Oral Presentation CD1-MR1 2024

The role of CD1a in the initiation of atopic dermatitis-like inflammation using an innate murine model (#50)

Karmella Naidoo 1 2 , Clare S Hardman 2 , Rosana Ottakandathil Babu 2 , Janina Nahler 2 , Esther Bridges 2 , John Ye 2 , Jessica Soo Weei Ng 2 , Adrian Kobiela 2 , Yi-Ling Chen 1 , Uzi Gileadi 2 , Alison Simmons 2 , Graham S Ogg 1 2
  1. Chinese Academy of Medical Sciences Oxford Institute, Oxford , United Kingdom
  2. MRC Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom

Background: Atopic dermatitis (AD) is a chronic heterogeneous relapsing skin disease with a broad range of clinical presentations. The pathogenesis of AD is a result of multiple factors including environmental, alterations in skin pH, itching, skin barrier disruption, immune dysregulation, and bacterial translocation. Cluster of differentiation 1a (CD1a) is an HLA class-I-like molecule that is highly expressed by Langerhans cells (LCs), which are upregulated in the skin of patients with AD. LCs are ideally positioned within the epidermal compartment to detect breaches in the cutaneous barrier as well as changes in the inflammatory milieu. Recent studies have explored the participation of CD1a in the development of inflammatory skin diseases and their role as skin sentinels, but specific mechanisms remain to be fully investigated. Our study aims to delineate the precise role of CD1a, using a murine model that closely resembles the type two cytokine profile observed in patients with AD. 

Methods: The vitamin D analogue, MC903, was topically applied to the skin of human CD1a transgenic mice (CD1atg) and controls, in the presence or absence of anti-CD1a-blocking antibodies. Pruritus, erythema, skin thickness and transepidermal water loss (TEWL) were assessed in addition to the associated immune cell infiltration and skin/systemic cytokine and chemokine response.

Results: Preliminary findings showed a pronounced skin alarmin signature (including TSLP, and IL-33) in the presence of CD1a, associated with increased skin thickness, itching, barrier dysfunction and an altered LC phenotype. Interestingly, blocking/depletion of CD1a-expressing cells, using specific anti-CD1a antibodies, resulted in an amelioration of the MC903 induced pathogenesis.

Conclusion: Together, the data suggests a novel role for CD1a far earlier in the AD inflammatory pathway than expected, including a potential direct innate effect.  Furthermore, our findings reveal potential indications and therapeutic targets for the prevention and treatment of inflammatory skin disease.