A3: G protein-coupled receptors orchestrating granulocytes in pemphigoid diseases

Background. Pattern recognition receptors (PRRs), including L-lectin receptors, are important for host defense. PRRs, however, also play a significant role in autoimmunity, and genetic variants of these receptors are associated with susceptibility for autoimmune diseases (Lancet. 387:156). We recently found that in experimental pemphigoid disease (PD), the L-lectin receptor Dectin-2, which is responsible for detection of molecular patterns of fungi, is upregulated on polymorphonuclear cells (PMNs). Intriguingly, Dectin-2-deficient mice are completely protected from PD induction (Fig. A3-1). Hence, in PD, the transition from autoreactivity to clinically present autoimmune disease depends on molecular patterns that are recognized by Dectin-2. To delineate the role of Dectin-2 in antibody-mediated tissue inflammation, we have recently generated Clec4n-flox mice. By this tool we will dissect the contribution of Dectin-2 on different myeloid cell lineages to skin inflammation.

Objectives. (i) To delineate mechanisms by which Dectin-2 drives skin inflammation and identify stimuli that engage Dectin-2 to initiate clinical PD manifestations. (ii) To profile PRR expression and search for genetic variants in PRRs, associated with PD, in patients.

Work program. We obtained a floxed Dectin-2 (Clec4n) mouse that will be used to identify the cell types that are critical for Dectin-2 actions in PD. We will (i) treat mice with antifungal substances to determine whether this modulates skin inflammation by eliminating potential Dectin-2 ligands, (ii) pinpoint the mode of action of Dectin-2 in PD, e.g., by inducing disease in mixed chimeric mice and performing RNA sequencing, (iii) investigate the therapeutic effect of pharmacological Dectin-2 inhibition in PD, and (iv) together with A9 profile Dectin-2 expression in bullous pemphigoid (BP) and mucous membrane pemphigoid (MMP) patients and conduct a genetic analysis focusing on the frequency of genetic variants of Dectin-2 and other PRRs in these patients.