Team OBINO

B cells and Skin Biology

Cutaneous fibrosis is a major complication of many chronic inflammatory dermatological diseases, as well as of pathologies associated with aging. It is characterized by excessive accumulation of extracellular matrix, particularly collagen, produced by pathologically activated fibroblasts. This aberrant production leads to progressive skin stiffening and lasting impairment of its function. In the absence of effective curative treatments, cutaneous fibrosis currently represents a major clinical challenge and a significant source of reduced quality of life for patients.

The mechanisms underlying cutaneous fibrosis are complex and rely on close crosstalk between immune system cells and the structural cells of the skin, notably macrophages and fibroblasts. Recent work has highlighted a previously underestimated contribution of B lymphocytes to the development and maintenance of the fibrotic process. However, the cellular and molecular basis of the dialogue between B lymphocytes, macrophages, and fibroblasts within cutaneous tissue remains largely unknown, which limits the identification of novel therapeutic targets.

In this context, our team is developing a research program structured around three complementary objectives:

• Characterizing the immune cell sub-populations present in fibrotic skin, particularly B lymphocytes and macrophages, in order to identify the sub-populations involved in fibrosis;
• Deciphering the cellular and molecular interactions between B lymphocytes, macrophages, and fibroblasts, as well as the signaling pathways deregulated during cutaneous fibrosis;
• Deciphering the cellular and molecular interactions between B lymphocytes, macrophages, and fibroblasts, as well as the signaling pathways deregulated during cutaneous fibrosis;

Autoimmune bullous dermatoses (AIBDs) of the dermo-epidermal junction constitute a heterogeneous group of rare autoimmune diseases affecting the skin and/or mucous membranes. They include in particular bullous pemphigoid, mucous membrane pemphigoid, and epidermolysis bullosa acquisita. These pathologies are characterized by the production of pathogenic autoantibodies directed against essential components of the dermo-epidermal junction (BP180, BP230, collagen VII), leading to loss of adhesion between the epidermis and dermis, responsible for blister formation and skin lesions.

While the central role of autoantibodies in disease pathogenesis is well established, the cellular and molecular mechanisms responsible for chronic inflammation and tissue damage remain incompletely understood. Current therapeutic strategies — including topical corticosteroids, treatments targeting B lymphocytes (Rituximab), the Th2 pathway (Dupilumab), or IgE (Omalizumab) — show variable efficacy and are often limited by adverse effects, incomplete tolerability, or relapses upon treatment discontinuation. This variability in therapeutic responses suggests the existence of distinct pathogenic mechanisms depending on the patient and/or the subtype of junctional AIBD.

In this context, a thorough understanding of the interactions between immune cells — particularly autoantibody-producing cells —, epithelial cells, and stromal cells at the tissue level appears essential for identifying novel therapeutic targets and developing more effective, safer, and durable approaches.

Our team is developing its work around three major objectives:

• Mapping the immuno-inflammatory landscape and intercellular communication networks specific to the different subtypes of junctional AIBDs;
• Defining the role of autoreactive B lymphocytes in the pathophysiology of bullous pemphigoid beyond autoantibody production;
• Evaluating the therapeutic potential of specific targeting of autoreactive B lymphocytes as an innovative therapeutic strategy.

Although present in small numbers, our work and that of other teams have demonstrated the existence of several B lymphocyte sub-populations in healthy skin. These include both conventional B lymphocytes (B2) and innate-type B lymphocytes (B1a/b). The coexistence of these different populations within cutaneous tissue raises fundamental questions about the spatiotemporal mechanisms governing their recruitment and local maintenance, as well as their respective roles in maintaining or restoring cutaneous homeostasis.

To address these questions, our team is working to decipher the cellular and molecular mechanisms that control B1 lymphocyte emergence and their trafficking to the skin during development. To this end, we combine cell fate tracking approaches (fate mapping/lineage tracing) with in vivo functional modulation strategies, allowing these populations to be followed and manipulated in their physiological environment.

In parallel, we study the respective functional contributions of B2 and B1a/b lymphocytes to the maintenance of cutaneous homeostasis, both under physiological conditions and in the context of aging. This work relies in particular on the use of transgenic murine models selectively lacking certain B lymphocyte sub-populations, thereby offering an integrated understanding of the role of these cells in cutaneous biology.

• Role of B lymphocytes and plasma cells in the pathophysiology of hidradenitis suppurativa with Laure GUENIN-MACÉ, Institut Pasteur, Paris
• Role of the transcription factor Ets1 in B lymphocyte development with Jean-Christophe BORIES, IRSL, Paris
• Cutaneous manifestations in WHIM syndrome with Karl BALABANIAN and Marion ESPÉLI, IRSL, Paris