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.
![A3: G protein-coupled receptors orchestrating granulocytes in pemphigoid diseases A3: G protein-coupled receptors orchestrating granulocytes in pemphigoid diseases](/fileadmin/_processed_/7/1/csm_uzl_dachfenster_da28f23bf5.jpg)
- Projects
- 1st Generation
- A: Defining Autoimmune Pre-Disease
- A1: Define the impact of shift work on autoimmunity and autoimmune diseases
- A2: B cells as drivers towards clinical SLE manifestation
- A3: G protein-coupled receptors orchestrating granulocytes in pemphigoid diseases
- A4: Epitope-dependent autoantibody-mediated skin inflammation in pemphigoid disease
- A5: Chronic danger signaling as driver of autoimmunity in granulomatosis with polyangiitis
- A6: T cell memory differentiation in early autoimmune disease
- A7: CD4+ T cell receptor sequences during progression towards experimental pemphigoid.
- A8: The C5aR2 pathway as a checkpoint for B cell activation in autoimmunity.
- A9: Genetic and molecular similarity of autoimmune disease
- B: Targeting of Autoimmune Pre-Disease
- Associated projects
- MD projects
- Concluded Projects
- A: Defining Autoimmune Pre-Disease
- 2nd Generation
- 1st Generation