CD1a promotes systemic manifestations of skin inflammation

Clare S. Hardman, Yi-Ling Chen, Marcin Wegrecki, Soo Weei Ng, Robert Murren, Davinderpreet Mangat, John-Paul Silva, Rebecca Munro, Win Yan Chan, Victoria O’Dowd, Carl Doyle, Prashant Mori, Andy Popplewell, Jamie Rossjohn, Daniel Lightwood and Graham S. Ogg ()
Additional contact information
Clare S. Hardman: University of Oxford
Yi-Ling Chen: University of Oxford
Marcin Wegrecki: Monash University
Soo Weei Ng: University of Oxford
Robert Murren: UCB Pharma
Davinderpreet Mangat: UCB Pharma
John-Paul Silva: UCB Pharma
Rebecca Munro: UCB Pharma
Win Yan Chan: UCB Pharma
Victoria O’Dowd: UCB Pharma
Carl Doyle: UCB Pharma
Prashant Mori: UCB Pharma
Andy Popplewell: UCB Pharma
Jamie Rossjohn: Monash University
Daniel Lightwood: UCB Pharma
Graham S. Ogg: University of Oxford

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Inflammatory skin conditions are increasingly recognised as being associated with systemic inflammation. The mechanisms connecting the cutaneous and systemic disease are not well understood. CD1a is a virtually monomorphic major histocompatibility complex (MHC) class I-like molecule, highly expressed by skin and mucosal Langerhans cells, and presents lipid antigens to T-cells. Here we show an important role for CD1a in linking cutaneous and systemic inflammation in two experimental disease models. In human CD1a transgenic mice, the toll-like receptor (TLR)7 agonist imiquimod induces more pronounced splenomegaly, expansion of the peripheral blood and spleen T cell compartments, and enhanced neutrophil and eosinophil responses compared to the wild-type, accompanied by elevated skin and plasma cytokine levels, including IL-23, IL-1α, IL-1β, MCP-1 and IL-17A. Similar systemic escalation is shown in MC903-induced skin inflammation. The exacerbated inflammation could be counter-acted by CD1a-blocking antibodies, developed and screened in our laboratories. The beneficial effect is epitope dependent, and we further characterise the five best-performing antibodies for their capacity to modulate CD1a-expressing cells and ameliorate CD1a-dependent systemic inflammatory responses. In summary, we show that a therapeutically targetable CD1a-dependent pathway may play a role in the systemic spread of cutaneous inflammation.

Date: 2022
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DOI: 10.1038/s41467-022-35071-1

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