CRU 303, Subproject: The Role of Lymphocyte-derived Factors in the Effector Phase of Pemphigoid Diseases

The effector phase of pemphigoid diseases (PDs) is driven by the influx of myeloid cells, particularly PMNs, into the skin. Our results of the 1st FP have uncovered a network of various lymphocyte populations, including γδ T cells, NKT cells, Tregs, and IL-10+ plasma cells, regulating the recruitment of PMNs, their activation, and, consequently, skin inflammation from the emergence of inflammatory skin lesions to their resolution in mouse models of PD. Thus, γδ T and NKT cells both significantly facilitate the influx of PMNs into the skin and activate them, especially in early stages of the emergence of skin lesions, while Tregs and IL-10+ plasma cells, in contrast, counteract and contain PD skin inflammation, in significant parts by the release of IL-10. Intriguingly, we have also highlighted that this network of lymphocytes can be manipulated. Thus, the induction of IL-10+ plasma cells is effective in ameliorating disease. Plasma cell-derived IL-10 was found to inhibit PMN activity directly but also reinforced the release of IL-10 from Tregs. We have also found evidence that a corresponding network of lymphocyte populations also exist in bullous pemphigoid (BP) patients. Collectively, our results suggest that different lymphocyte populations and their effector mechanisms are promising therapeutic targets in PDs. Particularly promoting IL-10+ plasma cells or Tregs, or application of IL-10 may constitute most effective therapeutic strategies to reverse PD skin inflammation with only few side effects. In the 2nd FP, we will therefore further investigate the mode of action of IL-10 and of these immunoregulatory cell types in PDs. We will develop and evaluate strategies exploiting these mechanisms for therapeutic purposes in PDs.