Interferon-γ-deficient mice are resistant to the development of alopecia areata

Background: Alopecia areata (AA) is a T-cell mediated putative autoimmune disease of hair follicles, which can be transferred by CD4+ T cells. However, whether T-helper (Th) 1 or Th2 cytokines are predominant has not yet been defined. Methods: To elucidate the importance of Th1 cells in the pathogenesis of AA we investigated the functional role of interferon (IFN)-gamma in the experimental induction of AA. Results: AA was experimentally induced by grafting full-thickness skin from AA-affected C3H/HeJ mice on to C3H/HeJ mice with a targeted deletion of the Th1 cytokine IFN-gamma gene (IFN gamma(-/-)) and on to wild-type mice (IFN gamma(+/+)). Results: While 90% of wild-type mice developed AA, none of the IFN gamma(-/-) mice exhibited hair loss. Immunohistochemistry of skin sections revealed a dense perifollicular and intrafollicular infiltrate of CD4+ and CD8+ T cells in controls, while in IFN gamma(-/-) mice skin-infiltrating CD8+ T cells were absent and the number of CD4+ cells was significantly reduced. Aberrant expression of major histocompatibility complex class I and II molecules in the putative immune-privileged infrainfundibular site of the hair follicle was found to be weaker in AA-resistant IFN gamma(-/-) mice than in control mice with AA. Flow cytometry revealed that leucocytes of IFN gamma(-/-) mice did not respond to the transfer of AA-affected skin. As distinct from IFN gamma(+/+) mice, neither T-cell activation markers nor Th1 cytokines were upregulated in draining lymph node cells or skin-infiltrating leucocytes of AA-resistant IFN gamma(-/-) mice. However, there was no evidence for a shift towards a Th2 cytokine profile, nor for upregulation of regulatory T cells in IFN gamma(-/-) mice. Conclusions: IFN gamma(-/-) mice fail to activate Th1 cells in response to the transplanted (auto)antigens, which suggests an essential requirement for IFN-gamma-mediated Th1 activation in the induction of AA.