood. Our objective is to characterize the cell populations — resident in the skin and circulating in the blood — involved in IgAV. We hope to characterize the immune cell populations involved in IgAV and their interactions with skin-resident cells, particularly endothelial cells. We also seek to differentiate the cellular and molecular specificities of purely cutaneous IgAV from IgAV with organ involvement. This characterization would allow us to define potential biomarkers and novel therapeutic targets.

Junctional autoimmune bullous dermatoses (AIBDs) form a heterogeneous group of rare autoimmune diseases affecting the skin and/or mucous membranes, characterized by the presence of pathogenic autoantibodies depositing on the dermo-epidermal membrane. The objective of this work is twofold. On one hand, we seek to explore the cutaneous inflammatory profiles in the less-described forms of junctional bullous dermatoses (epidermolysis bullosa acquisita, atypical borderline forms between bullous and mucous membrane pemphigoid) in order to propose new therapeutic targets. On the other hand, our objective is to study autoreactive B lymphocytes in bullous pemphigoid at both the circulating and tissue levels, and to evaluate the therapeutic potential of their specific targeting.