A new player in alopecia areata management: Butyrophilin-like 2 (BTNL2) to the rescue?

Summary: Abstract Body: In alopecia areata (AA), excessive secretion of IFN-g by T and NK cells promotes the collapse of the hair follicle’s (HF) immune privilege (IP), characterized, e.g., by overexpression of MHC class Ia and the NKG2D-stimulating “danger” signal, MICA. Pathogenic interactions between NKG2D expressed on T cells and MICA overexpressed by HF keratinocytes can trigger HF IP collapse and thus promote AA via an auto-antigen-independent, non-autoimmune pathway. Since JAK inhibitors fail to target this mechanism, we have explored if Butyrophilin-like 2 (BTNL2), a transmembrane protein known to down-modulate T-cell activation and maintain immune tolerance, can protect HF IP. IF microscopy showed that BTNL2 is predominantly expressed by outer root sheath keratinocytes of healthy human scalp HFs. Ex vivo, BTNL2 expression was significantly lower in stressed MICA-overexpressing HFs with weakened IP than in non-stressed HFs with intact IP. When isolated, autologous human scalp Vd1- g/dT and CD8 T cells were co-cultured with HFs NKG2D, and IFNg expression by Vd1-T cells was increased. In stressed HFs, NKG2D-driven cytotoxicity by Vd1-T and CD8+ T cells was heightened, leading to melanin clumping and premature catagen induction, i.e., hallmarks of AA-like HF damage. Conversely, non-stressed HFs with high levels of BTNL2 Vd1-T and CD8+ T cells failed to induce signs of IP collapse/HF damage. These pilot data support the novel working hypothesis that BTNL2 is an important player in human HF IP, whose reduced epithelial expression in stressed HFs promotes increased T-cell cytotoxicity and HF IP collapse and thus facilitates AA development. Instead, the therapeutic upregulation of BTNL2 may help to maintain HF IP and reduce NKG2D-mediated IFNg secretion by AA-pathogenic immune cells. Jennifer Gherardini¹, Aysun Akhundlu², Laura I. Padula³, Sujad Younis³, Ramtin Kassir⁴, Jeremy Cheret^{1, 2}, Natasa Strbo³, Ralf Paus^{2, 1} 1. CUTANEON-Skin&Hair Innovations GmbH, Hamburg&Berlin, Germany. 2. Dermatology, University of Miami Miller School of Medicine, Miami, FL, United States. 3. Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, United States. 4. Kassir Plastic Surgery, New York City, NY, United States. Adaptive and Auto-Immunity