Interferon-<i>γ</i>-deficient mice are resistant to the development of alopecia areata

TLDR

Alopecia areata is a T‑cell mediated autoimmune disease of hair follicles that can be transferred by CD4⁺ T cells. The study aimed to determine whether Th1 or Th2 cytokines predominate in AA by investigating the role of IFN‑γ in experimental induction. AA was induced by grafting skin from affected C3H/HeJ mice onto IFN‑γ knockout and wild‑type recipients, with 90 % of wild‑type but none of the knockouts developing hair loss. IFN‑γ deficiency prevented CD8⁺ T‑cell infiltration, reduced CD4⁺ T‑cell numbers, weakened MHC class I/II expression, and abolished Th1 activation without shifting toward Th2 or regulatory T cells, indicating that IFN‑γ–mediated Th1 activation is essential for AA induction.

Abstract

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.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.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 (IFNgamma(-/-)) and on to wild-type mice (IFNgamma(+/+)).While 90% of wild-type mice developed AA, none of the IFNgamma(-/-) 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 IFNgamma(-/-) 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 IFNgamma(-/-) mice than in control mice with AA. Flow cytometry revealed that leucocytes of IFNgamma(-/-) mice did not respond to the transfer of AA-affected skin. As distinct from IFNgamma(+/+) mice, neither T-cell activation markers nor Th1 cytokines were upregulated in draining lymph node cells or skin-infiltrating leucocytes of AA-resistant IFNgamma(-/-) mice. However, there was no evidence for a shift towards a Th2 cytokine profile, nor for upregulation of regulatory T cells in IFNgamma(-/-) mice.IFNgamma(-/-) 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.