Discover in one of our latest publications how we successfully employed our humanized mouse model for alopecia areata research
Alopecia Areata (AA) is one of the most common inflammatory hair loss disorders. For the development of efficient treatment strategies it is crucial to understand the pathogenesis of the disease. However, the exact mechanisms how AA develops and the pathobiology of its clinical variants remain to be fully characterized. Increasing evidence suggests that AA may result either from a CD8 T-cell mediated autoimmune response or from autoantigen independent disease-initiating factors.
In the current study, published in the scientific journal eLife, led by our long-standing collaboration partner, Prof. Amos Gilhar, Technion – Israel Institute of Technology, Haifa, Israel, the authors (among which the founder and the acting CEO of Monasterium Laboratory, Prof. Ralf Paus and Dr. Marta Bertolini) were exploring the role of the innate immune system in the pathobiology of AA. To this end, they employed a set of comprehensive methods including human hair follicle and immune cells co-culture culture, and the AA humanized mouse model.
The authors focused on innate lymphoid cells type 1-like cells (ILC1-like cells), since these cells produce large amounts of IFNy, the key cytokine promoting immune privilege (IP) collapse of the hair follicle (HF) bulb, a characteristic of AA. First, the authors analysed if ILC1-like cells are present in lesional skin samples obtained from AA patients. They found enhanced ILC1-like cell numbers around HFs in lesional AA skin, while almost none of these cells were present around HFs of healthy skin.
Intrigued by these findings the authors next questioned whether these cells were able to induce an AA-like phenotype in human scalp HFs ex vivo. Circulating immune cells from the blood of healthy volunteers were isolated and stimulated to expand the proportion of ILC1-like cells. Afterwards these ILC1-like cells were sorted by FACS and co-cultured with `stressed` (one day in culture), but otherwise healthy, human HFs. As shown by us previously, the culture-stress transiently weakens the HF’s physiological IP and induces expression of ‘distress’ signals (Uchida et al., J Autoimmun 2021) which are known to activate also innate cells as ILC1s to produce pro-inflammatory cytokines, i.e. IFNγ. Indeed, co-culture of ‘stressed’ HFs and ILC1-like cells resulted into HF dystrophy and cytotoxicity, as well as upregulation of IP collapse markers and downregulation of IP guardians. Additionally, the authors observed premature catagen induction, thus a shortened HF growth phase, in the presence of ILC1-like cells, which was dependent on IFNγ signalling. These clinically relevant ex vivo experiments demonstrate that ILC1-like cells can indeed induce the hallmarks of AA in human scalp HFs ex vivo.
Next, the authors probed if ILC1-like cells may also suffice to induce AA-like hair loss in vivo, by utilizing the AA humanized mouse model (also available at Monasterium Laboratory). In this model, CD8+/NKG2D+ cells injected into human scalp skin xenotransplants, which are grafted on SCID/beige mice, cause an AA-like phenotype. However, in the current study the authors not only injected CD8+/NKG2D+ cells as positive control, but also tested the effect of injected ILC1-like cells. Interestingly, the presence of ILC1-like cells resulted into hair loss similar to what was observed upon CD8+/NKG2D+ injection. This hair loss was accompanied by upregulation of IP collapse markers, downregulation of IP guardians and enhanced perifollicular immune cell infiltrations around anagen HFs.
Collectively, this study introduces IFN-γ secreting ILC1-like cells as important novel players in human AA pathobiology. Their location, their capability to recognize and respond to HF distress signals and their direct, pathogenic effects on human HFs ex vivo support the assumption that these cells might play a hitherto unappreciated role in early AA pathogenesis.
Read the full story here.